Merck shoots for KRAS all comers

Merck & Co already has a phase 3 trial under way with its KRAS G12C inhibitor MK-1084 in PD-L1-high first-line lung cancer, and now it’s aiming at all comers. The Kandlelit-007 trial, just listed on clinicaltrials.gov and set to start in October, is also notable for combining MK-1084 with subcutaneous Keytruda, recently FDA approved as Keytruda Qlex.Kandlelit-007 will compare this combo versus Keytruda plus chemo, with a primary endpoint of progression-free survival. However, this is limited to patients with PD-L1 expression of 1% or higher; PFS in all comers is a secondary endpoint.A look at other KRAS G12C inhibitor players show different groups taking varying approaches in first-line NSCLC. Amgen, for example, has focused on PD-L1 negatives with a Lumakras/chemo combo, a decision likely spurred by liver enzyme elevations with Lumakras plus PD-(L)1 inhibitors in a mostly pretreated patient population.Meanwhile, Roche is focused solely on all comers with the Krascendo-2 trial of its contender divarasib. That study looks to have been delayed: its start date on ct.gov was previously given as May 2025, but is now December 2025.EarlyRoche recently disclosed plans to go even earlier with divarasib, into the adjuvant setting; Lilly is the only other player to have ventured here so far.Both Lilly and Bristol Myers Squibb are separately assessing PD-L1-high patients and all comers with their G12C inhibitors, olomorasib and Krazati respectively. But, unlike Merck, both of those groups have plumped for a combo with Keytruda and chemo in the all-comers population.It could be a while before it becomes clear which approach is best. Lilly’s olomorasib could be the first of the Keytruda combos to yield data, with the Sunray-01 trial set to complete next year.Another contender could be Revolution Medicines, which has said it plans to start “one or more pivotal combination trials” next year incorporating either its G12C-selective elironrasib, or its G12D-selective zoldonrasib. Western phase 3 studies of KRAS G12C inhibitors in 1st-line NSCLCTrialSettingRegimenPrimary endpointNoteMK-1084 (Merck & Co)Kandlelit-004PD-L1 ≥50%+ IV Keytruda, vs IV KeytrudaPFS, OSCompletes Feb 2029Kandlelit-007PD-L1 all-comers+ SC Keytruda, vs SC Keytruda + chemoPFS in PD-L1 ≥1%To start 27 Oct 2025Lumakras (Amgen)Codebreak-202PD-L1-negative+ chemo, vs Keytruda + chemoPFS, OSCompletes Jun 2026Olomorasib (Lilly)Sunray-01PD-L1 ≥50%+ Keytruda, vs KeytrudaPFSCompletes Oct 2026PD-L1 all comers+ Keytruda + chemo, vs Keytruda + chemoPFSKrazati (Bristol Myers Squibb)Krystal-7Ph3 portion: PD-L1 ≥50%+ Keytruda, vs KeytrudaPFS, OSData due 2028Krystal-4PD-L1 all comers+ Keytruda + chemo, vs Keytruda + chemoPFS, OSData due 2029Divarasib (Roche)Krascendo-2PD-L1 all comers+ Keytruda, vs Keytruda + chemoPFS, OSTo begin Dec 2025 (prev May 2025)Source: OncologyPipeline & clinicaltrials.gov.