DESTINY-Breast03 trial: some questions remain

Abstract

In the updated analysis of the DESTINY-Breast03 study, Sara A Hurvitz and colleagues1Hurvitz SA Hegg R Chung WP et al.Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.Lancet. 2023; 401: 105-117Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar reported a remarkable and continued progression-free survival (PFS) benefit of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer who progressed on previous therapy.1Hurvitz SA Hegg R Chung WP et al.Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.Lancet. 2023; 401: 105-117Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar PFS is the key endpoint of clinical trials evaluating anticancer agents and is currently used for regulatory drug approvals.2Pazdur R Endpoints for assessing drug activity in clinical trials.Oncologist. 2008; 13: 19-21Crossref PubMed Scopus (212) Google Scholar, 3Mayor S Time to raise the bar for cancer drug approval?.Lancet Oncol. 2010; 11: 16-17Summary Full Text Full Text PDF Google Scholar Time to treatment failure, defined as the interval between the start of treatment and its discontinuation due to progression, death, toxicity, or patient choice, is instead a pragmatic endpoint especially used when long-term toxicity or long therapy duration are expected.4Arkenau HT Nordman I Dobbins T Ward R Reporting time-to-event endpoints and response rates in 4 decades of randomized controlled trials in advanced colorectal cancer.Cancer. 2011; 117: 832-840Crossref PubMed Scopus (5) Google Scholar This could apply to the DESTINY-Breast03 study. Besides an impressive median PFS of 28·8 months, the median duration of treatment was only 18·2 months. The authors showed that 21·4% of interruptions were due to treatment-emergent adverse events, specifically 12·7% to pulmonary toxicity of one kind or another. To speculate further, at least half of discontinuations associated with treatment-emergent adverse events were not due to life-threatening events. Accessing the other causes of premature cessation could be therefore important to inspect in patients who had non-serious toxicity or discontinued for any other reason a trastuzumab deruxtecan treatment rechallenge, which has been only partly evaluated to date.5Krop I, Park YH, Kim S-B, et al. Trastuzumab deruxtecan vs physician's choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized phase 3 study DESTINY-Breast02. San Antonio Breast Cancer Symposium; December 6–10, 2022 (abstr GS2-01).Google Scholar The difference between study median PFS and treatment duration suggests that people stopping treatment prematurely, and representing one fifth of the whole study population, could experience long-lasting treatment benefit, supporting the development of shorter or non-continuous, more tolerable, and sustainable trastuzumab deruxtecan schedules. SDC received consulting fees from Novartis, AstraZeneca, and Pierre-Fabre; honoraria from IQVIA and MEDSIR, and research funding paid to her institution from Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC IG 20774). All other authors declare no competing interests. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trialTrastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. Full-Text PDF Open AccessDESTINY-Breast03 trial: some questions remain – Authors' replyElif Hindié noted that the optimal treatment sequencing of trastuzumab deruxtecan is still not defined. We agree that the optimal treatment sequence of trastuzumab deruxtecan after disease progression and the outcomes of post-trial therapies are important to investigate. DESTINY-Breast03 was a global trial with participation from 15 different countries. Although data were collected on the post-trial anticancer therapies received, treatment crossover was not formally planned in the study and it was not designed to address sequencing. Full-Text PDF