Jury Out on Margetuximab in Advanced HER2+ Breast Cancer

CHICAGO -- Swapping out trastuzumab (Herceptin) in favor of a novel HER2-directed agent in the third-line appeared to help certain patients with metastatic HER2-positive breast cancer, the phase III SOPHIA trial found.

Given along with chemotherapy, margetuximab led to a 24% reduction in the risk of disease progression or death compared with trastuzumab (HR 0.76, 95% CI 0.59-0.98, P=0.033), reported Hope S. Rugo, MD, of the University of California San Francisco.

But for the 536 patients in the intent-to-treat (ITT) population, this translated to improvement of less than 1 month in median progression-free survival (PFS), at 5.8 months with margetuximab versus 4.9 months with trastuzumab, as described here at the American Society of Clinical Oncology (ASCO) annual meeting.

Planned exploratory analyses based on CD16A genotype, however, suggested that 158F allele carriers (FF or FV) were more likely to derive benefit from margetuximab than with trastuzumab.

"Controversy exists about the role of CD16A polymorphisms on the efficacy of trastuzumab," said Rugo, noting that conflicting results have been seen in retrospective studies. Most breast cancer patients carry either the FV (40% to 45%) or FF allele (about 40%), and about 15% carry the VV allele.

Among the 437 patients in the FF/FV subgroup, median PFS was 6.9 months with the novel agent compared with 5.1 months with trastuzumab (HR 0.68, 95% CI 0.52-0.90, P=0.005). By contrast, no significant difference was seen among the 69 patients with the VV allele, for whom margetuximab performed numerically worse.

Immature overall survival data in the ITT population showed a non-significant 1.7-month difference favoring the margetuximab arm, which grew to 6.7 months in the CD16A FV/FF allele group (94% of patients), but again was not statistically significant. A second interim analysis for overall survival is expected later this year.

"This is the first prospective analysis of CD16A genotype as a predictor of efficacy from anti-HER2 therapy, and we demonstrated an enhanced PFS benefit in patients carrying the low affinity CD16A F allele," Rugo said.

Current standard of care in first-line metastatic HER2-positive breast cancer consists of trastuzumab plus pertuzumab (Perjeta) in combination with chemotherapy, followed by ado-trastuzumab emtansine (Kadcyla) in the second-line. Beyond this there is no recognized standard, though continued HER2-directed therapies plus chemotherapy is generally preferred.

Margetuximab is an anti-HER2 agent that was engineered to activate CD16A while inhibiting CD32B, and can stimulate mechanisms of innate and adaptive immunity, Rugo said.

"Margetuximab plus chemotherapy may represent a new alternative combination for third-line treatment of HER2-positive metastatic breast cancer," said ASCO-invited discussant Carlos Barrios, MD, of Hospital São Lucas in Brazil, though he expressed concern over the open-label design of SOPHIA and questioned whether the 1-month PFS improvement in the ITT group was clinically relevant.

Some of the trial's strengths include the use of an appropriate third-line comparator along with a clearly-defined third-line patient population, he said, and the potential for patient selection according to genotyping, which should be confirmed in future studies.

"Importantly, overall survival needs follow-up," Barrios said, especially if the drug indeed enhances the immune system. "Remember that in some of the immunotherapy trials that had been conducted in other tumor types, we have found no, or very little, PFS advantages in the face of significant overall survival advantages."

SOPHIA was a phase III trial that randomized patients 1:1 to the investigator's choice of chemotherapy plus either margetuximab or trastuzumab. Patients (median age 55-56) were required to have received one to three prior lines of therapy in the metastatic setting. All had received prior trastuzumab and pertuzumab, over 90% had also received ado-trastuzumab emtansine, and about 15% had received lapatinib (Tykerb).

Stratification included choice of chemotherapy, number of prior therapies, and metastatic sites of disease. For chemotherapy, capecitabine (Xeloda) was used in 27% of patients, eribulin (Halaven) in about 25%, gemcitabine (Gemzar) in 12%, and vinorelbine (Navelbine) in about 35%. Roughly half of the patients in each arm had more than two sites of metastatic disease, and roughly one-third had been treated with more than two prior lines of therapy.

Overall response rate numerically favored the margetuximab group (22.1% vs 16.0%, P=0.060), and this group saw a significantly higher clinical benefit rate (36.6% vs 24.8%, P=0.003).

All-grade adverse events were similar between the margetuximab and trastuzumab groups, with nearly all patients experiencing at least one event. Similar rates were observed for grade 3/4 toxicity (52.3% vs 48.3%, respectively), serious adverse events (14.8% vs 17.4%), and treatment discontinuation for toxicity (3.0% vs 2.6%). Two deaths due to adverse events were reported in each arm but were not attributed to either antibody.

"There were more infusion-related reactions with margetuximab compared to trastuzumab, of course in this population patients had already received multiple lines of trastuzumab therapy," Rugo noted, but said most were low-grade in nature, occurred with the first infusion, and were easily managed with premedication.