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
Project | MK-1084 (Merck & Co) | Krazati (Mirati) |
---|---|---|
Trial | Ph1 (NCT05067283) | Krystal-7 (NCT04613596) |
PD-1 inhibitor | Keytruda | Keytruda |
N | 24 | 148* |
ORR | 71% (15/21) | 49% (26/53)** |
ORR in PD-L1 TPS ≥50% | 75% (9/12) | 63% (32/51)* |
ORR in PD-L1 TPS 1-49% | 67% (6/9) | 48% (10/21)** |
ORR in PD-L1 TPS <1% | N/A | 30% (3/10)** |
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.
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