ASCO 2024 – Krazati looks more similar than different to Lumakras

Bristol Myers Squibb must have high hopes for Krazati, having spent nearly $5bn on its originator, Mirati – but data presented at ASCO today from the KRAS G12C inhibitor’s confirmatory lung cancer trial suggest that its performance is similar to that of Amgen’s troubled rival, Lumakras.

Meanwhile, other KRAS players are following fast, and data on one of these contenders, Lilly’s olomorasib, were also presented at the meeting.

Krystal clear 

The Krystal-12 study of Krazati in second-line KRAS G12C-mutant NSCLC hit convincingly on PFS. The absolute numbers are in line with those seen in Lumakras’s confirmatory trial, Codebreak-200; however, the reliability of the PFS result in Codebreak-200 was later called into question by an FDA adcom, which ultimately led to a CRL for Lumakras in December.

Cross-trial comparison of KRAS inhibitors in 2L KRAS G12C-mutant NSCLC

Source: ASCO 2024 & Oncology Pipeline.

Codebreak-200 succeeded on PFS, but missed on OS; in Krystal-12, OS data are still maturing and weren’t presented today.

Bristol will hope to avoid the drama that has enveloped its KRAS competitor, but even if Krazati’s current second-line accelerated approval is smoothly converted to a full approval there will still be questions about whether the company overpaid for Mirati: Krazati sold just $27m in the first quarter.

KRAS followers

And other contenders are coming, many with a different approach. For example, Roche’s planned phase 3 Krascendo-1 trial will compare its project divarasib head to head against Krazati or Lumakras in second-line NSCLC; that trial is due to start in the second half.

Meanwhile, Merck & Co recently jumped straight into a phase 3 trial of its project, MK-1084, in first-line NSCLC in combination with Keytruda, and Lilly is taking a similar approach with the Sunray-01 trial of olomorasib.

Today, Dr Timothy Burns of the University of Pittsburgh Medical Center presented data at ASCO on an olomorasib and Keytruda combo from two cohorts of the phase 1/2 LOXO-RAS-20001 study, one in first-line and the other in later-line NSCLC.

In first-line disease, across a range of PD-L1 expression levels, 13 of 17 patients had a response, giving an ORR of 77%. This stacks up well against the 63% ORR seen with Krazati plus Keytruda in the Krystal-7 first-line study, in patients with PD-L1 expression ≥50%.

In second-line NSCLC, the ORR with olomorasib dropped to 40% (17/43), but many of these patients had received prior immunotherapy, and some had previously been treated with a KRAS G12C inhibitor. 

More data on olomorasib monotherapy in various solid tumours are due to be presented at ASCO later today, from the same trial.

With so much competition coming, Bristol will need to make its lead count.