Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with <i>KRAS</i> G12C-mutant advanced solid tumors.

3007 Background: Olomorasib is a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, which preclinically delivers &gt;90% sustained target occupancy. Here, we report updated results from LOXO-RAS-20001, a phase 1/2 study of olomorasib in patients with KRAS G12C-mutant advanced solid tumors (NCT04956640). Methods: Patients (pts) with advanced solid tumors positive for KRAS G12C (tissue or plasma) were eligible. Dose escalation used a mTPI-2 method, followed by expansion cohorts in NSCLC (with/without prior G12Ci), CRC, and other solid tumors. Safety was evaluated across all pts dosed. 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. Serial ctDNA analysis was performed using FoundationOne Liquid CDx. Results: As of 30 October 2023, 157 pts (58 NSCLC, 32 CRC, 24 PANC, 43 other solid tumors) received single agent olomorasib (50-200 mg BID PO); 29 pts with NSCLC had received a prior KRAS G12Ci. Median age was 65 yrs (range, 36-85), median number of prior systemic therapies was 3 (range, 0-11). Any grade TRAEs were 62%; TRAEs ≥10% were diarrhea (24%), fatigue (10%), and nausea (10%); grade ≥3 TRAEs were 5%. TRAEs led to dose hold in 10% of pts, dose reduction in 3%, and discontinuation in 2%. Among 10 pts treated after discontinuing prior G12Ci due to toxicity (5/10 due to LFT increase), 1 pt (10%) required olomorasib dose reduction and none discontinued due to toxicity. 68 pts are ongoing and 89 discontinued treatment. 146 pts were efficacy evaluable (120 G12Ci-naïve; 26 with prior G12Ci) with a median follow-up of 10 months (95% CI, 7-13). As anticipated, ORR was lower in 32 pts with CRC (9%, 3 PR; DCR 84%) 1 and higher in 88 pts with non-CRC tumors (40%, 30 PR and 5 uPR pending/ongoing in 13 unique tumor types; DCR 90%). mPFS ranged across tumor types from 4 months (CRC, 95% CI, 3-7) to 9 months (NSCLC, 95% CI, 3-NE). In the 26 efficacy evaluable NSCLC pts with prior KRAS G12Ci treatment (16 discontinued due to PD, 9 due to AE), the ORR was 39% (9 PR, 1 uPR pending/ongoing; DCR 73%); mPFS was 6 months (95% CI, 3-NE). In 37 pts with ctDNA results at baseline and ongoing, ctDNA response (&gt;50% KRAS G12C VAF reduction) was seen in pts with PR (11/11), SD (17/22), and PD (1/4). Conclusions: Olomorasib demonstrates efficacy across a range of KRAS G12C-mutant solid tumors with a favorable safety profile including in pts with prior G12Ci intolerance. Activity of the second-generation G12Ci olomorasib after prior exposure to G12Ci demonstrates the increased potency and target coverage these agents can deliver compared to first generation inhibitors. Phase 2 expansion is currently enrolling pts with PANC, and a global registrational study investigating olomorasib in combination with pembrolizumab in first-line NSCLC is ongoing (NCT06119581). 1. Hollebecque A. et al. ASCO-GI 2024. Clinical trial information: NCT04956640 .

Topic: Protein Kinase Regulation and GTPase Signaling
Subfield: Molecular Biology
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences