Krazati nearer to full FDA nod after confirmatory lung cancer study win

29 Mar 2024
firstwordpharma.com
Phase 3Clinical ResultDrug ApprovalAccelerated Approval
Bristol Myers Squibb is a step closer in its quest for full FDA approval of Krazati (adagrasib) in non-small-cell lung cancer (NSCLC), announcing that the KRAS blocker met the primary endpoint of progression-free survival (PFS) in a confirmatory trial.
The drug, originally developed by Mirati Therapeutics, was granted an accelerated approval in 2022 for second-line KRAS-mutated NSCLC based on results from the single-arm mid-stage KRYSTAL-1 trial demonstrating a 43% objective response rate (ORR).
The company now says that the pivotal Phase III KRYSTAL-12 study, which included 453 patients, showed a significant benefit with Krazati on time to disease progression or death when used as a second- or later-line treatment for locally advanced or metastatic NSCLC that carries a KRASG12C mutation. The drug was compared to standard-of-care chemotherapy.
Study ongoing to assess OS
Krazati also achieved the secondary goal of ORR in KRYSTAL-12, although Bristol Myers Squibb said the trial remains ongoing to assess the additional key secondary endpoint of overall survival (OS). There were no new safety signals and the safety results were consistent with the drug's known profile, it added.
"We are encouraged by the results from KRYSTAL-12," said Abderrahim Oukessou, global programme lead for Krazati at Bristol Myers Squibb, which got hold of the drug through its $5.8-billion takeout of Mirati that closed at the start of the year. A detailed analysis of the trial is underway, with results to be shared at an upcoming medical conference and with health authorities.
EU regulators approved Krazati in January for second-line NSCLC after reconsidering their initial intention of rejecting the drug.
Pulling ahead?
The KRYSTAL-12 top-line readout comes on the heels of Amgen's setback with rival KRAS inhibitor Lumakras (sotorasib). The drug has also received an accelerated approval by the FDA in second-line NSCLC patients, although about 18 months before Krazati, based on ORR data from the CodeBreaK 100 study.
Amgen later submitted Phase III CodeBreaK 200 results in its bid to convert that to a traditional approval. However, the FDA issued a complete response letter to Amgen in December, requesting an additional confirmatory study to prove Lumakras' benefit.
While CodeBreaK 200 met its primary endpoint with a PFS benefit of 34% for Lumakras over docetaxel, that failed to sway an FDA advisory panel, which voted that the data could not be reliably interpreted. Ahead of the vote, FDA staff scientists had also suggested the survival results were "uncertain," and cast doubt on whether the study could be considered "adequate and well-controlled." For more, see Vital Signs: Do KRAS blunders weigh down targeted therapy in lung cancer?
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