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Edging Closer to OS Benefit With Novel Anti-HER2 Drug

— Larger benefit with margetuximab in most common HER2 breast cancer phenotype

Last Updated December 16, 2019
MedpageToday

SAN ANTONIO -- An investigational anti-HER2 agent has yet to produce a survival benefit as third-line therapy for metastatic HER2-positive breast cancer, according to an updated analysis from the SOPHIA randomized trial.

Median overall survival (OS) was 21.6 months with margetuximab plus chemotherapy as compared with 19.8 months for trastuzumab (Herceptin) plus chemotherapy. The 1.8-month difference represented a small move in the right direction but still was not significantly different from a first analysis reported earlier this year.

A prespecified exploratory analysis of interaction with immune-activating CD16A produced a 4.3-month OS difference in favor of margetuximab in patients who were CD16A-185 F carriers, but this also was not significantly different from patients who received trastuzumab, as reported at the .

Still, the results were at least tentatively favorable for margetuximab, said lead investigator Hope Rugo, MD, of the University of California San Francisco. "This is the first trial to show PFS [progression-free survival] superiority of a novel antibody compared with trastuzumab," she said. "The second interim overall survival analysis favors margetuximab, although the difference is not yet statistically significant. The trial also represents the first prospective analysis of the role of CD16A genotype as a predictor of HER2 antibody efficacy. In this exploratory analysis, patients carrying the lower affinity CD16A F allele appear to have a better outcome with margetuximab compared with trastuzumab."

That a survival benefit will emerge with continued follow-up seemed unlikely to Adam Brufsky, MD, PhD, of the University of Pittsburgh Medical Center.

"It's hard for me to imagine that there will be a benefit a year from now," he told ֱ. "It could happen that the [survival] curves could separate some more, but I'm not sure they will."

Redesigning future trials to focus strictly on the CD16A population that benefited from treatment would seem to hold more promise.

"They showed here and previously at ASCO [American Society of Clinical Oncology] that if you have the phenylalanine allele of CD16A, you actually have a significant overall survival benefit," he added. "That may be the way to go, and I think it's a great idea."

First-line therapy for HER2-positive metastatic breast cancer consists of trastuzumab and pertuzumab (Perjeta) with chemotherapy. T-DM1 (Kadcyla) has an approved indication as second-line therapy. Thereafter, no recognized standard of care exists. Options include sequential chemotherapy with trastuzumab and/or lapatinib (Tykerb). Continued anti-HER2 therapy after progression is preferred, generally in combination with chemotherapy, said Rugo.

Trastuzumab and margetuximab have similar specificity and affinity for HER2 and cause similar disruption of signaling that drives cell proliferation and survival. The drugs differ in the engineering of the Fc region, which is involved in immune activation. Margetuximab has increased affinity for immune-activating CD16A and decreased affinity for inhibitory CD32B to increase antibody-dependent cell-mediated cytotoxicity and adaptive immunity.

Rugo presented an update to the for which an initial interim analysis was reported in June at the . Patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1 were randomized to investigator's choice of chemotherapy plus margetuximab or trastuzumab. The trial had sequential primary endpoints of PFS by central blinded analysis and OS. Investigator-assessed PFS was a secondary endpoint, along with objective response rate by blinded review. The intention-to-treat population comprised 536 patients.

That initial report showed less than a 1-month difference in median PFS (5.8 vs 4.9 months), which nonetheless met statistical criteria for significance. OS data remained immature, but the preliminary analysis showed a median of 18.9 months with margetuximab and 17.2 months with trastuzumab. Assessment of objective response and clinical benefit rate (CBR) by blinded review showed significant advantages for margetuximab.

An exploratory analysis of the low-affinity CD16A-158F phenotype (which accounts for about 85% of HER2-positive breast cancer) showed significantly better PFS with margetuximab in patients with the FF and FV genotypes. Patients with the VV genotype derived greater benefit from trastuzumab.

With investigator-assessed PFS at a data cutoff of October 2018, there was a statistically significant difference favoring margetuximab (5.6 vs 4.2 months, P=0.001). The difference represented a 30% reduction in the hazard for progression or death. The updated analysis (data cutoff September 2019) yielded a median PFS of 5.7 months for the margetuximab group and 4.4 months for the control arm, a statistically significant 29% reduction in the hazard ration (P=0.0006).

Analysis of investigator-assessed objective response and CBR (tertiary endpoints) showed significant differences favoring margetuximab, 25.2% vs 13.7% for objective response (P=0.0006) and 48.1% vs 35.6% for CBR (P=0.0025).

The updated, but still interim, OS analysis yielded median values of 21.6 months and 19.8 months for the margetuximab and trastuzumab arms, respectively, still falling short of statistical significance (P=0.89).

A planned exploratory analysis of OS by CD16A-185F phenotype yielded a median value of 23.7 months for the FF and FV genotypes combined versus 19.4 months with trastuzumab (HR 0.79, P=0.087). In contrast, the VV homozygous genotype was associated with numerically better outcomes when treated with trastuzumab (median OS 33.3 months vs 19.7 months, P=0.157). However, the VV subgroup comprised only 69 patients, and risk/prognostic characteristics were imbalanced in favor of the trastuzumab arm.

"Clearly, more data are needed," said Rugo. "However, at the present time it seems reasonable to conclude from these data that there is no evidence to support a benefit of margetuximab over trastuzumab in the VV homozygous population."

Rugo said a final OS analysis will likely occur late in 2020.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ֱ in 2007.

Disclosures

The study was supported by MacroGenics.

Rugo disclosed relationships with MacroGenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, Genentech, Merck, Immunomedics, Odonate Therapeutics, Daiichi Sankyo, Seattle Genetics, and Puma.

Primary Source

San Antonio Breast Cancer Symposium

Rugo H, et al "Phase III SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Second interim overall survival analysis" SABCS 2019; Abstract GS1-02.