Efficacy and safety of olomorasib, a second-generation KRAS G12C inhibitor, plus cetuximab in <i>KRAS</i> G12C-mutant advanced colorectal cancer.

3507 Background: Olomorasib, a potent and selective second-generation KRAS G12C inhibitor (G12Ci), has demonstrated promising efficacy and a favorable safety profile in KRAS G12C-mutant cancers. Based on emerging nonclinical and clinical data, combining a KRAS G12Ci with cetuximab offers a compelling opportunity to improve outcomes in patients (pts) with KRAS G12C-mutant colorectal cancer (CRC). Here we report updated results from a phase 1/2 study (NCT04956640) on the safety, tolerability and optimal dose of olomorasib + cetuximab in pts with KRAS G12C-mutant CRC. Methods: Pts with advanced KRAS G12C-mutant CRC (tissue or plasma) previously treated with ≥1 prior oxaliplatin- or irinotecan-containing regimen were eligible and enrolled into dose escalation/expansion or optimization at 2 doses of olomorasib (100 and 150 mg, orally BID). Dose escalation of olomorasib + cetuximab followed a mTPI-2 method. Key objectives were safety and to determine the optimal dose of olomorasib + cetuximab. Antitumor activity per RECIST v1.1 was studied in pts with ≥1 post-baseline response assessment or who discontinued before a first response assessment. Results: As of 13 November 2024, 93 pts received olomorasib + cetuximab in dose escalation/expansion (n=49) or optimization (n=44). Median age was 58 yrs (range, 35-82) and median number of prior therapies was 3 (range, 1-8). All grade TRAEs in ≥20% of pts were dermatitis acneiform (58%), diarrhea (38%), dry skin (31%), paronychia (28%), hypomagnesemia (26%), and rash (26%). The majority of TRAEs were grade 1-2, with grade ≥3 observed in 24% of pts. The most common TRAEs grade ≥3 were diarrhea, hypokalemia, and rash, each occurring in 2 pts. TRAEs led to olomorasib dose reduction in 2% of pts, olomorasib dose hold in 22% of pts, and cetuximab dose hold in 16% of pts. Of the 61 pts who discontinued treatment, 57 were due to PD. Two pts discontinued cetuximab due to TRAEs and continued on olomorasib. The AE profile was similar between doses. Median time on combination treatment was 6.5 mo (range, 0.8-24.1) and 32 pts remained on treatment. See Table 1 for efficacy data. Biomarker analysis will be reported. Conclusions: Olomorasib + cetuximab demonstrated similar antitumor activity and favorable safety at both dose levels in pts with KRAS G12C-mutant CRC, with the optimal dose of olomorasib + cetuximab determined as 100 mg BID. These results further support combining second-generation KRAS G12Ci with other anticancer therapies to improve outcomes in previously treated pts with KRAS G12C-mutant CRC. Clinical trial information: NCT04956640 . Endpoint Olomorasib (100 mg BID) + CetuximabN=64 Olomorasib (150 mg BID) + CetuximabN=29 TotalN=93 ORR, % (n/N) 44% (28/64) 38% (11/29) 42% (39/93) BOR, n (%) PR 28 (44) 11 (38) 39 (42) SD 31 (48) 16 (55) 47 (51) PD 5 (8) 2 (7) 7 (8) mDOR, mo (95% CI) 8.3 (5.6-12.7) 6.2 (2.8-NE) 7.6 (6.0-12.2) mPFS, mo (95% CI) 7.5 (6.7-9.7) 6.6 (4.2-7.6) 7.5 (6.6-8.8)