Margetuximab extends survival in relapsed HER2-positive metastatic breast cancer
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SAN ANTONIO — Margetuximab plus chemotherapy conferred a numerically small but statistically significant PFS and OS compared with trastuzumab plus chemotherapy for patients with relapsed or refractory HER2-positive metastatic breast cancer, according to results of a second interim analysis of the randomized phase 3 SOPHIA trial presented at San Antonio Breast Cancer Symposium.
In addition, CD16A genotyping indicated patients with 158F allele derived greater benefit.
“There is a persistent unmet need in HER2-positive metastatic breast cancer, with no recognized standard of care after first-line treatment with trastuzumab [Herceptin, Genentech] plus pertuzumab [Perjeta, Genentech], followed by ado-trastuzumab emtansine [Kadcyla, Genentech],” Hope S. Rugo, MD, clinical professor in the department of medicine and director of the breast oncology clinical trials program at University of California, San Francisco, said during a presentation. “Subsequent therapies usually include sequential chemotherapy with trastuzumab and/or lapatinib [Tykerb, Novartis]. Continued anti-HER2 therapy after progression is preferred, generally in combination with chemotherapy.”
Margetuximab (MacroGenics) is a novel Fc-engineered HER2-targeted antibody designed to activate immune responses.
The SOPHIA trial — the first prospective analysis of the effect of CD16A genotype on anti-HER2 antibody efficacy — included 536 patients with HER2-positive metastatic breast cancer whose disease progressed after at least two lines of anti-HER2 therapy, including pertuzumab, and one to three lines of therapy for HER2-positive metastatic breast cancer.
Researchers randomly assigned 266 patients (median age, 55 years; 100% women) to 15 mg/kg margetuximab every 3 weeks with chemotherapy. The other 270 patients (median age, 56 years; 98.9% women) received 6 mg/kg IV trastuzumab every 3 weeks, following an 8 mg/kg loading dose, with chemotherapy. Chemotherapy options included capecitabine, eribulin (Halaven, Eisal), gemcitabine or vinorelbine.
The study’s primary endpoints included central-blinded PFS and OS.
The first interim OS analysis — presented in June at ASCO Annual Meeting — was immature, with only 41% of the deaths needed.
In San Antonio, Rugo presented results of a second interim analysis performed after 270 patient deaths.
Researchers reported median PFS of 5.7 months (95% CI, 5.22-6.97) with margetuximab and 4.4 months (95% CI, 4.14-5.45) with trastuzumab (HR = 0.71; 95% CI, 0.58-0.86).
“As of Dec. 7, 20 patients remain on margetuximab compared with 10 patients on trastuzumab, which is consistent with the plateau we now see on the PFS curve,” Rugo said.
The investigator-assessed overall response rate was 25.2% (95% CI, 20.1-30.9) in the margetuximab group vs. 13.7% (95% CI, 9.8-18.4) with trastuzumab (P = .0006). Median duration of response was similar between the two arms (6.9 months vs. 7 months).
Researchers reported clinical benefit rates of 48.1% (95% CI, 42-54.3) with margetuximab and 35.6% (95% CI, 29.9-41.6) with trastuzumab (P = .0025).
Median OS was 21.6 months (95% CI, 18.86-24.05) with margetuximab vs. 19.8 months (95% CI, 17.54-22.28) with trastuzumab (HR = 0.89; 95% CI, 0.69-1.13).
The final OS analysis — planned after 385 patient deaths — is anticipated in late 2020, Rugo said.
Results of a subgroup analysis that included carriers of the lower-affinity CD16A F allele showed median OS of 23.7 months (95% CI, 18.89-28.32) with margetuximab vs. 19.4 months (95% CI, 16.85-22.28) with trastuzumab (HR = 0.79; 95% CI, 0.61-1.04).
“Interestingly, the population of VV heterozygotes, which includes a very small number of patients in this study, do not appear to benefit from margetuximab compared with trastuzumab,” Rugo said. “Clearly more data are needed but, at the present time, it seems reasonable to conclude from these data that there is no evidence to support benefit of margetuximab over trastuzumab in the VV homozygote population.”
Overall adverse events were similar between the two treatment groups, Rugo said. However, infusion-related reactions occurred more frequently among margetuximab-treated patients (13.3% vs. 3.4%).
“The Fc-engineering of margetuximab alters the affinity of Fc receptors and results in coordinate engagement of innate and adaptive immunity,” she said. “SOPHIA is the first trial to show PFS superiority of novel margetuximab compared with trastuzumab. ... Although the second interim OS analysis favors margetuximab, the difference is not yet statistically significant.” – by Jennifer Southall
Reference:
Rugo HS, et al. Abstract GS1-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: MacroGenics supported this trial. Rugo reports contracted research with Amgen, Daiichi Sankyo, Eisai, Eli Lilly, Genentech, Immunomedics, MacroGenics, Merck, Mylan, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, Puma Biotechnology, Sanofi and Seattle Genetics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Adam M. Brufsky, MD, PhD
This trial was designed with a co-primary sequential endpoint, meaning if the PFS endpoint was met, investigators would assess the OS endpoint. We heard at last year’s ASCO Annual Meeting that the trial did meet its PFS endpoint. However, the OS endpoint has not been met. A year from now, I suspect the data will be the same. I hope I am wrong.
The issue now is: Where do we go from here? Can we get drug approval based upon the data we have? I do not think so, but I am not the FDA.
There is one exciting thing about this trial, in that it really does prove the principal — in a large randomized trial — that the immune system does have something to do with trastuzumab response. This has been argued over the years and we have seen glimpses of data here and there, but now it clearly has been proven in a randomized trial.
Investigators re-engineered an antibody to bind the Fc receptors and it works better in the Fc receptors that do not bind a certain type of allele. This definitely shows us that the immune system is doing something for trastuzumab response. Where the investigators will go with this is interesting and unknown. There could be a neoadjuvant trial looking at pathologic complete response as an endpoint, which is a good idea. This research is not yet over.
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G. Thomas Budd, MD
Overall, this was a positive study, but in some ways it was disappointing because the benefit was relatively modest for the novel anti-HER2-antibody. It was greater in the patient population we thought it would be — namely those with low-affinity Fc receptors. It is worth keeping in mind these are very heavily pretreated patients. I think this study shows us that antibody-based anti-HER2 therapy has an immunologic component as part of its mechanism. I think that is hopeful because it is another weakness we can exploit and it is another way we can improve treatment for these patients.
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