Merck also goes for all-comers in adjuvant lung

As the first-line battleground for KRAS-mutant lung cancer intensifies, the real land grab is shifting upstream. Big pharma groups are now racing to anchor next-generation KRAS G12C inhibitors, widely regarded as more potent than their first-wave predecessors, in earlier-stage disease.

The latest contender is Merck & Co. The company has posted a pivotal study on clinicaltrials.gov, Kandlelit-013, pairing its KRAS G12C inhibitor calderasib with the newly approved subcutaneous Keytruda Qlex, in the adjuvant lung cancer setting. 

The study will enrol patients with resectable or already resected stage IIA-IIIB, KRAS G12C-mutant NSCLC, including those previously treated with neoadjuvant Keytruda plus chemotherapy or with adjuvant chemo. 

The clinicaltrials.gov entry makes no mention of PD-L1 expression as a requirement in the inclusion criteria, suggesting that it will recruit all comers. 

The study, which is expected to begin in April, will randomise patients to calderasib plus Keytruda Qlex, versus Keytruda Qlex alone, with a primary endpoint of disease-free survival.

Lilly divergence

The design distinguishes Merck from one of its rivals, Lilly, which has already started a pivotal adjuvant lung cancer study of its contender olomosorasib. Lilly’s Sunray-02 includes two parts: one in stage II-IIIB resected, and one in stage III unresectable KRAS G12Cm NSCLC. 

In the former, olomosorasib is being combined with Keytruda, and in the latter with AstraZeneca's Imfinzi, given the latter drug's . The primary endpoint for part A is disease-free survival, with PFS being the main metric for part B. That trial's enrolment criteria call for PD-L1 expression to be measured, but don't mandate PD-L1 positivity.

Meanwhile, Roche has yet to disclose full details of Krascendo-3, the adjuvant study of its G12C inhibitor divarasib, flagged during its pharma day last September. It is expected that the company will pursue a similar combination strategy with a checkpoint inhibitor, though its patient selection criteria could ultimately serve as the main differentiator.

Whichever company delivers positive data first would break new ground for the class. 

While Bristol Myers Squibb's Krazati and Amgen's Lumakras are established in later-line disease, neither has advanced through pivotal trials in the neoadjuvant or adjuvant settings, and some phase 2 investigator-initiated trials were withdrawn because of slow accrual. 

Meanwhile, all the major KRAS G12C players are racing towards the front line, with two trials set to complete this year: Codebreak-202 featuring Lumakras and the Sunray-01 trial of olomorasib.

Phase 3 trials of KRAS G12C inhibitors in adjuvant KRAS G12Cm NSCLC

Note: *assumed. Source: OncologyPipeline.