Mirati Therapeutics, Inc.

The future of Bristol Myers Squibb's Krazati (adagrasib) in colorectal cancer (CRC) may be on thin ice after the oral KRAS inhibitor failed its confirmatory study. A spokesperson for BMS on Friday confirmed to FirstWord that the Phase III KRYSTAL-10 trial missed its primary endpoint.BMS acquired the drug via its $5.8-billion purchase of Mirati Therapeutics in early 2024. Krazati was granted an accelerated approved by the FDA a few months later for use in combination with cetuximab to treat KRAS G12C-mutated, locally advanced or metastatic CRC in patients who previously received certain types of chemotherapy (see – Physician Views Results: BMS's Krazati will be a 'somewhat impactful' colorectal cancer treatment, say nearly two-thirds of oncologists).It was originally cleared in 2022 for KRAS-mutant locally advanced or metastatic non-small-cell lung cancer (NSCLC) in the second-line setting. The CRC nod was based on data from the Phase I/II KRYSTAL-1 study where Krazati demonstrated a confirmed overall response rate of 34% in 94 patients with the disease. Additionally, the cohort experienced a median duration of response of 5.8 months. KRYSTAL-10 was comparing Krazati plus cetuximab versus chemotherapy as a second-line treatment in 461 CRC patients with KRAS G12C mutations; overall survival and progression-free survival were the dual primary endpoints. It was slated to complete in July.BMS said it would share results at an upcoming scientific congress or publication, and will discuss the findings and potential next steps with regulators.'Broader opportunity' in lung cancerThe company spokesperson said, "We remain encouraged by the broader opportunity in lung cancer, where two pivotal trials in first-line NSCLC are actively underway," including KRYSTAL-4 and KRYSTAL-7.The drug generated sales of $205 million in 2025, which was up 62% from the year before.The setback cedes momentum to Amgen's rival KRAS inhibitor Lumakras (sotorasib), which won FDA approval early last year in second-line CRC as a combo with Vectibix (panitumumab) based on Phase III data from the CodeBreaK 300 study. The regimen was associated with a statistically significant 52% reduction in the risk of disease progression or death, compared to investigator's choice.Lumakras is currently being studied in the Phase III CodeBreaK 301 trial in treatment-naïve patients with CRC and KRAS p.G12C mutations. Primary completion is slated for early 2028. For an in-depth overview of the CRC space, including KRAS inhibitors, see – FirstWord's KOL Insight - Colorectal Cancer.

Bristol Myers Squibb’s cancer drug Krazati has failed its confirmatory study in second-line colorectal cancer, a company spokesperson confirmed to Endpoints News . Krazati had received accelerated approval in 2024 in this setting. But a Phase 3 study missed its primary endpoint, failing to confirm the benefit seen in an earlier trial and putting the drug at risk of losing its colorectal cancer approval. Earlier on Thursday, Bristol Myers disclosed it had removed a Phase 3 Krazati trial from its pipeline, but its status was unclear. A BMS spokesperson did not directly answer whether the study had failed Thursday morning. Later Thursday afternoon, Bristol Myers confirmed the study failure after Endpoints follow-ups. The full results will be disclosed at a future medical meeting, the company spokesperson said, and BMS plans to “discuss the findings and potential next steps with regulatory authorities.” The FDA has previously reprimanded Bristol Myers for publishing what it called “misleading” information about the drug’s efficacy in lung cancer on a website promoting it. In 2024, the agency said the company’s website inappropriately reported the depth of response and that 80% of patients experienced tumor shrinkage. The 80% figure included patients who had stable disease, often abbreviated as SD. As a single-arm trial, “the study did not establish that the SD result was attributable to the effect of the drug,” the FDA said at the time. Krazati is a first-generation KRAS inhibitor, targeting a tumor mutation long considered to be undruggable. Originally approved in lung cancer in 2022, Krazati earned a label expansion into colorectal cancer based on a Phase 1/2 trial showing patients’ tumors shrank by at least 30%. In that study, 32 of 94 patients reached that 30% threshold, while none of their tumors disappeared completely. The median duration of response was 5.8 months. Bristol Myers released updated data from that study earlier this month at AACR. But with the larger confirmatory trial missing its goal, Krazati could lose its colorectal cancer approval. The disease setting was expected to be a smaller market for Krazati than lung cancer — Jefferies analysts estimated colorectal cancer sales to peak at $420 million annually, compared to $1.4 billion in non-small cell lung cancer. Krazati is not the first KRAS drug to face a failed confirmatory trial. In 2023, Amgen’s Lumakras was denied full approval in lung cancer after an advisory committee determined key data could not be reliably interpreted. The FDA asked Amgen to conduct another trial, which the company has until 2028 to complete. Newer KRAS-targeting drugs have seen recent success in clinical trials, however. Krazati and Lumakras were developed for one mutation called G12C that makes up roughly one in eight non-small cell lung cancer cases. But Revolution Medicines’ daraxonrasib, which is a pan-RAS drug, doubled the survival time in patients with advanced pancreatic cancer. And a number of other drugmakers are attempting to outdo Lumakras and Krazati in lung cancer. Bristol Myers acquired Krazati in its $4.8 billion buyout of Mirati Therapeutics in 2023.

Wall Street’s expectations for Bristol Myers Squibb’s upcoming slate of data readouts are reaching a fever pitch. Analysts lobbed questions regarding at least half a dozen trial results expected by the end of 2026, in a year that’s shaping up to be a pivotal one for Bristol Myers . The studies will help BMS chart its future as the company manages two looming patent cliffs for the blood thinner Eliquis and immunotherapy Opdivo. If the trials succeed, Bristol Myers should be able to bridge those cliffs with an eye toward growth in the 2030s. But in a sobering reminder of the challenges of drug development, the company also said a Phase 3 confirmatory study for the KRAS drug Krazati failed in second-line colorectal cancer. Other first-generation KRAS drugs have struggled to gain full approval. In 2023, Amgen’s Lumakras was denied full approval in lung cancer. The full results will be disclosed at a future medical meeting, a company spokesperson said, and BMS plans to “discuss the findings and potential next steps with regulatory authorities.” Colorectal cancer had been projected as one of Krazati’s smaller markets. Jefferies analysts previously pegged peak sales in this area at $420 million annually. Bristol Myers acquired Krazati in its $4.8 billion buyout of Mirati Therapeutics. Pipeline excitement has been building for a while, and three drugs drew the most interest on the call: Cobenfy, which has three studies in Alzheimer’s-associated psychosis currently ongoing; milvexian, a next-generation blood thinner; and pumitamig, Bristol Myers’ PD-1xVEGF bispecific being developed in partnership with BioNTech. Cristian Massacesi, BMS’ new chief medical officer, said the Cobenfy studies should provide results around the same time later this year, noting BMS will need two of the three trials to be successful in order to get approval. Alzheimer’s-associated psychosis is a key area for Cobenfy, which is already approved for schizophrenia, to justify the $14 billion Bristol Myers spent for Karuna. Despite the landmark schizophrenia approval in 2024, Cobenfy failed to improve symptoms in the adjunctive setting last year. But “the confidence remains unchanged,” Massacesi said. Milvexian, meanwhile, is looking for a win after it failed a Phase 3 study last year, for appearing unlikely to prevent major heart events such as heart attack or stroke. Bristol Myers, which is developing milvexian with Johnson & Johnson, is still testing whether the drug can work in other heart conditions like atrial fibrillation and secondary stroke prevention. Both of those trials should have results this year. Given the earlier failure, analysts appeared particularly interested in the range of results for these trials, with one noting on the call there will likely be “a rich set of outcomes between a clean win and miss.” Massacesi did not get into specifics, saying only that the studies remain “on track” for this year. Pumitamig’s first pivotal data won’t arrive until at least 2028, but earlier-stage studies may have data this year. Editor’s note: This story and headline have been updated to new include information about the failure of a confirmatory study for Krazati.