A closely watched Summit Therapeutics lung cancer drug showed trending improvement on a pivotal study’s measure of how long patients treated with the therapy lived, but the result in the final analysis in Western patients was not enough to be statistically significant — a shortfall that could keep the blockbuster hopeful from securing U.S. and European regulatory approvals.
The results are important because they’re the first Phase 3 data for an emerging class of drugs, bispecific antibodies designed to block two targets, PD-1 and VEGF. The results are also notable because ivonescimab thrust itself into the spotlight a year ago with data topping Merck’s juggernaut Keytruda, a monoclonal antibody that blocks PD-1, in a head-to-head study. Ivonescimab’s dual approach could help patients whose disease does not adequately respond to a PD-1 inhibitor alone.
The positive results reported last year were from patients enrolled in China, where ivonescimab’s inventor, Akeso, is based. Summit holds right to the drug in much of the rest of the world. The latest results from a global test of the drug were presented Sunday during the World Conference on Lung Cancer in Barcelona.
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The Phase 3 study enrolled 438 patients with locally advanced or metastatic non-small cell lung cancer. Ivonescimab was tested alongside chemotherapy and was compared to a placebo plus chemotherapy. The trial, named HARMONi, had two main goals: measuring progression-free survival, which is how long patients live without their disease worsening, and overall survival, the measure of how long patients live after starting treatment.
At a prespecified data analysis reported in May of this year, ivonescimab and chemo achieved a median progression-free survival of 6.8 months compared to 4.4 months for the control arm, a result that was statistically significant. The primary analysis also showed a positive trend for overall survival. A statistically significant result on this measure is key, because the FDA has said meeting this goal is a requirement for regulatory approval.
At the time of the primary analysis, Asian patients had a median of 30 months of follow-up. The latest results included a longer-term look in Western patients to increase their follow-up time, but the median follow-up in these patients was just 13.7 months. The final analysis shows median overall survival in these Western patients was 16.8 months for participants treated with ivonescimab plus chemotherapy compared to 14.0 months for those received placebo plus chemotherapy. But in North American patients specifically, median overall survival had not been reached in the study drug arm and was 14.0 months for the placebo arm. Summit said the drug’s safety and tolerability was consistent with earlier tests of the drug alongside chemo and no new safety signals were reported.
In a note sent to investors, Leerink Partners analyst Daina Graybosch said HARMONi had a flawed trial design that failed to test whether the signal observed in Chinese patients would translate globally.
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“We believe it is unlikely FDA will grant approval based on HARMONi nor that Summit will partner ivo(nescimab) at the substantial valuation expected by investors — greater than $15 billion with more than half upfront,” she said.
The readout confirmed the hypothesis that patient survival data reported in China would degrade in tests of the drug in patients in North America and Europe, Graybosch added. But from the limited information presented at the conference, it’s unclear what’s driving that degradation. For Leerink, more information is needed to appreciate the relevance of the HARMONi study as a benchmark for other bispecific antibodies going after PD-1 (or PD-L1) and VEGF, she said.
Bispecific antibodies addressing PD-(L)1 and VEGF are seen as promising for their potential to serve as backbones for new cancer drug combinations. Other companies developing bispecific antibodies for the two targets include Bristol Myers Squibb and BioNTech, which announced a wide-ranging partnership in June. BioNTech gained its contender, BNT327, from its acquisition of China-based Biotheus. Other companies developing bispecific antibodies for PD-(L)1 and VEGF include Merck, Instil Bio, and Pfizer — all with drugs in-licensed from companies in China.
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