KRAS Inhibitors Will Struggle to Penetrate the First Line Treatment of NSCLC
KRAS remains one of the most attractive targets in oncology, and it is not considered undruggable anymore after the FDA approval of the KRAS G12C inhibitors Amgen’s Lumakras (sotorasib) and BMS’ Krazati (adagrasib). Lumakras received FDA accelerated approval first in May 2021, followed by Krazati in December 2022, both for metastatic previously treated KRAS G12C-mutant non-small cell lung cancer (NSCLC) patients.
Lumakras experienced a setback in December 2023 when the FDA refused to convert the accelerated approval to a full approval based on the results of the Phase III CodeBreaK 200 study where Lumakras barely managed to beat docetaxel (median progression-free survival [PFS] of 5.6 months vs 4.5 months for docetaxel). It also failed to show an overall survival (OS) advantage. Recently, BMS announced that the Phase III trial KRYSTAL-12 of Krazati met the primary endpoint of PFS, however the OS data were immature. If the PFS advantage over docetaxel is larger than Lumakras, Krazati stands a good chance of being converted to a full approval in the future.
Both drugs are in trial for newly-diagnosed patients as well, Lumakras in combination with chemotherapy and Krazati with Merck’s PD-1 inhibitor Keytruda (pembrolizumab). Recently, Eli Lilly entered the race of G12C inhibitors in newly-diagnosed NSCLC with the initiation of the Phase III SUNRAY-01 trial for the combination of LY3537982 + Keytruda ± chemotherapy. Arm B of the trial has the strange provision for enrolling patients with PD-L1 expression over 50% onto the triplet arm, even though the addition of chemotherapy for these patients has been shown to not generate any added benefit.
KRAS inhibitors in NSCLC so far have been plagued by problematic clinical trial designs and based on the data seen so far in the second line and beyond, it appears that KRAS inhibitors will have trouble penetrating the first line of therapy where immune checkpoint inhibitors with or without chemotherapy are currently the standard of care. However, there is also the possibility that next-generation KRAS G12C inhibitors will offer either substantially better efficacy or tolerability and succeed.
By Sakis Paliouras, PhD
