A combination of the personalized cancer vaccine intismeran autogene and Merck’s Keytruda just barely cleared analysts’ expectations for recurrence-free survival, leaving questions as to its applicability to tumor types beyond melanoma.
Data for Merck and Moderna’s highly anticipated personalized cancer vaccine leaked online Thursday morning, days ahead of a headlining reveal at the European Society of Medical Oncology meeting in Spain. The results left analysts disappointed—and hoping that the real presentation might be more optimistic.
Analysts had been hoping to see a recurrence-free survival (RFS) hazard ratio below 0.60 for the combination of intismeran autogene and Merck’s immuno-oncology blockbuster Keytruda. According to the leaked results, which were quickly removed after the erroneous posting, the combo achieved a 0.58 hazard ratio, reducing the risk of recurrence or death by 42%.
“Investors were looking for these data to demonstrate a benefit in melanoma but also read to efficacy in other tumors,” BMO Capital Markets wrote on Thursday afternoon. “These results are not enough to drive confidence amidst elevated expectations.”
The leak also revealed that 82.2% of patients who received the vaccine combo were alive after two years of treatment, which is higher than the 70% achieved by Keytruda alone, BMO said. The risk of distant metastases or death dropped by 38%.
“Taken together, we see support for intismeran autogene providing a benefit across both measures of distant metastases and measures of survival, supporting a potential commercial opportunity for the combination regimen,” BMO said.
Merck went ahead and posted a press release with the data on Thursday afternoon. Prior to the presentation, the company told BioSpace in an interview that the results had met their bar for efficacy, with Jane Healy, Merck’s head of oncology early clinical development, heralding the moment as the culmination of decades of learning in oncology.
“This is not a subtle benefit,” she said. “It’s really exciting to have all these advancements in genome sciences and AI and machine learning, which is very much part of the algorithm in IO therapy, and mRNA technology, that have all come together to give [patients] something that is very specific for their cancer.”
However, investors appeared to have been pinning their hopes on an earlier Phase 2 study, in which the combo achieved a hazard ratio of 0.51, according to RBC Capital Markets in a Thursday afternoon note. Investors had therefore hoped for the Phase 3 result to land between 0.50-0.59, putting the 0.58 “at the low end of expectations.
“While approval seems likely, commercial success is far less certain. The data raises fundamental questions about INT’s value proposition relative to standards of care, particularly neoadjuvant immunotherapy, which produces similar efficacy at potentially much less cost,” RBC wrote.
Shares of both Merck and Moderna declined after the leak. Merck fell by just over 1% to $147.93—with a sharp pitch into the red around the time the data leaked. Moderna, which has been looking to the vaccine for its post-COVID comeback, dropped more significantly in the aftermath of the release by 21% to $193.65 apiece.
Big reputation
The full dataset for the Phase 3 INTerpath-001 trial was set to be published on Saturday at the ESMO Congress. The companies announced the headline news that the trial met its primary endpoint in August, but investors were looking to this readout for more specific details. At the time, both Moderna and Merck enjoyed a market surge on the news as investors had been cautious about the personalized vaccine’s potential.
With expectations now sky high, the full data landed with a thud.
“While Merck shares appear to be reacting negatively to this hazard ratio, we assert this relative reduction in recurrence/death is clinically meaningful,” BMO wrote. “Such a reaction likely reflects inflated expectations into the full data release, rather than a true indictment on the efficacy of the combo therapy.”
With that said, BMO noted that Keytruda alone offered prior to surgery reached the same hazard ratio as compared to offering the therapy after surgery during prior Phase 2 trials. This could raise “questions on the need for added intismeran therapy,” the firm said.
Overall survival data were not yet available, Healy said. Analysts searched the data for scraps of information on this endpoint anyway, with RBC suggesting that the trend appears to be favorable.
William Blair was a bit more pragmatic on the data leak, pointing to the fact that Moderna’s shares are still up 525% this year even with the reduction today.
“The information also suggests efficacy was similar across lower and higher disease groups; we wonder if that is an indication of efficacy across patients with differing tumor mutational burden,” the firm offered.
That could suggest that intismeran autogene may work for other tumors, the analysts continued. Merck and Moderna are testing the vaccine in renal cell carcinoma, non-small cell lung cancer, bladder cancer and other types of melanoma. Analysts are keenly watching the renal cell trial, in particular, with a readout expected later this year or early 2027.
“While intismeran results in melanoma support a future use in the indication, we caution investors when extrapolating to broader tumors,” BMO said. “Future success of personalized cancer vaccines beyond melanoma remain possible, but we need to see further data beyond INTerpath-001 to increase expected probability of success in these tumors.”
The Phase 3 data expanded the program into more than a thousand patients, adding more different stages of disease to provide a larger potential patient population, Healy explained.
“[The study] showed that regardless of whether they were high risk, metastatic stage—which is the highest risk—or if they were [stage] 2b versus 3, they all had the same opportunity to benefit from the therapy, according to the results,” Healy said, adding that there weren’t any other major subgroup differences either.
Melanoma commonly recurs even though surgeons are typically available to fully resect the cancer, Healy explained. Adding something that has the tolerability profile of a standard vaccine that can cut down on recurrence is likely to be highly appealing to oncologists.
“If you could give something in addition to [Keytruda] that significantly reduced the rate of your cancer coming back, that will change the trajectory of your whole experience with that cancer,” Healy said.
RBC seemed to agree with Healy ‘s assessment. “The INTerpath-001 data is clinically meaningful and likely approvable, offering patients an important new treatment option in high-risk melanoma,” the analysts wrote. The firm believes that the 0.58 hazard ratio should be enough to clear regulators in the U.S. and Europe. An FDA approval could arrive in 2027, as the companies are already engaging with regulatory authorities.
As for safety, the most common adverse events in INTerpath-001 were typical vaccine-like reactions, including fever, fatigue and swelling at the injection site. There were eight deaths in the treatment arm, but five occurred before the patients had received intismeran and the remaining three were not attributed to the vaccine.
