Final Sophia readout could further sink Macrogenics’ Margenza

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Having failed to show an overall survival benefit at two interim readoutsthe Sophia trial has now yielded nothing at its final analysis. No statistically significant survival advantage was found for Margenza over Herceptin in late-line breast cancer patients, Macrogenics said, while once again talking up a genetic subgroup signal. Executives have long argued that Margenza should be most effective in those expressing F-allelic variants of CD16A. These subgroup findings can only be considered exploratory, and the FDA approved Margenza last year with an all-comers label. What might force a narrower indication is a suggestion that Margenza is doing harm in one small subgroup, a finding that perhaps explains the 5% drop in Macrogenics’ shares this morning, and raises the question of why this drug was approved at all. Still, Stifel analysts wrote that genotype-directed prescribing was already happening, and Margenza has disappointed commercially – consensus for 2026 sales has fallen by a third to $184m since the drug was launched, according to Evaluate Pharma. Investors are far more fixated on Macrogenics’ pipeline, with MGC018 a particular focus after a disappointing Asco presentation. An update is expected at Esmo.

A diminishing dataset? Overall survival analyses from Sophia
Sep 2021 (385 events)  Margetuximab Herceptin  Difference Hazard ratio
mOS – ITT population 21.6 months  21.9 months  -0.3 months  0.95 (p=0.62)
mOS – CD16A 158F allele* (around 82% of patients)  23.3 months  20.8 months  2.5 months  0.86 (p=0.19)
CD16A F/F* 23.6 months 19.2 months  4.4 months  0.72 (p=0.05)
CD16A F/V* 21.3 months 22 months  1.3 months  0.96 (p=0.78)
CD16A V/V* 22 months 31.1 months  -9.1 months  1.77 (p=0.04)
         
Oct 2019 (270 events) Margetuximab Herceptin  Difference Hazard ratio
mOS – ITT population 21.6 months 19.8 months 1.8 months 0.89 (p=0.326)
mOS – CD16A 158F allele* 23.7 months 19.4 months 4.3 months 0.79 (p=0.087)
         
Asco 2019 (158 events) Margetuximab Herceptin  Difference Hazard ratio
mOS – ITT population 18.9 months 17.2 months 1.7 months 0.95
mOS – CD16A 158F allele* 23.6 months 16.9 months 6.7 months 0.82
*Pre-specified, exploratory analysis. P values should be considered nominal. Source: company releases.

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