An unexpected missed interim study in ivonecicimab’s high-profile Harmoni-3 study has sent Summit Therapeutics’ stock price plummeting, clouding the company’s momentum as its star PD-1xVEGF bispecific drug heads into the ASCO annual meeting with a shot at plenary honors.
In a recently added interim analysis, the Harmoni-3 squamous cohort clearly missed statistical significance in terms of progression-free survival (PFS). Summit announced Thursday that an independent data monitoring committee recommended that the study continue as planned and maintain a double-blind design.
The trial is evaluating Merck & Co.’s Keytruda plus chemotherapy in combination with ivonecicimab and chemotherapy as a first-line treatment for metastatic non-small cell lung cancer.
Summit’s stock price fell more than 25% in early trading Friday morning on the news. Analysts were widely stunned and scrambled to figure out what happened inside the black box.
Analysts at Leerink Partners wrote in a May 1 note to clients that the negative market reaction was not surprising. Harmoni-3’s global testing is so important that Summit has tweaked its design at least twice. The first is to separate squamous and non-squamous patients into two cohorts, and the second, announced in February, is to add a new interim analysis of PFS in the squamous group in the second quarter.
At the time, Summit framed the addition as an opportunity to discuss the possibility of early submission with health authorities, while the trial continues toward final PFS and preliminary overall survival measurements, which the company still expects to be in the second half of 2026.
Just because statistical significance is lost in an interim analysis doesn’t mean it’s over.
Summit said in an April 30 press release that “the bar to achieve statistical significance was significantly higher than the final PFS analysis planned for the future based on the minimal alpha spent on the interim analysis.”
But it remains a huge disappointment for investors. Two Chinese first-line NSCLC trials, Harmoni-2 and Harmoni-6, conducted by Akeso, the original developer of ibonecimab, both met the PFS endpoint at interim analysis. Initial studies showed that ivonecicimab monotherapy was 49% superior to Keytruda in terms of PFS in PD-L1-positive NSCLC. In the second study, ivonecishimab plus chemotherapy showed a 40% PFS advantage over BeOne Medicines’ Tevinbra plus chemotherapy in squamous NSCLC.
Analysts have tried to crunch the numbers, but without knowing the exact statistical plan, the analysis so far remains speculative.
“The alpha spent in the interim is likely minimal (~0.001), the bar is certainly high, and we believe the majority of the alpha will be saved for the final and support ultimate success,” Citi analysts said in a note Thursday.
Citi analysts suspected that the total number of PFS events that occurred was lower than expected, causing the lack of statistical significance. However, we could not rule out the possibility that the extent of PFS improvement was simply weak.
Leerink’s base scenario suggests that the PFS effect size is approximately 10 percentage points lower than that seen in Harmoni-6 due to lack of statistical significance. But the researchers cautioned that “substantial uncertainties remain,” citing several unknowns, most importantly the statistical design of the summit.
Harmoni-3’s latest PFS miss comes as an update on overall survival from Harmoni-6 is scheduled for the plenary session of the American Society of Clinical Oncology annual meeting starting later this month in Chicago.
The results were announced at the conference, which excited investors. Analysts at Leerink said in a note dated April 21 that the combination of ivonecicimab and chemotherapy is likely to provide a significant overall survival benefit, with at least a 28% improvement over tevinbra and chemotherapy.
Analysts at both Leerink and Evercore ISI suggested the stakes are even higher for Harmoni-6’s measurements.
“(A) reduced PFS benefit from China-to-global testing will make this combination a less attractive option,” Leerink wrote in a note Friday.
Comparing Harmoni-3 and Harmoni-6, the research team added, “The bar for excitement is even higher as investors expect global research benefits from China to decline.”
Similarly, the Evercore team wrote in a note Thursday that “if degradation is not as dramatic as previously thought, this could provide relief until H-3’s final PFS and interim OS in the second half of 2026.”
