Cancer Therapy Advisor January/February 2019 Issue by Haymarket Media

JANUARY/FEBRUARY 2019 | VOL 5, ISSUE 3

13 FEATURE

Reducing Survival Disparities Across Cancer Sites of Care Better collaboration between community and academic cancer centers could benefit patients.

CancerTherapyAdvisor.com

FOCUS ASH 2018

New Standard of Care in CLL Proposed for Older Patients CAR-T and Ibrutinib: Better Together? New Standard of Care in Transplant-Ineligible Myeloma

15 IMMUNOTHERAPY REPORT

Hyperprogression Related to Treatment: Concerns Mount 19 VIEWPOINT

Liquid Biopsy as a Surveillance Tool for Breast Cancer Follow-Up 20 TREATMENT REGIMENS

Rectal Cancer ï&#x201A;&#x201E; Soft Tissue Sarcoma

17 IN THE CLINIC Gender-Based Differences in Chemotherapy: Efficacy and Safety

EUTOS Long-Term Survival Score Outperforms Sokal in CML

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Contact Us CONTACT THE EDITOR Questions or comments for the editor? Email us at editor.cancertherapyadvisor@ haymarketmedia.com

FOCUS ASH 2018

Recent Headlines from ASH 2018

New Standard of Care in Transplant-Ineligible Myeloma

EUTOS Long-Term Survival Score Outperforms Sokal in CML

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CONTENTS

CONNECT WITH CANCER THERAPY ADVISOR @CancerTherAdvsr

3 LATEST NEWS

Recent headlines in oncology research and practice, including findings in breast cancer, esophageal cancer, and sarcoma. 11 EXPERT PERSPECTIVE

The Patient Behind the EHR Daniel Vorobiof, MD

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Cancer Therapy Advisor (ISSN 2375-558X), January/February 2019, Volume 5, Number 3. Published 6 times annually by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales &amp; Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). Standard Postage paid at Orem, UT. Postmaster: Send changes of address to Cancer Therapy Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018.

13 FEATURE

Reducing Survival Disparities Across Cancer Sites of Care Bryant Furlow

15 IMMUNOTHERAPY REPORT

Hyperprogression Related to Treatment: Concerns Mount

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Unless otherwise indicated, persons appearing in photographs are not the actual individuals m entioned in the articles. They appear for illustrative purposes only.

Christina Bennett, MS

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Editorial and Business Staff Managing Editor, Haymarket Oncology Lauren Burke Oncology Editor Randi Hernandez

Group Art Director, Medical Communications Jennifer Dvoretz Graphic Designer Vivian Chang Production Manager Brian Wask; (646) 638-6066 Vice President, Sales & Business Development Scott Bugni; (917) 882-0658; scott.bugni@haymarketmedia.com Account Manager Henry Amato; (646) 638-6096; henry.amato@haymarketmedia.com Manager, Multi-Channel Business Development Marc A. DiBartolomeo; (609) 417-0628; marc.dibartolomeo@ haymarketmedia.com VP, Content; Medical Communications Kathleen Tulley President, Medical Communications Michael Graziani

CONTENTS 17

IN THE CLINIC

Gender-Based Differences in Chemotherapy: Efficacy and Safety C. Andrew Kistler, MD, PharmD

Chief Executive Officer Lee Maniscalco

Editorial Advisory Board Barbara Ann Burtness, MD Yale Cancer Center  New Haven, CT

Steven J. Cohen, MD

VIEWPOINT

Liquid Biopsy as a Surveillance Tool for Breast Cancer Follow-Up Christina Bennett, MS

TREATMENT REGIMENS 20

Rectal Cancer

Soft Tissue Sarcoma

CASE STUDY

Biomarker Testing in Advanced Non-Small Cell Lung Cancer 2 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

Thomas Jefferson University Hospital  Philadelphia, PA

E. David Crawford, MD University of Colorado, Denver  Aurora, CO

Isabel Cunningham, MD Columbia University College of Physicians & Surgery  New York, NY

Don S. Dizon, MD, FACP Lifespan Cancer Institute  Providence, RI

Jeffrey M. Farma, MD Fox Chase Cancer Center  Philadelphia, PA

Neal D. Shore, MD, FACS Atlantic Urology Clinics  Myrtle Beach, SC

Mark A. Socinski, MD Florida Hospital Cancer Institute  Orlando, FL

Mario Sznol, MD Yale Cancer Center  New Haven, CT

LATEST NEWS

Statins Repurposed to Slow Proliferation in Metastatic Breast Cancer Cells Statins were shown to slow proliferation in metastatic breast cancer cells but not primary tumor cells, suggesting the long-term use of statins in the adjuvant setting should be considered for patients with breast cancer. Statins have been found to reduce mortality in patients with breast cancer, but the mechanism by which statins influence mortality without affecting the growth of the primary tumor has been unclear. The study results were recently published in the British Journal of Cancer (doi: 10.1038/ s41416-018-0267-7). To elucidate the effect of statins on metastatic cell proliferation, study researchers created several models to mimic breast cancer metastasis. In vitro and ex vivo models were created to mimic breast cancer metastasis to the liver. The in vitro model was a 2-dimensional coculture, and the ex vivo model was a 3-dimensional microphysiological system. Two independent mouse models were created to mimic spontaneous breast cancer metastasis to the lung and liver. Statins were shown in each model to “directly affect the proliferation of breast cancer cells, specifically at the metastatic site,” the study authors wrote. In the in vitro model, atorvastatin slowed proliferation of mesenchymal but not epithelial breast cancer cells. When dormant breast cancer cells were stimulated in the 3-dimensional ex vivo microphysiological system, atorvastatin inhibited their emergence. In both mouse models, statins slowed proliferation of metastatic cells but not primary tumor cells. “As statins can block metastatic tumor outgrowth, they should be considered for use as long-term adjuvant drugs to delay clinical emergence and decrease mortality in breast cancer patients,” the study authors concluded.

Trial Identifies Marker for Response to Immunotherapy in Esophageal Cancer A multicenter, open-label, single-arm phase 2 clinical trial found a marker in the blood that identified which patients with advanced esophageal squamous cell carcinoma were most likely to respond to the immune checkpoint inhibitor nivolumab (doi: 10.1007/s00262-018-2225-x). To identify a marker for response, study investigators assessed the peripheral blood from 20 patients enrolled in the trial who had advanced esophageal squamous cell carcinoma who were treated with nivolumab at Osaka University Hospital in Japan. Of those 20 patients, 1 had complete response, 5 had a partial response, 6 had stable disease, and 8 had progressive disease.

The analysis revealed that after the first cycle of nivolumab was complete, the following markers in the blood could distinguish patients with a complete or partial response from those with stable or progressive disease: albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA−CD27−, and IL-1b. “When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden,” the study authors wrote. “Among them, elevations in %Tim3+CD4 had a marked impact on survival rates.” On the basis of these findings, the study authors concluded that “dynamic elevations” in %Tim-3 in T cells early on in nivolumab treatment could serve as a marker of response.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2019 | CANCER THERAPY ADVISOR 3

LATEST NEWS

In a paper presentation during the Connective Tissue Oncology Society (CTOS) 2018 Annual Meeting in Rome, Italy, Mandy Ballinger, PhD, of the Garvan Institute of Medical Research in Australia, revealed that through the use of whole-genome sequencing, she and her colleagues had identified POT1 as a sarcoma predisposition gene (Paper 043). The research team analyzed 4328 blood samples and approximately 600 formalin-fixed paraffin-embedded tissue blocks from 2933 probands — patients who are thought to be the first in their family to have a particular genetic defect — and from 2623 blood relatives of the probands. Background data was collected for approximately 105,000 family members of the probands and proband feedback was taken from 4836 questionnaires. Among the probands, 1109 individuals underwent whole-genome sequencing using HiSeqX. Most of the probands (82%) had only had 1 primary malignancy, whereas 18% of probands had experienced more than 1 primary malignancy. Undifferentiated pleomorphic sarcoma was the most common sarcoma subtype seen across the cohort. As controls, the researchers used genotypes from approximately 2570 healthy, elderly Australians from a publicly available repository. These individuals — which Dr Ballinger referred to as “the wellderly” — were all in their 70s at the time of blood draw. This type of comparison using extreme phenotype sampling allows for better detection of phenotype-genotype associations; one would expect a depletion of deleterious variants across control genotypes, noted Dr Ballinger, making these elderly individuals ideal controls. The research group determined there was an increased burden of rare pathogenic variants in patients with sarcoma, with a significantly increased frequency of deleterious variants in POT1 (P < .0001). POT1 protein is part of the Shelterin complex, and normally protects the ends of chromosomes, maintaining telomere length by inhibiting telomerase. When the POT1 variant is pathogenic, telomeres are longer than they should be. Defects in POT1 lead to chromosomal instability and germline mutations in the POT1 gene have been linked to melanoma, gliomas, chronic lymphocytic leukemia, and cardiac angiosarcoma, according to Dr Ballinger. The probands with sarcoma were observed to have mutations in Shelterin, suggesting that “Shelterin complex mutations are

an important genetic cause of sarcomas,” noted Dr Ballinger. This finding may have clinical utility: telomere length could be a good metric for personalized risk assessments in cancer. “Increasingly, germline information impacts treatment decisions, and that might be the case in these families,” she concluded.

New Epigenetic Cervical Cancer Test Outperforms Pap and HPV Testing An epigenetic cervical cancer test outperforms Pap or human papillomavirus (HPV) test-based screening, according to findings from the HPV FOCAL trial, which were published in the International Journal of Cancer. The “S5” methylation test detected epigenetic aberrations indicative of cervical cancer and had a 100% detection rate in the study, correctly identifying all 8 of 15,744 screened women who had developed cervical intraepithelial neoplasia grade 2 (CIN2) or worse, compared with a 50% detection rate through the use of HPV testing and a 25% rate following a Pap test. “We’re not only astounded by how well this test detects cervical cancer, but it is the first time that anyone has proven the key role of epigenetics in the development of a major solid cancer using data from patients in the clinic,” said senior study author Attila Lorincz, PhD, Wolfson Institute of Preventive Medicine. Epigenetic aberrations might be a more important factor in the progression of many malignancies — including cervical, colorectal, prostate, and oropharyngeal cancers — than are DNA mutations, Dr Lorincz said. Dr Lorincz was also involved in the development of the HPV test in 1988. That test is more accurate than traditional Pap test analysis — but it only confirms whether or not a woman has been infected with a high-risk strain of HPV. The new test detects epigenetic changes to cervical cells indicative of tumorigenesis. The HPV FOCAL trial screened Canadian women aged 25 years to 65 years. The epigenetic test detected early-stage cervical cancers years before they would have become symptomatic, including adenocarcinomas, which have proved to be difficult to detect using other screening tests, Dr Lorincz said. “Methylation showed a highly significant increased trend with disease severity,” the authors reported.1 “Methylation signatures can identify most HPV-positive women at increased risk of cervical cancer from their baseline screening specimens.” ■

4 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

POT1 Revealed as a Sarcoma Predisposition Gene

LATEST NEWS

FOCUS ASH

CAR-T Cells Successfully Manufactured at Point of Care Chimeric antigen receptor T (CAR-T) cells targeted to CD19 and CD20 were successfully generated at the point of care using a good manufacturing practice-compliant closed system, according to data presented at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, California (Abstract 4553). The authors stated that the study “successfully demonstrated feasibility for point-of-care CAR-T cell production for clinical use from patient apheresis products utilizing the CliniMACS Prodigy device.” The US Food and Drug Administration has approved 2 CAR-T products to date, but commercial CAR-T products are limited by the length of time of off-site production, which can also restrict use in rapidly progressing patients, and high cost. The purpose of this phase 1 trial was to determine if CAR-T cells could be generated at the point of care. The study used the CliniMACS Prodigy device to manufacture CAR-T cells at the Medical College of Wisconsin Cell Therapy Laboratory. Peripheral blood mononuclear cells were collected by apheresis and loaded into the Prodigy device to enrich CD4 and CD8 T cells. T cells were then cultured and stimulated, followed by transfection with lentiviral vectors expressing anti-CD19 and anti-CD20 with CD3ζ and 4-1BB stimulatory domains. The final products were harvested on day 14, and expression of the CD20.19 CAR was assessed by protein L staining. The ongoing trial has successfully generated CAR-T cells for all 6 currently enrolled patients, with no production failures. The mean CD20.19 expression was 20.8%, and the generated CAR-T cells demonstrated killing of CD19+ and CD20+ target cells in vitro and secreted interferon-gamma in response to the target cells. The CAR-T cell yield was higher than what was required for dosing, at a mean of 5.9e + 8 (range, 4.3-7.9e + 8), and the CAR-T cells included by CD4 and CD8 cells that were primarily of an effector-memory phenotype (82%). Though harvesting was performed on day 14, in-process testing demonstrated that sufficient numbers of CAR-T cells were available on day 8. The authors concluded that that the generation of CAR-T cells at the point of care was efficient and reproducible, although the processing time could be reduced. They noted that “a major clinical advantage of CAR-T cells generated on-site is the flexibility in treatment.”

Molecular Mechanisms Underlying Immunosurveillance in Multiple Myeloma Identified Building off recent findings, which suggested that bortezomib (BTZ) is able to induce immunogenic cell death (ICD), researchers from the Dana-Farber Cancer Institute in Boston,

Massachusetts, concluded that the genes located on chr17p13 have a role in ICD. They also determined that poor overall survival in patients with multiple myeloma may be partially due to a lack of ICD. These results were presented in a poster at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, California (Abstract 1932). Using a panel of 9 multiple myeloma cell lines, the

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LATEST NEWS

investigators confirmed by way of western blot the presence of the protein calreticulin (CALR). Following a series of other assays, the researchers determined “that bortezomib was able to induce ICD in vitro, and that CALR exposure does not represent a valid screening method to identify new potential ICD-inducers in multiple myeloma.” Next, the researchers wanted to test if the genetic abnormalities that can occur after treatment with BTZ — those that can negatively affect overall survival, and perhaps BTZ’s killing ability — were linked to alterations in specific genes. The group analyzed RNA-seq data from 400 patients who were newly diagnosed with multiple myeloma and identified a list of differentially expressed genes among patients with longer survival rates (longer than 5 years) compared with those who had poor survival (fewer than 1.5 years) after treatment with BTZ. “Gene set enrichment analysis (GSEA) revealed that pathways that positively regulate immune and inflammatory responses were enriched in patients with longest OS as well as genes located on chr17p13,” the investigators wrote, which led them to conclude that genes located on chr17p13 may have a novel role in the induction of ICD in multiple myeloma. They found that myeloma cells carrying deletions on chr17p do not undergo ICD after treatment with BTZ. Restoration of ICD, they hypothesized, and its benefit to antimyeloma immunosurveillance, could improve patient survival and could be harnessed via BTZ-based combination strategies. Furthermore, this strategy could improve outcomes, they postulated, even among those with high-risk disease. Disclosure: Multiple authors declared affiliations with industry. For a full list of disclosures, please refer to the original abstract.

CAR-T and Ibrutinib: Better Together? Based on some “preclinical evidence of synergy” between the anti-CD19 chimeric antigen receptor T-cell therapy (CART) CTL019 and ibrutinib, researchers from the University of Pennsylvania, Philadelphia; Novartis; and the Parker Institute for Cancer Immunotherapy, among other institutions, paired the 2 medications together with the goal of testing the hypothesis that pretreatment and concurrent treatment would boost the complete remission (CR) rate seen in chronic lymphocytic leukemia (CLL).

During a presentation on the results of the small pilot study at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, Saar Gill, MD, PhD, University of Pennsylvania, Philadelphia, reported that the duo together “results in a high rate of sustained responses” and high rates of minimal residual disease-negative marrow responses in patients with CLL (Abstract 298). Although CAR-T alone has the potential to spark CR in some cases of CLL, the outcome is not guaranteed — and this prompted the investigators to start searching for ways to also ensure remission remains durable. For the study, the investigators enrolled 20 patients with CLL/ SLL who were not in CR even after undergoing 6 months of treatment with ibrutinib. Investigators planned infusions for 19 of the study participants of 1-5×108 CTL119 cells dosed as 10%, 30%, and 60% of the total planned dose over 3 days, provided that no problems arose after a patient received their first dose. To manufacture CTL119, T cells were transduced (using lentiviral vectors) “to express a CAR comprising CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119).” Following lymphodepleting chemotherapy, the product was further prepared. Once made, the median number of modified CAR-T cells given back to the patient was 5.3 × 106/kg (range, 2.0-7.5). On days 7 through 10, there was a massive expansion of CAR-positive alleles, and by day 28, most of the CAR-T was not active, “reflecting eradication of antigen,” noted Dr Gill. At 3 months, iwCLL was 6 CR, 4 PR, 3 SD, and 1 PD; 17 of 18 patients had morphologic CR, and 15 of 17 had flow-negative MRD CR, confirmed by flow cytometry. At 12 months, 10 of 11 patients had bone marrow remission, exhibiting CRs. Two of 7 patients maintained a CR, while 17 of 19 patients had adverse prognostic biomarkers. Of 3 patients previously treated with CTL019, 2 were in MRD+ CR and 1 was refractory at 12 months. As of July 16, 2018, 18 of 19 (95%) patients were still alive. However, 18 of the 19 patients who received the CAR-T experienced cytokine release syndrome, but none of the cases were grade 5 or fatal. One patient died due to cardiac arrhythmia in the setting of grade 4 neurotoxicity. “In patients not achieving CR despite at least 6 months of ibrutinib who were treated with humanized CART19, we found an iwCLL CR rate of 43% and at 3 months, there was a high bone marrow remission rate, including a 78% MRD negative response by deep sequencing,” Dr Gill noted. “This compares favorably to prior CART19 cell studies in patients with progressive CLL (iwCLL CR rates of 21% to 29%).” Disclosure: This study was funded by Novartis.

6 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

ASH

FOCUS

LATEST NEWS

New Standard of Care in CLL Proposed for Older Patients Progression-free survival was higher with ibrutinib compared with bendamustine plus rituximab (BR, or chemoimmunotherapy [CIT]) in untreated, older patients with chronic lymphocytic leukemia (CLL), according to new data concurrently presented at the 2018 American Society for Hematology (ASH) Annual Meeting and Exposition, San Diego, California (Abstract 6). The rationale for the trial was based on the fact that the current strength of evidence for ibrutinib as a frontline treatment for CLL may be a bit weak: “While ibrutinib has been FDA-approved for untreated CLL since 2016, it has only been compared to chlorambucil, which is relatively ineffective, and never before to aggressive CIT,” the presenters of a plenary session at the ASH meeting noted in an abstract released before their talk. Of the 4 chemoimmunotherapy options for CLL, fludarabine/cyclophosphamide/rituximab (FCR) appears to be the best in terms of contributing to the longest progression-free survival, conferring a survival advantage of a median of 5 to 6 years. Although this is durable, the regimen is also the likeliest to produce adverse events, so it is generally not considered standard treatment for older individuals. In the phase 3 Alliance A041202 trial, backed by the National Cancer Institute’s National Clinical Trials Network, ibrutinib-containing regimens (ibrutinib alone, ibrutinib plus rituximab) led to superior PFS compared with standard CIT in older individuals with CLL. The investigators suggested it should now be the standard-of-care treatment for patients aged 65 years and older. The study’s lead investigator, Jennifer Woyach, MD, the Ohio State University Comprehensive Cancer Center, Columbus, said in a press briefing that ibrutinib was “more effective than the best available chemoimmunotherapy regimen.” The addition of rituximab did not improve outcomes or prolong PFS compared with ibrutinib alone (doi: 10.1056/ NEJMoa1812836). For the trial, 547 patients were analyzed from December 9, 2013 to May 16, 2016. The cohorts were distributed as follows: 183 patients (176 evaluable for primary end point) were assigned to receive bendamustine plus rituximab, 182 patients (178 evaluable for primary end point) to receive ibrutinib alone, and 182 (170 evaluable for primary end point) were slated to receive ibrutinib plus rituximab.

FOCUS ASH

Thirty patients crossed over from chemoimmunotherapy to ibrutinib. Median PFS was 43 months with BR, and has not yet been reached for either ibrutinib arm. The estimated progression-free survival at 2 years is near 75% with bendamustine plus rituximab, compared with 87% with ibrutinib and 88% with ibrutinib plus rituximab. Median OS has not been reached for any arm, although 2-year OS estimates for BR, ibrutinib, and ibrutinib plus rituximab were 95%, 90%, and 94%, respectively, the study abstract authors noted. Death occurred during treatment or within 30 days after treatment discontinuation in 2 patients (1%) in the bendamustine-plus-rituximab group, 13 (7%) people in the ibrutinib group, and 13 (7%) individuals in the ibrutinib-plus-rituximab group. Death occurred within the first 6 cycles of treatment, ie, within 30 days after the sixth cycle. Overall response rate is lower with BR compared with ibrutinib alone or ibrutinib/rituximab (81% v 93% v 94%, respectively). Complete response rates and rates of minimal residual disease negativity at 9 months, however, are higher with BR. “Responses with ibrutinib do tend to deepen over time, so this early time point may not be reflective of the overall MRD-negative responses in these patients,” Dr Woyach remarked. “As well, we do not yet have data showing that deeper responses lead to longer remissions with ibrutinib, so the prevalence of partial responses in this group is expected and not of concern.” Despite some new promising data, there were some serious adverse events (AEs) reported by the researchers, which they described in the New England Journal of Medicine article on December 1, 2018.2 Grade 5 AEs were seen in 5 (2.8%), 14 (7.8%), and 14 (7.7%) patients (P = .07), which the authors wrote in the journal was much higher than they expected. They attributed the higher-than-usual proportion of adverse effects to the crossover design of the trial and the fact that the patient sample was so small. In addition, the rate of secondary cancers was 13% for patients in the bendamustine-plus-rituximab group (excluding events that occurred after crossover), 13% in the ibrutinib group, and 16% in the ibrutinib-plus-rituximab group. By a median follow-up of 38 months, there had been 66 deaths, and overall survival at this time is not different among the arms. “BTK inhibition with ibrutinib is not without significant toxicity in old patients, so close monitoring is still warranted,” Dr Woyach concluded. Disclosures: Multiple authors declare affiliations with the pharmaceutical industry.

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FOCUS ASH

FEATURE

New Standard of Care in Transplant-Ineligible Myeloma

BRYANT FURLOW

dding daratumumab to standard treatment with lenalidomide and dexamethasone (DRd) reduced the risk of progression or death by 44% among patients with transplant-ineligible newly diagnosed multiple myeloma, according to an interim analysis of data from the randomized, open-label, multicenter phase 3 MAIA clinical trial (Clinical Trials.gov Identifier: NCT02252172). The interim findings were presented at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.1 “These results support DRd as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma,” said lead study author

Interim findings from the MAIA trial show that a triplet regimen may be the new standard of care for some patients with multiple myeloma. Thierry Facon, MD, of the Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France. “DRd induced significantly deeper responses, including more than a 3-fold higher minimal residual disease [MRD]-negative rate.” “Certainly, deeper remissions are a very exciting prospect,” commented Mark Crowther, MD, MSc, FRCPC, of McMaster University in Hamilton, Ontario, Canada. Dr Crowther was not involved in the study. “I think with time, longer follow-up data will be especially helpful in determining if it induces longterm benefits.” No new safety signals were observed, Dr Facon reported. “This regimen is relatively gentle for elderly and very elderly patients, but we still have to see the [currently immature] overall survival data,” he said. Rd and bortezomib, lenalidomide, and

8 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

dexamethasone (VRd) are considered standards of care for these patients. Previous research (the POLLUX study) found a 63% reduction in disease progression or death among patients receiving DRd for relapsed/refractory multiple myeloma. The phase 3 MAIA study assessed DRd versus Rd in patients with transplant-ineligible, newly diagnosed multiple myeloma. A total of 737 patients with ECOG performance scores of 0 to 2 and creatinine clearance of at least 30 mL/ minute were enrolled in the study and randomly assigned to receive Rd either with (DRd, 368 patients) or without (Rd, 369 patients) daratumumab on a 28-day cycle. Patient demographics were well balanced between the 2 study groups. Median progression-free survival (PFS) was 31.9 months for Rd patients and was not yet reached in DRd patients. Continued on page 10

VIEWPOINT

FOCUS ASH

BRYANT FURLOW

he EUTOS long-term survival score (ELTS) better discriminates patients for risk stratification than the standard Sokal score, according to findings from an analysis of data from patients treated with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML). The work was conducted by the Gruppo Italiano Malattie Ematologiche Adulto Chronic Myeloid Leukemia Working Party (GIMEMA CML WP), and the findings were presented at the 2018 American Society of Hematology (ASH) Annual Meeting.1 “The risk distribution with ELTS and Sokal score and the concordance between the 2 scores were different in adults younger than 30 years, adults aged 30 to 64 years, and elderly patients aged 65 years or older,” said lead study author Fausto Castagnetti, MD, PhD, the Institute of Hematology, University of Bologna, Italy. The ELTS score was developed with patients treated with first-line imatinib, “specifically to discriminate the probability of dying from CML,” Dr Castagnetti said. The findings bolstered previous evidence that ELTS scores better predict overall survival and leukemia-related survival than Sokal score or Euro score.2- 4 Because the Sokal system is the oldest and most widely used, and the ELTS is relatively new, many clinicians still had considered ELTS to be unproven. “Many clinicians still use the Sokal score and further evidence was required to support and implement the clinical use of the ELTS score,” he noted. But a third of patients stratified by ELTS

score had a different Sokal score, Dr Castagnetti and colleagues found. Half of Sokal high- and intermediate-risk patients were potentially misclassified, he reported. The risk of Sokal score misclassification was particularly notable among elderly patients. “In elderly CML patients treated with imatinib or nilotinib as frontline therapy, the ELTS score was able to predict the achievement of major molecular response and long-term leukemia-related survival [P = .027], whereas the Sokal score was not [P = .15, not significant],” Dr Castagnetti explained. “Consequently, in elderly patients, the use of ELTS score is strongly recommended to assess baseline disease risk and to select patients as candidates for frontline treatment with second-generation TKIs, minimizing their risk of unnecessary overtreatment.” ELTS and Sokal scores differently weigh age, which likely explains their different predictive value, the authors hypothesized. The formulas for Sokal and ELTS scoring are described online. The study analyzed data from 904 intention-to-treat (ITT) adult patients enrolled in 6 multicenter studies, 559 of whom were treated with imatinib and 345 who received nilotinib. The median patient age was 52 years (range, 18-86 years), with 70% of patients aged 30 years to 64 years and 22% aged 65 or older. At a median follow-up of 77 months (range, 24-109 months), the risk according to ELTS was 57% low-risk, 30% intermediate-risk, and 13% high-risk, compared with 40% low-risk, 39% intermediate-risk, and 21% high-risk with Sokal scores. Concordance was “good” between ELTS

EUTOS Long-Term Survival Score Outperforms Sokal in CML

EUTOS long-term survival score better predicted prognosis for those with chronic myeloid leukemia who had been treated with TKIs— especially among elderly patients.

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FOCUS ASH

VIEWPOINT

New evidence confirms that ELTS scores better predict overall survival and leukemia-related survival than Sokal score or Euro score. and Sokal scores for low- and high-risk categories among patients younger than 30 years, Dr Castagnetti noted. But ELTS stratified elderly patients (age ≥ 65 years) as 24% low-risk, 54% intermediate-risk, and 22% high-risk, compared with Sokal scoring of 9% low-risk, 70% intermediate-risk, and 21% high-risk. Those risk distributions were “comparable” between patients treated with imatinib and nilotinib. Among elderly patients, “only 8% of lowELTS patients had a low Sokal score, and only 48% of high-ELTS score patients had a high Sokal score,” he said. Overall, both ELTS and Sokal scores can significantly predict different probabilities of major molecular response, overall

survival, and leukemia-related deaths, but prognostic power was stronger for ELTS, particularly among elderly patients. “Interestingly, in elderly patients, both scores predicted the OS, while only the ELTS score predicted a significantly different LRD probability (cumulative incidence 2%, 6%, and 14% in low-, intermediate-, and high-risk patients, respectively; P = .049),” Dr Castagnetti reported. “The results were similar considering patients younger than 30 years, 30-59 years, or 60 years [or older].” ELTS and bone marrow examinations demonstrating non–chronic-phase CML can help identify more precisely which patients might benefit from a second-generation TKI, new biomarkers that predict

Feature

(P < .0001). The DRd regimen’s toxicity profile was consistent with previous studies, Dr Facon said. The rate of infusion-related reactions was 41% overall, but only 3% for grade 3 to grade 4 reactions. Fourteen percent of DRd group patients experienced grade 3/4 pneumonia, compared with 8% of patients in the Rd group. Deep vein thrombosis, pulmonary embolism, or both (any grade) occurred in 12% of DRd group patients and 13% of Rd group patients. “A total of 32% and 57% of patients discontinued DRd and Rd, respectively, primarily because of disease progression,” Dr Facon said. Treatmentemergent adverse events leading to patient death occurred in 7% of the

Continued from page 8

The estimated 30-month PFS was 71% for DRd-group patients versus 56% for Rd-gtoup patients — a 44% reduction in the risk of progression or death among patients receiving daratumumab (hazard ratio [HR] 0.56; 95% CI: 0.43-0.73; P < .0001). “The PFS benefit was observed across prespecified subgroups, including age, renal function, and ECOG function,” he noted. The study also showed a significantly higher response rate with DRd compared with Rd. Complete response (CR) rates were 48% for DRd and 25% for Rd.The MRD-negative rate was 24% for DRd compared with 7% for Rd

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treatment outcomes even more powerfully are still needed, other researchers have noted.3 BCR-ABL1 transcript biomarkers and other cytogenetic abnormalities are under investigation as potentially predictive biomarkers.3 ■ Disclosure: Dr Castagnetti disclosed payments from various pharmaceutical companies. References

1. Castagnetti F et al. The use of EUTOS Long-Term Survival Score instead of Sokal Score is strongly advised in elderly chronic myeloid leukemia patients. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 44. 2. Tiribelli M, et al. EUTOS score predicts long-term outcome but not optimal response to imatinib in patients with chronic myeloid leukaemia. Leuk

Res. 2013;37:1457-1460. 3. Chopade P, Akard LP. Improving outcomes in chronic myeloid leukemia over time in the era of tyrosine kinase inhibitors. Clin Lymph Myeloma

Leuk. 2018;18(11):710-723.

DRd study group and 6% for Rd-only patients. “The only thing we do not have yet is [overall] survival data because those data are not yet mature,” Dr Facon said. ■ Disclosure: The original study was sponsored by Janssen. Reference

1. Facon T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract LBA-2.

EXPERT PERSPECTIVE

The Patient Behind the EHR Dr Vorobiof discusses the important patient factors that can be missed via standard data collection methods. DANIEL VOROBIOF, MD

he journey of a patient with cancer is complex, intricate, and sometimes confusing. This is especially true for cancer, as it is considered to be a life-altering condition that impacts the physical, emotional, social, and economic reality for a patient and their family. When it comes to diagnosis and treatment, electronic health records (EHRs) serve an important purpose in providing up-to-date information about patients and streamlining coordination between different hospitals and clinic departments, with the goal of improving diagnosis and care. However, while EHRs are a crucial part of value-based health care, they are intrinsically limited in that they only capture half of the patient picture: the physician’s perspective. Patients with cancer, from early diagnosis through treatment and beyond, often have many medical experiences that don’t find their way into the EHR. These include a variety of symptoms, side effects, and lifestyle choices that can potentially affect their treatment in significant ways, including multivitamins, herbs, diets, cannabis, and exercise. Therefore, the question that arises is, how can health care organizations tap into the patient’s mindset and find the especially relevant information that is not necessarily recorded in the EHRs to improve care and outcomes even further?

Sharing Personal Information There is undeniable value in the information contained in EHRs, but, as mentioned previously, what is often missing are the patient perspectives. This may include information that patients purposely choose not to share with their health care providers, or information that patients believe is insignificant to report. Additionally, while clinicians input all the key patient data into the medical record, they sometimes choose to omit what may be seen as small or inconsequential details. Why are many patients not forthcoming when discussing complex and personal topics with their oncologists? The reasons to withhold information vary from person to person, but it is not uncommon to occasionally hold back due to discomfort and embarrassment. For example, controversial or highly personal topics such as cannabis or alcohol usage, sex life, and alternative therapies can be particularly difficult to discuss openly. In fact, many patients feel much more comfortable sharing and discussing this information anonymously with other patients who are in the same situation, rather than with their own health care team. Furthermore, patients with cancer commonly visit different physicians to receive further information regarding a variety of procedures and treatment options, but do not always inform their primary caregiver about them. Not being completely attuned to what the patient is doing on their own might

Daniel Vorobiof, MD Title Chief Medical Officer

Affiliation Belong.Life

Notable for Oncology

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EXPERT PERSPECTIVE affect the whole process. Also, between the date of prescribing a treatment to its initiation, a lot can happen. Writing a prescription for the patient is one thing, but it is difficult to know that they are actually filling it or if they are using it as prescribed. Another area of cancer care where patients may withhold vital information is when they are offered to participate in clinical trials. To be eligible for a clinical trial, patients must meet certain criteria, and there is often a list of requirements that they must fulfill in order to keep the harmonization of the trial. In their understandable desire to find a new treatment that might help them during such a difficult time in their lives, some patients may be less than forthcoming about factors related to their eligibility for the trial. Most physicians agree that EHRs are useful for the entire process of cancer diagnosis and treatment. However, we

further? The answer lies in the powerful combination of EHRs with the patient’s own recorded experiences. Tapping Into the Patient Mindset Through Social Media It is obvious that social media plays a major role in today’s society, and there are many social platforms that have changed the way that we form communities. What makes social networking so special is the ability to communicate with people outside of one’s immediate community, but who may share similar journeys and experiences. In this way, social media creates a larger, worldwide community that can help individuals find others to talk to and lean on in a time of need. For patients with cancer, this aspect of community interaction is especially crucial. Belong.Life is one such platform that provides access to a cancer-focused social

EHRs are a crucial part of value-based health care, but they are intrinsically limited, as they only capture half of the patient picture. are all also very familiar with the struggle that comes with patients who are not willing to share everything. Without all the information, the accuracy of diagnosis and treatment is affected. In this way, EHRs run up against the same issue that we’ve always had — the information is limited to what a patient chooses to share, and what health care providers currently know. That being said, how can health care systems gain better insight into how patients with cancer navigate the complex facets of their diagnosis and treatment to enable physicians to help them

network, including a full range of patient experiences, leveraging data and insights provided by more than 100,000 patients with cancer from around the world on all topics — even sensitive ones. Because social media offers patients the ability to speak freely and anonymously, nothing is off-limits, which creates a truly open and honest dialogue. In some cases, these virtual conversations can encourage others to speak openly about subjects they have avoided when speaking with their primary doctors and learn from the experience of others. Being able to ask questions,

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voice concerns, and speak without fear of judgment is certainly liberating for the patient, and has the added benefit of providing the health care team with a better idea of what patients with cancer are thinking and doing in the real world. Combining EHRs With Patient Social Media Communities EHRs are a powerful tool for medical professionals to accurately diagnose and treat patients with cancer. However, it is crucial that patient-reported experiences also be taken into consideration when making clinical decisions. For physicians and the medical community to fully gain such insight, harnessing the power of cancer-based communities on social media is an effective, forward-thinking way to accomplish this goal. Social applications hold the key to significant, previously unreported patient data. As more physicians and providers tap into large cancer-specific social communities, they will have access to added value that can positively impact the entire cancer treatment process. As oncologists, it is possible to use social apps to educate patients and their caregivers about the steps to be taking medications, including diverse treatment protocols and possible side effects and outcomes. At the same time, it is also possible to increase adherence by keeping patients informed with regular reminders, reports, measurements, and surveys to maximize their outcomes and facilitate their journeys. Together, I believe that the combination of EHRs and social insights will prove an invaluable tool for supporting patients, physicians, and health systems through the cancer treatment continuum and beyond. ■ Daniel Vorobiof, MD, is the chief medical officer of Belong.Life, the world’s largest cancer patient and caregiver social network.

FEATURE

Reducing Survival Disparities Across Cancer Sites of Care

BRYANT FURLOW

mong patients with metastatic non-small cell lung cancer (NSCLC), 2-year survival rates were found to be better for those who were treated at academic cancer centers compared with community-based hospitals — and survival improvements over time were more marked at academic centers — researchers from Duke University’s Duke Cancer Institute in Durham, North Carolina, reported in the Journal of Thoracic Oncology.1 Reducing the survival disparity between academic and community settings might require accelerated introduction of newer treatment options into the community setting, suggested lead study author Sendhilnathan Ramalingam, MD, and colleagues at Duke University.

The accelerated introduction of newer treatment options into the community setting may reduce the current survival disparity. And, the survival disparity appears to have worsened over time. Based on retrospective data from the National Cancer Database (NCDB) on 193,279 patients treated between 1998 and 2010, the study found that 2-year survival rates were 11.5% for patients at academic centers, 9.2% for patients who were treated at community-based centers in 1998, and in 2010, 17.4% compared with 13.1%, respectively (P < .001).1 “A number of factors could be responsible for this, including the specialized teams for each cancer disease site, multidisciplinary forums, patient selection, and access to clinical trials,” commented Suresh Ramalingam, MD, professor of hematology and medical oncology at the Emory University School of Medicine and Winship Cancer Institute in Atlanta, Georgia. Dr Suresh Ramalingam was not involved in the Duke study.

“Targeted therapies have made a major difference in improving outcomes for lung cancer,” he said. “Adoption of molecular testing, however, seems to lag in certain community centers. This could be partly responsible for the observations from the study. It is important that every patient with lung adenocarcinoma undergo thorough molecular testing to select the optimal treatment approach.” “Given advances in treatment, if dissemination of new treatments is slower to community practices, then this could explain the differences in outcomes,” agreed Joseph Unger, PhD, MS, of the SWOG Statistical Center in the public health sciences division of the Fred Hutchinson Cancer Research Center in Seattle, Washington. Diffusion of treatment advances can be “very inefficient,” Dr Unger explained.

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FEATURE “Sometimes, treatments with proven benefit permeate slowly through the treatment community, especially for disadvantaged populations, including those from lower income areas and those in poverty. The appropriate and rapid adoption of new cancer treatments could improve survival for patients with cancer.” Patients treated in community-based settings tended to be older and more comorbid, more often white than black, and more frequently covered under Medicare, the Duke team found.1 But survival remained associated with facility type in a multivariate analysis, even after controlling for age, gender, year of diagnosis, insurance type, and tumor histology.1 “We were not able to include comorbidity because it was not part of the dataset until well into our study period,” commented Dr Sendhilnathan Ramalingam. The Duke study team also found that in 1998, there was a small, histology-dependent, 2-year survival disparity between patients with adenocarcinoma compared with those with squamous cell carcinoma — but this gap in survival between subtypes had grown to a 7.2% difference by 2010 (17.3% vs 10.1%, respectively).1 That finding bolstered earlier work in the early 2000s that suggested an overall survival advantage for patients with adenocarcinoma. And, the arrival of novel targeted therapies is thought to have improved survival times among patients with adenocarcinoma.1,2 However, the NCDB data lacked details on systemic treatment agents, molecular testing, mutational status, or the extent or location of metastatic tumors, complicating efforts to retrospectively assess that hypothesis.1 It is too soon to yet say whether or not survival disparities between community and academic settings have begun to diminish in more recent years across

the NCDB data, Dr Sendhilnathan Ramalingam said. “One of the main takeaway points from our study is that the histology-related differences in outcomes between academic and community centers allude to potential treatment disparities — but more study is needed to determine if this trend has continued in more recent years, and to definitively determine an underlying cause for it,” Dr Sendhilnathan Ramalingam said. “[W] e are starting to look at more recent data, so hopefully [there will be] more to come in the coming months.” According to data from the National Comprehensive Cancer Network (NCCN), presented at the ESMO 2018 Congress in Munich, Germany, molecular testing and targeted therapy are starting to move from academic to community settings, with nearly 1 in 4 patients with advanced cancers undergoing such personalized care across NCCN centers in the United States.

undertaken at academic centers, Dr Unger pointed out. “The treatments developed in these studies are likely tailored to the greater resources that are available at academic centers, which makes dissemination of new, trial-proven treatments more challenging to community centers,” he said. The National Cancer Institute (NCI) has recognized this issue and has sought to establish a community oncology research program to allow patients at these facilities to participate in NCIsponsored trials. “This means the treatments developed by the network groups of the NCI are more likely to be more readily adopted by community sites,” Dr Unger explained. Dr Unger was lead author of the first comprehensive comparison of survival outcomes among rural and urban patients enrolled in clinical cancer trials.3 Published in August 2018 in JAMA Network Open, that study showed that

“Treatments with proven benefit permeate slowly through the treatment community, especially for disadvantaged populations.” Research advances are creating more options and hope for patients, but uptake can vary markedly between cancer treatment facilities, noted Emory’s Dr Suresh Ramalingam. “Disease-based specialization is increasingly necessary to incorporate research advances into clinical practice in a timely manner,” he said. “Better collaboration and exchange of patients between academic and community centers will help minimize the difference in outcomes.” More clinical trials — particularly single-institution studies — are typically

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clinical trial enrollment does indeed reduce survival disparities between urban patients who have ready access to academic cancer centers, and rural patients seeking care at community cancer centers.3 “We comprehensively examined nearly 37,000 patients with a wide variety of cancer types and cancer stages using big data strategies to link disparate data sources, including 44 clinical trials enrolling patients across 50 states, linked to geospatial data,” Dr Unger explained. Continued on page 18

IMMUNOTHERAPY REPORT

Evidence is growing that immune checkpoint inhibitors can speed up tumor growth. CHRISTINA BENNETT, MS

pproximately 3 months ago, a cancer patient traveled a few hundred miles to see medical oncologist Razelle Kurzrock, MD, chief of the hematology and oncology division in the UC San Diego School of Medicine, California. The patient had cancer and he knew what he wanted: immunotherapy. “Sometimes patients have their own ideas of what they want to be treated with,” Dr Kurzrock told Cancer Therapy Advisor. She explained to the patient that based on what she knew, he was actually a bad candidate for immunotherapy; his tumor had an MDM2 amplification. Dr Kurzrock does not treat patients with single-agent immune checkpoint inhibitors if their tumors have MDM2 amplifications or epidermal growth factor receptor (EGFR) mutations because these abnormalities are associated with a phenomenon called hyperprogression.1 Hyperprogression is a relatively new and controversial term to describe tumor growth that violently speeds up as a result of treatment with immune checkpoint inhibitor therapy. Different from pseudoprogression, tumors that hyperprogress are linked to poor survival and worse clinical symptoms. Studies have sought to pin down patient or tumor characteristics that predict which patients are at the highest risk for tumor hyperprogression during immune checkpoint inhibitor therapy,

but no widely accepted predictors have been identified. Not even advanced disease stage or poor performance status at baseline have been associated with hyperprogressive disease. 2 MDM2 amplification and EGFR mutations are the only suspected predictors. When Dr Kurzrock recommended a treatment other than immunotherapy, the patient refused her advice and sought treatment elsewhere. Eventually, the patient returned to Dr Kurzrock with displeasing news: his tumor had hyperprogressed after being treated with pembrolizumab. The tumor, he told her, almost seemed as if someone had lit a fire underneath it.

Oncologists who have observed the phenomenon firsthand are starting to share ad hoc stories like Dr Kurzrock’s. Timothy Chan, MD, PhD, vice chair of the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center, New York, recalls a patient’s tumor growing 20-fold larger in about 2 weeks after the start of immune checkpoint blockade. “It resulted in massive tumor growth that eventually caused a lot of issues,” he told Cancer Therapy Advisor. He wasn’t sure hyperprogression was real until he saw this particular case. “I have personally never seen a tumor grow this fast before.” This observation prompted him to post a query on Twitter: Had others seen this too? He received a stream of threaded replies: Yes, many had, across a slew of cancer types. “I’ve seen the phenomenon of really exploding growth right at the first scan,” Shilpa Gupta, MBBS, University of Minnesota, Minneapolis, told Cancer Therapy Advisor. She said the accelerated tumor growth is not unique to

PD-1 (red) extending from the surface of a T-cell and interacting with the ligand protein PD-L1 (yellow) from an antigen presenting cell.

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Hyperprogression Related to Treatment: Concerns Mount

IMMUNOTHERAPY REPORT immunotherapy; she has seen similar tumor behavior in patients on chemotherapy. “But I would say we are seeing more and more of this in immunotherapy now,” she added. Studies indicate hyperprogression can occur in any cancer type and the incidence may sit between 9% and 29%, depending on various factors.2 By comparison, immune checkpoint inhibitors are believed to provide benefit to approximately 20% of patients. The first group to investigate the phenomenon found accelerated tumor growth in 9% of cancer patients treated with a programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor as a monotherapy.3 They published their findings in late 2016, and other groups have since reported incidence rates they have observed in patients across various cancer populations. A French group found hyperprogression in 29% of patients with recurrent and/or metastatic head and neck squamous cell carcinoma who received PD-L1/PD-1 inhibitors.4 An Italian group reported hyperprogression in a quarter of patients with non-small cell lung cancer (NSCLC) during treatment with PD-1/PD-L1 inhibitors.5 Another French group found hyperprogression in 13.8% of patients with advanced NSCLC who received PD-1/ PD-L1 inhibitors and 5% of patients who were treated with chemotherapy, making it the first study to show that while hyperprogressive disease has the potential to occur with other classes of therapeutics, the incidence of it is higher with immunotherapies.6 An interim analysis for a phase 2 clinical trial revealed high rates of hyperprogression in germ cell tumor patients treated with durvalumab; 72.7% who received the drug had hyperprogressive disease. As a result, study investigators closed the durvalumab alone arm to further accrual.7

“The hard part of all of this is that, up to now, it’s still a very ad hoc observation,” Dr Chan said. He said that more institutions need to track hyperprogressive disease. However, despite mounting evidence that immunotherapies could have long-lasting adverse effects, not all

and dysregulation that results in the tumor winning over the host. That’s conceivable and possible, but I do think that what would convince me is a mechanistic study in which we actually show that in those patients, here’s what’s happened.”

Individual studies are beginning to emerge that explore the biology of hyperprogressive disease, but its mechanisms are still unclear. oncologists are convinced that hyperprogression is a real thing. A common argument against hyperprogression is that the observed acceleration in tumor growth could be the natural behavior of an aggressive tumor, not be the result of immunotherapy. Also, the current evidence is retrospectively obtained from clinical trials, and data on the rate of tumor growth prior to administration of an immunotherapy are lacking. “Without that initial time point, you can’t separate simple progression from hyperprogression,” Dr Chan said. “When you don’t have a lot of evidence, it leaves a lot of space for emotional responses,” Hussein Tawbi, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, told Cancer Therapy Advisor. Dr Tawbi is not fully convinced hyperprogression is real based on the current evidence available. He reasons, “I have seen cancer go wild, and I’ve seen it go wild regardless of what treatment you give patients.” “There is no question that the immune system is a very finely balanced community of cells that interact and have their own checks and balances,” he said. “It is possible that if we push too hard in one spot, the response to this could actually be a complete imbalance

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An article by Champiat and colleagues entertains the possible biological explanations at play among various immune cells, cytokines, and immune-checkpoint molecules, but the explanations are largely rooted in preclinical evidence.2 Individual studies are beginning to emerge that explore the biology of hyperprogressive disease, but the mechanism of how and why it occurs is still unclear.5,8 “More study needs to occur,” Dr Chan asserted. “But I do think it’s real, and so do a lot of other people who have seen it.” ■ References

1. Kato S, et al. Clin Cancer Res. 2017;23(15):4242-4250. 2. Champiat S, et al. Nat Rev Clin Oncol. 2018;15:748-762. 3. Champiat S, et al. Clin Cancer Res. 2017;23(8):1920-1928. 4. Saâda-Bouzid E, et al. Ann Oncol. 2017;28(7):1605-1611. 5. Lo Russo G, et al. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-1390 6. Ferrara R, et al. JAMA Oncol. 2018;4(11):1543-1552. 7. Necchi A, et al. Eur Urol. doi: 10.1016/j. eururo.2018.09.010 8. Xiong D et al. IScience. 2018;9:258-277.

IN THE CLINIC

Gender-Based Differences in Chemotherapy: Efficacy and Safety Reactions to therapy were gender-specific, but there were no significant differences in survival.

deally, a health care provider would be able to pick a chemotherapeutic agent that has the best efficacy and fewest number of side effects for each individual patient. These types of decisions are often guided by clinical trials and developing data on biomarkers and genetics. One part of the patient’s history that can be easily overlooked when considering different treatment options is the patient’s gender. The role of gender in the epidemiology of cancer is well known; it is well established that men have higher overall rates of cancer than women in North America.1,2 However, the impact of gender on specific outcomes, including efficacy and safety, is less recognized and understood, despite growing research. One recent example was published in the Annals of Oncology by Davison and colleagues.3 This study evaluated the interpatient variability of chemotherapy metabolism and dose-response based on gender in patients with esophagogastric (EG) cancer. A pooled analysis of 4 randomized clinical trials was performed in patients receiving a triple chemotherapy regimen including a platinum, anthracycline, and fluoropyrimidine. These 4 studies were all multicentered and took place in the United Kingdom. The studies included 1654 patients;

approximately 80% were male and 20% were female. There were no significant differences in all-grade toxicities between men and women, however, women did have statistically significant higher rates of certain toxicities, especially those within the gastrointestinal (GI) tract. These included all-grade stomatitis (49.5% vs 40.7%, P = .004), all-grade nausea and vomiting (89.3% vs 78.3%, P < .001) and all-grade diarrhea (53.8% vs 46.9%, P = .027). In addition to these GI toxicities, women also experienced more all-grade alopecia (81.4% vs 74.3%, P = .009). On the contrary, men had significantly higher rates of peripheral neuropathy compared

C. ANDREW KISTLER, MD, PharmD

with women (49.3% vs 42.6%, P = .03). There were no statistically significant differences in outcomes between men and women, including in the rates seen for progression free survival (PFS), overall survival (OS), and objective response rate (ORR). The more prominent GI toxicity profile among women was an interesting finding, although the exact reason for this phenomenon is unclear. It would be interesting to stratify gut microbiome profiles by gender to see if that played a role in GI toxicity differences. Also, whether the location of the malignancy within the GI tract played a prominent role in these toxicities compared with similar chemotherapy regimens in non- GI malignancies could be an area of future research. Regardless, this type of information could prove valuable when constructing treatment protocols and clinical trials for specific patients. It may allow for earlier identification of toxicities within women. The exact pathophysiology behind these gender-based differences is not entirely understood. The obvious factors that could play a role in all malignancies

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IN THE CLINIC

include lifestyle, different levels of gene expression, and varying levels of hormones. There can also be factors within specific types of cancer yet to be identified. A recent study conducted by Li and colleagues evaluated the differences in genetic mutations between men and women within several cancers.4 In all cancer types, malignancies found in men had higher levels of single nucleotide

Feature Continued from page 14

Importantly, Dr Unger and colleagues concluded that differences between urban and rural patient populations were less important to survival than the care they received at each of these types of institutions.3 “We found that cancer patients from rural areas receiving treatment on clinical trials had virtually the same outcomes as corresponding urban cancer patients in nearly all the cancers we examined,” he told Cancer Therapy Advisor. That finding may come as a surprise to many. “But clinical trials are a key difference here,” Dr Unger explicated. “In

variants (SNVs) compared with women (difference in means 0.17, 95% confidence interval [CI], 0.14-0.20). When evaluating specific types of cancer, these imbalances in SNVs were most prominent across 5 types of cancer within men: urothelial cancer, melanoma, renal papillary cell cancer, lung adenocarcinoma, and hepatocellular cancer. Glioblastoma was the only cancer that had a higher SNV rate in women compared with men. These elevated numbers of SNVs could correlate with defects in DNA mismatch repair (MMR), which can be measured via microsatellite instability (MSI). The authors were able to review MSI data within EG, pancreatic cancer, and colorectal cancer. There was an increased association of MSI in females compared with males in EG cancer (40% vs 25%, P < .001) and colorectal cancer (33% vs 25%, P = .025), but not pancreatic cancer. Chemotherapy outcomes and how they vary between genders is an intriguing topic that still requires further research. However, there is enough

evidence at this point to suggest that gender could play a more significant role in clinical trial development in the future to make more personalized treatment plans a reality. ■

trials, patients are uniformly assessed, treated, and followed under a strict, guideline-driven protocol.” The study outcomes suggest that improving rural cancer patients’ access to guideline-based cancer care available in clinical trials should improve their survival rates, Dr Unger said. Incentives for oncologists to work in rural areas could help, he suggested — just as could provider networks between academic and community clinics. Regardless of patient site of care, an oncologist’s commitment to staying up to date with evidence-based treatment options — and how to actually make them available to patients — is an important component to providing the best care possible. ■

References

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References

1. Cook MB, Dawsey SM, Freedman ND, et al. Sex disparities in cancer incidence by period and age. Cancer Epi-

demiol Biomarkers Prev. 2009;18(4): 1174-1182. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. 3. Davidson M, Wagner AD, Kouvelakis K, et al. Influence of sex on chemotherapy efficacy and toxicity in oesophagogastric (OG) cancer: a pooled analysis of four randomised trials [published online October 23, 2018]. Ann Oncol. 2018; 29(suppl_8). doi: 10.1093/annonc/ mdy424.032 4. Li CH, Haider S, Shiah YJ, Thai K, Boutros PC. Sex differences in cancer driver genes and biomarkers. Cancer Res. 2018;78(19):5527-5537.

1. Ramalingam S, Dinan MA, Crawford J. Survival comparison in patients with stage IV lung cancer in academic versus community centers in the United States [published online September 22, 2018]. J Thorac Oncol. doi: 10.1016/j.jtho.2018.09.007 2. Morgensztern D, Waqar S, Subramanian J, Gao F, Govindan R. Improving survival for stage IV non-small cell lung cancer: a Surveillance, Epidemiology, and End Results survey from 1990 to 2005. J Thorac Oncol. 2009;4(12):1524-1529. 3. Unger JM, Moseley A, Symington B, ChavezMacGregor M, Ramsey SD, Hershman DL. Geographic distribution and survival outcomes for rural patients with cancer treated in clinical trials. JAMA Netw Open. 2018;1(4):e181235.

VIEWPOINT

CHRISTINA BENNETT, MS

atients with high-risk early-stage breast cancer with detectable circulating tumor cells (CTCs) 2 years after chemotherapy completion had worse survival and greater risk of disease recurrence compared with patients without detectable CTCs.1 These findings come shortly after Sparano and colleagues reported a similar correlation between the presence of CTCs and risk of recurrence in patients with estrogen receptor-positive breast cancer.2 “Usually we are only able to determine the prognosis of our patients based on tumor biology and patient characteristics,” study coauthor Elisabeth Trapp, MD, Ludwig-Maximilians-University, Munich, Germany, told Cancer Therapy Advisor. “Using liquid biopsy will help us to answer the question in a more individualized and patient-targeted way.” The results are based on data from the SUCCESS A trial, which evaluated 2 adjuvant chemotherapy regimens followed by 2 years or 5 years of zoledronate in patients with high-risk early-stage breast cancer. Investigators used the CellSearch system to screen for CTCs both at baseline and at 2 years after the completion of chemotherapy. A positive CTC detection was defined as the presence of at least 1 CTC in 7.5 mL of peripheral blood. Overall survival and disease-free survival were also assessed at 2 years after chemotherapy; survival included death from any cause. In total, 1087 patients with high-risk early-stage breast cancer were included in the analysis, and at 2 years after

chemotherapy completion, 198 patients (18.2%) had detectable CTCs. Patients with detectable CTCs at 2-year follow-up had a nearly 4-fold elevated risk of death and more than 2-fold greater risk of disease recurrence compared with patients without detectable CTCs. Broken down, of the patients who were CTC-positive at follow-up, 10.6% died and 18.2% had disease recurrence. Of the patients who were CTC-negative at follow-up, 2.5% died and 7.3% had disease recurrence. Now the real question is whether a treatment can be given at this time point to reduce the risk of recurrence, said Julie Gralow, MD, of Seattle Cancer Care Alliance, in an interview with Cancer Therapy Advisor. An exploratory subgroup analysis in the Trapp et al study found that 25.6% of triple-negative breast cancer patients with CTC positivity had recurrence. For triple-negative patients who are CTC positive at follow-up, Dr Gralow postulated, would you give chemotherapy at that point when three quarters of patients won’t recur and a quarter will? Patients who have triple-negative breast cancer currently don’t have many approved therapy options besides chemotherapy. A trial called LATER-R that may provide insights into possible interventions is in the very early stages of planning. ■

Liquid Biopsy as a Surveillance Tool for Breast Cancer Follow-Up

High-risk early breast cancer patients with circulating tumor cells 2 years after chemotherapy had greater risk of recurrence. Possible interventions are needed.

References

1. Trapp E, et al. J Natl Cancer Inst. doi: 10.1093/ jnci/djy152 2. Sparano J, et al. JAMA Oncol. doi: 10.1001/ jamaoncol.2018.2574

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2019 | CANCER THERAPY ADVISOR 19

GASTROINTESTINAL CANCER

TREATMENT REGIMENS Rectal Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

General Treatment Notes1 • Consists of regimens that include both concurrent chemotherapy and radiotherapy and adjuvant chemotherapy. • Six months of perioperative therapy is preferred in the adjuvant therapy setting. • Following a shortage of leucovorin, the FDA approved levoleucovorin in combination with 5-FU for the palliative treatment of patients with advanced metastatic colorectal cancer. Levoleucovorin 200mg/m2 is the equivalent of leucovorin 400mg/m2.

uPostoperative

Adjuvant Therapy for Patients Not Receiving Preoperative Therapy1

Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

mFOLFOX6 (oxaliplatin + leucovorin + 5-fluorouracil [5-FU])2–4,a

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks for a total of 6 months perioperative therapy.

Capecitabine6,d

Days 1–14: Capecitabine 1,000–1,250mg/m2 orally twice daily. Repeat cycle every 3 weeks for 6 months perioperative therapy.

CapeOX (oxaliplatin + capecitabine)7,8,a,d

Day 1: Oxaliplatin 130mg/m2 IV. Days 1–14: Capecitabine 1,000mg/m2 orally twice daily. Repeat cycle every 3 weeks for 6 months perioperative therapy.

Simplified biweekly infusional 5-FU/LV (sLV5FU2)5

Day 1: Leucovorin 400mg/m2 IV, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48 hour continuous infusion. Repeat cycle every 2 weeks for 6 months perioperative therapy.

5-FU + leucovorin9

5-FU 500mg/m2 IV bolus weekly × 6 + leucovorin 500mg/m2 IV weekly × 6, each 8-week cycle. Repeat cycle every 8 weeks for 6 months perioperative therapy.

uConcurrent

Chemotherapy + Radiotherapy1

External beam radiotherapy [XRT] + 5-FU10

Days 1–5 OR 1–7: 5-FU 225mg/m2 IV over 24 hours during XRT.

XRT + 5-FU + leucovorin11,b

Days 1–4: 5-FU 400mg/m2 IV bolus + leucovorin 20mg/m2 IV bolus. Repeat cycle during weeks 1 and 5 of XRT.

XRT + capecitabine12,13,d

Days 1–5: Capecitabine 825mg/m2 twice daily + XRT. Repeat cycle weekly for 5 weeks.

uSystemic

Therapy for Advanced or Metastatic Disease1

mFOLFOX63,4,14,a,c

Day 1: Oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 IV followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks.

mFOLFOX715,a

Day 1: Oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 IV Days 1-2: 5-FU 1200mg/m2/day IV (total 2400mg/m2) as 46–48 continuous infusion. Repeat cycle every 2 weeks.

20 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

GASTROINTESTINAL CANCER

TREATMENT REGIMENS Rectal Cancer Treatment Regimens uSystemic

Therapy for Advanced or Metastatic Disease1 (continued)

REGIMEN

DOSING

FOLFOX6 + bevacizumab16,a

Day 1: Oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 IV, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

FOLFOX + panitumumab17,a (KRAS/NRAS wild-type gene only)

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion Day 1: Panitumumab 6mg/kg IV over 1 hour. Repeat cycle every 2 weeks.

FOLFOX + cetuximab18,a (KRAS/NRAS wild-type gene only)

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion PLUS Day 1: Cetuximab 400mg/m2 IV over 2 hours first infusion, then 250mg/m2 IV over 60 minutes weekly. OR Day 1: Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

CapeOX19,a,d

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 1,000mg/m2 orally twice daily. Repeat cycle every 3 weeks.

CapeOX + bevacizumab19,a,c,d

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 1,000mg/m2 orally twice daily Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

FOLFIRI5,20

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes + leucovorin 400mg/m2 IV, to match duration of irinotecan infusion, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks.

FOLFIRI + bevacizumab21,c

FOLFIRI + cetuximab22,23 (KRAS/NRAS wild-type gene only)

Day 1: Irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV, to match duration off irinotecan infusion, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks. PLUS Day 1: Cetuximab 400mg/m2 IV over 2 hours first infusion, then 250mg/m2 IV over 60 minutes weekly. OR Day 1: Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

FOLFIRI + panitumumab24 (KRAS/NRAS wild-type gene only)

FOLFIRI + ziv-aflibercept25

Day 1: Irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion Day 1: Ziv-aflibercept 4mg/kg IV. Repeat cycle every 2 weeks.

FOLFIRI + ramucirumab26

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2019 | CANCER THERAPY ADVISOR 21

GASTROINTESTINAL CANCER

TREATMENT REGIMENS Rectal Cancer Treatment Regimens uSystemic

Therapy for Advanced or Metastatic Disease1 (continued)

REGIMEN

DOSING

FOLFOXIRI ± bevacizumab27,28,a,c

Day 1: Irinotecan 165mg/m2 IV + oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 IV Days 1 and 2: 5-FU 1,600mg/m2/day continuous infusion IV over 48 hours

Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks. IROX29,a

Day 1: Oxaliplatin 85mg/m2 IV + irinotecan 200mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks.

Bolus or infusional 5-FU/ leucovorin (Roswell-Park Regimen)30

Days 1, 8, 15, 22, 29, and 36: Leucovorin 500mg/m2 IV over 2 hours, followed by 5-FU 500mg/m2 IV bolus 1 hour after start of leucovorin. Repeat cycle every 8 weeks.

Simplified biweekly infusional 5-FU/LV (sLV5FU2)5

Day 1: Leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks.

Weekly 5-FU + leucovorin31

Day 1: Leucovorin 20mg/m2 IV over 2 hours, followed by 5-FU 500mg/m2 IV bolus 1 hour after start of leucovorin. Repeat cycle weekly. OR Day 1: Leucovorin 500mg/m2 IV, followed by 5-FU 2,600mg/m2 continuous infusion. Repeat cycle weekly.

Capecitabine19

Days 1–14: Capecitabine 850–1,250mg/m2 orally twice daily. Repeat cycle every 3 weeks.

Capecitabine + bevacizumab32,c

Days 1–14: Capecitabine 850–1,250mg/m2 orally twice daily Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

Irinotecan33,34

Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks. OR Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes. Repeat cycle every 2 weeks. OR Day 1: Irinotecan 300–350mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks.

Cetuximab + irinotecan23,35 (KRAS/NRAS wild-type gene only)

Day 1: Cetuximab 400mg/m2 IV first infusion, then 250mg/m2 IV every 7 days OR Day 1: Cetuximab 500mg/m2 IV every 2 weeks

Day 1: Irinotecan 300–350mg/m2 IV over 30–90 minutes every 3 weeks. OR Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes every 2 weeks. OR Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes every 3 weeks. Irinotecan + cetuximab + vemurafenib (KRAS/NRAS wild-type gene only)36

Day 1: Irinotecan 180mg/m2 IV + cetuximab 500mg/m2 IV Days 1-14: Vemurafenib 960mg orally twice daily Repeat cycle every 2 weeks.

Irinotecan + panitumumab + vemurafenib (BRAF V600E mutation positive)1

Day 1: Irinotecan 180mg/m2 IV + panitumumab 6mg/kg IV over 60 minutes Days 1-14: Vemurafenib 960mg orally twice daily Repeat cycle every 2 weeks.

Cetuximab23,35 (KRAS/NRAS wild-type gene only)

Cetuximab 400mg/m2 first infusion, then 250mg/m2 IV weekly. OR Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

Panitumumab37 (KRAS/NRAS wild-type gene only)

Day 1: Panitumumab 6mg/kg IV over 60 minutes. Repeat cycle every 2 weeks. continued

22 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

GASTROINTESTINAL CANCER

TREATMENT REGIMENS Rectal Cancer Treatment Regimens uSystemic

Therapy for Advanced or Metastatic Disease1 (continued)

REGIMEN

DOSING

Regorafenib38,39,e,f

Days 1–21: Regorafenib 160mg orally once daily. Repeat cycle every 28 days OR First Cycle Days 1-7: Regorafenib 80mg orally daily Days 8-14: Regorafenib 120mg orally daily Days 15-21: Regorafenib 160mg orally daily Subsequent Cycles Days 1-21: Regorafenib 160mg orally daily. Repeat cycle every 4 weeks.

Trifluridine/tipiracil40

Days 1–5 and 8–12: Trifluridine/tipiracil 35mg/m2 up to a maximum of 80mg/m2 per dose (based on the trifluridine component) orally twice daily. Repeat every 28 days.

Pembrolizumab41

Day 1: Pembrolizumab 2mg/kg. Repeat cycle every 3 weeks.

Nivolumab42

Day 1: Nivolumab 3mg/kg. Repeat cycle every 2 weeks. OR Day 1: Nivolumab 240mg IV. Repeat cycle every 2 weeks.

Oxaliplatin may be given either over 2 hours, or may be infused over a shorter time at a rate of 1mg/m2/min. Leucovorin infusion should match time of oxaliplatin. Cercek A, Park V, Yaeger R, et al. Faster FOLFOX: oxaliplatin can be safely infused at a rate of 1mg/m2/min. J Oncol Pract. 2016;12:e548-553. b Bolus 5-FU/leucovorin/XRT is an option for patients not able to tolerate capecitabine or infusional 5-FU. c Bevacizumab may be safely given at a rate of 0.5mg/kg/minute (5mg/kg over 10 minutes and 7.5mg/kg over 15 minutes). d Most of the safety and efficacy data for this regimen have come from Europe, where a capecitabine starting dose of 1,000mg/m2 twice daily for 14 days, repeated every 21 days, is standard. Evidence suggests North American patients may experience greater toxicity with capecitabine (as well as with other fluoropyrimidines) than European patients, necessitating the use of a lower dose of capecitabine. e It is common practice to start at a lower dose of regorafenib (80 or 120mg) and escalate, as tolerated. f Regorafenib or trifluridine + tipiracil are treatment options for patients who have progressed through all available regimens. a

References 1. NCCN Clinical Practice Guidelines in Oncology™. Rectal Cancer. v 1.2018. Available at: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed July 11, 2018. 2. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351. 3. Cheeseman SL, Joel SP, Chester JD, et al. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87:393-399. 4. Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Ann Oncol. 2000;11:1477-1483. 5. Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer. 1999;35(9):1343-1347. 6. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-2704. 7. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25:102-109. 8. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29:1465-1471. 9. Petrelli N, Douglass Jr HO, Herrare L, et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989;7:1419-1426. 10. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for

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rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994; 331:502-507. Tepper JE, O’Connell M, Niedzwiecki D, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of Intergroup 0114. J Clin Oncol. 2002;20:1744-1750. O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014;32:1927-1934. Hofheinz R, Wenz FK, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: A randomized, multicentre, noninferiority, phase 3 trial. Lancet Oncol. 2012;13:579-588. deGramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced rectal cancer. J Clin Oncol. 2000;18:2938-2947. Hochster HS, Grothey A, Hart L, et al. Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT. Ann Oncol. 2014;25:1172-1178. Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007;7:91. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28:4697-4705. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5- FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLF-

continued

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TREATMENT REGIMENS

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OX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum [abstract]. ASCO Meeting Abstracts. 2014;32:LBA3. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25:4779-4786. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomized, open-label, phase 3 trial. Lancet Oncol. 2014. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345. Martín-Martorell P, Roselló S, Rodríguez-Braun E, et al. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008;99:455-458. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706-4713. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an OxaliplatinBased Regimen. J Clin Oncol. 2012;30:3499-3506. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomized, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16:499-508. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: The Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670-1676. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16:1306-1315. Haller DG, Rothenberg ML, Wong AO, et al. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single agent fluoropyrimidine

therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008;26:4544-4550. 30. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Protocol C-03. J Clin Oncol. 1993;11:1879-1887. 31. Jäger E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996;14:2274-2279. 32. Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1077-1085. 33. Cunningham D, Pyrhonen S, James R, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. The Lancet. 1998;352:1413-1418. 34. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21:807-814. 35. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study. J Clin Oncol. 2012;30:2861-2868. 36. Kopetz S, McDonough SL, Lenz, H-J, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol. 2017;35(suppl; abstr 3505). 37. Van Custem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-1664. 38. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303-312. 39. Bekaii-Saab, TS, Ou F-S, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—An ACCRU Network study. J Clin Oncol. 2018;36(suppl 4S;abstr 611). 40. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer (RECOURSE). N Engl J Med. 2015;372:1909-19. 41. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-2520. 42. Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab {+/-} ipilimumab in treatment of patients with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results [abstract]. ASCO Meeting Abstracts. 2016;34:3501. (Revised 7/2018) © 2018 by Haymarket Media, Inc.

uClinical

Trial Resources

ONGOING TRIALS IN GASTROINTESTINAL CANCER: Pilot Study Seeks to Assess Physical Activity Program in Patients With Gastrointestinal Cancer Researchers are seeking to assess a physical activity program in patients with gastrointestinal cancer. Read more at www.CancerTherapyAdvisor.com/GICancerPhysicalActivity. Early Phase 1 Trial Investigating Postoperative Treatment Selection After Preoperative Chemo Researchers are seeking to determine the feasibility of receiving either postoperative chemoradiation or chemotherapy. Read more at www.CancerTherapyAdvisor.com/GICancerPostoperativeTreatmentRisk.

To read more about recent FDA approvals, drug trials, and interviews with leading researchers visit www.CancerTherapyAdvisor.com/GastrointestinalCancers.

24 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

SARCOMA

TREATMENT REGIMENS Soft Tissue Sarcoma Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uSystemic

Therapy With Activity in Soft Tissue Sarcoma Subtypes With Non–specific Histologies1,a,b,c

Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Combination Regimens Doxorubicin + dacarbazine (AD)2-5

Days 1–4: Doxorubicin 60mg/m2 + dacarbazine 750mg/m2 as a continuous IV infusion over 96 hours. Repeat cycle every 3 weeks.

Doxorubicin + ifosfamide + mesna (AIM)4-7

Days 1 and 2: Doxorubicin 30mg/m2/day IV + ifosfamide 3,750mg/m2/day IV + mesna 750mg/m2 IV immediately preceding and then 4 and 8 hours after ifosfamide administration. Repeat cycle every 3 weeks.

Mesna + doxorubicin + ifosfamide + dacarbazine (MAID)4,5,8,9

Days 1–3: Doxorubicin 20mg/m2/day + ifosfamide 2,500mg/m2/day + dacarbazine 300mg/m2/day as continuous IV infusion over 72 hours, plus Mesna 2,500mg/m2/day IV for 84 to 96 hours. Repeat cycle every 3 weeks.

Ifosfamide + epirubicin + mesna10

Days 1 and 2: Epirubicin 60mg/m2/day IV Days 1–5: Ifosfamide 1.8g/m2/day IV over 1 hour + mesna at 20% of the ifosfamide dose IV immediately preceding and then 4 and 8 hours after ifosfamide administration. Repeat cycle every 3 weeks for 5 cycles.

Gemcitabine + docetaxel11,12

Days 1 and 8: Gemcitabine 900mg/m2 IV Day 8: Docetaxel 100mg/m2 IV. Repeat cycle every 3 weeks.

Gemcitabine + vinorelbine13

Days 1 and 8: Vinorelbine 25mg/m2 IV over 10 minutes + gemcitabine 800mg/m2 IV over 90 minutes. Repeat cycle every 3 weeks.

Gemcitabine + dacarbazine14

Day 1: Gemcitabine 1,800mg/m2 IV + dacarbazine 500mg/m2 IV. Repeat cycle ever 2 weeks for a total of 12 cycles; continuation of treatment after 24 weeks was allowed at investigator discretion.

Doxorubicin + olaratumab15,e

Day 1: Doxorubicin 75mg/m2 IV Days 1 and 8: Olaratumab 15mg/kg IV. Repeat cycle every 3 weeks for up to 8 cycles.

Single Agents Doxorubicin4,5,16

Doxorubicin 60–75mg/m2 IV every 3 weeks.

Ifosfamide10,17

Ifosfamide 2,000–3,000mg/m2/day IV for 3 to 4 days + mesna at 20% of the ifosfamide dose IV immediately preceding and then 4 and 8 hours after ifosfamide administration every 3 weeks. OR Ifosfamide 5,000mg/m2 + mesna 5,000mg/m2 as a continuous IV infusion over 24 hours followed by additional mesna 400–600mg/m2 IV over 2 hours after completion of ifosfamide administration. Repeat every 3 weeks. continued

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2019 | CANCER THERAPY ADVISOR 25

SARCOMA

TREATMENT REGIMENS Soft Tissue Sarcoma Treatment Regimens uSystemic

Therapy With Activity in Soft Tissue Sarcoma Subtypes With Non–specific Histologies1,a,b,c (continued)

REGIMEN

DOSING

Single Agents (continued) Epirubicin18

Epirubicin 160mg/m2 IV every 3 weeks.

Gemcitabine

Days 1 and 8: Gemcitabine 1,200mg/m2 IV over 90 to 120 minutes. Repeat cycle every 3 weeks.

Dacarbazine

Dacarbazine 250mg/m2/day IV for 5 days every 3 weeks. OR Dacarbazine 800–1,000mg/m2 IV every 3 weeks.

Liposomal doxorubicin19

Liposomal doxorubicin 30–50mg/m2 IV every 4 weeks.

Temozolomide20,d

Day 1: Temozolomide 200mg/m2 oral bolus dose once followed by temozolomide 90mg/m2 after 12 hours. Days 2-5: Temozolomide 90mg/m2 orally twice daily. Repeat cycle every 4 weeks.

Vinorelbine21,d

Vinorelbine 30mg/m2 IV weekly for 6 weeks during an 8-week interval.

Pazopanib22,d,f

Pazopanib 800mg orally once daily without food until disease progression or unacceptable toxicity.

Eribulin23,d,g

Days 1 and 8: Eribulin mesylate 1.4mg/m2 IV. Repeat every 3 weeks until disease progression or unacceptable toxicity.

Trabectedin24-26,d,h

Trabectedin 1.5mg/m2 as a 24-hour continuous IV infusion every 3 weeks.

c d e f g h a

Alveolar soft part sarcomas (ASPS), well-differentiated liposarcoma/atypical lipomatous tumor, and clear cell sarcomas are generally non sensitive to cytotoxic chemotherapy. Anthracycline-based regimens are preferred in the neoadjuvant and adjuvant setting. Regimens appropriate for pleomorphic rhabdomyosarcoma. Recommended only for palliative therapy. For use in STS histologies for which an anthracycline-containing regimen is appropriate. Pazopanib should not be used for lipogenic sarcomas. Category 1 recommendation for liposarcoma. Category 1 recommendation for liposarcoma and leiomyosarcoma (L-types).

References 1. Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™ Soft Tissue Sarcoma. V1.2018. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/sarcoma.pdf. Accessed February 2, 2018. 2. Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: A Southwest Oncology Group Study. J Natl Cancer Inst. 1991;83:926–932. 3. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase Ill randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11:1276–1285. 4. Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet. 1997;350:1647–1654. 5. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113:573–581. 6. Grobmyer SR, Maki RG, Demetri GD, et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15:1667–1672.

7. Edmonson J, Ryan L, Blum R, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11:1269–1275. 8. Elias A, Ryan L, Sulkes A, et al. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989;7:1208–1216. 9. Kraybill WG, Harris J, Spiro IJ, et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Cancer. 2010;116:4613–4621. 10. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19:1238–1247. 11. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20:2824–2831. 12. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine

continued

26 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

SARCOMA

TREATMENT REGIMENS and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Oncol. 2007; 25:2755–2763.

20. Talbot SM, Keohan ML, Hesdorffer M, et al. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer. 2003; 98:1942–1946.

13. Dileo P, Morgan JA, Zahrieh D, et al. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial. Cancer. 2007;109:1863–1869.

21. Kuttesch JF Jr, Krailo MD, Madden T, et al. Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children’s Oncology Group study. Pediatr Blood Cancer. 2009; 53:590–593.

14. Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, et al. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011;29:2528–2533.

22. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–1886.

15. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388:488-497. 16. Mack LA, Crowe PJ, Yang JL, et al. Preoperative chemoradiotherapy (modified Eilber protocol) provides maximum local control and minimal morbidity in patients with soft tissue sarcoma. Ann Surg Oncol. 2005;12:646–653. 17. Antman KH, Elias A. Dana-Farber Cancer Institute studies in advanced sarcoma. Semin Oncol. 1990;1(Suppl 2):7–15.

23. Schöffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol. 2011;12(11):1045–1052. 24. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2015;33:1–8.

18. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol. 2002;25:468–473.

25. Kawai A, Araki N, Sugiura H, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol. 2015;16(4):406–416.

19. Judson I, Radford J, Harris M, et al. Randomized phase II trial of pegylated liposomal doxorubicin versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001; 37:870–877.

26. Samuels BL, Chawla S, Patel S, et al. Clinical outcomes and safety with trabectedin therapy in patients with advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide expanded access program study. Ann Oncol. 2013;24(6):1703–1709. (Revised 04/2018) © 2018 by Haymarket Media, Inc.

uHighlights

from the CTOS 2018 Annual Meeting

CONNECTIVE TISSUE ONCOLOGY SOCIETY (CTOS) 2018 ANNUAL MEETING Most Utilized Frontline Treatment in Advanced STS Across 4 European Countries Approximately 70% of patients were administered anthracyclines as a primary therapy across patient datasets from France, Germany, Spain, and Italy. More Evidence to Support Active Surveillance as the Standard for Certain Desmoid Tumors Experts embrace the “less is more” approach to guide treatment decisions in primary sporadic desmoid tumors.

ALK Fusions Thought to Be Oncogenic Drivers in Some Leiomyosarcomas Analysis of transcriptomic data revealed that a subset of patients with these smooth muscle sarcomas have ALK fusions that retain targetable ALK kinase domains.

Unfavorable Prognosis in Sarcoma May Be Linked to Tumor Involvement of Fascia Patients with fascia-infiltrating sarcoma appeared to have worse survival.

To read more about the research presented during the meeting, visit www.CancerTherapyAdvisor.com/CTOS2018.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2019 | CANCER THERAPY ADVISOR 27

CASE STUDY

Biomarker Testing in Advanced Non-Small Cell Lung Cancer ÂŠ ANDREW BROOKES / GETTY IMAGES

FACULTY

Gaetane C. Michaud, MD Professor of Medicine Chief of Interventional Pulmonary Medicine New York University Langone Health New York City, New York

Chung-Che (Jeff) Chang, MD, PhD Professor of Pathology Medical Director Hematology and Molecular Pathology Laboratories Florida Hospital Cancer Institute Orlando, Florida

Mark A. Socinski, MD Medical Oncologist Executive Medical Director Florida Hospital Cancer Institute Orlando, Florida

INTRODUCTION Lung cancer is the leading cause of cancer-related death in the United States with a projected 234,030 new cases to be diagnosed in 2018.1 Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for approximately 85% to 90% of cases, with 60% of patients diagnosed with advanced-stage disease.2 Recent advances in our understanding of the underlying biology of NSCLC has led to the identification of multiple driver mutations.2 The development of agents that specifically target the corresponding molecular pathways has led to a paradigm shift in the treatment of patients with advanced NSCLC.3 Therefore, the management of NSCLC increasingly involves an individualized treatment plan that is guided by biomarker testing.3 Despite the critical role of biomarker testing in guiding treatment selection in advanced NSCLC, nearly 30% of patients are not tested for any of the known driver mutations, and the testing rate for all recommended mutations is even lower, approximately 8% of patients.2 Although biomarker testing presents logistical challenges for community-based physicians, opportunities exist to improve adherence to testing guidelines.2 Ultimately, increasing biomarker testing rates will help as a guide for the community oncologist to decide between standard systemic chemotherapy vs targeted therapies or eligibility for enrollment in clinical trials.2 In this featured case study interview, Gaetane C. Michaud, MD, a pulmonologist at New York University Langone Health; Chung-Che Chang, MD, PhD, a pathologist; and Mark A. Socinski, MD, a medical oncologist, both at Florida Hospital Cancer Institute, use a case-based approach to share their multidisciplinary perspectives on the need for biomarker-driven clinical decision-making in advanced NSCLC. In addition, they review their perspectives on optimizing biomarker testing. The conclusions, findings, and opinions expressed by Dr. Chang, Dr. Michaud, and Dr. Socinski, herein are based upon their experiences and expertise in the management of advanced NSCLC.

28 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

CASE STUDY

CASE STUDY Meet John*

64-year-old Caucasian male with stage IV adenocarcinoma of the lung presenting with progressive dyspnea

• Chest CT confirmed X-ray and revealed mediastinal lymphadenopathy • PET identified single lesion in the 7th rib • MRI was negative for intracranial metastases Diagnostics

Symptoms

• John presents to his physician with exertional dyspnea over a two-week period • Worsening symptoms are brought on by his routine daily activities including showering and dressing • Treated with several courses of antibiotics; however, his symptoms failed to resolve History

• Hypertension • Coronary artery disease • Prior myocardial infarction • Appendectomy • Percutaneous coronary intervention

• EBUS-guided core needle biopsy • Multiple specimens collected (including dedicated samples) • Rapid on-site evaluation • Biopsy confirmed lung adenocarcinoma (TTF-1 positive; napsin A positive; p63 negative) • Reflex genetic testing was negative for known driver mutations • Reflex IHC (22c3) detected PD-L1 expression in 25% of cells • Diagnosed with stage IVB NSCLC • CGP analysis Treatment plan

• 1st-line: chemotherapy + immunotherapy • 2nd-line: to be informed by CGP analysis

Medical/Social History

• Previous smoker, approximately a 50-pack year exposure to smoking • Quit smoking 10 years ago • Mother was diagnosed with breast cancer in her 70’s • Retained an ECOG PS 1 Imaging

• Chest X-ray revealed lung mass

CASE STUDY INTERVIEW WITH DR. CHANG, DR. MICHAUD, AND DR. SOCINSKI Q: As an interventional pulmonologist how would you

go about diagnosing John? DR. MICHAUD: So when patients are being considered for diagnostics for lung cancer it is important to ensure that we’re getting the most information from the biopsy site. So what we really want to do is minimize the number of procedures, especially invasive ones, and get the most information out of the biopsy that we’re doing. Demineralization of the bone impairs subsequent molecular analysis, so in John’s case I would prefer to biopsy both the lesion as well as the mediastinal lymphadenopathy. That said,

CGP=comprehensive genomic profiling; CT=computed tomography; EBUS=endobronchial ultrasound; ECOG PS=Eastern Cooperative Oncology Group performance status; IHC=immunohistochemistry; MRI=magnetic resonance imaging; PD-L1=programmed death ligand 1; PET=positron emission tomography; TTF-1=thyroid transcription factor 1. * Not an actual patient.

it is important to biopsy the highest stage lesion first, meaning biopsy the mediastinal lymph nodes first and go from N3 to N2 to N1 and then finally the primary mass. Furthermore, just like in John’s case, in my practice I use EBUS-guided biopsies for lung cancer diagnosis. I generally try to perform core biopsies because it yields a high volume of tissue. In fact, several studies have demonstrated that core biopsies increase the sample yield, as compared to fine needle aspirations (FNAs). The reason for wanting to get additional tissue is predicated on the fact that in this era of molecular testing many patients are still being put into clinical trials and FNAs, for the most part, are not allowed for clinical trial inclusion purpose. So approximately 10 years ago, I stopped doing FNAs and started doing core biopsies. Continues on page 30

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2019 | CANCER THERAPY ADVISOR 29

CASE STUDY NCCN NSCLC Guideline Principles of Diagnostic Evaluation3 • Concomitant staging is beneficial, because it avoids additional biopsies or procedures. It is preferable to biopsy the pathology that would confer the highest stage • The least invasive biopsy with the highest yield is preferred as the first diagnostic study

NCCN NSCLC Guideline Principles of Molecular and Biomarker analysis3 • A major limitation in obtaining molecular testing results for NSCLC occurs when minimally invasive techniques are used to obtain samples; the yield may be insufficient for molecular, biomarker, and histologic testing. Therefore, bronchoscopists and interventional radiologists should procure sufficient tissue to enable all appropriate testing. NCCN=National Comprehensive Cancer Network.

Q: What are some best practices to ensure that there

is sufficient specimen for histology and molecular characterization? DR. MICHAUD: I would recommend the two strategies that

are also used with John: dedicated samples and rapid onsite evaluation. In my institute, we obtain multiple specimens for both IHC and for molecular characterization. Generally, in my practice I collect 3 to 4 biopsy specimens per site for IHC alone. I then take additional samples that are dedicated for molecular characterization. We can also use rapid onsite sample evaluation and we certainly do that in my institution. This entails an assessment of the specimen’s cellularity that determines whether or not the sample is adequate for molecular characterization. DR. SOCINSKI: I completely agree with my colleague. The management of advanced NSCLC has become increasingly complex and it demands that sufficient material is obtained in the initial diagnostic approach so that the medical oncologist can serve the patient in the best manner.

NCCN NSCLC Guideline Principles of Pathologic Review3 • Judicious use of IHC is strongly recommended to preserve tissue for molecular testing. Most notably in small specimens • In small specimens, a limited number of immunostains with one lung adenocarcinoma marker (TTF-1, napsin A) and one squamous carcinoma marker (p40, p63) should suffice for diagnosis

Q: What are some best practices to decrease the front-

end turnaround time for biomarker testing in advanced NSCLC? DR. CHANG: It is important to keep in mind that biomarker

information should be given to the treating oncologist as soon as possible to initiate appropriate treatment. This is particularly important for critically ill and advanced stage patients, because these patients should not wait too much longer to initiate treatment. Similarly to John’s case, at my institute, all pathologists will reflex order biomarker testing for all lung adenocarcinoma specimens, regardless of the clinical staging. This can eliminate the phone call and waiting time between the oncologist and the pathologist and ultimately shorten the front-end turnaround time. College of American Pathologists/International Association for the Study of Lung Cancer/Associate of Molecular Pathology Guidelines4 • Molecular testing should be completed within 10 working days of ordering to be fast enough to guide initial therapy Waiting to order biomarker testing until the oncology consult introduces treatment delays, which may result in the initiation of less effective therapy. Alternatively, if biomarker testing is ordered reflexively by the pathologist, the results would be available to guide optimal treatment selection.5

Q: How are tumor specimens collected and processed

at your institution for molecular profiling and biomarker identification? DR. CHANG: Currently, in our laboratory, we actually accept all

Q: What are some important considerations for small

specimens when performing IHC? DR. CHANG: When we perform IHC, particularly in small specimens, we need to make sure not to overdo the panel because some tissue should be preserved for molecular characterization. The immunohistochemical profile of John’s tumor was TTF-1 positive, napsin A positive, and p63 negative, which is diagnostic for lung adenocarcinoma. This is a very concise panel for reaching the correct diagnosis.

types of specimens that have enough tumor cells and also have enough DNA for biomarker testing. It is important to remember that cytology specimens, including cellblocks of aspirate smears, NCCN NSCLC Guideline Principles of Molecular and Biomarker Analysis3 • Although tumor testing has been primarily focused on the use of formalin-fixed paraffin-embedded (FFPE) tissues, increasingly, laboratories accept other specimen types, notably cytopathology preparations not processed by FFPE methods.

30 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

CASE STUDY can also be used for molecular biomarker testing in addition to FFPE tissue. We routinely precut 30 unstained slides for every needle core biopsy in order to preserve the tissue for analysis. This practice allows us to obtain enough tissue from nearly all of our patients for biomarker testing. Q: What biomarker testing is recommended for patients like John and how would the results guide treatment selection? DR. SOCINSKI: As mentioned by my colleague, reflex biomarker testing was performed in John’s case and did not identify any driver mutation in the four entities that are recommended in the NCCN NSCLC Guidelines, particularly EGFR, ALK, BRAF, and ROS1.3 Given the fact that his tumor samples were negative for driver mutations and the diagnostic tests revealed a 25% PD-L1 expression, John was started on a combination of chemotherapy plus immunotherapy. Q: The NCCN NSCLC Guidelines recommend that biomarker testing should be conducted as part of broad molecular profiling. What are some emerging biomarkers that may help guide clinical decision making for patients like John with advanced NSCLC? DR. CHANG: In John’s case, because all the biomarker test-

ing showed no targetable mutations, the oncologist very appropriately ordered a CGP analysis. A CGP analysis can identify additional driver mutations that may have clinical trials available for John to participate in and it can also provide the percentage of mutation over the whole genome, which can guide the usage of immunotherapy. DR. SOCINSKI: That’s correct Dr. Chang. Some emerging

biomarkers include MET exon 14 skip mutations or very high MET amplification and RET rearrangements.2 Others include NTRK, HER2, and either high amplification or HER2 mutations.3 So there is a growing number of emerging biomarkers that physicians should consider because, although they may not alter first-line treatment choices, it may be very important to know about these for subsequent lines of therapy to provide additional options for patients with advanced NSCLC. To elaborate on Dr. Chang’s comment, there are emerging biomarkers that are going beyond PD-L1. In my opinion, PD-L1 testing is here to stay as it is a simple immunohistochemical test and the results are available within 48 hours. Although PD-L1 testing has been very helpful in identifying patients who get either greater or lesser benefit from immunotherapy,

I don’t think any of us feel that PD-L1 is the perfect biomarker to select patients for immunotherapy. There are a number of emerging biomarkers that will help us in the future to decide which patients are going to have either greater or lesser benefit from our current immunologic manipulations. Testing for emerging biomarkers may assist in identifying patients where perhaps immunotherapy alone will be the best treatment for that patient. Alternatively, we may identify a subset that may require new strategies as the current chemo-immunotherapy or immunotherapy strategies do not make a meaningful difference. Q: What are some best practices in incorporating CGP

into the clinical-decision making process for patients like John with advanced NSCLC? DR. SOCINSKI: This is a significant challenge for

community-based oncologists. In my opinion, it is essential to have a good working relationship with your pathologist and be aware of the ability to go beyond the standard NCCN recommended panel and consider CGP in patients like John. Every patient, in particular patients with adenocarcinoma, should undergo a CGP as a standard of practice today. DR. CHANG: I agree with my colleague and would also

emphasize that often times, the results of the CGP are overwhelming for the medical oncologist to interpret, because the test identifies many different driver mutations. It is imperative that medical oncologists consult with the pathologist to discuss the details about each mutation that may or may not contribute to patient treatment. Furthermore, the CGP analysis requires more tissue than a small-targeted panel testing for biomarkers, which is currently recommended by NCCN guidelines. As such, it’s very important to obtain as much tissue as possible during the EBUS- or the CT-guided biopsy. Q: Biomarker testing presents several logistical chal-

lenges for community-based physicians. From your experience, what are common gaps and challenges that delay the delivery of targeted therapy in patients with advanced NSCLC? DR. MICHAUD: There are several challenges that I have experienced over the years. Many times what happens is that a site or the primary tissue is biopsied, but we don’t actually have adequate staging. I have also experienced cases where we don’t have enough tissue for the molecular analyses, which does not allow a comprehensive panel to be performed in order to help guide treatment options.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2019 | CANCER THERAPY ADVISOR 31

CASE STUDY DR. SOCINSKI: In my practice over the years, I have witnessed the same challenges described by my colleague. I’ve seen a number of patients in which their initial diagnostic procedure did not obtain enough material. As a medical oncologist, it’s disappointing to begin the discussion with my patients by requesting another biopsy because their initial biopsy did not provide enough material or information in order to make a decision about the best therapeutic path moving forward based on biomarker testing and PD-L1 status. This delays treatment by 2 to 3 weeks, as we are unable to decide if this patient should get targeted therapy because they have an oncogenic driver. Should they get immunotherapy as monotherapy or should they receive chemotherapy with immunotherapy when they don’t fit into the other two categories? Physicians from the pulmonary medicine, interventional radiology, pathology and surgical departments, in particular thoracic surgeons, all need to be aware of the needs that medical oncologists have today in managing advanced NSCLC. It’s not just distinguishing between non-small cell and small cell lung cancer, as it was 10 to 15 years ago. ■

ABOUT THE EXPERTS Gaetane C. Michaud, MD • Professor of Medicine • Chief of Interventional Pulmonary Medicine • New York University Langone Health • New York City, New York Gaetane C. Michaud, MD is a board-certified pulmonary specialist with special interests in malignant disease of the lung, including lung cancer, asthma, pleural disease, and tracheobronchomalacia. She is a Professor of Medicine and Cardiothoracic Surgery at New York University (NYU) Langone Health, in New York. Dr. Michaud also serves as the Chief of Interventional Pulmonary Medicine at the NYU Pulmonary & Critical Care Associates, where she leads a team of board-certified interventional pulmonologists in the development of novel therapies that could significantly improve lung patient outcomes. Her research focuses on understanding the molecular mechanisms and tumor characteristics of patients with lung cancer. Dr. Michaud received her medical degree from the University of Ottawa Faculty of Medicine in 1997 and stayed until 2000 to complete her medical residency. She holds a professional membership with the American Thoracic Society. Chung-Che (Jeff) Chang, MD, PhD • Professor of Pathology • Medical Director • Hematology and Molecular Pathology Laboratories • Florida Hospital Cancer Institute • Orlando, Florida Dr. Chung-Che Chang, MD, PhD is board-certified in anatomic and clinical pathology, hematopathology

REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. 2. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities.

Clin Lung Cancer. 2017;18(6):651-659. 3. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. (Version 2.2019). https://www.nccn.org/professionals/physician_gls/pdf/ nscl.pdf. Accessed November 21, 2018. 4. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346. 5. Johnson M, Pennell NA, Borghaei H. “My patient was diagnosed with nontargetable advanced non-small cell lung cancer. what now?” diagnosis and initial treatment options for newly diagnosed patients with advanced NSCLC. Am Soc Clin Oncol Educ Book. 2018;(38):696-707.

and molecular genetics pathology with special interests and expertise in hematopathology, molecular oncology, and minimal residual disease monitoring. He is a Professor of Pathology at the University of Central Florida. Dr. Chang was a Professor of Pathology at Cornell University and Chief of Hematopathology Division at The Methodist Hospital. He was the Principle Investigator of several National Institute of Health (NIH)/National Cancer Institute (NCI) funded grants to study myeloma, myelodysplastic syndromes (MDS), and lymphoma. He currently serves as Associate Editor for Archives of Pathology & Laboratory Medicine, is a member of Diagnostic Immunology/Flow Cytometry Resource Committee and Molecular Oncology Resource Committee for College of American Pathologists (CAP) and is the CAP Liaison to the NCI Biomarker Committee. Dr. Chang completed his medical degree at National Yang-Ming Medical University, Taipei, Taiwan and obtained his PhD in Biomedical Engineering from Case Western Reserve University (CWRU), Cleveland, Ohio. He completed pathology residency training at CWRU and hematopathology fellowship training at the University of Utah. Dr. Chang served as a faculty member at the Medical College of Wisconsin and Baylor College of Medicine after training. Mark A. Socinski, MD • Medical Oncologist Executive Medical Director • Florida Hospital Cancer Institute • Orlando, Florida Dr. Mark A. Socinski is the Executive Medical

32 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2019 | CancerTherapyAdvisor.com

Director of the Florida Hospital Cancer Institute. Dr. Socinski is a board-certified, fellowshiptrained medical oncologist, specializing in all thoracic malignancies, including small cell and non-small cell lung cancers and mesothelioma. He is an internationally recognized expert in the development of novel chemotherapy agents and treatment strategies for advanced non-small cell lung cancer and small-cell lung cancer. His research has focused on incorporating personalized medicine and molecular biomarkers in the treatment of lung cancer. Dr. Socinski received his medical degree from the University of Vermont in Burlington. He completed his medical residency in internal medicine at Beth Israel Hospital/Harvard Medical School and completed training in medical oncology at the Dana-Farber Cancer Institute/ Harvard Medical School in Boston. Dr. Socinski holds memberships in numerous professional societies, such as the American College of Physicians, American Society of Clinical Oncology, International Association for the Study of Lung Cancer, and the American College of Chest Physicians. He serves as co-Chair of the Thoracic Malignancies Steering Committee for the NCI. He also serves on the Respiratory Core Committee of the Cancer and Leukemia Group B (Alliance) and has been instrumental in the development of many clinical trials. @ 2019 Haymarket Media, Inc. All rights reserved.

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