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SE / NO. 1 / 2023

Oncology

Breast Cancer Focus Pages 5 to 13

ESMO & Norsk Aften 2023 Pages 14 to 15

Hematology

The Link Between Breast Cancer and Hematologic Cancers Pages 22 to 23

Share clinical knowledge and best practice to improve health and patient care.

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Content 3

Table of contents

4

Editorial / Jan Andreasen

5

Oncology

Hematology

MEDtalk HIGHLIGHTS: ONCOLOGY

17 Belamaf and Dexamethasone – Safe, Effective

6 HER2-Low Treatment – The Future of This Important Biomarker / Paolo Tarantino

8

Trastuzumab and HER2 Targeted Cancer Treatment / Jan Trøst Jørgensen

12 Highlights from ASCO 2023 – New Insights

into Luminal Breast Cancer / Bent Ejlertsen

14

ESMO 2023

16 Three-Drug Regimen for Previously Untreated, Intermediate-Risk Patients Diagno-sed with

Multiple Myeloma Treatment / Evangelos Terpos

19 Navigating CLL Treatment: Decoding Small-

Molecule Inhibitor Sequencing and Combination Therapies / Clement Chung

22 The Link Between Breast Cancer and

Hematologic Cancers / Cathrine Fonnesbech Hjorth

24 High Expression of the Inhibitory Checkpoint Receptor TIGIT by CD8+ T-cells in Multiple Myeloma / Katrine Fladeland Iversen

Advanced Renal Cell Carcinoma / MEDtalk with Laurence Albiges

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

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Editorial Jan Andreasen / Editor in Chief, MD & Partner, BestPractice Nordic

BestPractice Nordic is an independent journal published by: BestPractice Nordic ApS Teknikerbyen 5, 2nd floor 2830, Virum, Denmark +45 4466 9210 Redaktion@bpno.dk www.bpno.fi Editor in chief Jan Andreasen MD & Journalist +45 5151 8831 jan@bpno.dk Editing and production Isabella Rosa Staffe Junior Editor & Digital Coordinator + 45 6147 4984 ist@bpno.dk The articles in BestPractice Nordic are independent of interests. Most pieces are written from the author’s professional perspective, and the message of the articles does not necessarily reflect an expression of the views of the editor.

This magazine is distributed to Danish Oncologists & Hematologists Advertising Peter Bøgkjær Partner & Co-founder +45 2245 7262 pbo@bpno.dk Copyright© 2023 BestPractice Nordic ApS Circulation: 610 Art director Helle Rindom

N VA

ENMÄRK

Every year, October marks Breast Cancer Awareness Month, which is a dedicated campaign aimed at promoting early detection and the prevention of

breast cancer, a disease that profoundly impacts millions of women worldwide

each year. In this issue of the BestPractice Nordic oncology-hematology magazine, we’ve adorned select pages in pink to show our solidarity and to highlight

the breast cancer research being done today.

Over the past 25 years, there have been remarkable strides in breast cancer treatment. Extensive research and the development of innovative therapies have significantly increased survival rates. Compared to earlier, twice as many patients are triumphing over the disease today, and even those who experi-

ence relapses are living longer. Notably, this year commemorates the 25th anni-

versary of the FDA’s approval of trastuzumab (Herceptin), a monoclonal anti-

body, for the treatment of HER2-positive metastatic breast cancer, alongside the immunohistochemical assay known as HercepTest.

Trastuzumab has revolutionized the landscape of HER2-positive breast cancer

treatment. The development of a diagnostic test to pinpoint the patients who

stand to benefit the most from this therapy marked a pivotal moment in the evolution of cancer treatment strategies. Since the approval of trastuzumab, a

multitude of new drugs with diverse modes of action have been developed,

and the future holds even more promising treatments for the well-being of cancer patients.

Welcome to BestPractice Nordic.

E T

S

Printing House Strandbygaard A/S

Breast Cancer Awareness

Jan Andreasen Trycksak 5041 0751

Editor in chief

Our mission is to share clinical knowledge and best practice to improve health and patient care.

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BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

MEDtalk HIGHLIGHTS

BREAST CANCER

Stine Bakkensen Bruun

Giuseppe Curigliano

Circulating Methylated-HOXA9 Tumor DNA as a Biomarker in Recurrent Breast Cancer

Trastuzumab Deruxtecan in HER2-Low Metastatic Breast Cancer Treatment

findings on a potential new biomarker for prognosis and mor-

has shown effectiveness in patients with HER2-low disease.

In this MEDtalk, MD Stine Bakkensen Bruun presents interesting tality in recurrent breast cancer. The biomarker is circulating

methylated-HOXA9 tumor DNA, as this gene may act as a tu-

mor suppressor in carcinomas and induce breast cancer progression.

Trastuzumab deruxtecan is an antibody-drug conjugate which In this MEDtalk Giuseppe Curigliano’s presents results from a

phase III trial (DESTINY-Breast04) investigating the effectiveness and safety profile of trastuzumab deruxtecan which should be considered in treatment algorithms for these patients.

Unraveling the HER2-Low Breast Cancer Puzzle – Treatment Sequencing and Targeted Therapies

In this MEDtalk, hematologist Arya Mariam Roy from the Roswell

Park Comprehensive Cancer Center in New York, presents a review of treatment options in HER2-low breast cancer and discusses treatment sequencing algorithms.

Arya Mariam Roy

Scan the QR code and find all MEDtalks on oncology at our site bpno.dk • bpno.no • bpno.se • bpno.fi

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

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HER2-Low Treatment – The Future of This Important Biomarker Paolo Tarantino, from the Dana-Farber Cancer Institute, highlights the transformative potential of novel antibody-drug conjugates in treating HER2-positive and HER2-low breast cancer. Through recent trials, Tarantino challenges traditional assumptions about HER2 expression and demonstrates promising outcomes for HER2-low tumours.

PAOLO TARANTINO, medical oncologist, clinical research-

significantly improved both progression-free survival

Boston, Massachusetts, PhD student, University of Milan

dian improvement of over six months). As a result, T-DXd

er, Dana-Farber Cancer Institute, Harvard Medical School,

This article explores the emerging significance of HER2low expression in breast oncology. The introduction of

novel antibody-drug conjugates (ADCs) has challenged

the conventional understanding of the targetability of

has become the standard of care for HER2-low meta-

static breast cancer patients who have progressed on prior endocrine therapy and chemotherapy. Of note, be-

yond being used in hormone receptor positive disease,

T-DXd is also used in patients with triple-negative, HER2-

HER2. Previously, HER2-positive breast cancer was known

low metastatic breast cancer that have progressed on

prior chemotherapy.

negative tumors did not benefit from such treatments.

Despite these advancements, there are still many chal-

with ADCs targeting HER2 in HER2-low tumors, namely

dress these issues, a recent consensus paper was pub-

to respond well to HER2-targeted agents, while HER2­However, recent trials have shown promising results

tumors with no HER2 amplification, but with detectable HER2 immunostaining (1+ or 2+/nonamplified).

ADCs Prove Effective in Targeting HER2 One notable phase 1 study presented in 2018 reported

on the activity and toxicity of trastuzumab deruxtecan

Experts Await Results of DESTINY-Breast06 Trial

lenges and unanswered questions in the field. To adlished in the Annals of Oncology, led by Dr. Tarantino

and involving 32 global experts from various disciplines.

The paper aimed to tackle questions regarding the bio­ logy, diagnostics, pathology support, and future clinical trials in HER2-low breast cancer.

While the consensus paper provides valuable insights,

(T-DXd), an ADC, in patients with HER2-low metastatic

additional data is needed to address some of the open

response rate and a median progression-free survival

tribute to this data. This phase 3 trial, similar to DESTINY­

breast cancer. Surprisingly, the trial demonstrated a 37% (PFS) of almost one year, which was unexpected given the lack of HER2 overexpression. Encouraging activity was observed with other ADCs like disitamab vedotin or trastuzumab duocarmazine, suggesting that HER2-low

expression, typically identified as immunohistochemistry 1+ or 2+ non-amplified tumors, can be targeted with novel ADCs.

These findings were confirmed from the DESTINY­-

Breast04 trial, a phase 3 study comparing T-DXd with

physician’s choice chemotherapy in patients with HER2low metastatic breast cancer who had received prior

endocrine therapy and 1-2 lines of chemotherapy. T-DXd

6

(from 5 to 10.1 months) and overall survival (with a me-

questions. The DESTINY-Breast06 trial is expected to con-

Breast04, includes patients with HER2-low metastatic

breast cancer. However, DESTINY-Breast06 also includes

patients with ultra-low HER2 expression (HER2 > null but < 1+) who have minimal detectable HER2 with immuno­

histochemistry. The trial compares T-DXd with physician’s choice chemotherapy (taxanes or capecitabine)

in chemotherapy-naive patients with hormone receptor positive, HER2-low metastatic breast cancer. The re-

sults of this trial, expected soon, may further expand the population eligible for treatment with T-DXd and enhance our understanding of this evolving biomarker.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

CONCLUSION: In conclusion, the emerging role of HER2-low expression, especially with the use of novel ADCs, has transformed the treatment landscape for metastatic breast cancer. Ongoing research and clinical trials, such as DESTINY-Breast06, will continue to shape the future of this important biomarker.

This article is based on the MEDtalk with Paolo Tarantino:

Advancements and Emerging Challenges in HER2-Low Treatment Scan the QR code to watch the MEDtalk CONFLICT OF INTERESTS: None.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

7

Trastuzumab and HER2 Targeted Cancer Treatment The success of trastuzumab has inspired the development of several other HER2-targeted drugs and companion diagnostic assays, paving the way for a more objective and effective approach to cancer therapy. This article explores the journey of trastuzumab, its impact on cancer therapy, and the inspiration it has provided for the development of future targeted treatments.

JAN TRØST JØRGENSEN, pharmacist, Ph.D., Dx-Rx Institute, Fredensborg, Denmark

On September 25, 1998, the FDA approved the mono-

results of these studies, Genentech had a negative atti-

mal growth factor receptor 2 (HER2)-positive meta-

Ullrich, who decided to leave the project and the com-

tech) for the treatment of patients with human epider-

static breast cancer. This approval was obtained simultaneously with the immunohistochemical (IHC) assay, HercepTest (Agilent/Dako), which could detect the

expression of the HER2 receptor protein in the tumor

tude towards the project, much to the frustration of Axel

pany. In 1988, he returned to Germany, where he later became professor at the Max Planck Institute in Munich.

Dennis Slamon continued the fight, and in 1990, he con­

vinced the management of Genentech to get involved

tissue. The simultaneous approval of the drug and the

with the project, and then things started to take off.4

cal studies had shown a link between HER2 receptor

tered to humans, it can result in an immunogenetic re-

IHC assay made good sense, as preclinical and cliniprotein expression and the effect of trastuzumab.1

However, if a mouse monoclonal antibody is adminis-

action, which could affect both efficacy and safety, as the patient will recognize it as being of foreign origin.

HER2 and Breast Cancer In 1987, Dennis Slamon, Axel Ullrich, and others published

an article in Science describing a link between HER2

gene amplification and a poor prognosis in women with breast cancer2. Based on this observation, they

concluded that the HER2 gene product might function

as a growth factor receptor that plays a role in the pathogenesis of breast cancer, and the identification

of its ligand and developing specific antagonists could have important therapeutic implications. Years later,

the antagonist mentioned in their Science publication became the monoclonal antibody trastuzumab.2

However, using a newly developed technique, Michael

Shepard and colleagues at Genentech humanized the MuMAb4D5 antibody so that it could be safely administered to the patients.5 Several preclinical studies with

the humanized version of the antibody (HuMAb4D5) de­ monstrated an additive effect when administered in combination with chemotherapy. Furthermore, it was

shown to be efficient in supporting immunological antibody-dependent cellular cytotoxicity (ADCC) against

the HER2-positive tumor cells. ADCC mediated by nat-

ural killer cells is likely to be the main mechanism of action of trastuzumab in relation to its antitumor ef-

fect. In 1992, HuMAb4D5 was ready to be administered

The Monoclonal Antibody Trastuzumab It was the German scientist Axel Ullrich who, for the Amer-

ican biotech company Genentech, cloned the gene for

to patients under the generic name trastuzumab, and the clinical development could be initiated.

HER2 and, together with his colleagues, developed a

Metastatic Breast Cancer

against the external part of the HER2 receptor protein.3

level of HER2 expression in tumor cells and the growth-in-

murine monoclonal antibody (MuMAb4D5) directed

The preclinical studies had shown a link between the

This antibody was tested in different preclinical in vitro

hibiting effect of trastuzumab.5 This knowledge was cru-

and in vivo studies and showed a growth-inhibiting ef-

8

fect on HER2-positive tumor cells. Despite the positive

clonal antibody trastuzumab (Herceptin; Roche/Genen-

cial for the design of the clinical trials. To select pa-

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

tients most likely to benefit from treatment, an IHC as-

unambiguously showed that treatment with trastuzum-

tor protein on the tumor cells. Approximately 20% of

improved disease survival.11 The use of trastuzumab as

say was developed that could detect the HER2 recepwomen with breast cancer overexpress the HER2 re-

ceptor protein.1 This assay was used throughout the clinical development, thereby introducing what is cur-

rently known as the clinical enrichment design. In the

ab significantly reduced the risk of relapse and thus an adjuvant treatment for HER2-positive breast cancer has been approved in Europe and the United States for more than 15 years.

period up to 1995, a number of phase I and II studies

Gastric Cancer

the level of the HER2 receptor protein and the effect of

the HER2 receptor protein occur not only in breast can-

were conducted, all of which confirmed a link between

Amplification of the HER2 gene and overexpression of

trastuzumab. In the same year, a final phase III trial

cer, but also in other cancers such as ovarian, endo-

6

was initiated to document the efficacy and safety of

trastuzumab in women with HER2-positive metastatic breast cancer. In this trial, 469 patients were rand7

omized to receive either trastuzumab plus chemother-

apy or chemotherapy alone. The study showed that

patients treated with trastuzumab had a significantly higher objective response rate (ORR) and better oneyear survival. Based on the positive results of the phase

III trial, the FDA approved trastuzumab and the com-

panion diagnostic assay HercepTest in the fall of 1998.

In Europe, trastuzumab was approved for the treat-

ment of HER2-positive metastatic breast cancer a couple of years later.

Adjuvant Treatment of Breast Cancer A few years after trastuzumab was approved for treat-

metrial, colorectal, cervical, lung, gastroesophageal

cancer, and more.12 As early as 1986, it was described for gastric cancer, where approximately 15% of the patients are HER2-positive.13 Around 2005, a phase III clini-

cal trial was initiated to investigate the efficacy of tras-

tuzumab in HER2-positive patients with advanced gastroesophageal cancer.14 This trial showed that the combination of trastuzumab and chemotherapy significantly improved overall survival compared to chemother-

apy alone. In particular, the group of patients with the highest HER2 expression levels (IHC3+) benefited most from this treatment.15 Trastuzumab has been approved for the treatment of HER2-positive gastroesophageal

cancer in Europe and the United States for more than 10 years.

ing HER2-positive metastatic breast cancer, clinical tri-

Other HER2 Targeted Drugs

apy. Several large clinical trials were conducted where

HER2-positive cancers. Over the past 15-20 years, sev-

als were initiated to investigate its use as adjuvant ther-

Trastuzumab is not the only drug developed to treat

HER2­positive early-stage breast cancer patients were

eral drugs that target the HER2 receptor in different

randomized to treatment with a combination of trastuzumab and chemotherapy or chemotherapy alone.8-10

These trials involved several thousand patients and

ways have been introduced. These drugs include mon-

oclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates (Table 1).

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

9

Table 1 – HER2 targeted drugs approved in Table 1 –and HER2 targeted drugs approved in Europe their overall indications Europe and their overall indications Monoclonal antibodies Trastuzumab (Herceptin)*

Figure 1 – HER2 receptor dimer

Figure 1 – HER2 receptor dimer

Breast cancer Gastroesophageal cancer

Pertuzumab (Perjeta)

Breast cancer

Pertuzumab + Trastuzumab (Phesgo)

Breast cancer

Pertuzumab

Tyrosine kinase inhibitors Lapatinib (Tyverb)

Breast cancer

Neratinib (Nerlynx)

Breast cancer

Tucatinib (Tukysa)

Breast cancer

Antibody-drug conjugates Trastuzumab emtansine (Kadcyla) Trastuzumab deruxtecan (Enhertu)

Breast cancer Breast cancer Breast cancer (low HER2 expression) Gastroesophageal cancer

Trastuzumab

Trastuzumab deruxtecan Trastuzumab emtansine

Cell membrane Lapatinib Neratinib Tucatinib

*Herceptin currently off-patent and aand several biosimilar drugs *Herceptinis is currently off-patent a several biosimilar have been introduced.

Information from: EMA. EPARs ofEPARs Humanof drugs have been introduced.

Information from: EMA. 23 Medicines.

June 2023.

Human Medicines.

June 2023.23

HER2 receptor dimer with binding sites for the various targeted HER2 drugs.

HER2 receptor dimer with binding sites for the various targeted HER2 drugs.

The monoclonal antibodies trastuzumab and pertu-

Outstanding Medical Research

tor protein. Trastuzumab binds to subdomain IV, where-

breast cancer is an outstanding achievement. This was

zumab target different subdomains of the HER2 recep-

The development of trastuzumab for HER2-positive

as pertuzumab binds to subdomain II.16 In breast can-

recognized when Dennis Slamon, Axel Ullrich, and Mi-

cer, the combination of these two antibodies has shown to be superior to trastuzumab alone.17

Tyrosine kinase inhibitors are small molecules that cross

the cell membrane to inhibit intracellular tyrosine kinase

activity. Lapatinib was the first tyrosine kinase inhibitor targeting the intracellular domain of the HER2 receptor

protein and was approved for the treatment of metastatic HER2-positive breast cancer in 2007.16

The newest group of HER2-targeted drugs is the anti-

body-drug conjugates (ADC) designed to deliver a cytotoxic payload directly to HER2-expressing tumor cells.

After binding to the HER2 receptor, the ADC undergoes receptor-mediated internalization and subsequent lys-

osomal degradation, resulting in the intracellular re-

lease of its cytotoxic payload and tumor cell death.

chael Shepard received the prestigious Lasker-DeBakey

Clinical Medical Research Award in 2019.20 Not only was the development of trastuzumab a scientific and med-

ical achievement. It has also served as an inspiration for a wide range of subsequently developed cancer drugs. Our increased understanding of the molecular

pathophysiology has transformed the treatment of can-

cer and led to the development of several new targeted drugs. Regarding drugs targeting HER2 receptor protein, the last drug has not been developed yet. In the years to come, we will see a number of new drugs being developed, which likely will include mono- and bispecific

antibodies, antibody-drug conjugates, tyrosine kinase inhibitors and therapeutic vaccines.21

Trastuzumab was the first drug to achieve regulatory

Trastuzumab emtansine (T-DM1) was approved 10 years

approval, along with a companion diagnostic assay

approval only a few years ago. The payload of T-DXd

treatment. By combining molecular diagnostic testing

ago, whereas trastuzumab deruxtecan (T-DXd) gained is the topoisomerase I inhibitor deruxtecan (DXd), an

exatecan derivative with a 10-fold higher potency than the active metabolite of irinotecan. T-DXd has been 18

approved for breast, gastroesophageal, and lung cancers, and recent data from the DESTINY-PanTumor02 trial, presented at the ASCO 2023 meeting, seem to in-

dicate a tumor-agnostic potential in patients with different HER2-positive solid tumors.19 Figure 1 shows the

that could identify patients most likely to benefit from

with pharmacotherapy, we have moved from an empirical treatment strategy to a more objective approach.

It is important to remember that this approach started

25 years ago, and today, there are more than 60 cancer drugs with a companion diagnostic assay linked to their

use.22 To a large extent, these drugs stand on the shoulders of trastuzumab.

binding of the different HER2-targeted drugs to the HER2 receptor dimer.

10

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

CONCLUSION: In conclusion, the development and approval of trastuzumab as a targeted therapy for HER2-positive breast cancer marked a significant milestone in medical research. Its success led to a paradigm shift in cancer treatment, emphasizing personalized and molecular-based approaches. The success of trastuzumab has inspired the development of several other HER2-targeted drugs and companion diagnostic assays, paving the way for a more objective and effective approach to cancer therapy. As research continues, we anticipate further advancements in targeted treatments, transforming the landscape of oncology and improving patient outcomes.

Original publication The content of this article is based on: Jørgensen JT. Twenty-five years with HER2 targeted therapy, Ann Transl Med 2023, doi: 10.21037/atm-23-153.

References 1. Jørgensen JT, Winther H, Askaa J et al. A Companion Diagnostic with Significant Clinical Impact in Treatment of Breast and Gastric Cancer.

Front Oncol. 2021; 11: 676939. 2. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177-182. 3. Hudziak RM, Lewis GD, Winget M et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989, 9, 1165-72. 4. Bazell, R. HER2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer. Random House, New York. 1998. 5. Shepard HM, Lewis GD, Sarup JC et al. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J Clin Immunol. 1991, 11, 117-127. 6. Baselga, J. Phase I and II clinical trials of trastuzumab. Ann Oncol. 2001, 12 Suppl 1, S49-55. 7. Slamon DJ, Leyland-Jones B, Shak S at al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001; 344: 783-792. 8. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005, 353, 1673-1684. 9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005, 353, 1659-1672. 10. Slamon D, Eiermann W, Robert N et al. Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011, 365, 1273-1283. 11. Perez EA, Romond EH, Suman VJ et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014, 32, 3744-52. 12. Oh DY, Bang YJ. HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol. 2020; 17(1): 33-48. 13. Sakai K, Mori S, Kawamoto T et al. Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas. J Natl Cancer Inst. 1986, 77, 1047-1052. 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-esophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010; 376: 687-97. 15. Jørgensen, JT. Role of human epidermal growth factor receptor 2 in gastric cancer: biological and pharmacological aspects. World J Gastroenterol. 2014; 20: 4526-35. 16. EMA. EPARs of Human Medicines. June 2023. https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_field/Human/ema_group_types/ema_ medicine. 17. Baselga J, Cortés J, Kim SB et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366: 109-119. 18. Indini A, Rijavec E, Grossi F. Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors. Int J Mol Sci. 2021; 22: 4774.

19. Meric-Bernstam F, Makker V, Oaknin A et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol 2023; 41 (suppl 17; abstr LBA3000). 20. 2019, Lasker-DeBakey Clinical Medical Research Award. Herceptin—a targeted antibody therapy for breast cancer. https://laskerfoundation.org/winners/herceptin-a-targeted-antibody-therapy-for-breast-cancer/ 21. Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions.

Nat Rev Drug Discov. 2023; 22: 101-126. 22. Jørgensen, JT. Oncology drug-companion diagnostic combinations. Cancer Treat Res Commun. 2021; 29: 100492. 23. EMA. EPARs of Human Medicines. June 2023. https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_ field/Human/ema_group_types/ema_medicine.

CONFLICT OF INTERESTS: The author has served as a consultant and advisor for Agilent Technologies, Alligator Biosciences, Argenx, AstraZeneca, Biovica, Visiopharm, Leo Pharma, and received royalties from Elsevier.

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Highlights from ASCO 2023 – New Insights into Luminal Breast Cancer Traditionally, the ASCO conference has mainly focused on other subtypes of breast cancer, but this year’s conference broke with that norm and brought forth a range of interesting presentations within the field of luminal breast cancer.

BENT EJLERTSEN, professor, chief physician, MD, PhD & medical director, DBCG

Every year, the American Society of Clinical Oncology

(ASCO) presents new and groundbreaking research findings in cancer treatment, and in 2023, it was no different. Among the many presentations at this year’s

conference, there was a significant focus on luminal breast cancer, i.e., hormone-sensitive breast cancer that is HER2-negative.

Menopause and Chemo Impact on Ovarian Suppression in Breast Cancer One of the remarkable presentations at ASCO23 came from Richard Gray, MA, MSc, a professor from Oxford, who presented a meta-analysis on ovarian suppression or

castration for women with hormone-sensitive breast cancer.1 The results showed an 11.9% reduction in the risk

of recurrence with ovarian suppression. It should be not-

ed that the study included data from studies conducted from 1948 to 2009, which posed challenges due to

differences in study design over time. An important observation from this meta-analysis was that the effect of ovarian suppression was primarily limited to women who were definitely still premenopausal after or had

not received chemotherapy. This highlights the importance of menopausal status and treatment history.

One of the remarkable presentations at ASCO23 came from Richard Gray, MA, MSc, a professor from Oxford, who presented a meta-analysis on ovarian suppression or castration for women with hormone-sensitive breast cancer.

12

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

CONCLUSION: ASCO 2023 has undoubtedly shed new light on luminal breast cancer and introduced exciting perspectives for future treatment. It is important to remember that while these results are promising, further research and follow-up are required before they can be implemented as standard treatment.

Age-Related Variation in Luminal A Subtype in Women with Breast Cancer

Another interesting result came from the monarchE

Another study, “The Landmark Suppression of Ovarian

endocrine therapy.4 The study demonstrated that the

Function Trial”, also known as the SOFT study, exam-

ined ovarian suppression in premenopausal breast cancer patients.2 Tumor samples from 1,084 out of 1,245

patients who successfully completed the PAM50 test were included.

study, which used adjuvant abemaciclib combined with

CDK4/6 inhibitor had an effect on patients of all age groups. However, there was an observation that older patients had lower functional levels and more comorbidities, leading to more dose reductions.

Two additional studies, PALMIRA and SONIA,5,6 explored

The results of this study identified an interesting trend.

the use of CDK4/6 inhibitors in different treatment lines.

decreased from 75% in those over 40 years to 50% in

cisions, but further follow-up and survival data will be

The proportion of women with the luminal A subtype those under 40 years. This is relevant in relation to pre-

vious data showing that younger women often have a

The results of these studies help inform treatment denecessary to confirm the findings.

more aggressive form of breast cancer.

Exploring the Possibility of Shorter Capecitabine Cycles

The Potential of CDK4/6 Inhibitors in Luminal Breast Cancer

In addition to these presentations, there were also excit-

On the luminal breast cancer front, Dennis Slamon, di-

ment regimens and dosing strategies. The X-7/7 trial

rector of The Jonsson Comprehensive Cancer Center

in Los Angeles, presented the groundbreaking NATALEE

study, where ribociclib was shown to reduce the risk of recurrence.3 This study included patients with different risk profiles and demonstrated that the addition of a

ing investigator-initiated trials exploring different treat-

showed that a 7-day cycle of capecitabine was as effective as a 14-day cycle.7 This could potentially change

the treatment approach and make it more manageable for patients.

CDK4/6 inhibitor to endocrine therapy was effective, even for those at lower risk of recurrence.

References 1. Gray RG, Bradley R, Braybrooke J, et al: Effects of ovarian ablation or suppression on breast cancer recurrence and survival: Patient-level meta-analysis of 14,993 premenopausal women in 25 randomized trials. 2023 ASCO Annual Meeting. Abstract 503. Presented June 2, 2023. 2. Brown LC, Luen SJ, Molania R, Caramia F, Savas P, VanGeelen C, ´Chic N, Fleming GF, Kammler R, Colleoni M, Viale G, Speed TP, Regan MM, Francis PA, Loi S. Evaluation of PAM50 intrinsic subtypes and risk of recurrence (ROR) scores in premenopausal women with early-stage HR+ breast cancer: A secondary analysis of the SOFT trial. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 504-504. DOI: 10.1200/JCO.2023.41.16_suppl.504 3.

Slamon DJ, Stroyakovskiy D, Yardley DA, Huang CS, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA500-LBA500. DOI: 10.1200/JCO.2023.41.17_suppl.LBA500 4. Hamilton EP, Kim JH, Eigeliene N, et al. Efficacy and safety results by age in monarchE: adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2, node-positive, high-risk early breast cancer (EBC). J Clin Oncol. 2023;41(suppl 16):501. doi:10.1200/JCO.2023.41.16_suppl.501 5. Llombart-Cussac A, Harper-Wynne C, A Perello, et al. Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial. J Clin Oncol 41, 2023 (suppl 16; abstr 1001).DOI: 10.1200/JCO.2023.41.16_suppl.1001 6. Sonke GS, Ommen – Nijhof AV, Wortelboer N, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA1000-LBA1000. DOI: 10.1200/JCO.2023.41.17_suppl.LBA1000 7. Khan QJ, Bohnenkamp C, Monson T, Smith HE, et al. Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: The X-7/7 trial. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 1007-1007. DOI: 10.1200/JCO.2023.41.16_suppl.1007.

CONFLICT OF INTERESTS: None.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

13

European Society for Medical Oncology Exploring the Latest Advances in Treatment

In October 2023, oncologists from all over the world gathered to participate in the European Society for Medical Oncology congress (ESMO) in Madrid. During the congress, BestPractice Nordic met with oncologists from the Nordic countries, Europe, the USA and Canada and recorded MEDtalks where leading experts gave their perspectives on several key topics from the ESMO congress.

ESMO 2023

MEDtalk HIGHLIGHTS Pembrolizumab + Chemotherapy: A New Standard of Care for Triple-Negative Breast Cancer

Peter Schmid

The 5-year follow-up data from the KEYNOTE 522 trial demonstrated the superior efficacy of the combination of pembrolizumab and chemotherapy, compared to chemotherapy alone, in treating triple negative breast cancer across various patients. Join us for an in-depth look at data from KEYNOTE 522, presented by Peter Schmid from the Barts Cancer Institute in London.

Keynote A39: Enfortumab Vedotin + Pembrolizumab – a Groundbreaking First Line Treatment in Untreated la/mUC

Thomas Powles

14

For over four decades, chemotherapy has been the cornerstone of treatment in locally advanced or metastatic urothelial carcinoma.

Today, we are at the cusp of a transformative shift. A groundbreaking combination therapy has emerged, achieving a notable 55% reduction in progression rates and an over 50% decrease in the risk of mortality. Dr. Thomas Powles states that if given the opportunity, he would change his treatment for these patients tomorrow.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

Perioperative Pembrolizumab Shows Significant OS in Resectable Non-Small-Cell Lung Cancer

Jonathan Spicer

The results of KEYNOTE 671 reveal that perioperative chemotherapy with pembrolizumab improves overall survival in resectable non-smallcell lung cancer. Jonathan Spicer presents the study and discusses the concerns regarding patient drop-off in neoadjuvant studies and the positive patient dispositions achieved with this approach.

Oesophageal Cancer: Active Surveillance vs.

Neoadjuvant Chemoradiotherapy Followed

by Surgery

Magnus Nilsson

In this MEDtalk Magnus Nilsson provides his perspective on the SANO-trial. The SANO-trial compares active surveillance with standard oesophagectomy for patients with oesophageal cancer and a clinically complete response compared to treatment with neoadjuvant chemoradiotherapy.

Although promising, the question remains: if and how can active surveillance be implemented as a standard of care?

Potential New Standard of Care for Locally Advanced Cervical Cancer

Kristina Lindemann

In this MEDtalk, Kristina Lindemann briefs us on the Keynote A18 study, where patients with high-risk locally advanced cervical cancer received pembrolizumab in addition to standard chemo-radiation, vs induction chemotherapy prior to chemoradiation in the same disease setting. These studies offer the potential to improve the standard of care for patients with locally advanced cervical cancer, also in low and middle-income countries where access to newer treatments like immunotherapy and radiation can be challenging.

Scan the QR code and find all MEDtalks from ESMO 2023 at our congress sites bpno.dk • bpno.no • bpno.se • bpno.fi

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

15

MEDtalk with Laurence Albiges

Three-Drug Regimen for Previously Untreated, Intermediate-­ Risk Patients Diagnosed with Advanced Renal Cell Carcinoma In this MEDtalk, Laurence Albiges, M.D., Ph.D., professor of Medical Oncology at Paris Saclay University and the Head of the Medical Oncology Department at Gustave Roussy, Villejuif, France, gives her perspective on the COSMIC-313 study.

The COSMIC-313 trial marks a significant milestone as the first study demonstrating that incorporating a tyros-

ine kinase inhibitor alongside double checkpoint inhibition can enhance progression-free survival in previ-

ously untreated, intermediate-risk patients diagnosed with advanced renal cell carcinoma (RCC). Further-

more, this phase III trial represents the initial instance of employing the standard of care with doubleimmune Laurence Albiges, M.D., Ph.D., medical oncologist and Head of the Genitourinary Unit at Gustave Roussy Institute, Villejuif

therapy as the control group.

The study’s findings confirm that the addition of cabozantinib to the combination of nivolumab and ipilimum-

ab results in better progression-free survival in this spe-

cific patient population. In evaluating efficacy, it is crucial to consider the balance with associated toxicity rates. The investigation has disclosed that the threedrug regimen is associated with higher adverse effects

rates than the dual immune therapy approach. Watch the MEDtalk and find out more.

Scan the QR code to watch the MEDtalk:

Triplets Frontline Therapy Increases PFS for Patients with Previously Untreated Advanced Renal-Cell Carcinoma

16

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

Belamaf and Dexamethasone – Safe, Effective Multiple Myeloma Treatment Results from EHA23 indicate that belantamab mafodotin (belamaf) in combination with lenalidomide and dexamethasone holds great potential as a safe and effective option for patients with newly diagnosed multiple myeloma (MM) who are not suitable candidates for a transplant.

Belamaf is a multi-­modal antibody-drug conjugate that targets BCMA and has shown effectiveness and manageable safety in previously treated MM patients.

EVANGELOS TERPOS, MD, PHD, Hematology, Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens

Updated safety and efficacy results from the BelaRd

The BelaRd Study – Purpose and its two parts

nation with lenalidomide and dexamethasone (Rd) for

­04808037) is ongoing and consists of two parts. In Part 1,

study on belantamab mafodotin (belamaf) in combi-

The prospective, open-label, phase 1/2 BelaRd study (NCT­

newly diagnosed multiple myeloma (MM) patients who

the safety and tolerability of different doses of belamaf

are not eligible for a transplant was presented at EHA23.

Belamaf is a multi-modal antibody-drug conjugate

that targets BCMA and has shown effectiveness and

manageable safety in previously treated MM patients.

Preclinical data also suggest synergy between belamaf and lenalidomide.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

with Rd are evaluated in 36 patients, with the aim of deter­

mining the recommended dose for further study. Part 2 assesses the safety and efficacy of the recommended

dose in two groups of 15 patients each and examines two sets of guidelines for managing ocular adverse events (OAEs) related to belamaf-induced corneal damage.

17

CONCLUSION: The combination of belamaf in combination with Rd was found to be safe and effective for newly diagnosed MM patients who are not eligible for a transplant. Ocular adverse events had a minimal impact on patients’ daily functioning, and rapid and deep responses were observed in all patient groups, with all patients achieving at least a partial response.

Treatment outcomes and adverse events in belantamab mafodotin clinical trial

96 (20%), with a median time to resolution of 3 months.

As of the cutoff date 31 (86%) out of 36 patients in Part

tions, Gr2 and Gr4 keratopathy was observed in 55 (11%)

1 are still receiving treatment, while 5 (14%) have discontinued. The median number of belamaf administrations and cycles reached were 6 and 15, respectively,

with a median follow-up time of 15 months. The most com-

mon non-ocular treatment-emergent adverse events (TEAEs) of grade 3 or higher, reported in at least 10% of

patients, included fatigue, rash, diarrhea, and COVID-19

Regarding corneal findings, in 501 slit lamp examinaand in 2 (<1%), respectively, with a median time to resolution of 4 months. The overall response rate [partial

response (PR) or better] was 100.0% [36 pts; stringent

complete response: 14% (5 pts); complete response: 19% (7 pts); very good partial response: 47% (17 pts); PR: 19% (7 pts)], with median time to first response of 1 month.

In terms of ocular manifestations, changes in visual

infection. No grade 3 or higher thrombocytopenias or

acuity of grade 2 or 3 were observed in 33% and 11% of

Regarding ocular manifestations suggesting an impair-

cline in visual acuity (worse than 20/50 in the better

infusion-related reactions were reported.

ment in vision, from a total of 499 ocular assessments, Gr2 and Gr3 BCVA (Snellen best corrected visual acuity,

BCVA) changes were noted in 164 (33%) and 54 (11%),

while a meaningful BCVA decline (worse than 20/50 in the better seeing eye) was observed in 38 (8%), with a median time to resolution of 1 month. In terms of ≥ Gr2

symptoms directly related to decreased vision, blurred vision and visual impairment were observed in 38 (8%) and 98 (20%) with a median time to resolution of 2

months. In terms of other ≥Gr2 ocular symptoms, ob-

served in ≥10% of assessments, dry eye was noted in

ocular assessments, respectively, with a meaningful deseeing eye) observed in 8% of patients. These ocular symp-

toms related to decreased vision resolved within a median time of 1 to 2 months. Other ocular symptoms of

grade 2 or higher, observed in at least 10% of assessments, included blurred vision, visual impairment, and dry eye, which resolved within a median time of 2 to 3 months.

Corneal findings showed keratopathy of grade 2 or 4 in 11% and less than 1% of slit lamp examinations, respectively, with a median time to resolution of 4 months.

The overall response rate to belamaf-Rd treatment

was 100%, with all patients achieving a partial response

or better. Stringent complete response (14%), complete

response, (19%) and very good partial response (47%) were observed in the group of patients.

EHA23 Abstract P884: Evangelos Terpos, Maria Gavriatopoulou, Ioannis Ntanasis-Stathopoulos, et al. Belantamab mafodotin plus lenalidomide and dexamethasone in transplant ineligible patients with newly diagnosed multiple myeloma: Updated results from the phase 1/2 BELARD study. 05/11/23. EHA Library.

CONFLICT OF INTERESTS: This study BMA117159 was funded by GlaxoSmithKline (GSK).

18

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

Navigating CLL Treatment: Decoding Small-Molecule Inhibitor Sequencing and Combination Therapies Deciphering the most effective treatment approach for chronic lymphocytic leukemia (CLL) has posed challenges due to limited data and the absence of long-term outcomes.

This article examines and evaluates the current evidence for sequencing vs. combination of small-molecule inhibitors for CLL. CLEMENT CHUNG, senior oncology clinical pharmacy

ties experience early progression with chemoimmu-

Texas, United States

hibitors.

specialist, Houston Methodist West Hospital in Houston,

Current data is limited in guiding the rational sequenc-

ing or combination of small-molecule inhibitors for CLL

notherapy and would benefit from small-molecule in-

Evidence for first-line treatment consideration is ex-

emplified by the improved kinase selectivity and hence improved adverse effect profile of acalabrutinib or zanu­

brutinib over ibrutinib. However, continuous adminis-

since conventional chemoimmunotherapy or chemo-

tration of covalent BTK inhibitors is associated with re-

ecule inhibitors. In addition, due to the lack of long-

tions, ranging from approximately 23% to 67% at 5 years

therapy were used as comparators for these small-molterm data, such as overall survival (OS), efficacy end-

points estimated based on progression-free survival

(PFS) from clinical trials were generally used to establish therapeutic sequencing or combination of thera-

sistance partly due to BTK C481 or PLCγ2 gene mutaof use. On the other hand, venetoclax is very active in

the clearance of bone marrow-predominate disease and possibly safer in the setting of autoimmunity.1

pies. Undetectable minimal residual disease (uMRD)

The Rationale for Combination Therapies

sponse, although it has not received regulatory ap-

ways, synergistically abrogate the proliferation of re-

has been increasingly used to document durable re-

Combination therapies target different signaling path-

proval as an endpoint in the United States (U.S.). This

sistant clones, induce deep responses (e.g., achieving

article examines and evaluates the current evidence for sequencing vs. combination of small-molecule inhibitors for CLL.

The Rationale for Sequencing of Small-Molecule Inhibitors

uMRD), and facilitate fixed-duration treatments. For in-

stance, the addition of an anti-CD20 monoclonal antibody to a BTK inhibitor is typically reserved when a rapid

response to treatment is indicated (e.g., in the presence of extra-nodal disease).

There are currently six small-molecule inhibitors (i.e.,

A Literature Review

and zanubrutinib) approved by the U.S. Food and Drug

diagnosed and relapsed or refractory (R/R) disease.*

acalabrutinib, duvelisib, ibrutinib, idelalisib, venetoclax,

The authors identified two treatment settings: newly

Administration for the treatment of CLL. Sequencing is

Individual comprehensive searches of the U.S. Nation-

based on durable clinical remission, favorable toxicity,

and improved tolerability (especially in older CLL patients with comorbidities) vs. traditional chemoimmunotherapy (or other small molecule inhibitors).

Among small-molecule inhibitors, treatment sched-

ule and toxicity management differ between fixed-duration therapy (i.e., venetoclax) and continuous ther-

al Library of Medicine PubMed database were performed

using medical subject heading terms for each small­-

molecule inhibitor. Pertinent information from ongoing clinical trials, meeting abstracts, and published expert opinions were screened.

apy (i.e., BTK inhibitors).1 Historically, patients who were

Newly Diagnosed (First-Line) Therapies

11q-, unmutated IGHV, or TP53 mutation have improved

Single agents

evidence that biomarkers can be used to guide treat-

line option for CLL patients with high-risk genetics, its

once considered high genomic risk because of 17p-,

clinical outcomes with BTK inhibitors. There is emerging

Although ibrutinib monotherapy is an established first-

ment selections. For example, patients with TP53 muta-

comparator (i.e., chlorambucil) is no longer considered

tions have inferior results with venetoclax. Treatment-naïve patients with unmutated IGHV and/or TP53 abnormali-

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

an appropriate therapy for the first-line setting (RESONATE-2 trial).2

19

pared with ibrutinib monotherapy in the treatment-naïve

Relapsed or Refractory Disease (Second-Line Therapies)

tinib are associated with similar efficacy and favora-

It must be noted that in the relapsed or refractory dis-

suggested PFS and OS associated with zanubrutinib were

immunotherapy, not upfront small-molecule inhibitors

Acalabrutinib monotherapy has not been directly compopulations (Elevate-TN). Acalabrutinib and zanubruble toxicity profile over ibrutinib. A pooled analysis also

significantly longer in the first and second-line settings

than in later-line settings, lending support to its firstline use.3 The new formulation (i.e., tablet) of acalabru-

tinib facilitates its co-administration with proton­-pump

inhibitors or antacids. Ibrutinib may be used in patients who prefer daily dosing. Single-agent BTK inhibitors of-

ease setting, patients likely have received upfront chemo-

in clinical trials. In real-world practice, patients likely have failed first-line BTK inhibiotors or venetoclax. Thus,

the clinical efficacy of small-molecule inhibitors must be carefully interpreted in this setting.

Single Agents

fer the feasibility of decreased burden with laboratory

Treatment options for second-line therapy are dictated

are a useful option for patients with certain morbidities

therapies, duration of response, resistance mechanisms,

tolerate increased fluids.

VATE-RR trial confirmed the non-inferiority of acalabru-

monitoring or frequent infusion visits vs. venetoclax. They (e.g., baseline renal dysfunction) and are not able to

by factors such as type and the number of previous

molecular prognostic features, and toxicity profiles. ELE­

tinib vs. ibrutinib and its fewer cardiac and bleeding

Combination Therapies The contribution of individual agents to the overall ef-

side effects.10

ficacy in combination therapies is yet to be defined.

These four sequences below may be considered in

ported for ibrutinib-rituximab combination vs. chemo-

1. Initial BTK inhibitor intolerance, then another BTK in-

For instance, although improved PFS and OS were re-

immunotherapy (i.e., fludarabine-cyclophosphamide-­ rituximab [FCR]) for treatment-naïve patients with age <70, the addition of rituximab to ibrutinib did not pro-

vide any additional benefit (such as improvement in

OS) vs. ibrutinib alone (NCT01886872).4 No long-term

second-line therapy settings:

hibitor (second-line). Patients with relapsed disease may be offered another covalent BTK inhibitor if they have not developed resistance mutations to BTK but

discontinued a first-line BTK inhibitor due to intolerance. Data is limited.

survival endpoint has been reached based on the ibru-

2. Initial BTK inhibitor, then venetoclax (second-line).

tion (ILLUMINATE trial). Meanwhile, a combination of a

venetoclax after failure to a first-line BTK inhibitor.

tinib-rituximab vs. ibrutinib-obinutuzumab combina5

second-generation covalent BTK inhibitor, namely, acalabrutinib, has been investigated in combination with

an anti-CD20 agent, obinutuzumab, which has improved antibody-dependent cytotoxicity and apoptosis over rituximab (ELEVATE-TN trial).6

Venetoclax-obinutuzumab combination has been stud-

ied in both CLL 147 and CLL 13 trials,8 demonstrating improved three-year PFS rates versus chemoimmuno-

therapy regardless of patients’ fitness. This regimen is also efficacious in patients with high-risk genomic features (e.g. unmutated IGHV).

7

Venetoclax-ibrutinib combination is being studied

Two studies11,12 demonstrated the durable response of

Retreatment with venetoclax (with or without an anti-­ CD20 monoclonal antibody) is known to be associated with durable responses with acceptable toxicity profiles in patients who developed either resist-

ance or intolerance to BTK inhibitors.13 Venetoclax has activity in both patients who were intolerant of ibrutinib or discontinued ibrutinib because of disease progression.14

3. Initial venetoclax, then BTK inhibitor (second-line).

Both long-term follow-up data15 and real-world expe­

rience16 support the sequencing of venetoclax, then

BTK inhibitor. Current data (CLL14 trial)17 support the

in the CAPTIVATE trial. Patients with high-risk genomic

use of venetoclax before BTK inhibitor, with a fixed du-

IGHV (56%), and complex karyotype (19%) were included.

therapy for 1 year, and the option for retreatment prior

9

features such as 17p-/TP53 mutation (17%), unmutated

A durable response that lasted at least 12 months after

ration of venetoclax-obinutuzumab used as first-line to a subsequent BTK inhibitor.

treatment was observed in 93% of these patients. OS and

4. Initial venetoclax, then retreatment (second-line).

This combination is expected to receive regulatory ap-

Combination Therapies

survival benefit over chemoimmunotherapy (chloram-

rituximab combination demonstrated superior PFS (53.6

PFS rates at 36 months were 98% and 88%, respectively. proval in the U.S. when longer follow-up confirms the

Compared to BR chemoimmunotherapy, venetoclax-­

bucil-obinutuzumab).

months vs. 17 months) and 5-year OS rate (82.1% vs. 62.2%)

20

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

CONCLUSION: Both ibrutinib and acalabrutinib-obinutuzumab demonstrate long-term (>5 years) survival benefits in the treatment-­ naive setting. Data support fixed-duration venetoclax (as in venetoclax­obinutuzumab combination) as a first-line agent before BTK inhibitors.

Conversely, venetoclax can also be offered after a BTK inhibitor, particularly for those who are considered BTK-inhibitor intolerant (i.e., those who had to stop a BTK inhibitor because of toxicity). Optimal treatment sequencing or combination must consider patient fitness/convenience, cost or access to therapy, and clinical trial availability. Further research will be needed to better inform treatment decisions based on head-to-head comparisons among different small-molecule inhibitors.

across all subgroups of patients in the phase III MURA-

time. Several clinical trials evaluating various aspects

NO trial.18 A phase II (CLARITY trial)19 demonstrated that

of the BCL-2 inhibitor/BTK inhibitor combination (with or

status, and the depth of MRD reduction improved over

way.

fixed-duration venetoclax-ibrutinib can achieve uMRD

without anti-CD20 monoclonal antibodies) are under-

*Original publication Chung C, Umoru G, Abboud K, Hobaugh E. Sequencing and combination of current small-molecule inhibitors for chronic lymphocytic leukemia: Where is the evidence? Eur J Haematol. 2023 Apr 10. DOI: 10.1111/ejh.13973. Epub ahead of print. PMID: 37037657.

References 1. Brown JR. Relapsed CLL: sequencing, combinations, and novel agents. Hematology Am Soc Hematol Educ Program. 2018;1: 248-255. 2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015; 373(25): 2425-2437. 3. Xu W, Yang S, Tam CS, et al. Zanubrutinib monotherapy for naïve and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: a pooled analysis of three studies. Adv Ther. 2022;39(9): 4250-4265. 4. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379: 2517-2528. 5. St-Pierre F, Ma S. Use of BTK inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): a practical guidance. Blood Lymphat Cancer. 2022;12: 81-98. 6. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015; 373(25): 2425-2437. 7. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21: 1188-1200. 8. Doyle C. Study reports time-limited venetoclax-based regimens of benefit in front-line treatment of CLL. ASCO Post. Accessed November 24, 22022. https://ascopost.com/issues/july25-2022/ study-reports-time-limited-venetoclax-based-regimens-of-benefit-in-front-line-treatment-of-cll. 9. Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39: 3853-3865. 10. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Cin Oncol. 2021;39(31): 3441-3452.

11. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1): 65-75. 12. Eyre TA, Lamanna N, Roeker LE, et al. Comparative analysis of targeted novel therapies in relapsed, refractory chronic lymphocytic leukaemia. Haematologica. 2021;106(1): 284-287. 13. Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14): 3589- 3596. 14. Burke JM. SOHO state of the art updates and next questions- management of most difficult cases of chronic lymphocytic leukemia: relapse after both BTK and BCL2 inhibition and Richter transformation. Clin Lymphoma Myeloma Leuk. 2022;22(7): 427-435. 15. Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood. 2020;135(25): 2266-2270. 16. Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5): 1050-1056. 17. Al-Sawaf O, Lilienweiss E, Bahlo J, et al. High efficacy of venetoclax plus obinutuzumab in patients with complex karyotype and chronic lymphocytic leukemia. Blood. 2020;135: 866-870. 18. Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (pts) following fixed-duration venetoclax rituximab (VenR) therapy (Tx). Blood. 2020;136: 19-2. 19. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: The CLARITY Study. J Clin Oncol. 2019;37(30): 2722-2729.

CONFLICT OF INTERESTS: None.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

21

The Link Between Breast Cancer and Hematologic Cancers A recent population-based study conducted in Denmark shows that breast cancer survivors have an increased risk of acute and chronic myeloid leukemia (AML and CML) compared to the general population.

CATHRINE FONNESBECH HJORTH, MSc, PhD, Postdoc, Department of Clinical Medicine, Aarhus University

Today, tamoxifen is the primary endocrine treatment for

premenopausal women with estrogen receptor-posi­ tive tumors. Aromatase inhibitors were introduced in

Previous studies suggested increased incidences of hematologic cancers such as myeloid and lymphoid

pausal women since 2007.

The impact of the abovementioned treatment advanc-

leukemia and non-Hodgkin’s lymphoma in breast can-

es on the incidence of hematological cancers in con-

cancer-directed treatments. Increased incidence of

date of the current evidence is therefore needed.

cer survivors,1-6 either due to shared aetiologies or breast

AML has been linked to several types of chemotherapy,

temporary breast cancer survivors is not clear. An up-

radiotherapy, and immunosuppressive therapy.7-9

Long-term Follow-up Study in Denmark

creasingly effective treatments have contributed to the

-based and medical registries, we compared the risk

Population-based mammography screening and in-

Taking advantage of Denmark’s network of population­-

increased prevalence of long-term breast cancer sur-

of hematologic cancers in breast cancer survivors, com-

vivors. As such, compared with those diagnosed in the past, contemporary breast cancer patients survive longer

and have a longer time at risk of developing subsequent malignancies, including hematological cancers. More-

over, these patients receive contemporary treatments, in contrast to those included in most previous studies.

Changes in Breast Cancer Treatments Systemic treatment is a key component of breast cancer treatment and has evolved over the past 30-40 years.

Findings from clinical trials have prompted the intro-

duction of new chemotherapy combinations, in addition to other targeted treatments, such as endocrine thera-

py for the treatment of estrogen receptor-positive tumors and trastuzumab for the treatment of human epidermal growth factor 2 positive tumors.

pared with the general population during 38 years of

follow-up. Our cohort included women diagnosed with non-metastatic breast cancer between 1980 and 2017, with follow-up through 2018. To avoid biases arising from

surveillance or immortal time, we restricted to those who were alive and cancer-free one year after diagnosis. We

computed the cumulative incidence proportion (CIP) of hematologic cancers, and age and calendar–period standardized incidence ratios (SIR) and associated 95%

confidence intervals (CI), as measures of absolute and relative risks, respectively. In sensitivity analyses, we re-

stricted our analyses to hematologic cancers diagnosed 0–6 months after breast cancer diagnosis to eval-

uate surveillance bias. To handle potential confounding by comorbidities, we sampled a matched comparison cohort and applied comorbidity-adjusted Cox re-

Combination chemotherapy with cyclophosphamide,

gression models.

breast cancer chemotherapy in the 1980s. In Denmark,

methotrexate was replaced by epirubicin in the 1990s,

The Risks 1–<5 Years After Diagnosis were Similar Across Diagnostic Periods

and in 2007, 5-fluorouracil was replaced by taxanes. In 2008, granulocyte colony-stimulating factor was includ-

Our cohort amounted to 101,117 women diagnosed with

ed to mitigate toxicities from chemotherapy. The selec-

breast cancer. During up to 38 years of follow-up, we

observed 815 hematologic cancers among breast can-

methotrexate, and 5-fluorouracil was a cornerstone of

tive estrogen receptor modulator tamoxifen was intro-

duced in 1982 but limited to high-risk postmenopausal women – those with node-positive disease, tumors >5

cer survivors (CIP: 1.53%);

• 361 women with non-Hodgkin’s lymphoma (CIP: 0.71%).

cm, and tumors that had spread to the skin or pectoral

• 109 lymphoid leukemias (CIP: 0.21%).

mended for one year only. However, the recommend-

• 185 with other types of hematologic cancers

fascia. Treatment with tamoxifen was initially recomed duration of tamoxifen therapy has since expanded.

22

2004 and have been guideline treatment for postmeno­

• 160 myeloid leukemias (0.29%).

(CIP: 0.32%).

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

CONCLUSION: Given the increasing prevalence of breast cancer survivors, oncologists and healthcare personnel caring for breast cancer survivors ought to be aware of this excess risk, particularly the increased risk of AML in women treated with chemotherapy. Still, our study highlights that the absolute risk of subsequent diagnoses of hematological cancers remains low.

Compared with the expected numbers in the general

population, our findings suggested that breast cancer

survivors had increased risk of myeloid leukemia (both AML and CML) 1–<5 years (SIR 1.92, 95% CI: 1.47–2.47) and

the risk of CML did not differ across age groups (during

the entire follow-up, as numbers were too low to assess risks within the specified follow-up periods).

The association with chemotherapy was highest in

5–<10 years (SIR 1.81, 95% CI: 1.35–2.39) and more than 10

AML (SIR 3.33, 95% CI: 2.24–4.75), but also increased in

CI: 1.01–1.80). The risks 1–<5 years after diagnosis were

cently diagnosed (2007–2017), the risk of AML was twice

years after their breast cancer diagnosis (SIR 1.36, 95%

similar across diagnostic periods but were especially

increased among those aged 18–55 years (SIR 3.63, 95% CI: 2.18–5.66) and/or treated with chemotherapy (SIR 3.37,

CML (SIR; 2.23, 95% CI: 1.02–4.24). For the women recompared with the general population risk (95% CI: 1.23-3.20).

We observed a lower risk of chronic lymphoid leu-

95% CI: 1.99–5.32). Notably, the risks were also elevated

kemia (CLL) in breast cancer survivors 1–10 years after

1.63, 95% CI: 1.18–2.20). We observed similar patterns in

was attributable to intensified diagnostic efforts around

among those who did not receive chemotherapy (SIR the 5–<10 years and 10+ year follow-up periods.

When examining AML and CML separately, we found

that the increased risk among the youngest, aged 18–55

years, was distinct for AML (SIR 3.23, 95% CI: 2.41–4.25), as

breast cancer, but our analyses suggested that this

the time of breast cancer diagnosis and primary treat-

ment. The risk of non-Hodgkin’s lymphoma was similar in breast cancer survivors and the general population.

The results were not confounded by comorbidities.

*Original publication Chung C, Umoru G, Abboud K, Hobaugh E. Sequencing and combination of current small-molecule inhibitors for chronic lymphocytic leukemia: Where is the evidence? Eur J Haematol. 2023 Apr 10. DOI: 10.1111/ejh.13973. Epub ahead of print. PMID: 37037657.

References 1. Mellemkjaer L, Friis S, Olsen JH, Scélo G, Hemminki K, Tracey E, et al. Risk of second cancer among women with breast cancer. Int J Cancer.

2006 May 1;118(9): 2285–2292. 2. Andersson M, Jensen MB, Engholm G, Storm HH. Risk of second primary cancer among patients with early operable breast cancer registered or randomized in Danish Breast Cancer Cooperative Group (DBCG) protocols of the 77, 82, and 89 programs during 1977–2001. Acta Oncol. 2008 Jan 1;47(4): 755–764. 3. Bazire L, De Rycke Y, Asselain B, Fourquet A, Kirova YM. Risks of second malignancies after breast cancer treatment: Long-term results. Cancer/Radiothérapie. 2017 Feb 1;21(1): 10–15. 4. Jabagi MJ, Vey N, Goncalves A, Tri TL, Zureik M, Dray-Spira R. Evaluation of the Incidence of Hematologic Malignant Neoplasms Among Breast Cancer Survivors in France. JAMA Netw Open.

2019 Jan 4;2(1):e187147–e187147. 5. Wei JL, Jiang YZ, Shao ZM. Survival and chemotherapy-related risk of second primary malignancy in breast cancer patients: a SEER-based study. Int J Clin Oncol. 2019 Aug;24(8): 934–940. 6. Beadle G, Baade P, Fritschi L. Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers. Ann Oncol. 2009 Jan 1;20(1): 103–109. 7.

Rosenstock AS, Niu J, Giordano SH, Zhao H, Wolff AC, Chavez-MacGregor M. Acute myeloid leukemia and myelodysplastic syndrome after adjuvant chemotherapy: A population-based study among older breast cancer patients. Cancer. 2018;124(5): 899–906. 8. Smith RE, Bryant J, DeCillis A, Anderson S. Acute Myeloid Leukemia and Myelodysplastic Syndrome After Doxorubicin-Cyclophosphamide Adjuvant Therapy for Operable Breast Cancer: The National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol. 2003 Apr 1;21(7): 1195–1204. 9. Godley LA, Larson RA. Therapy-related Myeloid Leukemia. Semin Oncol. 2008 Aug;35(4): 418–429.

CONFLICT OF INTERESTS: None.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

23

High Expression of the Inhibitory Checkpoint Receptor TIGIT by CD8+ T-cells in Multiple Myeloma

A new study demonstrates that the T-cell immunoglobulin and ITIM domain (TIGIT) is the most frequently expressed inhibitory checkpoint receptor on CD8+ T-cells in MM patients.

This suggests that TIGIT may play a central role in the immune evasion of malignant plasma cells.

KATRINE FLADELAND IVERSEN, MD, PhD student, Department of Re-

clonal antibodies lived significantly longer. Therefore, a

ment of Medicine, Hospital of Lillebaelt, Vejle, Denmark

tumour site is needed.

gional Health Research, University of Southern Denmark & Depart-

Daratumumab (DARA) is an anti-CD38 antibody ap-

Multiple myeloma is an incurable disease characterized

by the unregulated growth of malignant plasma cells in the bone marrow (BM). Tumour-induced dysfunction of T-cells may be responsible for immune evasion and fail-

ure of immunotherapy. Several checkpoint inhibitors that block programmed cell death protein 1 (PD-1), program­

med death ligand 1 (PD-L1), and cytotoxic T-lympho-

cyte-associated antigen 4 (CTLA-4) have been appro­ ved for therapy of solid cancers. Still, so far, neither of

these have not shown convincing efficacy in MM. The expression of T-cell immunoglobulin and ITIM domain (TIG-

24

better understanding of the phenotype of T-cells at the

proved for treatment of MM as monotherapy or in combination with several standard-of-care anti-myeloma drugs. It has indeed improved the treatment of MM and

has proved to increase both progression-free survival

and overall survival in several clinical trials. We wanted to assess whether the T-cell subsets in patients progressing on DARA (DRMM) showed signs of impairment

compared to T-cells from newly diagnosed MM patients (NDMM). Using multicolor flow cytometry, we as-

sessed the expression of immune regulatory receptors on T-cell subsets from peripheral blood (PB) and BM.

IT) by T-cells from MM patients still needs to be well ex-

Flow Cytometry on T-cell Subsets

TIGIT by CD8+ T-cells is higher than the expression of

diagnosed, treatment naïve myeloma patients (NDMM)

amined. A few studies have found that the expression of

Paired PB and BM samples were collected from newly

PD-1 and that MM mice treated with anti-TIGIT mono-

(n = 19) and patients progressing during treatment with

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

CONCLUSION: Our study supports the hypothesis that TIGIT may play a more important role as an immune checkpoint in MM than PD-1 and CTLA-4 and that anti-TIGIT monoclonal antibodies could be effective in MM. Whether or not the DNAM-1+CD4+ T-cells play a role in developing resistance to DARA needs further exploration and characterization of the involved T-cells.

DARA, alone or in combination with other anti-myelo-

ma drugs (DRMM) (n = 39). BM mononuclear cells (BM-

MCs) and PB mononuclear cells (PBMCs) were isolat-

Figure 1 – The Expression of Inhibitory Immune Checkpoint Receptors

ed by density-gradient centrifugation using FicollPaque™ PLUS. Cells were cryopreserved until further

p<0.0001

analysis.

p<0.0001

The cryopreserved cells were thawed, and the con-

100

viability in PBMC and BMMC were 89% (range 57–98%) and 79% (range 60–90%), respectively.

The cells were stained with the following antibodies:

anti-TIGIT, anti-CD45, anti-DNAX accessory molecule-1

(DNAM-1), anti-CD3, anti-CTLA-4, anti-PD-1, anti-CD4, and anti-CD8. The technique fluorescence-minus-2

% of CD8+ T-cells

centration and viability were determined. The median

80 60 40

was used for objective gating of the immune regula-

20

after staining on an ACEA NovoCyte Quanteon 4025

0

tory receptors. Samples were analysed immediately flow cytometer. Data were analysed using FlowJo™.

High Expression of TIGIT We used multicolour flow cytometry to measure the

p<0.0001

TIGIT

PD-1

CTLA-4

The expression of inhibitory immune checkpoint receptors on CD8+ T-cells from all patients (n=58).

expression of checkpoint inhibitors by subsets of T-cells

isolated from the PB and BM of patients with newly diagnosed MM compared to patients with MM progressing on DARA. We looked at CD4+ T-cells and CD8+ T-cells separately. We found no difference in the expression

of the inhibitory checkpoint receptors (CTLA-4, PD-1, and TIGIT) on CD4+ or CD8+ T-cells. However, we found that the costimulatory receptor DNAM-1 was higher ex-

pressed on CD4+ T-cells from DARA refractory patients compared with newly diagnosed MM patients. The

meaning of this observation has yet to be discovered.

Furthermore, when looking at CD8+ T-cells from all patients included in the study, newly diagnosed and DARA

refractory, we found that TIGIT was by far the most ex-

We found that TIGIT was by far the most expressed inhibitory checkpoint molecule.

pressed inhibitory checkpoint molecule, see Figure 1.

Original publication This is a summary of a recently published peer-reviewed paper: Katrine Fladeland Iversen, Line Nederby, Thomas Lund, and Torben Plesner.

High expression of the costimulatory checkpoint factor DNAM-1 by CD4+ T-cells from multiple myeloma patients refractory to daratumumab-containing regimens. Clin Hematol Int. 2022 Sep;4(3): 107-116.

CONFLICT OF INTERESTS: None.

BestPractice Nordic / SE / Oncology and Hematology / NO. 1 / 2023

25

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6 26

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