HER2-targeting monoclonal antibodies (mAbs) are the standard of care in early-to-advanced HER2+ breast cancer. However, for relapsed/refractory disease, limited options exist after progression with trastuzumab, pertuzumab, and ado-trastuzumab emtansine. Margetuximab is an Fc-engineered anti-HER2 mAb that targets the same epitope as trastuzumab and exerts similar antiproliferative effects. In the phase 3 SOPHIA trial of 536 heavily pretreated patients with HER2+ metastatic breast cancer (MBC), the combination of margetuximab plus chemotherapy was shown to lead to significant improvements in progression-free survival (PFS), response, and clinical benefit compared with trastuzumab/chemotherapy. The benefits were enhanced in patients with low-affinity CD16A-158F-genotypes.1 However, controversy exists about the role of CD16A polymorphisms on the efficacy of trastuzumab.
Patients with disease progression after ≥2 lines of anti-HER2 therapy, including pertuzumab, and 1 to 3 lines of therapy for HER2+ MBC were randomized 1:1 to chemotherapy plus either margetuximab (15 mg/kg intravenously every 3 weeks) or trastuzumab. Randomization was stratified by number of metastatic sites (≤2, >2), lines of treatment for MBC (≤2, >2), and chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Primary end points were central-blinded review of PFS and overall survival (OS). The first interim OS analysis was immature, and the second interim OS analysis was planned after 270 deaths and was reported at SABCS 2019.2
OS results favored margetuximab plus chemotherapy compared with trastuzumab and chemotherapy in the intention-to-treat (ITT) population; however, these data did not reach statistical significance at this second interim analysis as of a September 2019 cutoff after 270 events (median OS, 21.6 months vs 19.8 months; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.69-1.13; P = .326). The final, prespecified OS analysis is planned after 385 events have accrued, which is projected to occur in the second half of 2020. A prespecified, exploratory objective of the study was to evaluate the effect of CD16A (Fcγ receptor) allelic variation on margetuximab activity. Among the genetically defined subpopulation of patients carrying a CD16A 158F allele, who represent approximately 85% of the human (and SOPHIA study) population, the median OS at the second interim analysis was prolonged by 4.3 months in the margetuximab arm compared with the trastuzumab arm (23.7 months vs 19.4 months; HR, 0.79; 95% CI, 0.61-1.04; nominal P = .087). Among the approximately 15% of patients who were homozygous for the CD16A 158V allele, the trastuzumab arm performed better than the margetuximab arm.
As previously reported,1 margetuximab plus chemotherapy showed a statistically significant improvement in independently assessed PFS compared with trastuzumab plus chemotherapy in this study as of an October 2018 cutoff after 256 events (median PFS, 5.8 months vs 4.9 months; HR, 0.76; 95% CI, 0.59-0.98; P = .033). An updated investigator-assessed analysis as of a September 2019 cutoff showed consistent results after 430 PFS events (median PFS, 5.7 months in the margetuximab arm vs 4.4 months in the trastuzumab arm; HR, 0.71; nominal P = .0006). Similarly, at the time of this updated analysis, additional patients were evaluable for response in the ITT population. Investigator-assessed objective response rate was 25.2% (95% CI, 20.1-30.9) in the margetuximab arm compared with 13.7% (95% CI, 9.8-18.4) in the trastuzumab arm (nominal P = .0006). The clinical benefit rate, which includes complete response + partial response + stable disease >6 months, was 48.1% (95% CI, 42.0-54.3) in the margetuximab arm versus 35.6% (95% CI, 29.9-41.6) in the trastuzumab arm (nominal P = .0025).
Margetuximab plus chemotherapy has shown a safety profile generally comparable to that of trastuzumab plus chemotherapy in this study. As of the April 2019 cutoff for safety, grade 3 or greater adverse events (AEs) occurred in 142 (54%) patients on the margetuximab arm compared with 140 (53%) patients on the trastuzumab arm. Serious AEs occurred in 43 (16%) patients on the margetuximab arm compared with 49 (18%) patients on the trastuzumab arm. Infusion-related reactions were more common with margetuximab treatment than with trastuzumab (13% versus 3%) and were mostly grade 1 or grade 2 and associated with the first dose.
The authors concluded that margetuximab plus chemotherapy in patients with treated HER2+ MBC improves PFS versus trastuzumab plus chemotherapy, with comparable safety. CD16A genotyping suggests a greater benefit in patients with a 158F allele. OS results favored margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy in the ITT population; however, these data did not reach statistical significance at this second interim analysis as of a September 2019 cutoff after 270 events.
References
- Rugo HS, et al. ASCO 2019. Abstract 1000.
- Rugo HS, et al. SABCS 2019. Abstract GS1-02.