The immuno-oncology revolution will have to wait.
The FDA has issued a complete 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 drug class that many industry heavyweights believe could eventually dethrone Merck & Co.’s Keytruda.
Summit’s initial application targeted a niche, and as Leerink Partners analysts pointed out in a Nov. 5 note, the limitations of the clinical trial behind the application are not directly transferable to Summit’s broader development program for ivonescimab.
To industry watchers, the regulatory snub does not come as a total surprise. In their Nov. 5 note, Leerink analysts assigned Summit’s bid a 40% probability to approval. That’s because the phase 3 Harmoni trial underpinning Summit’s application failed to meet its overall survival (OS) endpoint, even as the FDA specifically demanded a statistically significant death reduction.
At the primary overall survival analysis of the global Harmoni trial last year, the OS hazard ratio was 0.98 in the Western subgroup, indicating no survival benefit for ivonescimab plus chemotherapy versus chemo alone at that time. Summit argued that the OS data in the Western cohort was too immature compared to the China cohort, and subsequent data cuts showed that Western results improved to 0.76 by June 2026, matching the result from the entire trial. The FDA, however, apparently decided to stick with its OS requirement.
In the CRL, the FDA noted that, without a statistically significant OS improvement, Summit has not established substantial evidence of effectiveness, and that a progression-free survival (PFS) benefit in the absence of a statistically significant OS does not support a positive benefit-risk profile in support of approval, according to Summit.
“We are disappointed for patients and their families awaiting additional treatment options in this setting,” Robert Duggan, chairman and co-CEO of Summit said in a Nov. 15 release.
Before FDA handed out the rejection, Summit had parted ways with its chief commercial officer Robert LaCaze and several senior commercial and marketing leaders who were tasked with building ivonescimab’s launch plan.
Meanwhile, back 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 tyrosine kinase inhibitor-pretreated EGFR-mutated nonsquamous NSCLC. Then, the China-only Harmoni-A trial, part of which was merged into the global Harmoni trial, met its OS endpoint at the final analysis with a 26% death risk reduction.
Ivonescimab’s setback has narrowed its potential first-mover advantage as several pharma giants—including Merck—race to advance their own PD-(L)1xVEGF bispecifics.
Pfizer’s 3SBio-partnered tivunatamig (PF-08634404), BioNTech and Bristol Myers Squibb’s pumitamig, Merck’s MK-2010 and AbbVie’s ABBV-1480 are all getting pushed into global phase 3 trials.
Even in the second-line EGFR-mutated NSCLC space, ivonescimab’s absence 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’ dual-targeting EGFRxHER3 bispecific ADC, iza-bren.
Now, attention around the PD-(L)1xVEGF class is shifting to the all-important first-line NSCLC setting. As Leerink’s analysts noted, the real test for ivonescimab remains the upcoming readout from the Harmoni-3 trial in first-line NSCLC.
Summit scared investors in April, when a newly added interim analysis of the trial’s squamous cohort missed statistical significance on PFS. The squamous subgroup is now moving toward a final PFS analysis by the end of this year, and the nonsquamous group could report PFS data in the first half of 2027.
Despite the regulatory sting, Summit is far from defeated. Just weeks before the FDA’s decision, the biotech secured a $2 billion cash injection from AZ.
The company now has the financial firepower to fund additional trials for ivonescimab, and AZ plans to pair its sprawling ADC pipeline with the PD-1xVEGF drug, an approach that some considered the next-frontier in immuno-oncology.
“With five positive Phase III studies between Summit and Akeso, nothing changes with respect to our ever-growing belief in the opportunity for ivonescimab and our determination to advance ivonescimab’s development,” Duggan said. “Our mission remains to improve outcomes for patients facing significant unmet needs, which is work worth doing, and we will continue through our expansive clinical development program.”