Summit Therapeutics Takes FDA Rejection For Ivonescimab In EGFR-Mutated NSCLC, Delaying U.S. Entry For PD-1xVEGF

The FDA has issued a complete response letter to Summit Therapeutics, declining to approve ivonescimab for patients with previously treated, EGFR-mutated non-small cell lung cancer. The decision blocks the drug’s immediate U.S. launch and delays the domestic arrival of a PD-1xVEGF bispecific class that many industry players have viewed as a potential challenger to established PD-1 therapy.

The rejection lands on a filing that always carried more risk than enthusiasm around the broader class suggested. Summit’s initial application covered a niche setting, and the outcome indicates the FDA stayed anchored to a specific evidentiary bar on survival rather than accepting progression-free survival alone as sufficient support for approval.

The regulatory setback

According to Summit, the FDA said that without a statistically significant overall survival improvement, the company had not established substantial evidence of effectiveness. The agency also said that a progression-free survival benefit in the absence of a statistically significant overall survival result did not support a positive benefit-risk profile.

That logic tracks with the history of the filing. The phase 3 Harmoni trial behind the application failed to meet its overall survival endpoint even though the FDA had specifically demanded a statistically significant death reduction. At the primary overall survival analysis of the global Harmoni trial last year, the overall survival hazard ratio in the Western subgroup was 0.98, indicating no survival benefit for ivonescimab plus chemotherapy versus chemotherapy alone at that point.

Summit had argued that the Western overall survival data were too immature compared with the China cohort. The company also pointed to later data cuts showing the Western result improved to 0.76 by June 2026, matching the result from the full trial. The FDA, however, apparently did not move off its original overall survival requirement.

Why this matters beyond one filing

The immediate commercial impact is limited by the narrow indication, but the strategic effect is broader. A rejected niche filing removes what could have been the first U.S. commercial foothold for ivonescimab and gives competing PD-(L)1xVEGF developers more time as their own programs advance.

Fierce competition is already building. 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 being pushed into global phase 3 trials. In second-line EGFR-mutated NSCLC, ivonescimab’s absence also leaves more room for other mechanisms, including TROP2-directed antibody-drug conjugates such as AstraZeneca and Daiichi Sankyo’s Datroway and Merck’s Kelun-Biotech-partnered sac-TMT, along with Bristol Myers Squibb’s EGFRxHER3 bispecific ADC iza-bren.

The result also suggests that excitement around the PD-(L)1xVEGF class will not by itself lower the approval bar. For developers in the group, class momentum still has to translate into endpoint packages that satisfy the FDA in the exact setting being pursued.

What comes next for Summit

Attention now shifts to first-line NSCLC, which Leerink Partners analysts described in a Nov. 5 note as the real test for ivonescimab. In April, Summit unsettled investors when a newly added interim analysis of the Harmoni-3 trial’s squamous cohort missed statistical significance on progression-free survival. The squamous subgroup is now heading to a final progression-free survival analysis by the end of this year, while the nonsquamous cohort could report progression-free survival data in the first half of 2027.

Summit enters that next phase with financing in hand despite the CRL. Just weeks before the FDA decision, the biotech secured a $2 billion cash injection from AZ, giving it additional capacity to fund more ivonescimab trials. Before the rejection, Summit had also parted ways with chief commercial officer Robert LaCaze and several senior commercial and marketing leaders involved in launch planning, a sign that commercial preparations had already become harder to justify.

Outside the U.S., the asset still has regulatory and clinical support. In China, where Akeso developed the drug, authorities granted ivonescimab its first approval in May 2024 in tyrosine kinase inhibitor-pretreated EGFR-mutated nonsquamous NSCLC. The China-only Harmoni-A trial, part of which was merged into the global Harmoni trial, later met its overall survival endpoint at final analysis with a 26% death risk reduction.