According to results from the phase 1a/1b LOXO-RAS-20001 study (NCT04956640) showcased at the 2023 American Association for Cancer Research (AACR) annual meeting, the KRAS G12C inhibitor LY3537982 exhibited clinical efficacy in patients with non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors.

This is a phase I study of LY3537982 treating locally advanced/metastatic solid tumor patients with KRAS G12C mutation. It involves patients with an ECOG PS of 0-1, measurable disease according to RECIST v1.1 standards. The main objectives are to determine the recommended phase II dose (RP2D) of LY3537982, its safety, pharmacokinetics (PK), and antitumor activity. Patients were divided into four dosage groups: 50 mg, 100 mg, 150 mg, and 200 mg taken twice daily. Dose expansion cohorts included combination treatments of LY3537982 with pembrolizumab (for NSCLC) and cetuximab (for CRC).

Tumor response rate: Out of 75 patients with KRAS G12C mutated tumors, the overall response rate (ORR) in NSCLC patients who hadn’t been treated with a KRAS G12C inhibitor was 38%. For those who had previously received such treatment, the ORR was 7%. In CRC, pancreatic cancer, and other tumor types, the ORRs were 10%, 42%, and 52%, respectively. Disease control rate: 88% for NSCLC patients being treated with KRAS G12C inhibitor for the first time, 64% for those who had been previously treated, and 90%, 92%, and 95% for CRC, pancreatic cancer, and other cancers, respectively. The median time to response was 1.4 months, and at a median follow-up of 4.2 months, 73% of those with disease response were still ongoing.

Yonina R. Murciano-Goroff from Memorial Sloan Kettering Cancer Center presented this data at the 2023 AACR meeting. She highlighted the preliminary efficacy of LY3537982 across all dosage groups and various tumor types. Considering the challenges previous KRAS G12C inhibitors faced when combined with anti-PD-(L)1 drugs due to toxicity, LY3537982, a new, effective, oral, highly selective KRAS G12C inhibitor with unique pharmacological properties, aims for high target occupancy with lower absolute exposure. This may translate to improved safety profiles, potentially leading to safer combination therapy strategies.

For cohort B4, which includes NSCLC patients receiving LY3537982+ pembrolizumab treatment: 1) Among the 9 evaluable KRAS G12C inhibitor-naive patients, the ORR (Objective Response Rate) was 78% (7/9), with all 7 responders achieving partial response (PR). The remaining 2 patients had stable disease (SD), with a DCR (Disease Control Rate) of 100%. 2) For the 4 patients previously treated with a KRAS G12C inhibitor, the ORR was 25% (1/4), with 1 patient achieving PR and 2 patients reporting stable disease. The DCR was 75%. At the time of analysis, treatment was still ongoing for all 8 responders in this cohort. The median time to response was 1.4 months.”

In the C2 cohort receiving LY3537982 + cetuximab treatment, 11 evaluable CRC (Colorectal Cancer) patients were assessed: The ORR (Objective Response Rate) was 45% (5/11), with 5 patients achieving PR (Partial Response) and the best response for 6 patients was stable disease, making the DCR (Disease Control Rate) 100%. As of January 3, 2023, all 11 patients were still undergoing treatment. The median time to response was 1.3 months. Evaluable patients are defined as those who have received at least one post-baseline response assessment, or those who discontinued treatment before the post-baseline assessment.

Safety Data:

LY3537982 Monotherapy: No dose-limiting toxicities (DLT) were observed. Treatment-emergent adverse events (TEAE) of any grade across all dose levels included diarrhea (36%), fatigue (17%), constipation (16%), nausea (16%), and elevated aspartate aminotransferase (AST; 12%). Most of these were grade 1 events, with the mentioned TEAEs having 6%, 2%, 1%, 1%, and 1% at grade 2 respectively; one case of grade 3 AST and one case of grade 4 diarrhea were attributed to the intolerance of contrast agents in CT scans. Treatment-related adverse events (TRAEs) of any grade were as follows: diarrhea (25%), fatigue (8%), constipation (5%), nausea (10%), and elevated AST (7%). Murciano-Goroff stated: “Overall, LY3537982 monotherapy is tolerable, with very few cases of dose reduction or permanent discontinuation due to drug-related adverse events (AE) (one case each). Interestingly, in the monotherapy cohort, seven patients who previously discontinued KRAS G12C inhibitor treatment due to toxicity only experienced TEAEs of grade ≤2, and as of the data cutoff, all seven patients are still on treatment.

LY3537982 combined with Pabrolizumab: The median treatment duration was 2.5 months (range, 0.2-6 months), and no DLT (Dose Limiting Toxicity) was observed in any dosage group. The doses of LY3537982 included three levels: 50 mg (n=4), 100 mg (n=6), and 150 mg (n=6). In the 50 mg and 100 mg dose groups, no patients reported a dose reduction, and one patient discontinued due to TRAE in the 50 mg dose group. In the combined analysis of the 50 mg and 100 mg doses (n=10), the most common TEAEs of any grade were diarrhea (30%), nausea (20%), vomiting (20%), joint pain (10%), hypomagnesemia (10%), and itching (10%), with one grade 3 diarrhea event; the most common TRAEs of any grade were diarrhea (30%), nausea (10%), joint pain (10%), and itching (10%). Murciano-Goroff believes: ‘Using doses of 50 mg and 100 mg of LY3537982 combined with Pabrolizumab to treat NSCLC, the incidence of immune-related adverse reactions is relatively low, including good liver safety.'”

In combination with pembrolizumab, LY3537982 at doses of 100 mg or 150 mg was administered. In the 100 mg dose group, one patient experienced a dose-limiting toxicity (DLT) event with a grade 3 elevation in alanine transaminase (ALT) and aspartate transaminase (AST) levels, and one patient reported a dose reduction due to treatment-emergent adverse events (TEAE). In the 100 mg and 150 mg dose groups, the most common any-grade TEAEs were acneiform dermatitis (39% and 71%), diarrhea (23% and 43%), headache (31% and 29%), dry skin (39% and not applicable [NA]), fatigue (23% and 29%), vomiting (23% and 29%), elevated AST (23% and 14%), nausea (23% and 14%), elevated ALT (23% and NA), increased creatine kinase (15% and 14%), hypokalemia (15% and 14%), hypomagnesemia (15% and 14%), itching (15% and 14%), and fever (8% and 29%). Grade ≥3 TEAEs included diarrhea (8%) and elevated ALT (8%) in the 100 mg dose group. Any-grade treatment-related adverse events (TRAEs) were acneiform dermatitis (39% and 43%), diarrhea (15% and 29%), headache (31% and 14%), dry skin (39% and NA), fatigue (8% and 14%), vomiting (8% and 14%), elevated AST (23% and 14%), nausea (8% and NA), elevated ALT (23% and NA), increased creatine kinase (8% and 14%), hypokalemia (8% and NA), hypomagnesemia (15% and 14%), itching (15% and 14%), and fever (8% and 14%). Grade ≥3 TRAEs included diarrhea (8%) and elevated ALT (8%) in the 100 mg dose group.