Results from the phase 3 SOPHIA trial demonstrated that margetuximab plus chemotherapy had an acceptable safety profile which was comparable to that observed with trastuzumab plus chemotherapy.
Results from the randomized, open-label, phase 3 SOPHIA trial (NCT02492711) suggest that among patients with pretreated ERBB2-positive advanced breast cancer, a disease that is typically incurable, margetuximab (Margenza) plus chemotherapy resulted in a statistically significant improvement in progression-free survival (PFS) compared with trastuzumab (Herceptin) plus chemotherapy following progression on 2 or more prior anti-ERBB2 therapies.1
The study, published in JAMA Oncology, also indicated that margetuximab plus chemotherapy had an acceptable safety profile which was comparable to that observed with trastuzumab plus chemotherapy.
“Alternatives for this patient population include neratinib [Nerlynx], tucatinib [Tukysa], and trastuzumab deruxtecan [Enhertu], which have emerged as active regimens, albeit with different levels of effectiveness, and all with notable toxic effects,” wrote the study authors who were led by principle investigator Hope S. Rugo, MD, FASCO. “Margetuximab may have a role for patients in this setting who are unable, or unwilling, to tolerate toxic effects of these novel therapies.”
The SOPHIA trial enrolled a total of 536 patients from August 26, 2015 to October 10, 2018 at 166 sites across 17 countries. Patients were eligible following disease progression on 2 or more prior anti-ERBB2 therapies and between 1 to 3 lines of therapy for metastatic disease.
Sequential primary end points of the study were PFS by central blinded analysis and overall survival (OS). Secondary end points included investigator-assessed PFS and objective response rate (ORR) per central blinded analysis.
Overall, 266 patients were randomized to the margetuximab arm and 270 were randomized to the trastuzumab arm. All but 1 patient had previously received pertuzumab (Perjeta), and 489 (91.2%) had previously received ado-trastuzumab emtansine (Kadcyla).
At the primary analysis date of October 10, 2018, patients on margetuximab were found to have a median PFS of 5.8 months (95% CI, 5.5-7.0) versus 4.9 months with trastuzumab (95% CI, 4.2-5.6), with a 24% relative reduction in the risk of disease progression or death (HR, 0.76; 95% CI, 0.59-0.98; P = .03). The ORR was 22% with margetuximab and 16% with trastuzumab at that time point (P = .06).
A second planned interim analysis took place on September 10, 2019, following 270 reported deaths. Median OS was revealed to be 21.6 months with margetuximab versus 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33). Moreover, the secondary end point of investigator-assessed PFS demonstrated a 29% relative risk reduction favoring margetuximab, with medians of 5.7 months and 4.4 months, respectively (HR, 0.71; 95% CI, 0.58-0.86; P <.001). The ORR was also found to have improved with margetuximab at 25% versus 14% with trastuzumab (P <.001).
Regarding safety, the incidence of infusion-related reactions was found to be higher with margetuximab, at 13.3% versus 3.4% with trastuzumab, though they were predominantly recorded in cycle 1. Otherwise, safety between the 2 groups was comparable. Commonly observed adverse events (AEs) occurring in 20% of patients or more, regardless of causality, included fatigue, nausea, diarrhea, and neutropenia in both groups, as well as vomiting in the margetuximab group and anemia in the trastuzumab group. Grade 3 or higher AEs occurring in at least 5% of patients included neutropenia and anemia in both groups, as well as fatigue in the margetuximab group and febrile neutropenia in the trastuzumab group.
“Up to one-fifth of all breast cancers are HER2-positive, and identifying new treatment options for patients in the metastatic setting represents a serious unmet medical need,” Rugo, professor of Medicine and director of Breast Oncology and Clinical Trials Education at University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said in a press release.2 “These results show that [margetuximab] provides improvement, for this patient population, beyond what we can achieve with trastuzumab, which is good news for patients with advanced disease.”
In December 2020, the FDA granted approval to margetuximab as therapy for the indicated patients population based on the results from SOPHIA.3 MacroGenics, the developer of the agent, indicated that it expects margetuximab will be available in the United States in March 2021.
Notably, margetuximab is also being evaluated in combination with checkpoint blockade in the phase 2/3 MAHOGANY trial for the treatment of patients with HER2-positive gastroesophageal cancer (NCT04082364), and in combination with tebotelimab in various ERBB2-positive tumors (NCT03219268).
1. Rugo HS, Im S, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer. JAMA Oncol. Published online January 22, 2021. doi: 10.1001/jamaoncol.2020.7932
2. MacroGenics Announces Publication of SOPHIA Trial Results for MARGENZA™ in JAMA Oncology. News release. MacroGenics. Published January 25, 2021. http://ir.macrogenics.com/news-releases/news-release-details/macrogenics-announces-publication-sophia-trial-results
3. FDA approves margetuximab for metastatic HER2-positive breast cancer. FDA. December 16, 2020. Accessed February 2, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-margetuximab-metastatic-her2-positive-breast-cancer