The immuno-oncology revolution will have to wait.
The FDA has issued a comprehensive response letter to Summit Therapeutics, declining to approve the highly anticipated PD-1xVEGF bispecific ivonescimab for patients with previously treated EGFR-mutated non-small cell lung cancer.
The rejection derails the immediate U.S. launch of a class of drugs that many industry heavyweights say could eventually dethrone Merck & Co.’s Keytruda.
Summit’s initial application was niche and, as analysts at Leerink Partners pointed out in a Nov. 5 note, the clinical trial limitations behind the application are not directly transferable to Summit’s broader development program for ivonescimab.
For industry observers, the regulatory snub is not entirely a surprise. In their November 5 note, Leerink analysts gave Summit’s offer a 40% probability of approval. Indeed, the Phase 3 Harmoni trial that underpinned Summit’s application failed to meet its overall survival (OS) endpoint, even though the FDA specifically required a statistically significant reduction in deaths.
In the first overall survival analysis of the global Harmoni trial last year, the OS hazard ratio was 0.98 in the Western subgroup, indicating that at that time there was no survival benefit from ivonescimab plus chemotherapy and chemotherapy alone. Summit argued that the OS data in the Western cohort was too immature compared to the Chinese cohort, and subsequent data cuts showed that the Western results improved to 0.76 in June 2026, matching the result of the entire trial. The FDA, however, has apparently decided to stick with its operating system requirements.
In the CRL, the FDA noted that, without a statistically significant improvement in OS, Summit has not established substantial evidence of effectiveness, and that a progression-free survival (PFS) benefit in the absence of statistically significant OS does not support a positive benefit-risk profile to support approval, according to Summit.
“We are disappointed for patients and their families who are awaiting additional treatment options in this setting,” Robert Duggan, Summit’s president and co-CEO, said in a Nov. 15 statement.
Before the FDA’s denial, Summit had parted ways with its chief commercial officer, Robert LaCaze, and several senior sales and marketing executives responsible for developing the ivonescimab launch plan.
Meanwhile, in China, where ivonescimab’s original developer, Akeso, is in charge, authorities granted the drug its first approval in May 2024 in the same indication of EGFR-mutated non-squamous NSCLC pretreated with a tyrosine kinase inhibitor. Then the China-only Harmoni-A trial, part of which was merged into the global Harmoni trial, met its final OS endpoint with a 26% reduction in the risk of death.
Ivonescimab’s setback has reduced its potential first-mover advantage as several pharmaceutical giants, including Merck, race to advance their own PD-(L)1xVEGF bispecifics.
Tivunatamig (PF-08634404) in partnership with Pfizer’s 3SBio, BioNTech’s pumitamig and Bristol Myers Squibb, Merck’s MK-2010 and AbbVie’s ABBV-1480 are all being pushed into global Phase 3 trials.
Even in the second-line EGFR-mutated NSCLC space, the absence of ivonescimab means one less competitor for TROP2-directed antibody-drug conjugates such as AstraZeneca and Daiichi Sankyo’s Datroway and Merck’s Kelun-Biotech-partnered sac-TMT, as well as BMS’s dual-targeting EGFRxHER3 bispecific ADC, iza-bren.
Now, the focus around the PD-(L)1xVEGF class is shifting to the very important endpoint of first-line NSCLC. As Leerink analysts noted, the real test for ivonescimab remains the upcoming Harmoni-3 trial in first-line NSCLC.
The peak spooked investors in April, when a newly added interim analysis of the trial’s squamous cohort failed to have statistical significance on PFS. The squamous subgroup is now moving toward a final PFS analysis by the end of this year, and the non-squamous group could report PFS data in the first half of 2027.
Despite the regulatory challenges, Summit is far from defeated. Just weeks before the FDA’s decision, the biotech got a $2 billion cash infusion from AZ.
The company now has the financial muscle to fund additional trials of ivonescimab, and AZ plans to combine its extensive ADC pipeline with the PD-1xVEGF drug, an approach that some consider the next frontier in immuno-oncology.
“With five positive Phase III studies between Summit and Akeso, nothing changes regarding our ever-increasing confidence in the opportunity for ivonescimab and our determination to advance ivonescimab development,” Duggan said. “Our mission remains to improve outcomes for patients with significant unmet need, making it worthwhile, and we will continue our extensive clinical development program.” »
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