Carlos H. Barrios, MD

“Margetuximab pLUS capecitabine may represent a new alternative combination for third-line treatment of HER2-positive metastatic breast cancer,” said -SOPHIA’s invited discussant Carlos H. Barrios, MD, of the Centro de Pesquisa em Oncologia and Latin American Cooperative Oncology Group in Porto Alegre, Brazil. “The study raises an important and interesting issue regarding the potential selection of patients, in this case according to genotyping and identifying patients with FF/FV CD16A,” he said.

In the planned exploratory analysis by CD16A genotype, patients with the low-affinity genotype demonstrated a larger difference in progression-free survival. These findings aligned with the hypothesis of the trial: enhancing immune effects may lead to better results, Dr. Barrios noted.

Practical Implications

Multiple regimens are already in use for patients whose disease progresses after two or more lines of therapy. All of these regimens are a means of continuing HER2 blockade after disease progression, and their selection often depends on physician preference and patient access to the drugs. However, the potential for long-term efficacy with any of these combinations is limited. Better outcomes will depend on identifying drugs with new mechanisms of action that address additional signaling pathways and creating combinations of such agents. Margetuximab is a new engineered antibody that allegedly works by enhancing immune effects; thus, it falls into the category of novel agents that could improve outcomes, he said.

“We await longer follow-up to assess whether ‘enhanced’ immune effects may influence overall survival, despite the modest difference (1–2 months) in progression-free survival shown in the SOPHIA trial,” he commented. In other tumor types, added Dr. Barrios, immunotherapies have improved survival “in the face of little to no progression-free survival benefit.”

The strengths of SOPHIA are its inclusion of a “clearly defined” third-line population—ie, all had received trastuzumab and pertuzumab, and more than 90% had received trastuzumab emtansine—and the use of an “appropriate” comparator, “the most commonly used third-line regimen,” he said. “However, potential questions can be raised. It’s an open-label trial, and is a 1-month statistically significant benefit in progression-free survival also clinically relevant?” ■

DISCLOSURE: Dr. Barrios owns stock in Biomarker, MedSIR, and Tummi; has received honoraria from Boehringer Ingelheim, Eisai, GlaxoSmithKline, Novartis, Pfizer, Roche/Genentech, and Sanofi; has consulted or advised for AstraZeneca, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Libbs, MSD Oncology, Novartis, Pfizer, Roche/Genentech, and United Medical; has received travel expenses from -AstraZeneca, Bristol-Myers Squibb Brazil, MSD Oncology, Novartis, Pfizer, and Roche/Genentech; and has received research funding from AB Science, AbbVie, Abraxis BioScience, Amgen, Asana Biosciences, Astellas Pharma, AstraZeneca, Atlantis Clinica, Biomarin, -Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Covance, Daiichi Sankyo, Exelixis, GlaxoSmithKline, Halozyme, ImClone Systems, INC Research, inVentiv Health, Janssen, Leo Pharma, Lilly, Medivation, Merck, Merrimack, Millennium, Mylan, Novartis, Pfizer, Roche/Genentech, Sanofi, Taiho Pharmaceutical.