As Bristol Myers Squibb attempts to convert two accelerated oncology nods for Krazati into traditional FDA approvals, the company has detailed a phase 3 flop in the KRAS G12C inhibitor’s smaller-opportunity indication of colorectal cancer.
The confirmatory phase 3 Krystal-10 study—which pitted a combo of Krazati (adagrasib) and Eli Lilly’s Erbitux (cetuximab) against chemotherapy in 461 patients with previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC)—failed to achieve statistical significance on either of its dual primary endpoints of progression-free survival (PFS) and overall survival (OS).
The study’s secondary endpoints revolved around objective response rate (ORR) and safety, according to an abstract of the data, which were presented late last week at the ESMO Gastrointestinal Cancers Congress 2026 in Munich, Germany.
Endpoints news and other outlets reported earlier this year that the trial had failed, although BMS did not divulge details around the miss until this past week.
Krazati—which BMS inherited in its $5.8 billion buyout of Mirati Therapeutics—scored an accelerated FDA approval in combination with Erbitux in chemotherapy-experience adults with KRAS-mutated locally advanced or metastatic CRC in June of 2024, at the time securing an edge over its first-to-market KRAS rival, Amgen’s Lumakras.
Under the FDA’s accelerated approval pathway, companies must run confirmatory studies like Krystal-10 to further validate their drugs and ultimately turn those speedy green lights into full approvals.
“While the study did not meet its primary endpoints, results from the final analysis of the study presented at ESMO GI support the clinical activity of the adagrasib plus cetuximab combination in this patient population,” a BMS spokesperson said of the data in a statement to Fierce.
BMS is now “discussing the data and potential next steps with regulatory authorities” and continues to be “encouraged by the broader opportunity in lung cancer, where two pivotal trials in first-line NSCLC are actively underway,” the spokesperson continued.
Krazati’s original U.S. nod, itself still an accelerated approval, was in KRAS-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) back in late 2022.
Overall, lung cancer represents a much larger market opportunity for Krazati in the U.S. than CRC. For all of 2025, Bristol’s KRAS inhibitor reeled in (PDF) $205 million, signaling growth of 62% over 2024.
Digging deeper into the Krystal-10 results, the Krazati-Erbitux regimen helped patients chart a median PFS of 7.5 months, lower than the 8.1-month figure achieved in the chemotherapy cohort. Meanwhile, at a minimum follow-up of 26.4 months, median overall survival (OS) also came down in favor of chemo (21.7 months) versus the Krazati combo (21.6 months). However, risk reductions on PFS and OS were in favor of the Krazati regimen at 11% and 17%, respectively.
BMS did point to a numerically higher ORR in the trial’s study drug arm, adding that Krystal-10 did not uncover any new safety signals for Krazati. The company has additionally pledged that “[f]urther analysis will be presented.”
“Together, while KRYSTAL-10 did not meet its primary endpoints, these results support the clinical activity of the adagrasib plus cetuximab combination therapy in previously treated patients with KRAS612C-mutated mCRC,” BMS said in an ESMO presentation slide shared at the weekend oncology conference.
The company also flagged a number of trial limitations that it argues may have complicated the study readout.
Namely, BMS pointed to limitations around PFS interpretation given the initiation of subsequent therapies before blinded independent central review (BICR) confirmation, as well as the fact that the higher proportion of patients in the chemotherapy arm subsequently receiving KRAS inhibitors “may have confounded OS outcomes.”
Lastly, BMS noted that its open-label trial design could have “introduced bias in efficacy assessment,” noting that discontinuation of treatment was “disproportionately high in the chemotherapy arm.”
While the fate of the drug in mCRC now hangs in limbo, data in Krazati’s inaugural NSCLC indication has posed problems for BMS before, too.
In the summer of 2024, the FDA sent an untitled letter to BMS taking issue with data presented on the efficacy page of a Krazati website targeted at healthcare professionals. At the time, the FDA argued that certain efficacy assertions on the site were misleading and not moored in the trial data that led to the drug’s accelerated lung cancer nod.
Beyond Krazati, Bristol has more colorectal cancer arrows in its quiver via its approved products Opdivo and Yervoy, indicated in a different patient population than the KRAS inhibitor.
On the clinical side of the equation, the company is currently running its BioNTech-partnered, clinical-stage bispecific antibody pumitamig through a phase 2/3 study in combination with chemotherapy in patients with previously untreated, unresectable or metastatic CRC.