ESMO 2023 – Merck makes its KRAS entrance

So far, efforts to move KRAS G12C inhibitors into first-line non-small cell lung cancer have largely fallen flat. Now first-in-human human data on Merck & Co’s MK-1084 combined with Keytruda, presented in an ESMO poster, suggest that the group could have a contender here. On the face of it, a 71% ORR across all patients, rising to 75% in those with PD-L1 expression of 50% or more, compares favourably with the 63% ORR that Mirati reported on Friday with Krazati plus Keytruda in PD-L1 ≥50% expressers in the Krystal-7 trial. However, there are reasons to be cautious: Merck’s study did not include <1% PD-L1 expressers, who dragged down the overall Krystal-7 result. And neither trial was controlled; Mirati, soon to be part of Bristol Myers Squibb, plans a phase 3 first-line trial of Krazati plus Keytruda versus Keytruda alone in ≥50% expressers. Amgen’s Lumakras, meanwhile, produced an unimpressive 29% ORR in its PD-(L)1 combo study, but this was not exclusively in first-line disease, so is not really comparable. As for adverse events, there was one dose-limiting toxicity of liver enzyme elevations with MK1084 plus Keytruda, despite Merck’s claim that it could have a more tolerable agent.

Cross-trial comparison of KRAS G12C/PD-1 combos in 1L NSCLC

Note: Mirati cites 39% & 45% ORR in Keynote-42 & Keynote-24 as SOC benchmark in TPS ≥50%; TPS=tumour proportion score; *reported at ESMO 2023; **reported at ESMO-IO Dec 2022.