Margetuximab, an Fc-engineered anti-HER2 monoclonal antibody, presents a promising alternative for patients with HER2-positive advanced breast cancer (ABC) who have progressed on multiple prior lines of therapy. While the final results of the Phase 3 SOPHIA trial, published in the Journal of Clinical Oncology, did not demonstrate a statistically significant overall survival (OS) benefit compared to trastuzumab, margetuximab did show an improvement in progression-free survival (PFS). This suggests a potential role for margetuximab in specific patient populations who have limited treatment options.
SOPHIA Trial Results
The SOPHIA trial was a multinational, open-label, randomized Phase 3 study involving 536 patients with HER2-positive ABC who had progressed on two or more prior HER2-directed therapies. Almost all patients had previously received trastuzumab and pertuzumab, and a significant majority (91.2%) had been treated with ado-trastuzumab emtansine (T-DM1). Patients were randomized to receive either margetuximab (n = 266) or trastuzumab (n = 270), in combination with investigator-selected single-agent chemotherapy (capecitabine, gemcitabine, vinorelbine, or eribulin).
The primary endpoints of the trial were PFS by central blinded analysis (CBA) and OS. The final results indicated that margetuximab plus chemotherapy prolonged PFS compared to trastuzumab plus chemotherapy (5.7 vs. 4.4 months by investigator assessment, p = 0.001), representing a 27% relative risk reduction. However, no statistically significant difference in OS was observed (median: 21.6 months in the margetuximab group vs. 21.9 months in the trastuzumab group, p = 0.620). The objective response rate (ORR) was higher in the margetuximab arm (26% vs. 14% by investigator assessment).
Mechanism of Action and FcγR Variants
Margetuximab is designed with an Fc domain engineered to enhance binding affinity to the activating Fcγ receptor (FcγR) CD16A (FcγRIIIA) and reduce binding affinity to the inhibitory FcγR CD32B (FcγRIIB). This modification aims to augment antibody-dependent cell-mediated cytotoxicity (ADCC), a crucial mechanism by which anti-HER2 antibodies target tumor cells. The affinity of anti-HER2 antibodies to FcγRs can influence clinical benefit. For example, the CD16A-158F allele, present in 80%-90% of the global population, has lower affinity for IgG1. Margetuximab's Fc engineering seeks to improve binding to all CD16A V/F alleles.
Exploratory analysis of the SOPHIA trial investigated the impact of FcγR variants on efficacy. In patients with the CD16A-158FF genotype (38% of the study population), margetuximab was associated with a nominally prolonged median OS of 4.4 months compared to trastuzumab. Conversely, in CD16A-158VV homozygotes (14% of the study population), margetuximab was associated with a nominally shortened median OS of 9.1 months. These findings suggest that CD16A genotyping might influence the OS advantage between margetuximab and trastuzumab. However, it's important to note that the unfavorable prognostic profile was imbalanced between the two treatment groups, warranting further investigation.
Current Treatment Landscape and the Role of Margetuximab
While first-line treatment for HER2-positive ABC typically involves dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy, subsequent lines of therapy present challenges. Agents like T-DM1 and trastuzumab deruxtecan (T-Dxd) have demonstrated efficacy in the second-line setting. However, there is no established standard of care for third-line or later anti-HER2 treatment. Options include T-DM1, T-Dxd (if not previously used), and tucatinib, each with varying efficacy and toxicity profiles. Margetuximab offers an alternative for patients who may not tolerate the toxicities associated with other available therapies, without increased myelosuppression, gastrointestinal effects, or cardiotoxicity.
Ongoing Research
Several ongoing trials are further exploring the role of margetuximab. The SOPHIA CHINA trial (NCT04262804) is evaluating the efficacy and safety of margetuximab plus chemotherapy in pretreated HER2-positive ABC patients in China, with efficacy by FcγR genotype as a secondary outcome measure. Initial results from this study have indicated consistent safety and efficacy. The MARGOT trial (NCT04425018) is comparing neoadjuvant margetuximab to trastuzumab (both with pertuzumab plus paclitaxel) in patients with stage II-III HER2-positive breast cancer who are low-affinity CD16A-158F carriers. These studies aim to refine our understanding of which patients are most likely to benefit from margetuximab-based treatment strategies.
In conclusion, while margetuximab plus chemotherapy did not demonstrate an OS benefit in the overall SOPHIA population, it offers an active alternative for patients with HER2-positive ABC after second-line therapy. Further research is needed to identify the optimal patient population and explore the potential of Fc-engineered anti-HER2 antibodies in HER2-positive breast cancer and other HER2-positive carcinomas.
