NE Oncology Issue – February 2014

Following the 2013 European Cancer Congress (ECC) in Amsterdam, New Evidence interviewed Dr. Sunil Verma for his impressions of the first results from the TH3RESA study,1 which evaluated the efficacy and safety of trastuzumab emtansine compared with those of a treatment of physician’s choice (TPC) for patients with advanced breast cancer.

New Evidence: Please describe the study design of TH3RESA.

Dr. Verma: TH3RESA was a multi-national, phase III study investigating the efficacy and safety of trastuzumab emtansine as compared with those of TPC for patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. Around 600 patients were randomized in a 2:1 manner to trastuzumab emtansine and TPC, respectively.

New Evidence: What were the main characteristics of the patient population in this study?

Dr. Verma: The main characteristics of the patient population in the TH3RESA study were that patients had to have been previously treated with at least two or more HER2-directed therapies, including trastuzumab and lapatinib, and had to have received prior treatment with a taxane. This was a more heavily pretreated population compared with patients who were in the EMILIA study.2

New Evidence: Given that the control arm for TH3RESA comprised treatment of physician’s choice (TPC), what were the main treatments that physicians chose to use?

Dr. Verma: In the TPC arm, about 83% of patients received combination therapy that included a HER2-directed agent, which was primarily composed of chemotherapy plus trastuzumab (68.5%). The rest of the HER2-directed therapies in the TPC arm were lapatinib plus trastuzumab (10.3%), hormonal therapy plus trastuzumab (1.6%), or chemotherapy plus lapatinib (2.7%). Approximately 17% of patients received single-agent chemotherapy. The most commonly used chemotherapies were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel.

New Evidence: Does this represent what is practised in Canada for this patient population?

Dr. Verma: It depends on where you live in Canada. In Ontario, for instance, physicians are only allowed two lines of anti-HER2 therapy in the metastatic setting. In this case, patients in Ontario who have fulfilled the same criteria as the TH3RESA study (i.e., ≥2 lines of HER2-directed therapy) would likely receive single-agent chemotherapy. In some other parts of the country, physicians have access to more than two lines of anti-HER2 therapy, and those same patients would likely receive a combination of chemotherapy plus an anti-HER2 agent.

New Evidence: How did the fact that many different treatments were allowed as comparators affect the interpretation of the results?

Dr. Verma: In many ways, this was a very practical study because patients in the comparator arm were receiving treatments that would normally be offered to them. This was also an important study because one of the discussion points for the EMILIA study2 was not knowing how the results for trastuzumab emtansine would have compared if patients in the control arm had received chemotherapy plus trastuzumab instead of capecitabine plus lapatinib. With TH3RESA, we can now make that comparison, and having that flexibility allows the interpretation of the results to be even more practical.

New Evidence: Please describe the efficacy results for trastuzumab emtansine versus TPC, in terms of the coprimary end points of progression-free survival (PFS) and overall survival (OS).

Dr. Verma: The analysis presented at ECC 2013 showed that median PFS improved from 3.3 months with TPC to 6.2 months with trastuzumab emtansine, with a hazard ratio (HR) of 0.528, which was statistically significant. Across the patient subgroups, PFS benefit with trastuzumab emtansine was still observed regardless of age, race, world region, baseline performance status, estrogen receptor status, visceral involvement of disease, number of prior lines of therapy, and the presence or absence of brain metastasis at baseline. Furthermore, trastuzumab emtansine significantly prolonged median PFS, from 3.2 to 6.2 months, when compared with those who received a trastuzumab-containing regimen as part of the TPC arm.

The first interim OS analysis was also presented, although data are still immature. The median OS was 14.9 months for TPC and was not yet reached for trastuzumab emtansine. The HR was 0.552 (95% CI: 0.369–0.826; p = 0.0034), but the efficacy stopping boundary (HR <0.363 or p <0.0000013) was not crossed.

New Evidence: How did the objective response rate (ORR) of the trastuzumab emtansine arm compare with that of the TPC arm?

Dr. Verma: The ORR by investigator assessment was 8.6% with TPC and significantly improved to 31.3% with trastuzumab emtansine, a difference of 22.7% (p <0.0001).

New Evidence: Given that 80% of patients in the TPC arm received a trastuzumab-based regimen, were the efficacy results for trastuzumab emtansine expected?

Dr. Verma: Yes, the results were what we had expected; trastuzumab emtansine offers patients with HER2-positive advanced breast cancer improved outcomes compared to those with chemotherapy plus an anti-HER2 agent, regardless of which anti-HER2 agent is used. The data from this trial and EMILIA2 have shown that, for patients who have progressed on chemotherapy plus trastuzumab or lapatinib, physicians should consider trastuzumab emtansine.

New Evidence: How did the general safety profile of trastuzumab emtansine compare with that of TPC in this trial?

Dr. Verma: Overall, the safety profile was more favourable with trastuzumab emtansine than with TPC. Fewer grade ≥3 adverse events (AEs) were reported in patients who received trastuzumab emtansine compared with those who received TPC, with incidences of 32% vs. 43%, respectively. Also, the trastuzumab emtansine arm reported fewer AEs that led to treatment discontinuation or to dose reduction compared with those in the TPC arm. Overall, trastuzumab emtansine was better tolerated than TPC. However, the key AEs that were observed with trastuzumab emtansine included thrombocytopenia and liver transaminase elevations.

New Evidence: Was the safety profile for trastuzumab emtansine in this trial expected based on previous trials with trastuzumab emtansine in HER2-positive metastatic breast cancer?

Dr. Verma: Yes, the observed safety profile of trastuzumab emtansine in this trial was consistent with what has been previously observed. Trastuzumab emtansine has an excellent safety profile. That being said, it is still important to monitor platelets and liver function tests of patients who are receiving this drug and physicians need to modify the dosing based on these parameters.

New Evidence: What main conclusions can be drawn from the TH3RESA study, based on the data that were presented at ECC 2013?

Dr. Verma: The results of the TH3RESA study have reaffirmed the conclusions from the EMILIA study.2 In other words, trastuzumab emtansine provided consistent efficacy benefit and tolerability compared with chemotherapy plus an anti-HER2 agent, which in this case was mainly trastuzumab. Furthermore, the benefit with trastuzumab emtansine was observed in patients who had prior therapy with trastuzumab, lapatinib, and a taxane, demonstrating the efficacy of trastuzumab emtansine for treating HER2-positive advanced breast cancer in and beyond the second line of therapy.

New Evidence: How would you use trastuzumab emtansine in your clinical practice and where do you see trastuzumab emtansine best fitting into the lines of treatment for HER-positive breast cancer based on the results from TH3RESA as well as the previously reported results from the EMILIA study?

Dr. Verma: Trastuzumab emtansine is not currently funded, but it has been approved by Health Canada. At present, we have two key patient subgroups who are candidates for this therapy. The first is for patients who had received adjuvant trastuzumab but then relapsed within six months of completion of their trastuzumab-containing therapy; I would consider using trastuzumab emtansine in the first-line setting for these patients. The second is for patients who have progressed on first-line anti-HER2 therapy; I would consider using trastuzumab emtansine in the second-line setting. The results of EMILIA2 are very much in line with this.

The role for trastuzumab emtansine in the first-line setting is still being assessed in the MARIANNE study, which is comparing trastuzumab emtansine plus pertuzumab vs. trastuzumab emtansine plus placebo vs. trastuzumab plus a taxane. Also, we do not currently have prospective data for the use of trastuzumab emtansine after patients have received chemotherapy plus trastuzumab and pertuzumab, but based on the treatment profile of these agents, trastuzumab emtansine would also make a very reasonable second-line option for these patients.

References: 1. Wildiers H, Kim SB, Gonzalez-Martin A, et al. T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs. treatment of physician’s choice. ECC 2013:LBA15. 2. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783–91.

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Spotlight Article

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Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

 

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Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

Canadian Perspective

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Matthew Seftel, MBChB, MPH, MRCP(U.K.), FRCPC

Dr. Seftel is a hematologist/oncologist based at Princess Margaret Hospital in Toronto. He is a member of the Leukemia Group and leads the Allogeneic Blood and Marrow Transplantation Program. He is an Associate Professor at the University of Toronto in the Division of Internal Medicine. He is actively involved in clinical trials and outcomes-based research related to hematological malignancies and blood and marrow transplantation.

Investigator Commentary

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Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal investigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, Lancet Oncology, Lancet, and The New England Journal of Medicine.