Background: LY3537982 is an oral, potent, and highly selective inhibitor of GDP-bound KRAS G12C with unique pharmacologic properties that achieve high target occupancy at low absolute exposures. Here we present results of GI tumors treated on LOXO-RAS-20001, a phase 1 study of LY3537982 in patients (pts) with a KRAS G12C mutation. Methods: Dose escalation followed a mTPI-2 method. Dose expansion included a combination with cetuximab in colorectal cancer (CRC). All pts were KRAS G12C inhibitor naïve. Key objectives were to determine the RP2D, safety, PK, and antitumor activity per RECIST v1.1. Results: As of 24 July 2023, 73 pts with CRC (32), PANC (24), BTC (10), and other GI tumors (7) were treated with 50-200 mg BID LY3537982. Median age was 62 yrs (range, 36-85) and median number of prior lines of therapies was 3 (range, 0-11). No DLTs were observed. Grade 1 diarrhea was the highest frequency TEAE regardless of attribution (33%). At a median time on treatment of 4 months (range, 0.1-18), 20 pts are ongoing and 53 discontinued treatment. In the combination cohort, 46 pts with CRC were treated with 100 or 150 mg BID LY3537982 and cetuximab. Median age was 57 yrs (range, 35-77) and median number of lines of prior therapies was 3 (range, 1-8). 1 pt at 100 mg BID had a DLT (ALT/AST increased) and required a dose reduction. TEAEs ≥30% were dermatitis acneiform (59%), diarrhea (44%), dry skin (44%), hypomagnesemia (33%), and fatigue (30%). Vomiting, pruritus, skin fissures, headache, nausea, pyrexia, and rash were mostly grade 1 with 20-24% occurrence. At a median time on treatment of 6 months (range, 0.6-11), 37 pts are ongoing and 9 discontinued treatment (none due to AE). Table shows efficacy data. Conclusions: In pts with GI tumors, LY3537982 alone or in combination with cetuximab demonstrated preliminary efficacy and a favorable safety profile. Clinical trial information: NCT04956640.

^aEfficacy evaluable pts are those who had at least 1 post-baseline response assessment or had discontinued treatment before the first post-baseline assessment.

^bDCR = PR+SD.

^c1 CRC, 2 PANC, and 1 duodenal cancer pt (other GI) have unconfirmed PR, ongoing and pending confirmation.

^dOther GI includes duodenal cancer (n=3), small intestine (n=2), esophageal cancer, jejunal adenocarcinoma (both n=1).

^e1 pt with small intestine cancer is not yet evaluable.

^f8 pts are not yet evaluable.

^g3 pts have unconfirmed PR, ongoing and pending confirmation.