Fc-engineered HER2-targeted antibody preferentially benefits carriers of CD16A-F allele

By oncoXchange

June 12th 2019

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By Wayne Kuznar for oncoXchange

An investigational Fc-engineered HER2-targeted antibody, margetuximab, extended progression-free survival (PFS) compared with trastuzumab in patients with pretreated HER2-positive metastatic breast cancer enrolled in the open-label SOPHIA trial. A preferential benefit to margetuximab on the PFS endpoint was observed in the subset of patients who were carriers of the CD16A-158F allele.

SOPHIA represents “the first prospective analysis of the impact of Fc-gamma receptor genotype on the efficacy of anti-HER2 antibody therapy,” said the study’s lead investigator Hope Rugo, MD, at the 2019 ASCO annual meeting.

In the intent-to-treat (ITT) population, patients randomized to margetuximab had a median PFS of 5.8 months versus 4.9 months in those randomized to trastuzumab, corresponding to a 24% reduction in the risk of disease progression (HR 0.76; P=0.033). In a planned exploratory analysis by Fc-gamma receptor genotype, median PFS was 6.9 months in the margetuximab arm compared with 5.1 months in the trastuzumab arm, reflecting a 32% reduction in risk of progression (HR 0.68; P=0.005).

After first-line trastuzumab and pertuzumab, together with chemotherapy, and second-line T-DM1, no recognized standard of care exists for patients with HER2-positive metastatic breast cancer, said Dr. Rugo, clinical professor, Department of Medicine, and director, Breast Oncology Clinical Trials Program, University of California, San Francisco.

Margetuximab is an Fc-engineered antibody designed to activate immune responses.

Based on clinical preclinical work showing enhanced antibody-dependent cellular cytotoxicity compared with a trastuzumab surrogate in cells with the F allele, investigators hypothesized that margetuximab would show a greater benefit in patients carrying the lower affinity CD16A-F allele due to the increased affinity of margetuximab for this allele over trastuzumab.

SOPHIA enrolled 536 patients with HER2-positive metastatic breast cancer. All patients received at least two prior anti-HER2-targeted therapies, including pertuzumab, and one to three prior lines of treatment in the metastatic setting. As part of their regiomen, all patients received investigator’s choice of chemotherapy—either capecitabine, eribulin, gemcitabine, or vinorelbine. They were randomized to margetuximab (15 mg/kg every 3 weeks) or trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks). All patients also received investigator’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). A total of 506 (94%) patients in the study had genotyping performed. In the exploratory analysis, 86% of patients had the CD16A-F allele. Whereas PFS was enhanced with margetuximab in patients with the CD16A-F allele, median PFS was relatively not significantly different between margetuximab and trastuzumab in patients homozygous for the V allele (HR 1.78; P =0.110). A test for interaction for effect by CD16A genotype was significant (P =0.012).

An interim overall survival (OS) analysis after 41% of the 385 events needed for final OS analysis showed a median OS was 18.9 months in the margetuximab arm versus 17.2 months in the trastuzumab arm in the ITT population (HR 0.95; 95% CI, 0.69-1.31). In patients carrying at least 1 F allele, median OS was 23.6 months in patients randomized to margetuximab compared with 16.9 months in those assigned to trastuzumab (HR, 0.82; 95% CI, 0.58-1.17). A second interim OS analysis is planned after 270 deaths.

The rates of adverse events of any grade were similar between the margetuximab and trastuzumab arms (97.7% vs. 96.2%, respectively). Serious adverse events occurred in 14.8% and 17.4%, respectively, and the rates of grade-3 or higher adverse events were 52.3% and 48.3%, respectively. Treatment was discontinued due to adverse events in 3.0% and 2.6% of the arms, respectively.

SOPHIA “raises the very important and interesting issue of potential selection of patients, in this case according to genotyping,” said Carlos Barrios, MD, from Latin American Cooperative Oncology Group, Porto Alegre, Brazil. However, the 1-month absolute benefit in PFS in the overall cohort, even though statistically significant, can be questioned in regard to its clinical relevancy.

Longer follow-up of SOPHIA is awaited to assess whether the enhanced immune effects of margetuximab may influence OS in spite of the modest PFS difference, added, Dr. Barrios.

Dr. Rugo discloses the following financial relationships: Amgen, Mylan, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Roche/Genentech, and Sanofi, and institutional relationships with MacroGenics, Daiichi Sankyo, Eisai, Genentech, Immunomedics, Lilly, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics.

Dr. Barrios discloses the following financial relationships: Biopmarker, MedSIR, Tumi, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Novartis, Roche/Genentech, Sanofi, AstraZeneca, Libbs, MSD Oncology, and United Medical, in addition to research funding from several pharmaceutical companies.