Novel KRAS G12C Inhibitor Shows Early Signs of Efficacy Across Solid Tumors, Pretreated NSCLC

LY3537982, an investigative KRAS G12C inhibitor, demonstrated clinical efficacy across patients with non–small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors, according to findings from cohorts of the dose-escalation and expansion portions of the phase 1a/1b LOXO-RAS-20001 study (NCT04956640).

As a monotherapy in the dose-escalation portion of the trial, 75 patients with KRAS G12C mutant tumors were evaluable after treatment with LY3537982. The overall response rate (ORR) across doses for patients with NSCLC who did not receive prior treatment with a KRAS G12C inhibitor was 38% (n = 3 of 8). For patients with NSCLC who received prior KRAS G12C inhibition, the ORR was 7% (n = 1 of 14). Across patients with CRC (n = 20), pancreatic (n = 12), or other tumor types (n = 21), the ORRs were 10%, 42%, and 52%, respectively.

The disease control rate (DCR) for KRAS G12C inhibitor–naïve patients was 88%. For patients who received prior KRAS G12C inhibitors the DCR was 64%. The DCR for CRC, pancreatic, and other cancers, was 90%, 92%, and 95%, respectively. The median time to response was 1.4 months and at a median follow-up of 4.2 months, 73% of responses were ongoing.

“LY3537982 monotherapy demonstrated preliminary efficacy across all dose levels and in multiple tumor types,” Yonina R. Murciano-Goroff, MD, MSc, DPhil, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York said in a presentation of the data at the 2023 AACR Annual Meeting. “Maximizing the potential of KRAS G12C inhibition in the clinic requires us to think about combination strategies including potentially for the first line in NSCLC. But previous KRAS G12C inhibitor agents have run into some toxicity challenges when combining with [anti–]PD-L1. LY3537982 is a novel, potent, oral, highly selective inhibitor of KRAS G12C.”

Outcomes from 2 combination arms in the dose-expansion portion of the study were also reported. In cohort B4, which included patients with NSCLC who received LY3537982 plus pembrolizumab (Keytruda). Nine patients who were KRAS G12C inhibitor naïve were evaluable and had an ORR of 78% with all 7 responders achieving a partial response (PR). The remaining 2 patients had stable disease for a DCR of 100%. Four patients who had prior treatment with a KRAS G12C inhibitor had an ORR of 25% with 1 patient achieving a PR and 2 patients reporting stable disease for a DCR of 75%. At the time of the analysis, treatment was ongoing for all 8 responders in this cohort. The median time to response was 1.4 months.

In cohort C2, 11 patients with CRC who received LY3537982 in combination with cetuximab (Erbitux) were evaluable. The ORR was 45% with 5 patients achieving a PR. Six patients had stable disease as their best response for a DCR of 100% and all 11 patients remained on treatment at data cutoff of January 3, 2023. The median time to response was 1.3 months.

Evaluable patients were determined as those who had at least 1 postbaseline response assessment or those who had discontinued treatment before postbaseline assessment.

At the time of data cutoff 84 patients were enrolled to 1 of 4 doses: 50 mg (n = 18), 100 mg (n = 55), 150 mg (n = 37), or 200 mg (n = 13). “Looking at the pharmacokinetics, at steady state exposures at all doses, they exceeded the EC90 throughout the majority of the dosing interval,” Murciano-Goroff said. “[LY3537982] has unique pharmacologic properties and is designed to achieve high target occupancy at low absolute exposures. In particular, the predicted targeted occupancy at trough is approximately 90% and that has interest in terms of safety if we can give lower amounts of drug we may be able to do it more safely and facilitate combinations”

The mean half-life of the agent was 2.9 hours.

Dose-escalation cohort

Among patients in the monotherapy dose-escalation cohort, other tumor types included patients with cholangiocarcinoma (n = 5), ovarian (n = 3), biliary tract (n = 2), tracheal basaloid squamous cell carcinoma (n = 2), chondrosarcoma (n = 1), distal bile duct cancer (n = 1), duodenal carcinoma (n = 1), jejunal adenocarcinoma (n = 1), large cell neuroendocrine of the lung (n = 1), nasal malignant melanoma (n = 1), salivary gland cystic carcinoma (n = 1), small intestine (n = 1), and upper tract urothelial carcinoma (n = 1).

Among patients in this cohort the median age was 64 years (range, 36-85) with men making up 58% of the population. Patients had an ECOG performance status of 0 (52%) or 1 (48%) and NSCLC (31%) made up most of the tumors represented, followed by CRC (27%), and pancreatic cancers (17%).

Patients received 50 to 200 mg of LY3537982 and the maximum-tolerated dose was not reached.

“This was a heavily pretreated population, with a median of 3 lines of prior systemic therapy [range, 0-9], you can also see that we treated patients across a variety of histologies. In particular looking at the [patients with] NSCLC, a majority of those patients had received prior treatment with a KRASG12C inhibitor. Most of them came off that prior inhibitor for progressive disease, you can see that 41% came off due to toxicity,” Murciano-Goroff said.

In a review of the safety data, Murciano-Goroff noted that no dose-limiting toxicities were observed. Across all dose levels, treatment-emergent adverse events (TEAEs) of any grade included diarrhea (36%), fatigue (17%), constipation (16%), nausea (16%), and aspartate aminotransferase increase (AST; 12%). These were mostly grade 1 events. Grade 2 events occurred in 6%, 2%, 1%, 1%, and 1% of patients for these AEs, respectively. One grade 3 AST event was reported and 1 grade 4 diarrhea event was attributed to contrast intolerance from the CT scan. Treatment-related AEs (TRAES) of any grade were as follows: diarrhea (25%), fatigue (8%), constipation (5%), nausea (10%), and increased AST (7%).

“Overall, this was well tolerated in clinic, dose reductions or permanent discontinuation due to drug-related adverse events [AEs] were rare events occurring and only 1 patient each,” Murciano-Goroff said. “Interestingly, there were 7 patients in the monotherapy [cohort] who had prior KRAS G12C inhibitor therapy and came off due to toxicity, and of those patients we only saw low-grade AEs here and as of the data cutoff all 7 remained on therapy.”

LY3537982 plus pembrolizumab

In cohort B4, the median age of patients was 70 years (range, 48-79) and most were women (56%) with an ECOG performance status of 1 (81%). The median number of prior lines of therapy was 2 (range, 0-8). Most patients (63%) were treated with platinum-based chemotherapy in combination with an anti–PD-L1 therapy. Five patients had received no prior therapy. Among the 5 patients who received prior treatment with a KRAS G12C inhibitor, all discontinued because of progressive disease. Six patients had brain metastases at baseline.

Among those with evaluable PD-L1 status, 31% had a score of less than 1%, 25% had a score of 1% to 49%, and 25% has a score of 50% or higher. The median time on treatment was 2.5 months (range, 0.2-6) and no dose-limiting toxicities (DLTs) were observed across doses. Patients received pembrolizumab at 200 mg every 3 weeks and either 50, 100, or 150 mg of LY3537982.

In terms of safety, Murciano-Goroff noted that events in the 50 mg (n = 4) and the 100 mg (n = 6) were of interest as those 2 cohorts are actively enrolling patients. Noe dose reductions were reported at these levels and 1 discontinuation was reported due to a TRAE with the 50-mg dose. The most common any-grade TEAEs in the combined 50- and 100-mg doses were diarrhea (30%), nausea (20%), vomiting (20%), arthralgia (10%), hypomagnesaemia (10%), and pruritus (10%). One grade 3 diarrhea event was reported. The most common TRAEs of any grade were diarrhea (30%), nausea (10%), arthralgia (10%), and pruritus (10%).

“Pembrolizumab NSCLC combination safety data at 50 mg and 100 mg had a notable low rate of immune-related AEs, including favorable liver safety profile,” Murciano-Goroff said.

LY3537982 plus cetuximab

In cohort C2, the median age was 56 years (range, 35-77) and most patients were men (60%) with an ECOG performance status of 1 (65%). The median number of prior lines of therapy was 3 (range, 1-8) and all patients had received fluoropyrimidine. Other therapies included oxaliplatin (85%), irinotecan (90%), anti-VEGF (70%), anti-EGFR (5%), and regorafenib (Stivargo) and/or trifluridine/tipiracil (25%).

Patients received cetuximab at 400 mg/m² on day 1 of cycle 1 and then 250 mg/m² every week with LY3537982 at 100 or 150 mg.

At 100 mg, 1 DLT was reported as grade 3 alanine aminotransferase (ALT)/AST increase, and 1 patient reported a dose reduction due to TEAEs. The most common any-grade TEAEs among the 13 patients who received 100-mg and the 7 patients who received 150-mg dose, respectively, were dermatitis acneiform (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%), AST increase (23% and 14%), nausea (23% and 14%), ALT increase (23% and NA), blood creatine phosphokinase increase (15% and 14%), hypokalemia (15% and 14%), hypomagnesaemia (15% and 14%), pruritus (15% and 14%) and pyrexia (8% and 29%). Grade 3 events included diarrhea (8%) and ALT increase (8%) at the 100-mg dose.

TRAEs of any grade were reported across the 2 doses as follows: dermatitis acneiform (39% and 43%), diarrhea (15% and 29%), headache (31% and 14%), dry skin (39% and NA), fatigue (8% and 14%), vomiting (8% and 14%), AST increase (23% and 14%), nausea (8% and NA), ALT increase (23% and NA), blood creatine phosphokinase increase (8% and 14%), hypokalemia (8% and NA), hypomagnesaemia (15% and 14%), pruritus (15% and 14%) and pyrexia (8% and 14%). Grade 3 events included diarrhea (8%) and ALT increase (8%) at the 100-mg dose.

Enrollment is ongoing for both the NSCLC and CRC combination cohorts, as well as the other dose-expansion cohorts.

Reference

Murciano-Goroff YR, Heist RS, Kuboki Y, et al. A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors. Cancer Res. 2023;83(suppl 8):CT028. doi:10.1158/1538-7445.AM2023-CT028