Margetuximab holds promise in metastatic HER2-positive breast cancer
Click Here to Manage Email Alerts
Following the promising findings of the second interim analysis of the randomized phase 3 SOPHIA trial — presented at San Antonio Breast Cancer Symposium in December 2019 — the manufacturer of the investigational agent, margetuximab, submitted a biologics license application for use in patients with metastatic HER2-positive breast cancer.
However, the FDA has not yet approved margetuximab (MacroGenic Inc.) for use in this patient population.
“The availability of more effective treatments for patients with metastatic, heavily treated HER2-positive breast cancer is important,” Hope S. Rugo, MD, professor of medicine and director of Breast Oncology and Clinical Trials Education at University of California, San Francisco Comprehensive Cancer Center, told Healio. “While it is difficult to know how this drug fits into the rapidly expanding treatment paradigm for this disease, despite the data presented at the most recent San Antonio Breast Cancer Symposium, patients are still progressing on their disease and dying from HER2-positive metastatic breast cancer.”
The only current first-line treatment option is trastuzumab (Herceptin, Genentech) plus pertuzumab (Perjeta, Genentech) followed by the antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla, Genentech) and trastuzumab deruxtecan (Enhertu, AstraZeneca).
However, no recommendations for second-line treatments in this patient population currently exist. Margetuximab — an investigational immune-enhancing monoclonal antibody that targets the HER2 oncoprotein — could be the answer to that unmet need.
“The only other FDA-approved treatment is trastuzumab plus deruxtecan,” Rugo told Healio. “There is another agent that we are looking forward to seeing FDA approval for — tucatanib [Seattle Genetics], which is an investigational small molecule inhibitor of HER2. We also just saw the approval for an agent already approved for early-stage HER2-positive breast cancer as extended adjuvant therapy, neratinib [Nerlynx, Puma Biotechnology], which was approved in the metastatic setting in combination with capecitabine based upon the results from the NALA trial. Having additional available agents would be very useful for this patient population.”
SOPHIA trial
In the SOPHIA trial, Rugo and colleagues assessed and compared 15 mg/kg margetuximab every 3 weeks among 266 patients (median age, 55 years; 100% women) vs. 6 mg/kg IV trastuzumab every 3 weeks, following an 8 mg/kg loading dose, among 270 patients (median age, 56 years; 98.9% women) with HER2-positive metastatic breast cancer.
All patients were previously treated with trastuzumab and pertuzumab, and 90% received ado-trastuzumab emtansine. For the current study, patients additionally received eribulin (Halaven, Eisai), gemcitabine, capecitabine or vinorelbine.
According to the most recent results presented during San Antonio Breast Cancer Symposium, median PFS was 5.7 months (95% CI, 5.22-6.97) with margetuximab vs. 4.4 months (95% CI, 4.14-5.45) with trastuzumab (HR = 0.71; 95% CI, 0.58-0.86; P = .0006).
Moreover, investigator-assessed ORR was 25.2% (95% CI, 20.1-30.9) in the margetuximab group compared with 13.7% (95% CI, 9.8-18.4) in the trastuzumab group. 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; P = .326).
“The data from the SOPHIA trial were overall positive and met the primary endpoint,” Rugo told Healio. “We have very interesting data from the exploratory endpoint, however, before this agent can hit the market, we need longer OS data, which is anticipated in late 2020.”
Subgroup analysis
Rugo and colleagues performed an additional subgroup analysis that included patients who carried the lower affinity IgG Fc gamma CD16A F allele.
Results of a subgroup analysis that included carriers of the lower affinity IgC Fc gamma 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; P = .087).
Eighty-five percent of this population of patients have the CD16A F allele receptor, which margituximab is engineered to bind more tightly to. Theoretically, there should be more of an immune response of this agent to metastatic breast cancer,” Adam Brufsky, MD, PhD, codirector of the Comprehensive Breast Cancer Center at University of Pittsburgh and a HemOnc Today Editorial Board member, told Healio. “When looking at the SOPHIA trial, those who had the specific CD16A F allele receptor fared better with margetuximab, actually achieved a survival benefit and the adverse events were similar to trastuzumab.
These are fascinating data, Rugo added.
“The data suggest there may be a subpopulation of patients, and not a small number, who could benefit from receiving the engineered antibody, margituximab,” she told Healio. “In contrast, patients who were VV homozygotes did not appear to benefit from margituximab. Of note, the population of patients in this trial were very small — there were only 69 patients who were VV homozygotes. Still, the clinical characteristics in this subgroup were imbalanced and favored the trastuzumab arm.”
Looking ahead
Looking ahead, experts are hopeful that margetuximab will gain FDA approval for this population of patients that greatly needs it.
“This is a fascinating research area right now,” Rugo told Healio. “There is also a lot of interest in margituximab in the neoadjuvant setting where we have a short-term endpoint of response and pathologic complete response in certain patients.”
“Other than patients with a CD16A genetic profile, there are no other subgroups at this time that may benefit from margituximab,” Brufsky told Healio. “We need to perform other trials in patients with this CD16A receptor. There is actually a trial going on now looking at margituximab, carboplatin, trastuzumab and docetaxel compared with trastuzumab, carboplatin, docetaxel and pertuzumab. This is where the science appears to be headed and I am hopeful that this agent will eventually receive FDA approval. There is an interesting mechanism of action with margetuximab that can hopefully be exploited in the very near future.” – by Jennifer Southall
References
Rugo HS, et al. Abstract 1000. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Rugo HS, et al. Abstract GS1-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Collapse
Click Here to Manage Email Alerts