SOPHIA: Margetuximab boosts HER2-positive advanced breast cancer PFS
medwireNews: Treatment with the novel HER2-targeted agent margetuximab improves the outcomes of heavily pretreated patients with HER2-positive advanced breast cancer, indicate phase 3 trial results.
The open-label study showed “a head-to-head advantage” of margetuximab over trastuzumab, when both were given alongside single-agent chemotherapy, in this patient population, say the SOPHIA investigators in JAMA Oncology.
They explain that HER2-positive advanced breast cancer “remains typically incurable with optimal treatment undefined in later lines of therapy,” and the team therefore evaluated margetuximab, which is a chimeric monoclonal antibody that “shares [HER2] specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation.”
The 536 trial participants – all of whom had received at least two prior HER2-directed therapies and 1–3 nonhormonal treatments for metastatic disease – were randomly assigned to receive either margetuximab 15 mg/kg or trastuzumab 6 mg/kg (loading dose 8 mg/kg) once every 21 days alongside physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.
The primary analysis of centrally assessed progression-free survival (PFS; data cutoff, October 10, 2018) showed a significant improvement with margetuximab relative to trastuzumab, at a median of 5.8 versus 4.9 months, and a hazard ratio for progression or death of 0.76.
The 6-month PFS rate was 48% in the margetuximab group and 36% in the trastuzumab group, while the 9-month rates were 30% and 22%, respectively.
Overall survival was assessed in an interim analysis conducted after 270 deaths had occurred (data cutoff, September 10, 2019) and did not differ significantly between margetuximab- and trastuzumab-treated patients, at a median of 21.6 and 19.8 months, respectively.
The researchers note, however, that the “final analysis of the effect of margetuximab vs trastuzumab on survival will occur after 385 deaths,” which is expected in 2021.
Among response-evaluable participants, the objective response rate was numerically higher in the margetuximab than trastuzumab arm at the October 2018 timepoint (22 vs 16%), with the between-group differences reaching statistical significance at the September 2019 analysis (25 vs 14%).
The most common adverse event (AE) of at least grade 3 was neutropenia in both the margetuximab and trastuzumab groups, observed in 19.7% and 12.4% of patients, respectively, followed by decrease in neutrophil counts (8.7 vs 10.5%) and anemia (4.9 vs 6.4%).
Discontinuations due to AEs occurred in a comparable 3.0% and 2.6% of participants given margetuximab and trastuzumab, respectively, and the rates of death due to AEs were also similar, at 1.1% and 0.8%, although “none were considered treatment related,” report Hope Rugo (University of California San Francisco, USA) and co-researchers.
“This trial demonstrates a small but statistically significant PFS benefit of margetuximab plus chemotherapy over trastuzumab plus chemotherapy in patients with [HER2]-positive [advanced breast cancer] who progressed after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine,” they write.
“Alternatives for this patient population include neratinib, tucatinib, and trastuzumab deruxtecan, which have emerged as active regimens, albeit with different levels of effectiveness, and all with notable toxic effects.”
The study authors therefore conclude: “Margetuximab may have a role for patients in this setting who are unable, or unwilling, to tolerate toxic effects of these novel therapies.”
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