Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC.
Authors: Burns Timothy F. , Dragnev Konstantin H. , Fujiwara Yutaka , Murciano-Goroff Yonina R. , Lee Dae Ho , Hollebecque Antoine , Koyama Takafumi , Cassier Philippe Alexandre , Italiano Antoine , Heist Rebecca Suk , Han Ji-Youn , Deming Dustin A. , Spira Alexander I. , Sabari Joshua K. , Chisamore Michael Jon , Fink Aaron Alan , Chen Aaron , Willard Melinda D , Oxnard Geoffrey R. , Ammakkanavar Natraj Reddy 
Published: June 2024

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Background: While immunotherapy (IO) is established as the cornerstone of first-line treatment for KRAS-mutant NSCLC, outcomes remain suboptimal. Further progress may be achieved with the addition of targeted therapy to IO, an established first-line paradigm in some other cancer types (RCC), but historically challenging in NSCLC. Here, we study pembrolizumab plus olomorasib, a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, in NSCLC patients treated on LOXO-RAS-20001, a phase 1/2 study of olomorasib in KRAS G12C-mutant solid tumors (NCT04956640). Methods: Patients (pts) with advanced KRAS G12C mutant NSCLC (tissue or plasma) in any treatment line, including prior KRAS G12Ci and/or prior IO were eligible. Dose escalation of olomorasib plus pembrolizumab followed a mTPI-2 method. Safety was evaluated across all pts dosed with the combination. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Results: As of 30 October 2023, 50 pts with advanced NSCLC received 50-150 mg BID PO olomorasib plus 200 mg Q3W pembrolizumab. Median age was 66 yrs (range, 42-83), median number of prior systemic therapies was 2 (range, 0-8), and 34% had received a prior KRAS G12Ci. During escalation, 2 of 6 ptstreated at 150 mg BID developed grade ≥3 LFTs, precluding further evaluation of this dose. In 44 pts treated at 50 or 100 mg BID, TRAEs ≥10% (related to olomorasib and/or pembrolizumab) were diarrhea (30%), ALT increased (20%), AST increased (18%), fatigue (14%), nausea (14%) and pruritus (11%); grade 3 TRAEs in ≥10% of pts were diarrhea (16%); pneumonitis was seen in 3 pts (grades 2/3/4). TRAEs led to olomorasib dose reduction in 14% of pts, olomorasib dose hold in 27%, and pembrolizumab dose hold in 18%. Due to TRAEs, 9% of pts discontinued olomorasib or pembrolizumab and 9% discontinued both. 27 pts remain on treatment, and 17 discontinued treatment (10 due to PD, 4 due to AE). Among the 30 efficacy evaluable KRAS G12Ci-naïve pts (60% IO pre-treated, 60% chemotherapy pre-treated), at a median follow-up of 6 months (95% CI, 4-7) ORR was 63% (15 PR, 4 unconfirmed PR pending/ongoing; 95% CI, 44-80) and DCR was 93% (28/30; 95% CI, 78-99); the median PFS was not estimable (95% CI, 5-NE); ORR was 75% (9/12) in PD-L1 ≥50%, 56% (10/18) in PD-L1 < 50%/unknown (3 pts PD-L1 unavailable). In 9 first-line pts, ORR was 78% (6 PR, 1 unconfirmed PR pending/ongoing; 95% CI, 40-97) and DCR was 100%. Conclusions: Olomorasib (50 or 100 mg BID) in combination with pembrolizumab demonstrated favorable safety and antitumor activity in pts with KRAS G12C-mutant advanced NSCLC, supporting further development in first-line NSCLC. A global, registrational study investigating this combination in first-line NSCLC is currently enrolling (SUNRAY-01, NCT06119581). Clinical trial information: NCT04956640 .