Margetuximab Superior to Trastuzumab on PFS in HER2-Positive Metastatic Breast Cancer Carriers of CD16A-F Allele

Hope Rugo, MD

Margetuximab, a novel Fc-engineered HER2-targeted antibody, improved progression-free survival (PFS) compared with trastuzumab (Herceptin) in patients with pretreated HER2-positive metastatic breast cancer in the open-label phase III SOPHIA clinical trial. In a planned exploratory analysis, the PFS benefit observed with margetuximab was enhanced in CD16A-158F carriers.

By central blinded analysis, PFS was prolonged in patients randomized to margetuximab (HR, 0.76; P = .033), reported Hope Rugo, MD, at the 2019 ASCO Annual Meeting. Median PFS was 5.8 months in the margetuximab arm compared with 4.9 months in the trastuzumab arm. Investigator-assessed PFS was also longer in the margetuximab arm (HR, 0.70; P = .001).¹

In the planned exploratory PFS analysis by Fc-gamma receptor genotype, PFS appeared to be enhanced with margetuximab in patients who were carriers of the CD16A-F allele compared with that in the intent-to-treat (ITT) population. In patients with the CD16A-F allele, the median PFS was 6.9 months in patients randomized to margetuximab compared with 5.1 months in those randomized to trastuzumab (HR, 0.68; P = .005).

At data cutoff of October 10, 2018, an interim overall survival (OS) analysis after 41% of the 385 events needed for final OS analysis was performed. In the ITT population, median OS was 18.9 months in the margetuximab arm versus 17.2 months in the trastuzumab arm (HR, 0.95; 95% CI, 0.69-1.31). In patients carrying at least 1 F allele, median PFS was 23.6 months in patients randomized to margetuximab compared with 16.9 months in those assigned to trastuzumab, an absolute difference of 6.7 months favoring margetuximab (HR, 0.82; 95% CI, 0.58-1.17). A second interim analysis is planned after 270 deaths.

After first-line trastuzumab and pertuzumab (Perjeta) with chemotherapy and second-line T-DM1, there is no recognized standard of care for patients with HER2-positive metastatic breast cancer, and subsequent therapies are poorly defined, said Rugo, clinical professor, Department of Medicine, and director, Breast Oncology Clinical Trials Program, University of California, San Francisco.

Controversy exists about the role of CD16A polymorphisms on the efficacy of trastuzumab. Two retrospective studies of patients with HER2-positve metastatic breast cancer and early breast cancer had suggested that those who carry the low affinity F allele have a lower PFS and overall response rate (ORR) with trastuzumab compared with patients homozygous for the higher affinity V allele,^2,3 she said.

In contrast, 2 other retrospective studies have shown no association between Fc-gamma receptor genotypes and outcome with adjuvant trastuzumab in early breast cancer.^4,5

Margetuximab is an Fc-engineered antibody designed to activate immune responses. “Fc-gamma polymorphisms influence immune responses, and margetuximab’s Fc portion is engineered to have enhanced affinity for binding to both the low affinity F and high-affinity V alleles for the activating Fc-gamma CD16A receptor, as well as decreased affinity for the inhibitory Fc-gamma receptor CD32B,” she said.

In a preclinical assay, margetuximab was shown to enhance innate immunity in vitro. Margetuximab enhanced antibody-dependent cellular cytotoxicity compared with a trastuzumab surrogate in cells with the F allele and to a lesser degree cells homozygous for the V allele.⁶ CD16A genotypes include VV in about 15% the population, FV in 40% to 45%, and FF in about 40%.

The hypothesis was 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 is also the first prospective analysis of the impact of FC-gamma receptor genotype on the efficacy of anti-HER2 antibody therapy,” Rugo said.

In SOPHIA, 536 patients with HER2-positive metastatic breast cancer despite ≥2 prior anti-HER2 therapies, including pertuzumab, and who received 1 to 3 prior lines of treatment in the metastatic setting, were randomized to margetuximab, 15 mg/kg every 3 weeks, or trastuzumab, using an 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). Sequential primary endpoints are PFS and OS. A preplanned exploratory secondary endpoint included evaluation of the effect of margetuximab by Fc-gamma receptor alleles.

Baseline characteristics were balanced between the arms, with a median age of 55 years in the margetuximab arm and 56 years in the trastuzumab arm. The backbone chemotherapy regimens were capecitabine in 27% in each arm, eribulin in about one-fourth, gemcitabine in 12%, and vinorelbine in about one-third of patients. More than 90% of patients received prior T-DM1 (ado-trastuzumab emtansine; Kadcyla), and 59% in the margetuximab arm and 54% in the trastuzumab arm received prior adjuvant and/or neoadjuvant therapy. About one-third in each arm received >2 lines of prior therapy in the metastatic setting.

Subgroup analysis in the ITT population showed a relatively enhanced impact of margetuximab on PFS in patients with IHC 3+ disease, those with >2 metastatic sites, hormone receptor-negative disease, and those who had received prior (neo)adjuvant therapy, she said.

Some 506 (94%) of patients in the study were genotyped. In the exploratory analysis, 86% of patients had the CD16A-F allele. In contrast to the enhanced PFS benefit with margetuximab in patients with the CD16A-F allele, median PFS was relatively similar between margetuximab and trastuzumab in patients homozygous for the V allele (HR, 1.78; P = .110). A test for interaction for effect by CD16A genotype was significant (P = .012).

For patients with the FF and FV alleles, the PFS hazard ratios favoring margetuximab were similar (HR, 0.69 and 0.71, respectively; P = .080 and P = .055). The absolute difference in median PFS favoring margetuximab in patients homozygous for the CD16A-F allele was 2.6 months.

The ORRs were 22.1% and 16.0% in the margetuximab and trastuzumab arms, respectively (P = .060). The clinical benefit rates were 36.6% and 24.8%, respectively (P = .003). The duration of response was about 6 months in both arms.

The rates of adverse events (AEs) of any grade were similar between the margetuximab and trastuzumab arms, 97.7% and 96.2%, respectively. The rates of serious AEs were 14.8% and 17.4%, respectively, and the rates of grade ≥3 AEs were 52.3% and 48.3%, respectively. Treatment discontinuation due to AEs occurred in 3.0% and 2.6%, respectively.

Infusion-related reactions were more frequent with margetuximab compared with trastuzumab (12.9% vs 3.8%). Most were low grade and occurred with the first infusion “and were easily managed with premedications,” Rugo said.

References

1. Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(suppl; abstr 1000).
2. Musolino A, Naldi N, Bortesi B, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008;26:1789-1796.
3. Gavin PG, Song N, Kim SR, et al. Association of polymorphisms in FCGR2A and FCGR3A with degree of trastuzumab benefit in the Aadjuvant treatment of ERBB2/HER2-positive breast cancer: analysis of the NSABP B-31 Trial. JAMA Oncol. 2017;3:335-41.
4. Hurvitz SA, Betting DJ, Stern HM, et al. Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin Cancer Res. 2012;18:3478-86.
5. Norton N, Olson RM, Pegram M, et al. Association studies of Fcγ receptor polymorphisms with outcome in HER2+ breast cancer patients treated with trastuzumab in NCCTG (Alliance) Trial N9831. Cancer Immunol Res. 2014;2:962-9.
6. Berlato C, Chan KV, Price AM, et al. Alternative TFAP2A isoforms have distinct activities in breast cancer. Breast Cancer Res. 2011;13:R23.

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