Cancer Therapy Advisor September/October 2018 Issue by Haymarket Media

SEPTEMBER/OCTOBER 2018 | VOL 5, ISSUE 1

24 FEATURE

Depression as a Side Effect of Treatment for Cancer Researchers promote awareness about the potential for mental health risks associated with certain treatments. 32 IMMUNOTHERAPY REPORT

Assessing the Feasibility of Re-Treating NSCLC With Checkpoint Inhibitors 35 VIEWPOINT

Informed Consent Considerations in Patients With Advanced Cancer 37 TREATMENT REGIMENS

Acute Myeloid Leukemia  Gastric Cancer  Mesothelioma

34 IN THE CLINIC Pancreatic Cancer and New-Onset Diabetes

CancerTherapyAdvisor.com

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Recent Headlines in Multiple Myeloma Research Bone Imaging With Improved Modalities in Multiple Myeloma Treatment Considerations Should Match Patient, Disease, and Therapy Bispecific Antibodies in Cancer

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CONTACT THE EDITOR Questions or comments for the editor? Email us at editor.cancertherapyadvisor@ haymarketmedia.com SUBMIT AN ARTICLE Cancer Therapy Advisor welcomes original content submissions in the form of viewpoints/perspectives, case studies, feature articles, and more. Visit CancerTherapyAdvisor.com/ submissions to learn more. RECEIVE NEWSLETTERS Receive concise news articles and in-depth feature stories to you inbox on a daily or weekly basis. CancerTherapyAdvisor. com/register to sign up. DOWNLOAD THE APP The Cancer Therapy Advisor app is a free, easy-to-use app that offers the latest oncology news, cancer treatment regimens, fulllength features, slideshows, case studies, and drug information for a variety of cancer types and therapeutic areas. Download Cancer Therapy Advisor for free and access us on the go! Register for CTA directly from your device or log in using your existing account details.

Recent Headlines in Multiple Myeloma

Bone Imaging With Improved Modalities in Multiple Myeloma

Treatment Considerations 14 Should Match Patient, Disease, and Therapy

Bispecific Antibodies in Cancer

CONTENTS 10 LATEST NEWS

Recent headlines in oncology research and practice 24 FEATURE

Depression as a Side Effect of Treatment for Cancer Carlos Harrison

32 IMMUNOTHERAPY REPORT

Assessing the Feasibility of Re-Treating NSCLC With Checkpoint Inhibitors Michelle Dalton, ELS

34 IN THE CLINIC

Pancreatic Cancer and New-Onset Diabetes C. Andrew Kistler, MD, PharmD

35 VIEWPOINT

Informed Consent Considerations in Patients With Advanced Cancer

CONNECT WITH CANCER THERAPY ADVISOR

Leah Lawrence

@CancerTherAdvsr facebook.com/cancertherapyadvisor

37 TREATMENT REGIMENS

Acute Myeloid Leukemia, Gastric Cancer, Mesothelioma

4 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

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Individualized Lenalidomide Plus Chlorambucil and Rituximab May Be Feasible in Advanced CLL An individualized, dose-escalation schedule of lenalidomide plus chemotherapy may be a safe and effective strategy among patients with chronic lymphocytic leukemia (CLL), according to a study published in Haematologica. Although first-line treatment for elderly patients and patients unfit for fludarabine, cyclophosphamide, and rituximab (FCR) therapy, such as chlorambucil plus rituximab, are effective, they still face significant challenges including resistance/relapse, adverse events, and high costs. Previous studies have shown that lenalidomide may be effective, but due to its toxicity profile, its feasibility in combination therapy for CLL is in question. For this phase 1/2 study, researchers enrolled 53 treatment-naive patients with CLL and treated them with 6 cycles of chlorambucil, rituximab, plus individual-dosed lenalidomide 2.5-10 mg (induction I), followed by 6 months of lenalidomide 10 mg monotherapy (induction II). The median follow-up was 27.0 months. Overall, 89% (47) and 68% (36) of patients were able to complete induction I and II, respectively. Results showed that the overall response rate was 83%. The median progression-free survival (PFS) was 49 months, with 2- and 3-year PFS rates of 58% and 54%, respectively. The 2-year overall survival (OS) rate was 98%, and the 3-year OS rate was 95%.

Predictors of Response to Checkpoint Inhibitors in Melanoma Revealed Researchers developed a new method to predict whether a patient with melanoma will respond to treatment with a checkpoint inhibitor. The tool, described in Nature Medicine, is reportedly more robust than other regression predictors because it works across many different sets of patients with melanoma, according to the authors of the study. With the understanding that checkpoint inhibitors do not work in every patient, investigators analyzed samples across different studies (which included public records of tumor molecular profiles) to test the robustness of their proprietary computational forecasting framework, which they called Tumor

Immune Dysfunction and Inclusion (TIDE). They postulated that the TIDE signature could reflect a late stage of T-cell breakdown. They computed reliable TIDE signatures for 5 different cancer types, but chose melanoma to investigate further, as “only melanoma has publicly available data on tumor expression and clinical outcome of patients treated with anti-PD1 or anti-CTLA4.” The researchers hypothesized that measurement of the gene expression in tumors coupled with the level of infiltration of cytotoxic T lymphocytes (CTL) could be used to predict survival in those who had been treated with anti-PD1 or anti-CTLA4 agents more accurately than through the measurement of PD-L1 levels, tumor mutation load, and interferon gamma. To hunt for the potential sources of tumor immune evasion, they reasoned “that by combining profiles of transcriptome profiles of treatment-naive tumors with patient survival outcome,” they could find known regulators of T-cell dysfunction/ exclusion: those that work to keep cytotoxic T cells within the tumor from fighting back, and those that prevent T cells from even getting into the tumor. The investigators used pretreatment RNA-seq or NanoString tumor expression profiles – also known as transcriptome signatures – to identify the genes that influence the function of cytotoxic T cells. The authors observed that “[a]mong the data sets, TIDE predicted different numbers of genes to interact with CTL with statistical significance,” and that TIDE was significantly predictive of overall survival. To model tumor immune escape in tumors with various levels of CTL, TIDE factored in both T-cell dysfunction and exclusion signatures — whereas other biomarker tests involving drug response only search for one component. Using TIDE, it was also determined that SERPINB9, which is overexpressed in melanoma, regulates resistance to T-cell killing and therefore, immune evasion. The authors said small-molecule inhibition of SERPINB9 is druggable, hinting that it will be a promising new focus for drug developers. However, TIDE only worked as a prognostic tool in tumors of patients who were treatment-naive, so it is not a relevant tool for tumors that have progressed after first-line treatment with an immunotherapy, the authors warned. The impact of TIDE could be widespread, according to the authors. “With additional data, cancer-type-specific regulators may be identified on the basis of the biological variations of T-cell dysfunction scores across different cancer types.” In anticipation of this endeavor, the investigators created an online portal for response forecasting using transcriptome profiles. ■

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LATEST NEWS

Measurement of Excess Abdominal Fat, Not BMI, May Be a More Accurate Risk Factor for Blood Cancers Although a high body mass index (BMI) has been linked to an increased risk for hematological malignancies, Swedish researchers found that excess belly fat, not BMI, is a more appropriate predictor of risk for these types of cancers. The population-based study, published in PLoS One, included body composition measurements of 27,557 individuals who were part of the Malmö Diet and Cancer study in Sweden between 1991 and 1996. Various body composition measurements were calculated for all individuals, including values for hip and waist, for BMI, waist circumference (WC), waist-hip ratio (WHR), waist-toheight ratio (WHtR), waist-to-hip-to-height ratio (WHHR), the A Body Shape Index (ABSI), and body fat percent. Patients were followed for a median of 20 years, during which time 564 subjects developed a hematologic malignancy. The reason the researchers were interested in the influence of measures of body composition outside of BMI and their influence on the development of blood cancers was because, as they wrote, BMI often relies on self-reported weight and height values, and therefore, may be less accurate than alternative markers for obesity. Plus, BMI often misclassifies those who have a high muscle mass as overweight. Extra belly fat was found to be a more precise indicator of the risk of blood cancer. Although individuals with a BMI of more than 30 kg/m2 were found to have a statistically significant risk of MM (P = .01), in individuals with a BMI between 25 kg/m2 and 30 kg/m2, standardized WHR was significantly associated with MM (P = .047). The strongest estimators of risk for multiple myeloma (MM) were high WC, high WHR, and high WHtR; all of these measurements reflect higher adiposity around the waist. The investigators wrote that these values better mirror the specific type of fat that individuals have, and may be better values for cancer risk calculations. This type of abdominal obesity has been shown to better predict cardiovascular and liver diseases compared with BMI, so they reasoned it may also be more accurate for risk assessment in blood cancer. Though the authors did not provide reasoning for why this type of excess fat may increase the risk of disease, they wrote that prior studies have suggested that increases in the levels of glucose, adiponectin, or leptin (as a result of more belly fat) have been associated with an increased risk of various blood

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cancers. They did not calculate how changes to this type of fat over time could influence the risk of developing a blood cancer, however, which was cited as a study limitation.

Evaluation of Available Frontline Induction Therapies for Multiple Myeloma Triplet regimens combining immunomodulatory drugs and proteasome inhibitors are the most effective frontline therapeutic approaches among patients with transplant-eligible multiple myeloma (MM), according to a study published in Hematological Oncology. Autologous transplantation, preceded by frontline induction therapy, is the current standard of care for younger, fit patients with MM. Evidence suggests that the success of frontline induction therapies affects post-transplant results, but because of the rapid development of various agents, there is a paucity of comparative or efficacy data on these novel agents when they are administered in combination. For this systematic review and mixed-treatment comparison meta-analysis, researchers evaluated the outcomes of 21 clinical studies encompassing 6474 newly diagnosed, transplant-eligible patients with MM and 11 unique frontline induction regimens. Overall survival (OS) analyses revealed that the CRD (cyclophosphamide, lenalidomide, dexamethasone) regimen was superior compared with TD-based (thalidomide, dexamethasone, with or without cyclophosphamide; hazard ratio [HR], 0.76), VAD-based (mainly doxorubicin, dexamethasone, vincristine, and variants including cyclophosphamide and/or etoposide; HR, 0.71), and Z-Dex (idarubicin, dexamethasone; HR, 0.37) regimens. Progression-free survival (PFS) analyses showed that the VTD (bortezomib, thalidomide, dexamethasone) regimen was superior to TD-based regimens (HR, 0.66), VAD-based regimens (HR, 0.61), Z-Dex (HR, 0.42), and high-dose dexamethasone (HR, 0.62). Bortezomib/thalidomide regimens were found to not be superior to lenalidomide. The VTD regimen led to the highest overall and complete response rates compared with the other protocols, and demonstrated superiority over regimens that contained thalidomide alone. The authors concluded that “further studies comparing directly these treatment approaches (together with pipeline drugs), should be able to establish the role of even newer agents on frontline therapy framework and clarify optimal sequence of protocols to be applied on conventional practice.” ■

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VIEWPOINT

Bone Imaging With Improved Modalities in Multiple Myeloma ANDREA S. BLEVINS PRIMEAU, PhD, MBA

Coming to a consensus about the incorporation of new modalities into clinical practice has been a challenge for many clinicians.

one imaging is a critical aspect of care for patients with multiple myeloma (MM), and recent advances in imaging modalities have improved detection of lytic lesions and bone marrow involvement. Incorporating these new modalities into clinical practice, however, has been challenging for many clinicians, according to an article published in the 2018 American Society of Clinical Oncology (ASCO) Educational Book and a corresponding presentation at the 2018 ASCO Annual Meeting.1 “We need to educate the community about the appropriate time to order these scans and also the pros and cons of each test,” Ravi Vij, MD, MBA, of the Washington University School of Medicine in St. Louis, Missouri – who is an author of the article – told Cancer Therapy Advisor. Modalities of Bone Imaging The International Myeloma Working Group (IMWG) states that the presence of at least 1 lytic bone lesion with radiography or computed tomography (CT) or fluorine-18–2-fluoro-2-deoxy-d-glucose positron emission tomography and CT (FDG-PET/CT) or more than 1 focal lesion by MRI is indicative of MM. Bone involvement is present in about two-thirds of patients at diagnosis, and nearly all patients will develop bone disease at some point during their disease course. Bone imaging is therefore a cornerstone of MM management.

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The conventional modality was wholebody skeletal survey by radiography (WBXR), but because more than 30% of trabecular bone loss must occur before this modality can detect a lytic lesion, more advanced imaging techniques were developed. “Skeletal surveys have been the modality that we used in the work-up and follow-up of patients with MM, but the newer imaging techniques like wholebody CT scan, MRI, and PET/CT offer much more information,” Dr Vij said. The novel modality whole-body low-dose CT (WBLDCT) is superior to WBXR for detecting lytic lesions because it has higher sensitivity, increased detection rate, and greater accuracy. WBLDCT does not require contrasting agents and uses low doses of radiation that are 2- to 3-fold lower than conventional CT. Dr Vij noted, however, that “in the United States, it is not reimbursed by Medicare [or] most private insurance [companies], although the guidelines do recommend it.” He said that, “we feel that many doctors in the United States are not able to get [WBLDCT] for their patients, whereas Europe has done away with skeletal surveys.” WBLDCT is now the preferred imaging modality of the European Myeloma Network and the European Society for Medical Oncology for the initial assessment of MM bone disease. FDG-PET/CT detects bone lesions with a sensitivity and specificity between 80% and 100% and is the most accurate technique for detecting extramedullary

MULTIPLE MYELOMA

VIEWPOINT disease. It can also be used for prognostication, as the number and metabolism of focal lesions prior to stem cell transplantation has been established as an independent prognostic factor. FDG-PET/CT is also the preferred modality for monitoring metabolic response to MM treatment. According to Dr Vij, MRI is used in the initial work-up of any plasma cell dyscrasia. “If patients have a normal set of imaging on skeletal survey, whole-body CT, and PET/CT, then an MRI may help distinguish smoldering MM from MM,” he said. Dr Vij also noted that it is used “to evaluate any episode of back pain because it is the best test to rule out spinal cord compression.” Using New Modalities There is no clear consensus about when to use each test, whether as part of the initial work-up, during follow-up, or upon progression, Dr Vij said. “The first test is WBXR or WBLDCT, whichever you have access to,” he said. The next step is less clear. “Then the question is, does everybody get a PET/CT for prognosis or should you reserve it for those patients with X-rays that are normal?” Dr Vij said. He commented that the field is split on this issue because “it doesn’t really lead to any changes in treatment if the diagnosis of MM has already been established by other criteria.” PET/CT use at the time of progression is also controversial. In most cases, M protein levels indicate progression. Some patients, however, are asymptomatic or do not show body or organ deterioration despite blood tests indicating progression. “In that scenario, PET scan is increasingly being done to adjudicate the need for treatment and the aggressiveness of the treatment,” Dr Vij said.

He also noted that PET/CT is the only way to detect progression in more advanced disease, at which point M protein is no longer produced and therefore cannot be used to detect further progression.

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Selection between bisphosphonates and denosumab comes down to cost and renal disease. Bisphosphonate are “literally a tenth of the cost of denosumab, but denosumab has little in the way of renal side effects,” Dr Vij said.

There is no clear consensus about when to use each test, whether it be in the initial work-up, follow-up, or upon progression. Dr Vij said that the use and frequency of PET/CT during follow up of various plasma cell dyscrasias is still the subject of study. The IMWG is currently developing guidelines to address questions in this area. Agents for Bone Disease There are 2 classes of agents available for the treatment of bone disease in MM: bisphosphates and an anti-RANKL antibody. These agents inhibit osteoclast activity, thereby preventing new osteolytic lesions, pathologic fractures, and hypercalcemia. The RANKL inhibitor denosumab was shown to be noninferior to the bisphosphonate zoledronic acid, with similar rates of skeletal-related events and overall survival. Osteonecrosis of the jaw occurred at similar rates between groups. 1 Progression-free survival (PFS), however, was prolonged by over 10 months with denosumab (compared with those receiving zoledronate), raising the question of whether denosumab may have an anticancer effect. Dr Vij pointed out, however, that PFS “was not the primary end point of the study,” and this PFS advantage has not made denosumab a preferred agent in the guidelines.

This is important given that many patients with MM have renal dysfunction at diagnosis or develop it as their disease progresses. For these patients, “denosumab is certainly the best option,” he said, “but to give it to everybody, is certainly not something that most physicians or opinion leaders currently recommend because of the cost.” Conclusions Ongoing research is expected to further improve options and capabilities in imaging for bone disease for patients with MM and the clinicians who treat them. Dr Vij highlighted a novel MR technique called diffusion-weighted MRI, which “provides a functional aspect to MRI in addition to the structural and anatomical aspects.” He also described novel tracers to improve PET/CT. “The other area where I think research is focused is the utility of MRI and especially PET/CT in the follow-up of patients with MM and other plasma cell dyscrasias,” Dr Vij said. ■ Reference

1. Zamagni E, Cavo M, Fakhri B et al. Bones in multiple myeloma: Imaging and therapy. Am

Soc Clin Oncol Educ Book. 2018;38:638-646. doi: 10.1200/EDBK_205583

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VIEWPOINT

Treatment Considerations Should Match Patient, Disease, and Therapy LEAH LAWRENCE

Selecting therapies for patients with multiple myeloma is challenging because the disease is inherently heterogeneous.

electing the appropriate treatment for patients with multiple myeloma is a complex decision that needs to be based on multiple patient and disease characteristics. Treatment selection in patients with newly diagnosed multiple myeloma has been streamlined as a result of recent clinical trials that showed the benefit of treatment with 3-drug combinations.1 But treating relapsed disease has become quite difficult for the practicing clinician, according to Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation. “It is really a very heterogeneous disease, meaning some patients will succumb to disease after only a few years and some can live 10, 15, or 20 years,” Dr Mikhael said. “Tailoring treatment to an individual can be a challenge because there is not an ideal sequence or algorithm that has been developed.” This difficulty reflects the increasing number of treatment choices available to patients and clinicians. In recent years, the US Food and Drug Administration has granted numerous approvals including daratumumab combined with lenalidomide and dexamethasone or bortezomib and dexamethasone,2 elotuzumab combined with lenalidomide and dexamethasone,3 ixazomib combined with lenalidomide and dexamethasone,4 single-agent daratumumab,5 carfilzomib with lenalidomide and dexamethasone,6 and more. The simplest way to approach treatment selection, Dr Mikhael said, is to

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consider the 3 major classes of drugs available for these patients: proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Most regimens will involve 2 out of the 3, plus a steroid, he said. “There have been a series of phase 3 studies presented and published in the last 2 to 3 years validating the use of these combinations,” Dr Mikhael said. Guiding Factors Among the factors that clinicians should consider when selecting therapy for patients with relapsed myeloma are their prior therapies or any maintenance therapies. If a previous therapy successfully controlled the disease with a partial response of at least 6 months, that therapy could be considered for reuse. In contrast, if a patient relapsed while on maintenance therapy, a new treatment regimen should not contain that therapeutic agent.1 Clinicians should also consider patient frailty and comorbidities such as neuropathy, infections, or the presence of kidney disease. For example, generally if someone had preexisting neuropathy, it is best to keep that individual away from a bortezomib-containing regimen, Dr Mikhael said. A patient’s risk category may also play a role in treatment decisions. According to Dr Mikhael, approximately 25% of patients are classified as having higher-risk disease. In these patients, it might be best to treat more aggressively, trying to get the disease down to its lowest level, to a point where there is no measurable disease. Continued on page 23

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Bispecific Antibodies in Cancer SUSAN JENKS

Interest in these bioengineered antibodies has been rekindled by the striking success seen in the treatment of some cancers with immunotherapies.

ispecific antibodies, as the name suggests, simultaneously target 2 or more tumor antigens on the same or separate cells to disrupt cancer development or progression. Others engage and tether cancer cells and immune cells together to increase cancer-cell destruction. No matter the strategy researchers take, however, interest in these bioengineered antibodies has been rekindled by the striking success seen in the treatment of some cancers with immunotherapy — notably, checkpoint inhibitors and chimeric antigen receptor T-cell (CART) therapy — in the past few years. “Bispecific antibodies were stalled for a bit, but in this new era of immunotherapy, there’s definitely renewed interest,” said Nikhil Munshi, MD, a medical oncologist at Dana-Farber Cancer Institute and director of basic and correlative science at the Jerome Lipper Multiple Myeloma Center in Boston, Massachusetts. “And, we have newer, more modern methodologies that have propelled the field forward.” An estimated 50 clinical trials using bispecific antibodies for various malignancies are now underway, while biotechnology companies and academic labs purportedly have hundreds of different products in development and awaiting testing.1 Still, the US Food and Drug Administration (FDA) has approved only 1 bispecific antibody with a cancer indication so far, underscoring the need for further research, before these targeted biologics can emerge as viable and less costly alternatives to other types of immunotherapy that are highly tailored to an individual’s cancer. In July 2017, the FDA approved the bispecific antibody blinatumomab (Blincyto) for acute lymphoblastic

leukemia (ALL) in adults and children with advanced disease.2 Blinatumomab targets and binds 2 proteins, one, CD19, that is found on the surface of B-lineage cells and the other, CD3, that is found on T cells — essentially bringing the 2 in close enough proximity that T cells better recognize leukemic cells to kill them. Other investigators are using similar tacks in creating these dual-targeting agents. Researchers at The Ohio State University Comprehensive Cancer Center in Columbus, for example, used an approach comparable to blinatumomab in a humanized mouse model for multiple myeloma, according to Ilan Zipkin, PhD, a vice president at the Parker Institute for Cancer Immunotherapy in San Francisco, California. But the investigators extended the approved drug’s approach, he says, by tethering a common tumor antigen in this cancer, CS1, to a receptor, NKG2D, expressed on several types of immune system cells that kill. Dr Zipkin wrote in an email that the Ohio researchers “are showing activity with a bispecific that promotes several different cell types to kill the myeloma cells,” including, importantly, natural killer cells. Results of that study were among those highlighted at the American Association for Cancer Research Annual Meeting in Chicago, Illinois, earlier this year.3 In multiple myeloma, CS1 is considered a well-defined antigen, which investigators already are targeting with CAR-T therapy, according to Dr Munshi. “But this group put it together with NKG2D, an interesting molecule, which is scientifically intriguing,” he says. “They showed a good response.” Nevertheless, for this and other bispecific antibodies to work best in patients,

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VIEWPOINT Dr Munshi said there is a prerequisite: a functional immune system must be present. CAR-T therapy has a clear advantage over bispecific antibodies right now, he explained, because “you can overcome some of the immune-suppressive environment” that occurs. Still, given the prohibitive costs of CAR-T’s customized

Although the need for intact immunity and a lack of persistent therapeutic effect pose barriers right now, he says, bispecific antibodies have considerable upside, as well. “These are modular, relatively small molecules that can be quick to produce,” he said. “If ‘A’ and ‘B’ don’t work, you can keep on mixing and matching until

“Bispecific antibodies were stalled for a bit, but in this new era of immunotherapy, there’s definitely renewed interest.”

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antibodies in the first-line setting exist yet, he is confident that clinical trials in patients with early-stage cancers eventually will take place, when chemotherapy damage to their immune systems is not so extensive. Dr Verneris said he has watched unlikely strategies in immuno-oncology gradually unfold successfully before, and the same could happen with bispecific antibodies. “It’s been hugely gratifying to see some of these ideas come raging forward.” ■ References

1. Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: a review.

Pharmacol Ther. 2018;185:122-134. 2. FDA grants regular approval to blinatumomab

approach, Dr Munshi and others believe bispecific antibodies could provide an economical alternative for patients in the future, broadening access to treatment. Michael Verneris, MD, director of bone marrow transplant and cellular therapy at Children’s Hospital in Denver, Colorado, also sees an evolving role for these next-generation designer antibodies.

you can create whatever you want.” One obvious advantage to patients is that if complications arise, they can be addressed quickly, he said. “The great hope is that these will be in the deck of options for patients,” as an integral part of a multipronged strategy against cancer, Dr Verneris said. Although no bispecific monoclonal

Treatment Considerations

Dr Mikhael admitted. “There isn’t a clear consensus,” he said. “The [National Comprehensive Cancer Network] guideline provides some guidance, but is essentially a laundry list of what is available.” However, Dr Mikhael noted that he is currently leading an effort at the American Society of Clinical Oncology (ASCO) to write a clinical practice guideline for the treatment of multiple myeloma. “We have been working on it for several months and are hoping to launch it at some point this fall,” Dr Mikhael said. “The goal of the guideline will be to provide practical advice as to how decisions are made for these patients now that there are so many choices.” ■

Continued from page 14

Whereas in patients with standard-risk disease, the condition can be treated more slowly and not as aggressively if the patient is responding, he said. “More often than not, the key differentiators for treatment are patient choice and convenience,” Dr Mikhael said. “The patient may want an oral regimen or an IV regimen. We have to find what fits with their lifestyle.” Developing Guidelines For physicians looking for greater guidance on how to select the appropriate treatment for patients with relapsed disease, there are few available resources,

and expands indication to include Philadelphia chromosome positive B-cell. https://www. fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm566708.html. Updated July 12, 2017. Accessed August 20, 2018. 3. Chan, WK, Kang S, Youssef Y, et al. A CS1-NKG2D bispecific antibody collectively activates cytolytic immune cells against multiple myeloma.

Cancer Immunol Res. 2018;6(7):776-787.

References

1. Laubach JP et al. Practical considerations for antibodies in myeloma. Am Soc Clin Oncol

Educ Book. 2018;38:667-674. 2. Daratumumab (DARZALEX) [press release]. Silver Spring, MD: US FDA; Updated November 22, 2016. Accessed July 16, 2018. 3. Elotuzumab [press release]. Silver Spring, MD: US FDA; Updated November 30, 2015. Accessed July 16, 2018. 4. Ixazomib [press release]. Silver Spring, MD: US FDA; Updated November 20, 2015. Accessed July 16, 2018. 5. Daratumumab injection [press release]. Silver Spring, MD: US FDA; Updated November 16, 2015. Accessed July 16, 2018. 6. Carfilzomib/Kyprolis [press release]. Silver Spring, MD: US FDA; Updated July 24, 2015. Accessed July 16, 2018.

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FEATURE

Depression as a Side Effect of Treatment for Cancer

CARLOS HARRISON

ore than a third of all Americans were prescribed 1 or more drugs that have been tied to the adverse events of depression or suicidal ideation, according to a study published in JAMA.1 Furthermore, the study reported that the prevalence of depression was 15% for those who reported use of 3 or more medications concurrently with depression as an adverse effect. Patients who were prescribed at least 3 medications reported 3 times as many instances of depression compared with individuals who were not taking any medications. The types of drugs identified as being linked to depression and suicide include: birth control medications, beta blockers, steroids, sedatives, proton pump

Researchers are promoting physician and patient awareness about the potential tie between depression and certain therapies. inhibitors, and a number of cancer therapy medications. More than 200 drugs were found to list depression or suicidal symptoms as adverse effects, including the cancer-focused medications. The list, though, was hardly comprehensive. In all, it identified 7 oncology medications, some of which were used as direct therapeutic agents for cancer and others, as in the case of the antiemetic dronabinol, that are prescribed as supportive therapies to help patients tolerate the negative effects of other treatments. While the study made mention of erlotinib and tamoxifen, for example, it did not include other drugs known to be linked to depression, such as temozolomide or asparaginase. “One thing that we’ve advocated [for] is awareness, because I think a lot of patients and physicians might not

24 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

necessarily be aware of [depression as a potential side effect] ,” Paul Nguyen, MD, director of the genitourinary clinical center for radiation oncology and vice-chair for clinical research in the department of radiation oncology at the Dana-Farber Cancer Institute/Brigham and Women’s Cancer Center in Boston, Massachusetts, said in a telephone interview with Cancer Therapy Advisor. “Now sometimes you just have to give the drug,” he continued. “In some cases, patients just really need it to stay alive. So, you have to accept those side effects. But there are definitely borderline cases where [these side effects are] something that tilts the risk-benefit for select patients.” The issue may be of particular concern for patients with cancer because they report much higher rates of depression compared with the general population.

FEATURE “Cancer survivors in the United States reported medication use for anxiety and depression at rates nearly 2 times those reported by the general public, likely a reflection of greater emotional and physical burdens from cancer or its treatment,” wrote a group of researchers from the Centers for Disease Control and Prevention (CDC).2 Similarly, the suicide rate among patients with cancer is about double that of individuals with no history of cancer, according to an analysis of 3,604,229 patients in the Surveillance, Epidemiology, and End Results (SEER) database. 3 Across 40 years of data, researchers found 6661 suicides associated with a cancer diagnosis. The rate of depression within the cancer patient population may be more significant than that of suicide. A study published in 2014 found that nearly 1 in 3 people with cancer (31.8%) experienced depression, anxiety, or some form of adjustment disorder.4 “The highest prevalence for any mental disorder was found in patients with breast cancer (41.6%; 95% CI, 36.8% to 46.4%), followed by patients with head and neck cancer (40.8%; 95% CI, 28.5% to 53.0%),” the authors wrote. “The lowest prevalence was found in patients with pancreatic cancer (20.3%; 95% CI, 8.9% to 31.6%) and stomach/esophagus cancers (21.2%; 95% CI, 12.8% to 29.6%).” As the CDC researchers explained, “A multitude of factors can arise to cause this distress, from fears of death and suffering, to changes in social roles and the physical pain caused by cancer or its treatments, to having a personal history of depression or anxiety disorders. Although some survivors might be affected minimally or temporarily, others might experience overwhelming anxiety, depression, or both, for significant periods of time, causing disruption and a reduced quality of life.”

And, they continued, the effects are not limited to purely psychological impacts. Depression can affect patient outcomes, as well. “If left unaddressed and untreated,” they wrote, “anxiety and depression in cancer survivors have been found to negatively affect health behaviors, the body’s inflammatory response, and even survival.” Despite the widespread recognition of the association between cancer and depression, researchers suspect the reported rates may only be the tip of the iceberg. “Depression in cancer patients is thought to be highly underdiagnosed, with one study pointing out that 93% of patients self-reported symptoms of depression, whereas only 22% were actually classified as depressed at some

of depression for patients who received ADT.6 However, it could be that the side effects of ADT, rather than the hormone therapy itself, sparked depression symptoms. “When you put a man on androgen deprivation therapy,” Dr Nguyen explained, “he gets fatigue, he gains weight, he loses interest in sex, his muscles start to decline, [his] testicles start to shrink. And these are events that could, in theory, lead to depression.” The researchers from the King’s College study found a potentially causal link between temozolomide and depression by examining the drug’s impact on neurogenesis in mice. “The results from numerous studies in which neurogenesis is depleted using various methods show the development of some depressive-like symptoms in

According to 2014 research, nearly 1 in 3 people with cancer experienced depression, anxiety, or some form of adjustment disorder. point during treatment,” wrote researchers from King’s College London, England, in a 2017 study examining the potential link between the chemotherapy drug temozolomide and depression.5 “The devastating nature of cancer makes it difficult to discern any effects of psychosocial stress from potential side effects of the treatment…” wrote the investigators. And, the actual mechanism by which a medication might trigger depression is difficult to ascertain. In the case of prostate cancer, patients are commonly treated with androgen deprivation therapy (ADT). A meta-analysis by Dr Nguyen and colleagues found a 41% higher relative risk

some studies but not others, indicating that the idea that a decrease in neurogenesis simply results in immediate depression is unlikely,” the researchers stated. “However, a consistent finding is that new neurons are required for antidepressant efficacy.”5 Extrapolating from there, the researchers were able to demonstrate that “chemotherapy-induced decreases in neurogenesis results in previously unreported behavioral and biochemical consequences.” “These results, we argue, are indicative of a biological mechanism, which may contribute to the development of depression in patients being treated with chemotherapy and is separate from the

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 25

FEATURE mental distress resulting from a cancer diagnosis.” The significance of their findings, they concluded, extended beyond a possible link between temozolomide and depression. “Although no changes in depressive-like behavior have been noted in other studies, it is likely that other types of chemotherapy may similarly affect behaviors and biological parameters, which have the potential to contribute to depression.” ■

of prescription medications with depression

4. Mehnert A, Brähler E, Faller H, et al. Four-week

as a potential adverse effect among adults in

prevalence of mental disorders in patients

the United States. JAMA. 2018;319(22):2289-

with cancer across major tumor entities. J Clin

2298. doi:10.1001/jama.2018.6741

Oncol. 2014 32(31);3540-3546. doi: 10.1200/

2. Hawkins NA, Soman A, Lunsford NB, Leadbetter S, and Rodriguez JL. Use of med-

JCO.2014.56.0086 5. Egeland M, Guinaudie C, Du Preez A, et al.

ications for treating anxiety and depression

Depletion of adult neurogenesis using the che-

in cancer survivors in the United States. J

motherapy drug temozolomide in mice induces

Clin Oncol. 2017;35(1):78-85. doi: 10.1200/

behavioural and biological changes relevant to

JCO.2016.67.7690 3. Rahouma M, Kamel M, Nasar A, et al. Lung

depression. Transl Psychiatry. 2017;7(4):e1101. 6. Nead KT, Sinha S, Yang DD, Nguyen PL.

cancer patients have the highest malignan-

Association of androgen deprivation therapy

cy-associated suicide rate in USA: a popu-

and depression in the treatment of prostate

lation-based analysis. Abstract presented

cancer: a systematic review and meta-anal-

References

at: American Thoracic Society International

ysis. Urol Oncol. 2017;35(11):664.e1–664.e9.

1. Qato DM, Ozenberger K, Olfson M. Prevalence

Conference; May 23, 2017; Washington, DC.

doi: 10.1016/j.urolonc.2017.07.016

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IMMUNOTHERAPY REPORT

Even after an adverse event due to treatment, some patients may benefit from re-treatment. MICHELLE DALTON, ELS

ore patients with non-small cell lung cancer (NSCLC) are being treated with anti-programmed cell death ligand 1 (PD-L1) checkpoint inhibitors, but immune-related adverse events (irAEs) can occur and can lead to treatment discontinuation. Once this type of AE occurs, the safety and benefit of re-treatment is not as clear-cut. “These events are infrequent,” said Fernando Santini, MD, of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York. The center’s large retrospective analysis suggested select patients may benefit from re-treatment, and that in these patients, re-treatment is both safe and feasible.1 “[These are] good retrospective data giving guidance about how to navigate a very tricky issue,” said John Wrangle, MD, an immunologist at the Hollings Cancer Center at the Medical University of South Carolina in Charleston, who was not involved in the study. “As a treating oncologist, there is a fear we experience when we [re-treat patients with an] agent [that caused] a severe side effect, but there’s a compelling rationale [for] why you [would] want to do it, especially in patients who have responded to the therapy in question.” Dr Wrangle said this study is “not definitive by any means,” but it does help

oncologists make “a tough decision while better data [are] being accumulated.” When Dr Santini presented initial data at the 2017 American Society of Clinical Oncology Annual Meeting, he said, “there is no standard protocol for how long to treat a patient with NSCLC using checkpoint inhibitors,” and that treatment is typically discontinued when there is a grade 3 or grade 4 toxicity.2 The current study is the first to retrospectively analyze data on more than just a few case reports.1 Study Details This retrospective study evaluated patients with advanced NSCLC who were treated with anti-PD-1 and antiPD-L1 therapy either as a monotherapy

32 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

or in combination with either anticytotoxic T-lymphoctye–associated antigen (CTLA)-4 at Memorial Sloan Kettering Cancer Center from April 2011 to May 2016.1 Of 482 patients with NSCLC treated with a PD-L1 or PD-1 inhibitor, 68 (14%) developed a serious irAE requiring treatment interruption. Of these patients, 38 (56%) were re-treated once the reaction resolved and 30 (44%) discontinued treatment. In the re-treatment cohort, 18 (48%) patients had no subsequent irAEs, 10 patients (26%) had recurrence of the initial irAE, and 10 patients had a new irAE. “This was a 500-patient study, but the true study population of interest is 68 patients. That suggests that to have something definitive, thousands of treated patients would have to be observed to generate a population that could then be randomized to re-treatment or discontinuation [cohorts] stratified by irAE severity, and that is unlikely to ever happen,” Dr Wrangle said. Baseline characteristics of those 68 patients were fairly similar, although patients in the re-treatment cohort were more likely to be treated in the first-line setting (66% vs 30%; P = .007).

Assessing the Feasibility of Re-Treating NSCLC With Checkpoint Inhibitors

IMMUNOTHERAPY REPORT The most common initial irAEs that led to treatment interruption or discontinuation included pneumonitis (19%), colitis (17%), rash (16%), and liver enzyme abnormalities (10%). There were no differences in the types of events or in the timing of the first irAE between the re-treatment and discontinuation groups (a median onset of 69 and 73 days, respectively). Initial irAEs were less severe in the re-treatment group and required fewer hospitalizations, a shorter course of ste-

When the patient develops a grade 3 or grade 4 AE, that’s transitioning [a response] from [simply] affecting quality of life to [an effect that is] life-threatening.” Study authors reported recurrent and new irAEs were more likely if the initial irAE had required hospitalization, with a higher frequency of recurrent/new irAEs in patients who initially experienced arthralgia or myalgia. Drug selection in the second-line setting may have influenced the decision

The most common initial irAEs that led to treatment interruption/discontinuation included pneumonitis, colitis, and rash.

The study authors wrote that even though they determined re-treatment could be a viable option for some patients — it is not an approach that necessarily should be used in routine practice. “The efficacy analysis of patients who had an objective response prior to the onset of an irAE were similar in the re-treatment cohort and discontinuation cohorts,” wrote the authors. “We conclude that for patients who achieved an objective response and developed an irAE that requires holding immunotherapy, re-treatment upon improvement/recovery of the irAE should not be encouraged.” ■ References

1. Santini FC, Rizvi H, Plodkowski AJ, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events

roids, and no instances of tumor necrosis factor-alpha inhibitor use compared with the discontinuation cohort. The majority of the recurrent or new irAEs were mild (58% were grade 1 or grade 2), and manageable, with 84% resolving or improving to grade 1. There were two treatment-related deaths, however. “It’s very frustrating when an AE does happen when we’re using immunotherapy,” Dr Wrangle said. “It can be devastating.

to discontinue treatment; Dr Wrangle noted that the patients across the discontinuation group received different drugs as second-line therapies. Although re-treatment with a checkpoint inhibitor is now generally discouraged and counter to treatment guidelines, according to Dr Wrangle, his team’s analysis reflects a period in which “no data previously existed [to aid] in this decision.”1

in patients with NSCLC [published online July 10, 2018]. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-17-0755 2. Santini FC, Rizvi H, Wilkins O, et al. Safety of retreatment with immunotherapy after immune-related toxicity in patients with lung cancers treated with anti-PD(L)-1 therapy. Abstract presented at: the American Society of Clinical Oncology Annual Meeting; June 2017; Chicago, IL. doi: 10.1200/ JCO.2017.35.15_suppl.9012

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CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 33

IN THE CLINIC

New-onset adult diabetes mellitus appears to be both a risk factor for and a sequelae of pancreatic cancer. C. ANDREW KISTLER, MD, PharmD

ancreatic cancer is a lethal malignancy and represents the fourth leading cause of cancer-related death in the United States.1 Patients who develop pancreatic cancer can clinically present in various ways. The most common symptoms include weight loss, decreased appetite, fatigue, abdominal pain, jaundice, dark urine, and acholic stools.2 A patient’s symptoms are typically related to the location of the malignancy within the pancreas. Up to 70% of malignancies are found within the head of the pancreas and are more likely to present with weight loss, jaundice, acholic stools, and steatorrhea.3 In comparison, up to 25% of malignancies are found in the body or tail of the pancreas and are less likely to present with these “classic” symptoms and more likely to be linked with reports of back pain. Outside of these traditional presentations, new-onset adult diabetes mellitus (DM2) can represent a subtler manifestation of pancreatic cancer. “Newonset” usually refers to DM2 that has been diagnosed in fewer than 36 months. Hyperglycemia and DM2 can be present in up to 80% of patients with pancreatic cancer.4 Long-standing DM2 (a diagnosis of longer than 36 months) has been recognized as a risk factor for developing pancreatic cancer and confers an approximately 2-fold increased risk based on

epidemiological studies.5 Despite this link, the role of DM2 as a potential screening test for pancreatic cancer is under investigation.4-6 The connection between these two factors can be challenging to study, however, because many patients may have had undiagnosed DM2 for years but are characterized as “newly” diagnosed when the presence of the condition is finally recognized. In addition, both DM2 and pancreatic cancer share similar risk factors such as age, family history, and obesity.6 Therefore, many of the studies evaluating diabetes as a marker for pancreatic cancer have produced mixed findings. A population-based cohort study conducted by Chari and colleagues evaluated over 2000 patients who were aged at least

34 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

50 years with newly diagnosed diabetes for the development of pancreatic cancer within 3 years of initial diagnosis.4 Of the 2122 patients with diabetes, 18 (0.85%) were diagnosed with pancreatic cancer within 3 years. This represented a 3-year incidence of close to 8 times that of the general population. Most of these patients did not have a family history of diabetes and 50% had “cancer-related” symptoms (although these were not defined in the study), and 10 out of 18 patients had their cancer diagnosed less than 6 months after meeting the diagnostic criteria for DM2. A more recent study conducted by Setiawan and colleagues focused on African American and Latino patients and the link between recent-onset DM2 and pancreatic cancer.5 These patient populations were chosen because both groups have an increased risk of developing DM2, although African Americans have a significantly higher risk of pancreatic cancer compared with Latinos. This prospective, population-based cohort study identified 48,995 African American and Latino patients in California, of which 15,833 (32.3%) developed diabetes. A total of 408 Continued on page 36

Pancreatic Cancer and New-Onset Diabetes

VIEWPOINT

Informed Consent Considerations in Patients With Advanced Cancer LEAH LAWRENCE

Approximately half of patients with advanced cancer who are enrolled in phase 1 clinical trials do not know the ultimate goal of the study.

n patients with advanced cancer, cognitive functioning may play a role in their ability to recall and understand informed consent for participation in phase 1 clinical trials, according to the results of a study published in The Journal of Clinical Oncology.1 In the study, only a minority of patients (45%) recalled the physician disclosing dosage or toxicity as the primary phase 1 research purpose, and only half of patients were able to identify the research purpose of the experimental study. “Clinicians must gain awareness and recognize that cancer-related cognitive impairments may adversely impact the advanced cancer patient’s decisional capacity and understanding of the nature of informed consent for phase 1 trials,” study researcher Fay Hlubocky, PhD, of the University of Chicago in Illinois, told Cancer Therapy Advisor. “Routine assessment of cognitive symptoms during the informed consent process should be practiced and standardized for all patients considering trial participation in order to identify potential deficits and address these symptoms by targeting treatment.” According to Dr Hlubocky, prior research has consistently shown that patients with advanced cancer maintain an imperfect understanding of the nature of informed consent for phase 1 clinical trial participation. “Despite a rigorous informed consent process involving physician disclosure of the phase 1 purpose as determining drug safety, and with this explanation further emphasized and highlighted

within the consent form, only a minority of these patients report an adequate understanding of this purpose as safety or dosage,” she explained. “This inability to correctly state the phase 1 purpose is due in part to multiple factors, including the patient’s underlying hope and motivation for therapeutic benefit, as well as oncologist communication.” Dr Hlubocky and colleagues wanted to investigate the role of cognitive function and its effect on patient comprehension of informed consent. They looked at 118 patients with advanced cancer enrolled in phase 1 trials that were being conducted by the University of Chicago’s developmental therapeutics clinic. Patients underwent neuropsychological assessment to evaluate cognitive functioning. Testing included evaluation of several domains including memory, executive functioning, language, attention, comprehension, and quality of life. Cognitive function ranged from mild impairment to superior performance. “Our finding is consistent with previous research indicating only 25% to 43% of patients could correctly recall and state the phase 1 purpose after the consent discussion,” Dr Hlubocky said. “However, for our study, these same patients who correctly recalled this purpose had enhanced cognitive function for memory and attention [compared with] those [who were] unable to recall the purpose. Although [it is] not a formal decisional capacity domain, recall is an essential cognitive task that is unique to memory and [is] also representative within all domains; it declines with increasing age and thus, [is] important to evaluate.”

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 35

VIEWPOINT In addition, only 50% of study participants could identify the purpose of the trial. The patients who correctly identified the purpose had greater cognitive functioning compared with the patients who

purpose given they receive and seek out information regarding phase 1 [studies] differently, [and are] utilizing additional resources outside [of] the clinical encounter, including [information learned from]

Researchers found that only 45% of patients recalled the disclosure of dosage or toxicity as the primary phase 1 research purpose. did not, with greater scores for memory (P = .001), attention (P < .001), visual attention (P = .001), and executive function (P < .001). Patients who were highly educated were also more likely to identify the trial purpose compared with patients who were less educated (53% vs 27%; P = .03). “It may be that these patients [are] more likely to identify the phase 1

family/friends, the internet, or research [collected from] phase 1,” Dr Hlubocky said. “Indeed, our results provide critical evidence for the need for cognitive and educational interventions designed to address the unique decision-making and information needs of this population.” Younger patients had a greater likelihood of recalling the purpose of the

In the Clinic

pancreatic cancer. However, to evaluate whether or not newly diagnosed DM2 was related to malignancies other than pancreatic cancer, Aggarwal and colleagues conducted a retrospective chart review of 500 patients with cancer.6 This cohort included 100 patients each with pancreatic, colorectal, lung, breast, and prostate cancer, and these patients were compared with 100 control patients without cancer. The study found a higher prevalence of DM2 (68%) in patients with pancreatic cancer compared with all other groups: lung cancer (19.6%), breast cancer (19.4%), prostate cancer (14.8%), colorectal cancer (20.7%), and noncancer controls (23.5%). Forty percent of patients with pancreatic cancer developed DM2 within the 36 months preceding the cancer diagnosis, which was significantly higher than the rates seen across other patient groups (ranging from 3.3% to 5.7%, P < .0001).

Continued from page 34

patients developed pancreatic cancer, of which 128 were diagnosed with new-onset diabetes compared with 280 who did not have incident diabetes. Diabetes was associated with pancreatic cancer at ages 65 and 75 (HR = 4.6 and HR = 2.39, respectively). In patients with pancreatic cancer who developed DM2, 52.3% developed the condition during the 36 months preceding a cancer diagnosis. At age 75, patients with new-onset diabetes (defined as < 3 years) had a 2.3-fold greater association with pancreatic cancer compared with long-standing DM2 (> 3 years). The authors concluded that new-onset diabetes is a manifestation of pancreatic cancer. Based on anatomy and pathophysiology, it would appear that new-onset DM2 could be unique to patients who develop

36 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

trial compared with those aged 60 or older (70% vs 30%; P = .02). Older patients also had greater deficits in total memory (P = .002), attention (P < .001), and executive function (P = .01). “Although cognitive impairment is likely multifactorial, involving many contributors such as fatigue, psychological distress, insomnia, or poor physical functioning and quality of life, a formal assessment of these cognitive symptoms in the clinical setting during the informed consent discussion is vital to ensure that patients have the ability to make a decision to participate in a phase 1 trial,” Dr Hlubocky said. “These symptoms, if left unaddressed, are likely to impair decisional capacity.” ■ Reference

1. Hlubocky FJ et al. J Clin Oncol. 2018;36(24):2483-2491. doi: 10.1200/ JCO.2017.73.3592

DM2 appears to be both a risk factor for and a sequelae of pancreatic cancer. Health care practitioners should be cognizant of this when evaluating adult patients with both long-standing and new-onset diabetes. More studies are needed in the future to further clarify how screening tests for pancreatic cancer could be coupled with available tests for DM2. ■ References

1. Siegel RL et al. CA Cancer J Clin. 2018;68(1):7-30. 2. Porta M et al. Clin Transl Oncol. 2005 Jun; 7(5):189-197. 3. Modolell I et al. Ann Oncol. 1999; 10(suppl-4):S82-S84. 4. Chari ST et al. Gastroenterology. 2005; 129(2):504-511. 5. Setiawan VW, Stram DO, Porcel J, et al.

J Natl Cancer Inst. doi: 10.1093/jnci/djy090 6. Aggarwal G et al. Pancreas. 2013; 42(2):198-201.

HEMATOLOGIC CANCER

TREATMENT REGIMENS Acute Myeloid Leukemia (AML) 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 only provided 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 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.

uInduction

Therapy1

Note: All recommendations are Category 2A unless otherwise indicated. The NCCN believes the best option for any patient with cancer is in a clinical trial and strongly encourages this option for all patients.

PATIENT CRITERIA

REGIMEN AND DOSING

Age <60 years2-8

Days 1–3: An anthracycline (daunorubicin 60–90mg/m2 IV OR idarubicin 12mg/m2) Days 1–7: Cytarabine 100–200mg/m2 continuous IV (Category 1). OR Days 1–3: Daunorubicin 60mg/m2 IV Days 1–7: Cytarabine 200mg/m2 continuous IV Days 1–5: Cladribine 5 mg/m2. OR Days 1–3: An anthracycline (daunorubicin 60mg/m2 IV OR idarubicin 12mg/m2 for 1 cycle) Days 1–6: High-dose cytarabine 2g/m2 IV every 12 hours OR Days 1–4: High-dose cytarabine 3g/m2 IV every 12 hours (Category 1 for patients ≤45 years, category 2B for other age groups). OR Days 1–3: Daunorubicin 60mg/m2 IV Days 1–7: Cytarabine 200mg/m2 continuous IV every 12 hours Days 8–21: Midostaurin 50mg orally every 12 hours.a OR Days 1, 3, 5: Dual-drug liposomal encapsulation of cytarabine 100mg/m2 +daunorubicin 44mg/m2 IV over 90 minutes (Category 2B).b OR Days 1, 4, 7: Daunorubicin 60mg/m2 + gemtuzumab ozogamicin 3mg/m2 (up to one 4.5 mg vial) Days 1–7: Cytarabine 200mg/m2 continuous IV OR Days 1–7: SC granulocyte-colony stimulating factor (G-CSF) Days 2–6: Fludarabine 30mg/m2 plus high-dose cytarabine 2g/m2 over 4 hours after starting fludarabine on days 2–6 Days 4–6: Idarubicin 8mg/m2 IV (Category 2B).

Age ≥60 years6-10 De novo AML without unfavorable cytogenetics or molecular markers; no antecedent hematologic disorder; and no therapy-related AML

Days 1–3: An anthracycline (daunorubicin 60–90mg/m2 IV OR idarubicin 12mg/m2 IV OR mitoxantrone 12mg/m2 IV) Days 1–7: Cytarabine 100–200mg/m2 continuous IV. OR Days 1–3: Daunorubicin 60mg/m2 IV Days 1–7: Cytarabine 200mg/m2 continuous IV Days 8–21: Midostaurin 50mg orally every 12 hours.a OR Days 1, 4, 7: Daunorubicin 60mg/m2 + gemtuzumab ozogamicin 3mg/m2 (up to one 4.5 mg vial) Days 1–7: Cytarabine 200mg/m2 continuous IV (for CD33-positive AML).

Age ≥60 years6,7,9,10 Unfavorable cytogenetics or molecular markers; antecedent hematologic disorder; therapy-related AML

Lower-intensity therapy Days 1–7: 5-azacytidine 75mg/m2 IV every 28 days OR Days 1–5: Decitabine 20mg/m2 IV for a 4-week cycle. OR Days 1–3: An anthracycline (daunorubicin 60–90mg/m2 IV OR idarubicin 12mg/m2 IV OR mitoxantrone 12mg/m2 IV) Days 1–7: Cytarabine 100–200mg/m2 continuous IV. OR Days 1–3: Daunorubicin 60mg/m2 IV Days 1–7: Cytarabine 200mg/m2 continuous IV Days 8–21: Midostaurin 50mg orally every 12 hours.a OR Days 1, 3, 5: Dual-drug liposomal encapsulation of cytarabine 100mg/m2 + daunorubicin 44mg/m2 IV over 90 minutes (Category 1).b Clofarabine-based regimens (Category 3). continued

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 37

HEMATOLOGIC CANCER

TREATMENT REGIMENS Acute Myeloid Leukemia (AML) Treatment Regimens uInduction

Therapy1 (continued)

PATIENT CRITERIA

REGIMEN AND DOSING

Age ≥60 years11-15 Not a candidate for intensive therapy or declines intensive therapy

Lower-intensity therapy Days 1–10: Cytarabine 20mg SC twice daily. OR Days 1–7: 5-azacytidine 75mg/m2 IV every 28 days (preferred). OR Days 1–5: Decitabine 20mg/m2 IV every 28 days (preferred). OR Day 1: Gemtuzumab ozogamicin 6mg/m2 IV Day 8: Gemtuzumab ozogamicin 3mg/m2 IV (CD-33 positive). OR Enasidenib 100mg orally once daily (IDH-2 mutated AML). OR Best supportive care (hydroxyurea, transfusion support).

uPost-Remission

Therapy1

Age <60 years12,13 Core binding factor cytogenetic translocations without KIT mutation or favorable-risk molecular abnormalities

Days 1, 3, and 5: High-dose cytarabine 3g/m2 IV over 3 hours every 12 hours for 3–4 cycles (Category 1) OR Days 1–3: High-dose cytarabine 3g/m2 IV over 3 hours every 12 hours for 3–4 cycles. OR Days 1–4: Cytarabine 1g/m2 every 12 hours Day 1: Gemtuzumab ozogamicin 3mg/m2 (up to 4.5mg vial) for 2 cycles Day 1 (Cycle 1) or Days 1–2 (Cycle 2): Daunorubicin 60mg/m2 IV (For CD33-positive AML).

Age <60 years Intermediate-risk and/or molecular abnormalities

Matched sibling or alternative donor HCT. OR Days 1, 3, 5, OR Days 1–3: High-dose cytarabine 1.5–3g/m2 IV over 3 hours every 12 hours for 3–4 cycles. OR Days 1, 3, 5, OR Days 1–3: High-dose cytarabine 1.5–3g/m2 IV over 3 hours every12hours Days 8–21: Midostaurin 50mg orally every 12 hours.a OR Days 1–4: Cytarabine 1g/m2 every 12 hours Day 1 (Cycle 1) or Days 1–2 (Cycle 2): Daunorubicin 60mg/m2 IV Day 1: Gemtuzumab ozogamicin 3mg/m2 (up to one 4.5mg vial) for 2 cycles (for CD33-positive AML).

Age <60 years Treatment-related disease other than CBF and/or poor-risk cytogenetics and/or molecular abnormalities

Matched sibling or alternative donor HCT. OR Days 1, 3, and 5 OR Days 1–3: High-dose cytarabine 1.5–3g/m2 IV over 3 hours every 12 hours for 3–4 cycles. OR Days 1, 3, and 5 OR Days 1–3: High-dose cytarabine 1.5–3g/m2 IV over 3 hours every 12 hours. Days 8–21: Midostaurin 50mg orally every 12 hours.a OR Days 1 and 3: Dual-drug liposomal encapsulation of cytarabine 65mg/m2 + daunorubicin 29mg/m2 IV over 90 minutes (Category 2B).b

Age ≥60 years Complete Response After Previous Intensive Therapy

Reduced-intensity HCT. OR Cytarabine 100–200mg/m2 IV for 5–7 days for 1–2 cycles ± anthracycline (idarubicin or daunorubicin). OR Cytarabine 1–1.5g/m2 IV for 4–6 doses for 1–2 cycles for patients with good performance status, normal renal function, better-risk or normal karyotype with favorable molecular markers. OR Days 1, 3, and 5: Cytarabine 1–1.5g/m2 over 3 hours every 12 hours Days 8–21: Midostaurin 50mg orally every 12 hours.a OR Days 1 and 3: Dual-drug liposomal encapsulation of cytarabine 65mg/m2 + daunorubicin 29mg/m2 IV over 90 minutes.b OR Days 1–4: Cytarabine 1000mg/m2 IV every 12 hours

38 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

HEMATOLOGIC CANCER

TREATMENT REGIMENS Acute Myeloid Leukemia (AML) Treatment Regimens uPost-Remission

Therapy1 (continued)

PATIENT CRITERIA

REGIMEN AND DOSING

Age ≥60 years Complete Response After Previous Intensive Therapy (continued)

Day 1 (Cycle 1) OR Days 1–2 (Cycle 2): Daunorubicin 60mg/m2 IV Day 1: Gemtuzumab ozogamicin 3mg/m2 (up to one 4.5mg vial) for 2 cycles (for CD33-positive AML). OR Maintenance therapy with hypomethylating regimen (5-azacytidine, decitabine) every 4–6 weeks until progression. OR Observation.

Age ≥60 years Induction Failure After Previous Intensive Therapy

Allogeneic HCT (preferably in clinical trial). OR Best supportive care.

Age ≥60 years Response After Previous Lower Intensity Therapy

Reduced-intensity HCT. OR Continue hypomethylating regimens (5-azacytidine, decitabine) every 4–6 weeks until progression. OR Day 1: Gemtuzumab ozogamicin 2mg/m2 every 4 weeks up to 8 continuation courses (CD33-positive AML). OR Continue enasidenib until progression (IDH-2 mutated AML).

Age ≥60 years No Response or Progression After Previous Lower Intensity Therapy

Best supportive care.

uTherapy

for Relapse or Refractory Disease1

Age <60 years Early Relapse (<12 months) Age <60 years Late Relapse (≥12 months) Age ≥60 years Early Relapse (<12 months) Age ≥60 years Late Relapse (≥12 months)

*Chemotherapy Options8-10, 14-19, 23, 24

Chemotherapy* followed by matched sibling or alternative donor HCT. Chemotherapy* followed by matched sibling or alternative donor HCT. OR Repeat initial successful induction regimen. Chemotherapy* followed by matched sibling or alternative donor HCT. OR Best supportive care. Repeat initial successful induction regimen. OR Chemotherapy* followed by matched sibling or alternative donor HCT. OR Best supportive care. Aggressive therapy for appropriate patients: Days 1–5: Cladribine 5mg/m2 IV Days 1–5: Cytarabine 2g/m2 IV Days 0–5: G-CSF 300mcg SC, ± Days 1–3: Mitoxantrone 10mg/m2 IV OR idarubicin 10mg/m2 IV. OR High-dose cytarabine (if not previously used in treatment) ± anthracycline. OR Days 1–5: Fludarabine 30mg/m2 IV over 0.5 hours Days 1–5: Cytarabine 2g/m2 IV over 4 hours Days 0 to polymorphonuclear recovery (>0.5 x 109/L): G-CSF 5mcg/kg or 300mcg/m2 (G-CSF may also start on Day +6 until engraftment) ± Days 1–3: Idarubicin 10mg/m2 IV. OR Days 1–6: Etoposide 80mg/m2 IV over 1 hour + cytarabine 1g/m2 IV over 6 hours ± mitoxantrone 6mg/m2 IV bolus. OR Days 1–5: Clofarabine 22.5mg/m2–25mg/m2 IV ± Days 2–6: Cytarabine 0.75g/m2–2g/m2 IV Days 0 to neutrophil recovery: G-CSF 5mcg/kg/day ± Days 1–3: Idarubicin 6-8 mg/m2 IV. continued

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 39

HEMATOLOGIC CANCER

TREATMENT REGIMENS Acute Myeloid Leukemia (AML) Treatment Regimens uTherapy

for Relapse or Refractory Disease1 (continued)

PATIENT CRITERIA

REGIMEN AND DOSING

*Chemotherapy Options8-10, 14-19, 23, 24 (continued)

Less aggressive therapy: Hypomethylating agents (5-azacytidine or decitabine). OR Low-dose cytarabine (Category 2B). Therapy for patients with FLT3-ITD disease: Days 1–7: 5-azacytidine 75mg/m2 IV + sorafenib 400 mg orally twice daily continuously. OR Decitabine + sorafenib. Therapy for patients with IDH-2 disease Enasidenib 100mg orally daily. Therapy for CD33-positive disease Days 1, 4, 7: Gemtuzumuab ozogamicin 3mg/m2 IV over 2 hours.

This regimen is for FLT3 mutation-positive AML (both ITD and TKD) mutations. While midostaurin was not FDA approved for maintenance therapy, the study was designed for consolidation and maintenance midostaurin for a total of 12 months. For cytotoxic therapy-related AML other than core binding factor [CBF]/APL, or patients with antecedent MDS/CMML, or cytogenetic changes that are consistent with MDS

References 1. NCCN Clinical Practice Guidelines in Oncology™. Acute Myeloid Leukemia. v1.2018. Available at: http://www.nccn.org/professionals/physician_gls/pdf/aml. pdf. Accessed March 29, 2018. 2. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13): 1249–1259. 3. Kern W, Estey EH. High-dose cytosine arabinoside in the treatment of acute myeloid leukemia review of three randomized trials. Cancer. 2006;107(1):116–124. 4. Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of highdose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996:88(8):2841–2851. 5. Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996;87(5):1710–1717. 6. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016;34(suppl):abstract 7000. 7. Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open label, phase 3 study. Lancet. 2012;379:1508-1516. 8. Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29:369-377. 9. Krug U, Röllig C, Koschmieder A, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet. 2010;376(9757):2000–2008. 10. Löwenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361(13): 1235–1248. 11. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans r etinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114–1124. 12. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223–232. 13. Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28(4):556–561 14. Kantarjian HM, Erba HP, Claxton D, et al. Phase II study of c lofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic f actors. J Clin Oncol. 2010;28(4):549–555. 15. Stein EM, DiNardo CD, Altman JK, et al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients

16. 17. 18.

19.

20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

with advanced hematologic malignancies: results of a phase 1/2 trial. Blood. 2015. 2015:126(23):323 Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994;331(14):896–903. Jaramillo S, Benner A, Krauter J, et al. Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia. Blood Cancer J. 2017;7:e564, Löwenberg B, Pabst T, Vellenga E, et al; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364(11):1027–1036. Wierzbowska A, Robak T, Pluta A, et al; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80(2):115-126. Fridle C, Medinger M, Wilk MC, et al. Cladribine, cytarabine and idarubicin (CLAIda) salvage chemotherapy in relapsed acute myeloid leukemia (AML). Leuk Lymphoma. 2017;58(5):1068–1075. Martin MG, Welch JS, Augustin K, et al. Cladribine in the t reatment of acute myeloid leukemia: a single-institution e xperience. Clin Lymphoma Myeloma. 2009;9(4):298–301. Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998;58(2):105–109. Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997;99(4):939–944. Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991;9(7):1210–1214. Becker PS, Kantarjian HM, Appelbaum FR, et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapse and refractory acute myeloid leukaemia. Br J Haematol. 2011;155(2):182–189. Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combinations as acute myeloid leukemia salvage therapy. Cancer. 2008; 113(8):2090–2096. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013:121(23):4655–4662. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–731. Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia. 2007;21: 66–71. (Revised 3/2018) © 2018 by Haymarket Media, Inc.

40 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

GASTRIC CANCER

TREATMENT REGIMENS Gastric Cancer Treatment Regimens Clinical Trials: The National Comprehensive Cancer Network 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 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.

Principles of Systemic Therapy1 • Systemic therapy regimens recommended for advanced esophageal and esophagogastric junction (EGJ) adenocarcinoma, squamous cell carcinoma of the esophagus, and gastric adenocarcinoma may be used interchangeably (except as indicated). • Regimens should be chosen in the context of performance status (PS), medical comorbidities, and toxicity profile. • Trastuzumab should be added to chemotherapy for HER2 overexpressing metastatic adenocarcinoma. • Two-drug cytotoxic regimens are preferred for patients with advanced disease because of lower toxicity. Three-drug cytotoxic regimens should be reserved for medically fit patients with good PS and access to frequent toxicity evaluation. • Modifications of category 1 regimen or use of category 2A or 2B regimens may be preferred (as indicated), with evidence supporting a more favorable toxicity profile without compromising efficacy. • Doses and schedules for any regimen that is not derived from category 1 evidence are a suggestion, and are subject to appropriate modifications depending on the circumstances. • Alternate combinations and schedules of cytotoxic based on the availability of the agents, practice preferences, and contraindications are permitted. • Perioperative chemotherapy, or postoperative chemotherapy plus chemoradiation is the preferred approach for localized gastric cancer. • Postoperative chemotherapy is recommended following primary D2 lymph node dissection. • In the adjuvant setting, upon completion of chemotherapy or chemoradiation, patients should be monitored for any long-term therapy-related complications.

uPreoperative

Chemoradiation (esophagogastric junction and gastric cardia)1

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

REGIMEN

DOSING

Preferred Regimens Paclitaxel + carboplatin (Category 1)6

Day 1: Paclitaxel 50mg/m2 IV + carboplatin AUC 2mg·min/mL IV. Repeat cycle weekly for 5 weeks.

Cisplatin + 5-fluorouracil (5-FU) (Category 1)7,8

Days 1 and 29: Cisplatin 75–100mg/m2 IV Days 1–4 and 29–32: 5-FU 750–1000mg/m2 continuous IV infusion over 24 hours daily. OR Days 1–5: Cisplatin 15mg/m2 IV once daily + 5-FU 800mg/m2 continuous IV infusion over 24 hours daily. Repeat cycle every 21 days for 2 cycles.

Oxaliplatin + 5-FU (Category 1)9

Day 1: Oxaliplatin 85mg/m2 + leucovorin 400mg/m2 + 5-FU 400mg/m2 IV push followed by Days 1–2: 5-FU 800mg/m2 24-hour continuous infusion. Repeat cycle every 14 days for 3 cycles with radiation and 3 cycles after radiation.

Cisplatin + capecitabine50

Day 1: Cisplatin 30mg/m2 IV Days 1–5: Capecitabine 800mg/m2 orally twice daily. Repeat cycle weekly for 5 weeks.

Oxaliplatin + capecitabine51

Days 1, 15, and 29: Oxaliplatin 85mg/m2 IV Days 1–5: Capecitabine 625mg/m2 orally twice daily for 5 weeks.

Other Regimens Paclitaxel + 5-FU (Category 2B)11

Day 1: Paclitaxel 45–50mg/m2 IV weekly Days 1–5: 5-FU 300mg/m2 IV continuous infusion. Repeat cycle weekly for 5 weeks.

Paclitaxel + capecitabine (Category 2B)11

Day 1: Paclitaxel 45–50mg/m2 IV Days 1–5: Capecitabine 625-825mg/m2 orally twice daily. Repeat cycle weekly for 5 weeks. continued

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 41

GASTRIC CANCER

TREATMENT REGIMENS Gastric Cancer Treatment Regimens uPerioperative

Chemotherapy (including esophagogastric junction)1

REGIMEN

DOSING

Epirubicin + cisplatin + 5-FU (ECF) (Category 2B)3

Day 1: Epirubicin 50mg/m2 IV bolus + cisplatin 60mg/m2 IV Days 1–21: 5-FU 200mg/m2/day IV continuous infusion over 24 hours daily. Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.

ECF modification: epirubicin + oxaliplatin + 5-FU (Category 2B)4

Day 1: Epirubicin 50mg/m2 IV + oxaliplatin 130mg/m2 IV Days 1–21: 5-FU 200mg/m2/day IV continuous infusion over 24 hours. Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively

ECF modification: epirubicin + cisplatin + capecitabine (Category 2B)4

Day 1: Epirubicin 50mg/m2 IV + cisplatin 60mg/m2 IV Days 1–21: Capecitabine 625mg/m2 orally twice daily. Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.

ECF modification: epirubicin + oxaliplatin + capecitabine (Category 2B)4,5

Day 1: Epirubicin 50mg/m2 IV + oxaliplatin 130mg/m2 IV Days 1–21: Capecitabine 625mg/m2 orally twice daily. Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.

5-FU + cisplatin (Category 1)2

Day 1: Cisplatin 75–80mg/m2 IV Days 1–5: 5-FU 800mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 28 days for 2–3 cycles preoperatively and 3–4 cyclespostoperatively for a total of 6 cycles.

5-FU + leucovorin + oxaliplatin16,19

Day 1: Oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 + 5-FU 400mg/m2 IV push followed by: Days 1–2: 5-FU 1200mg/m2 continuous IV daily over 24 hours. OR Day 1: Oxaliplatin 85mg/m2 + leucovorin 200mg/m2 + 5-FU 2600mg/m2 continuous IV infusion over 24 hours. Repeat cycle every 14 days.

Capecitabine + oxaliplatin20

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 1000mg/m2 orally twice daily. Repeat cycle every 21 days.

uPostoperative

Chemoradiation (including esophagogastric junction)1

5-FU + leucovorin (Category 1)12,52

Cycles 1, 3, and 4 (before and after radiation) Days 1–5: Leucovorin 20mg/m2 IV push + 5-FU 425mg/m2/day IV push Repeat cycle every 28 days. Cycle 2 (with radiation) Days 1–4 and 31–33: Leucovorin 20mg/m2 IV push Days 1–4: 5-FU 400mg/m2/day IV push. Repeat cycle every 35 days. The NCCN panel acknowledges that the Intergroup 0116 Trial formed the basis for postoperative adjuvant chemoradiation strategy. However, the panel does not recommend the above specified doses or schedule of cytotoxic agents because of concerns regarding toxicity. The panel recommends one of the following modifications instead.

Capecitabine53

Days 1–14: Capecitabine 750–1000mg/m2 orally twice daily. Repeat cycle every 28 days; 1 cycle before and 2 cycles after chemoradiation.

5-FU + leucovorin54

Days 1, 2, 15, and 16: Leucovorin 400mg/m2 IV followed by 5-FU 400mg/m2 IV push and a 24-hour infusion of 5-FU 1200mg/m2; 1 cycle before and 2 cycles after chemoradiation. Repeat cycle every 28 days.

5-FU with radiation55

Days 1–5 OR Days 1–7: 5-FU 200–250mg/m2 IV continuous infusion over 24 hours once daily; weekly for 5 weeks.

Capecitabine with radiation56

Days 1–5 OR Days 1–7: Capecitabine 625–825mg/m2 orally twice daily; weekly for 5 weeks.

uPostoperative

Chemotherapy (for patients who have undergone primary D2 lymph node dissection)

Capecitabine + oxaliplatin (Category 1)13

Days 1–14: Capecitabine 1000mg/m2 orally twice daily Day 1: Oxaliplatin 130mg/m2 IV. Repeat cycle every 21 days for 8 cycles.

42 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

GASTRIC CANCER

TREATMENT REGIMENS Gastric Cancer Treatment Regimens uUnresectable

Locally Advanced, Recurrent or Metastatic Disease (where local therapy is not indicated)1

REGIMEN

DOSING

First-line Therapy Trastuzumab + chemotherapy (NOTE: for HER2-neu overexpressing adenocarcinoma)14

Day 1: Trastuzumab 8mg/kg IV loading dose (Cycle 1 only); followed by trastuzumab 6mg/kg IV every 3 weeks, plus chemotherapy OR Day 1 of Cycle 1: Trastuzumab 6mg/kg IV loading dose, then 4mg/kg IV every 14 days. Chemotherapy: Day 1: Cisplatin 80mg/m2 IV, plus Days 1–14: Capecitabine 1000mg/m2 orally twice daily. (Category 1) OR Days 1–5: 5-FU 800mg/m2 continuous IV infusion. (Category 2B) Repeat cycle every 21 days for 6 cycles.

Preferred Regimens Fluoropyrimidine and cisplatin (5-FU + cisplatin) (Category 1)15

Day 1: Cisplatin 75−100mg/m2 IV Days 1–4: 5-FU 750−1,000mg/m2 IV continuous infusion over 24 hours daily.

Fluoropyrimidine and cisplatin (5-FU + cisplatin + leucovorin) (Category 1)16,17

Day 1: Cisplatin 50mg/m2 IV + leucovorin 200mg/m2 IV + 5-FU 2,000mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 14 days.

Fluoropyrimidine and cisplatin (capecitabine + cisplatin) (Category 1)18

Day 1: Cisplatin 80mg/m2 IV Day 1–14: Capecitabine 1000mg/m2 orally twice daily. Repeat cycle every 3 weeks.

Fluoropyrimidine and oxaliplatin (oxaliplatin + capecitabine) 20

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 1000mg/m2 orally twice daily. Repeat cycle every 21 days.

Fluoropyrimidine and oxaliplatin (oxaliplatin + leucovorin + 5-FU)16,19

Day 1: Oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 IV + 5-FU 400mg/m2 IVP Days 1−2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 14 days. OR Day 1: Oxaliplatin 85mg/m2 IV + leucovorin 200mg/m2 IV + 5-FU 2,600mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 14 days.

Other Regimens Modified DCF (docetaxel + cisplatin + leucovorin + 5-FU)33

Day 1: Docetaxel 40mg/m2 IV + leucovorin 400mg/m2 IV + 5-FU 400mg/m2 IV Days 1−2: 5-FU 1000mg/m2 IV continuous infusion over 24 hours Day 3: Cisplatin 40mg/m2 IV. Repeat cycle every 14 days.

Modified DCF (docetaxel + oxaliplatin + 5-FU)34

Day 1: Docetaxel 50mg/m2 IV + oxaliplatin 85mg/m2 IV Days 1−2: 5-FU 1,200mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 14 days.

Modified DCF (docetaxel + carboplatin + 5-FU) (Category 2B)35

Day 1: Docetaxel 75mg/m2 IV Day 2: Carboplatin AUC 6mg·min/mL IV Days 1–3: 5-FU 1,200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 21 days.

ECF (Category 2B)36

Day 1: Epirubicin 50mg/m2 IV bolus + cisplatin 60mg/m2 IV Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 21 days.

ECF modifications (epirubicin + oxaliplatin + 5-FU) (Category 2B)4,5

Day 1: Epirubicin 50mg/m2 IV + oxaliplatin 130mg/m2 IV Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 21 days.

ECF modifications (epirubicin + cisplatin + capecitabine) (Category 2B)4,5

Day 1: Epirubicin 50mg/m2 IV + cisplatin 60mg/m2 IV Days 1–21: Capecitabine 625mg/m2 orally twice daily. Repeat cycle every 21 days. continued

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GASTRIC CANCER

TREATMENT REGIMENS Gastric Cancer Treatment Regimens uUnresectable

Locally Advanced, Recurrent or Metastatic Disease (where local therapy is not indicated)1 (continued)

REGIMEN

DOSING

First-line Therapy (continued) Other Regimens (continued) ECF modifications (epirubicin + oxaliplatin + capecitabine) (Category 2B)4,5 Fluorouracil and irinotecan (irinotecan + leucovorin + 5-FU)32 Paclitaxel + cisplatin or carboplatin21–23

Docetaxel + cisplatin24,25 Fluoropyridimine17,26,27

Taxane28–31

Day 1: Epirubicin 50mg/m2 IV + oxaliplatin 130mg/m2 IV Days 1–21: Capecitabine 625mg/m2 IV orally twice daily. Repeat cycle every 21 days. Day 1: Irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV + 5-FU 400mg/m2 IV push followed by Day 1−2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 14 days. Day 1: Paclitaxel 135–200mg/m2 IV Day 2: Cisplatin 75mg/m2 IV. Repeat cycle every 21 days. OR Day 1: Paclitaxel 90mg/m2 IV + cisplatin 50mg/m2 IV. Repeat cycle every 14 days. OR Day 1: Paclitaxel 200mg/m2 IV + carboplatin AUC 5mg·min/mL IV. Repeat cycle every 21 days. Day 1: Docetaxel 70–85mg/m2 IV + cisplatin 70–75mg/m2 IV. Repeat cycle every 21 days. Day 1: Leucovorin 400mg/m2 IV + 5-FU 400mg/m2 IV push Days 1−2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 14 days. OR Days 1–5: 5-FU 800mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 28 days. OR Days 1–14: Capecitabine 1000–1250mg/m2 orally twice daily. Repeat cycle every 21 days. Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days. OR Day 1: Paclitaxel 135–250mg/m2 IV. Repeat cycle every 21 days. OR Days 1, 8, 15 and 22: Paclitaxel 80mg/m2 IV once weekly. Repeat cycle every 28 days.

Second-line Therapy and Subsequent Therapy Preferred Regimens Ramucirumab (Category 1)42 Ramucirumab + paclitaxel (Category 1)37 Docetaxel (Category 1)28,29 Paclitaxel (Category 1)30,31,38

Day 1: Ramucirumab 8mg/kg IV. Repeat cycle every 14 days. Day 1 and 15: Ramucirumab 8mg/kg IV Day 1, 8, and 15: Paclitaxel 80mg/m2. Repeat cycle every 28 days. Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days. Day 1: Paclitaxel 135–250mg/m2 IV. Repeat cycle every 21 days. OR Day 1: Paclitaxel 80mg/m2 IV once weekly. Repeat cycle every 28 days. OR Days 1, 8, and 15: Paclitaxel 80mg/m2 IV. Repeat cycle every 28 days.

44 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

GASTRIC CANCER

TREATMENT REGIMENS Gastric Cancer Treatment Regimens uUnresectable

Locally Advanced, Recurrent or Metastatic Disease (where local therapy is not indicated)1 (continued)

REGIMEN

DOSING

Second-line Therapy and Subsequent Therapy (continued) Preferred Regimens Irinotecan (Category 1)38–41

Day 1: Irinotecan 250–350mg/m2 IV. Repeat cycle every 21 days. OR Day 1: Irinotecan 150–180mg/m2 IV. Repeat cycle every 14 days. OR Days 1 and 8: Irinotecan 125mg/m2 IV. Repeat cycle every 21 days.

5-FU + irinotecan (if not previously used in first-line therapy)39

Day 1: Irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV + 5-FU 400mg/m2 IV push followed by Day 1 and 2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 14 days.

Other Regimens Irinotecan + cisplatin19,45

Days 1 and 8: Irinotecan 65mg/m2 IV + cisplatin 25–30mg/m2 IV. Repeat cycle every 21 days.

Docetaxel + irinotecan (Category 2B)49

Days 1 and 8: Docetaxel 35mg/m2 IV + irinotecan 50mg/m2 IV. Repeat cycle every 21 days.

Pembrolizumab (for second-line or subsequent therapy for MSI-H/dMMR tumors; for third-line or subsequent therapy for PD-L1-positive adenocarcinoma)48

Days 1: Pembrolizumab 200 mg IV. Repeat cycle every 21 days.

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Gastric Cancer. V5.2017. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/gastric.pdf. Accessed March 23, 2018. 2. Ychou M, Boige V, Pignon J-P, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29:1715-1721. 3. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11-20. 4. Sumpter K, Harper-Wynne C, Cunningham D, et al. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer. 2005;92:1976-1983. 5. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. 6. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074-2084. 7. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26:1086-1092. 8. Bedenne L, Michel P, Bouche O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25:1160-1168. 9. Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014;15:305-314.

10. Khushalani NI, Leichman CG, Proulx G, et al. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol. 2002;20:2844-2850. 11. Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006;24:3953-3958. 12. Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012;30:2327-2333. 13. Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15:1389-1396. 14. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697. 15. Lorenzen S, Schuster T, Porschen R, et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009;20:1667-1673 16. Al-Batran S-E, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26:1435-1442. 17. Bouche O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric can-

continued

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 45

GASTRIC CANCER

TREATMENT REGIMENS Gastric Cancer Treatment Regimens References (continued) 18. 19.

20. 21. 22. 23. 24.

25. 26.

27. 28.

29. 30. 31. 32.

33.

34.

35. 36.

cer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004;22:4319-4328. Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20:666-673. Enzinger PC, Burtness BA, Niedzwiecki D, et al. CALGB 80403 (Alliance)/E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancers. J Clin Oncol. 2016;34:2736-2742. Kim GM, Jeung HC, Rha SY, et al. A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer. 2012;48:518-526. Ilson DH, Forastiere A, Arquette M, et al. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer. J 2000;6:316-323. Petrasch S, Welt A, Reinacher A, et al. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer. 1998;78:511-514. Gadgeel SM, Shields AF, Heilbrun LK, et al. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003;26:37-41. Ajani JA, Fodor MB, Tjulandin SA, et al. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005;23:5660-5667. Kim JY, Do YR, Park KU, et al. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010;66:31-36. Ohtsu A, Shimada Y, Shirao K, et al. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003;21:54-59. Hong YS, Song SY, Lee SI, et al. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004;15:1344-1347. Albertsson M, Johansson B, Friesland S, et al. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007;24:407-412. Ford HE, Marshall A, Bridgewater JA, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014;15:78-86. Ajani JA, Ilson DH, Daugherty K, et al. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994;86:1086-1091. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007;18:898-902. Guimbaud R, Louvet C, Ries P, et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: A French Intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) Study. J Clin Oncol. 2014;32: 3520-3526. Shah MA, Janjigian YY, Stoller R, et al. Randomized multicenter phase II study of modified docetaxel, cisplatin, and fluorouracil (DCF) versus DCF plus growth factor support in patients with metastatic gastric adenocarcinoma: a study of the US Gastric Cancer Consortium. J Clin Oncol. 2015;33:3874-3879. Shankaran V, Mulcahy MF, Hochster HS, et al. Docetaxel, oxaliplatin, and 5-fluorouracil for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinomas: Preliminary results of a phase II study. Gastrointestinal Cancers Symposium 2009:Abstract 47. Elkerm YM, Elsaid A, AL-Batran S, Pauligk C. Final results of a phase II trial of docetaxel-carboplatin-FU in locally advanced gastric carcinoma [abstract] [abstract]. Presented at the 2008 Gastrointestinal Cancers Symposium 2008. Abstract 38. Ross P, Nicolson M, Cunningham D, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002;20:1996-2004.

37. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224-1235. 38. Hironaka S, Ueda S, Yasui H, et al. Randomized, open- label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013;31:4438-4444. 39. Sym SJ, Hong J, Park J, et al. A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy. Cancer Chemother Pharmacol. 2013;71:481-488. 40. Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47:2306- 2314. 41. 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. 42. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, r andomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31-39. 43. Sym SJ, Ryu MH, Lee JL, et al. Salvage chemotherapy with biweekly irinotecan, plus 5-fluorouracil and leucovorin in patients with advanced gastric cancer previously treated with fluoropyrimidine, platinum, and taxane. Am J Clin Oncol. 2008;31:151-156. 44. Assersohn L, Brown G, Cunningham D, et al. Phase II study of irinotecan and 5- fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma. Ann Oncol. 2004;15:64-69. 45. Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004;18:22-25. 46. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-413. 47. 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. 48. Fuchs CS, Doi T, Jang RW-J, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer [abstract]. Journal of Clinical Oncology. 2017;35:4003-4003. 49. Burtness B, Gibson M, Egleston B, et al. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009;20:1242-1248. 50. Lee SS, Kim SB, Park SI, et al. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three d ifferent settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007;37:829-835. 51. Javle MM, Yang G, Nwogu CE, et al. Capecitabine, oxaliplatin and radiotherapy: a phase IB neoadjuvant study for esophageal cancer with gene expression analysis. Cancer Invest. 2009;27:193-200. 52. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725-730. 53. Jansen EP, Boot H, Saunders MP, et al. A phase I-II study of postoperative capecitabine-based chemoradiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys. 2007;69: 1424-1428. 54. Andre T, Quinaux E, Louvet C, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007;25:3732-3738. 55. Leong T, Joon DL, Willis D, et al. Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2011;79:690-695. 56. Lee HS, Choi Y, Hur WJ, et al. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006;12:603-607. (Revised 3/2018) © 2018 by Haymarket Media, Inc.

46 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2018 | CancerTherapyAdvisor.com

LUNG CANCER

TREATMENT REGIMENS Mesothelioma 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 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.

uFirst-line

Combination Chemotherapy1

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

REGIMEN

DOSING

Pemetrexed + cisplatin (Category 1)2

Day 1: Pemetrexed 500mg/m2 IV day 1 followed 30 minutes later by cisplatin 75mg/m2 over 2 hours. Repeat every 21 days up to 12 cycles.

Pemetrexed + cisplatin + bevacizumab (Category 1)3,a

Day 1: Pemetrexed 500mg/m2 IV + cisplatin 75mg/m2 IV + bevacizumab 15mg/kg IV. Repeat every 21 days for 6 cycles, followed by: Maintenance bevacizumab 15mg/kg every 21 days until disease progression.

Pemetrexed + carboplatin4-6,c

Day 1: Pemetrexed 500mg/m2 IV + carboplatin AUC 5mg·min/mL IV. Repeat every 21 days for a max of 9 cycles.

Pemetrexed + carboplatin + bevacizumab4-7,c

Day 1: Pemetrexed 500mg/m2 IV + carboplatin AUC 5mg·min/mL IV + bevacizumab 15mg/kg. Repeat every 21 days for 6 cycles, followed by: Maintenance bevacizumab 15mg/kg every 21 days until disease progression.

Gemcitabine + cisplatin8,9

Day 1: Cisplatin 80–100mg/m2 IV over 1 hour Days 1, 8, and 15: Gemcitabine 1000–1250mg/m2 IV over 30 minutes. Repeat every 21-28 days for 6 cycles.

Pemetrexed10

Day 1: Pemetrexed 500mg/m2 IV. Repeat every 21 days for 4 cycles.

Vinorelbine11

Vinorelbine 25–30mg/m2 (max 60mg) IV every week for 12 weeks.

uSubsequent

Systemic Therapy1

Pemetrexed (if not administered as first-line) (Category 1)12,13,b

Day 1: Pemetrexed 500mg/m2 IV. Repeat every 3 weeks for 8 cycles.

Vinorelbine14,15

Vinorelbine 30mg/m2 (max 60mg) IV weekly. Repeat every 6 weeks for 11 cycles.

Gemcitabine15-17

Days 1, 8, and 15: Gemcitabine 1250mg/m2 IV. Repeat every 28 days for a max of 10 cycles.

Nivolumab ± ipilimumab (Category 2B)18,19

Day 1: Nivolumab 3mg/kg IV over 1 hour every 2 weeks Day 1: Ipilimumab 1mg/kg IV over 1.5 hours every 6 weeks. Repeat until disease progression or unacceptable toxicity.

Pembrolizumab20

Day 1: Pembrolizumab 10mg/kg IV every 2 weeks. Repeat for 2 years or until disease progression or unacceptable toxicity.

The combination regimen of pemetrexed + cisplatin + bevacizumab is only for unresectable disease. Consider rechallenge if good sustained response at the time initial chemotherapy was interrupted. The carboplatin/pemetrexed regimen is recommended for patients with poor performance score and/or comorbidities.

b c

continued

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2018 | CANCER THERAPY ADVISOR 47

LUNG CANCER

TREATMENT REGIMENS Mesothelioma Treatment Regimens References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines®) for Malignant Pleural Mesothelioma. V2.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf. Accessed March 9, 2018. 2. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–2644. 3. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnoised pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled open-label, Phase 3 trial. Lancet. 2016;387: 1405-1414. 4. Castagneto B, Botta M, Aitini E, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma. Ann Oncol. 2008;19:370–373. 5. Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006; 24:1443–1448. 6. Santoro A, O’Brien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma. J Thorac Oncol. 2008;3:756–763. 7. Ceresoli GL, Zucali PA, Mencoboni M, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer. 2013;109:552–558. 8. Nowak AK, Byrne MJ, Willianson R, et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer. 2002;87:491–496. 9. Van Haarst JM, Baas J, Manegold CH, et al. Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer. 2002; 86:342–345. 10. Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaive and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. J Thorac Oncol. 2008;3:764–771. 11. Muers MF, Stephens RJ, Fisher P, et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural

12.

13. 14. 15. 16.

17.

18.

19.

20.

mesothelioma (MS01): a multicentre randomised trial. Lancet. 2008;371: 1685–1694. Jassem J, Ramlau R, Santoro A, et al. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol. 2008;26: 1698–1704. Zucal PA, Simonelli M, Michetti G, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung Cancer. 2012;75: 360–367. Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer. 2009;63:94–97. Zauderer MG, Kass SL, Woo K, et al. Vinorelbine and gemcitabine as secondor third-line therapy for malignant pleural mesothelioma. Lung Cancer. 2014;84:271–274. Manegold C, Symanowski J, Gatzemeier U, et al. Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol. 2005; 16:923–927. van Meerbeeck JP, Baas P, Debruyne C, et al. A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer. 1999;85: 2577–2582. Scherpereel A, Mazieres J, Greiller L, et al. Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: results of the IFCT-1501 MAPS2 randomized phase 2 trial [abstract]. J Clin Oncol. 2017;35: Abstract LBA8507. Zalcman G, Mazieres J, Greiller L, et al. Second or 3rd line nivolumab (Nivo) versus nivo plus ipilimumab (ipi) in malignant pleural mesothlioma (MPM) patients: Updated results of the IFCT-1501 MAPS2 randomized phase 2 trial [abstract]. Ann Oncol. 2017;28:Abstract LBA58_PR. Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomized, open-label, phase 1b trial. Lancet Oncol. 2017; 18:623–630. (Revised 3/2018) © 2018 by Haymarket Media, Inc.

u Resources

for the Treatment of Lung Cancer

RECENTLY FEATURED TOPICS INCLUDE: Researchers Use Artificial Intelligence to Predict Patient Survival from Pathology Images in Lung Cancer Artificial intelligence techniques are being employed to build complex new multivariate prognostic models for patients with lung cancer and other malignancies. The International Association for the Study of Lung Cancer (IASCL) Publishes Liquid Biopsy Recommendations Guidance on the use of biopsies for the detection of EGFR and other tumor mutations in NSCLC.

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

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