ASCO: Bristol Myers' KRAS Data Clear of Amgen's Issues but FDA Approval Uncertain

Bristol Myers Squibb (BMS) faces a challenging path to securing full FDA approval for Krazati, a drug targeting KRAS G12C-mutated non-small cell lung cancer (NSCLC). Despite promising data from its KRYSTAL-12 trial, questions linger about the drug's effectiveness and overall survival (OS) benefits.

BMS's KRYSTAL-12 trial showcased Krazati's ability to reduce the risk of tumor progression or death by 42% compared to the chemotherapy drug docetaxel. This result was presented at the American Society of Clinical Oncology annual meeting in Chicago. The trial aimed to demonstrate Krazati's progression-free survival (PFS) advantage, revealing a median PFS of 5.49 months for Krazati versus docetaxel's 3.84 months. However, this 1.65-month difference may not be sufficient to meet the FDA's expectations for clinical meaningfulness.

The FDA has previously expressed concerns about the clinical significance of PFS improvements. In a 2019 meeting regarding Amgen's KRAS inhibitor, Lumakras, the FDA indicated that a PFS improvement of 3.2 months might not be clinically meaningful without accompanying OS data. BMS’s Chief Medical Officer Samit Hirawat, M.D., emphasized that PFS should be viewed in the context of the entire range of results rather than just the median value. In KRYSTAL-12, Krazati's PFS ranged from 4.5 to 6.7 months, compared to docetaxel's 2.7 to 4.7 months, suggesting a broader benefit.

Despite these results, KRYSTAL-12 has not yet accumulated enough data for an OS analysis, leaving BMS unable to provide definitive survival benefits. This is a critical concern, as the FDA has previously required either clinically meaningful PFS improvements or statistically significant OS differences for drug approvals. BMS remains blinded to the OS endpoint and awaits further data accrual.

Krazati received accelerated approval in December 2023 for second-line treatment of KRAS G12C-mutated NSCLC. The KRYSTAL-12 trial serves as the confirmatory study for this approval. In contrast, Amgen's Lumakras faced regulatory hurdles when the FDA refused to convert its accelerated approval into a full approval due to issues in the phase 3 CodeBreaK 200 trial. Challenges in patient dropout rates and early progression assessments for chemotherapy patients in the open-label trial raised concerns about the reliability of its results.

To address similar potential issues, BMS's KRYSTAL-12 trial employs a blinded independent central review to assess progression before allowing patients to cross over to receive Krazati. This approach aims to mitigate biases seen in the Amgen trial. Additionally, Krazati demonstrated a 43% improvement in PFS by investigators' analysis, with fewer discontinuations due to adverse events (13% for Krazati versus 18% for chemotherapy).

Liver toxicity remains a significant concern in KRAS inhibitor treatments. BMS reported that most liver-related adverse events in KRYSTAL-12 were manageable and of grade 1 severity, following established protocols.

While the FDA denied Lumakras a full approval, it has allowed the drug to remain on the market pending further confirmatory studies, expected to conclude by February 2028. BMS may face a similar scenario with Krazati if it seeks full approval based on current data. Hirawat refrained from commenting on BMS's regulatory strategy but highlighted PFS as a potential endpoint for discussions with drug authorities.

BMS acquired Krazati through the purchase of Mirati Therapeutics for up to $5.8 billion, aiming to expand the drug's reach. Ongoing phase 3 studies are evaluating Krazati in combination with Merck's Keytruda for first-line treatment of KRAS G12C-mutated NSCLC with high PD-L1 expression. Another phase 3 trial will explore combining Krazati, Keytruda, and chemotherapy for patients with lower PD-L1 expression, including those with PD-L1-negative tumors. BMS plans to finalize and announce the trial design later this year, aiming for initiation by early next year.