BOSTON and SOUTH SAN FRANCISCO, Calif. — October 25, 2026
Frontier Medicines Corporation announced preliminary Phase 1a results for FMC-376, an investigational dual ON- and OFF-state KRAS G12C inhibitor, in patients with advanced KRAS G12C-mutated non-small cell lung cancer (NSCLC). Presented during a rapid oral session at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain, the findings showed confirmed tumor responses in patients who were either previously untreated with KRAS G12C inhibitors or had received prior OFF-state inhibitors. Among 18 response-evaluable NSCLC patients treated with FMC-376 at 500 mg twice daily, the confirmed objective response rate (ORR) was 56% (10 of 18 patients). The ORR was 67% among nine patients who had not previously received a KRAS G12C inhibitor and 44% among nine patients previously treated with an OFF-state KRAS G12C inhibitor. Median duration of response (DOR) was 7.5 months, with six of the 10 responders continuing treatment at the time of the data update. The disease control rate (DCR) was 89% overall, including 100% in the inhibitor-naïve group and 78% in the previously treated group. The efficacy analysis included patients who had received prior chemotherapy and immunotherapy in the metastatic setting and had a median of three prior lines of therapy. Fifteen of the 18 patients had at least one co-alteration associated with clinical resistance to KRAS G12C inhibitors. Notably, nine of the 10 responders had at least one such co-alteration, including KRAS G12C amplification in four responders. Frontier reported a favorable safety profile at the 500 mg twice-daily dose, with one Grade 2 treatment-related hepatic transaminase elevation and no Grade 3 or Grade 4 gastrointestinal toxicities. The findings support continued clinical evaluation of FMC-376, including ongoing monotherapy and combination studies. However, the reported efficacy results come from a small, early-phase cohort and do not establish superiority over currently available treatments. FMC-376 remains investigational.
Confirmed Responses in Patients With Prior KRAS G12C Inhibitor Exposure
The Phase 1/2 PROSPER trial (NCT06244771) is evaluating FMC-376 in patients with advanced KRAS G12C-mutated solid tumors, with the reported ESMO findings focused on NSCLC. The Phase 1a analysis included 18 response-evaluable patients treated at 500 mg twice daily, with response confirmation and treatment status updated through July 14, 2026. Nine patients had previously received and failed up to two OFF-state KRAS G12C inhibitors, while the other nine were KRAS G12C inhibitor-naïve. The confirmed ORR of 56% represents 10 patients with a confirmed response. Response rates were 67% in the inhibitor-naïve subgroup and 44% in the previously treated subgroup. The DCR was 89% across the cohort, indicating that 16 of 18 patients achieved a response or stable disease. In the previously treated group, the DCR was 78%, compared with 100% in the inhibitor-naïve group. Median DOR was 7.5 months, with a reported range of 2.7 months or longer to 13.7 months or longer. Six responders remained on treatment at the data update, suggesting that responses were ongoing in a subset of patients. The analysis also highlighted the prevalence of co-alterations linked to resistance. Fifteen patients, or 83% of the response-evaluable population, carried at least one clinical resistance-associated co-alteration. Nine of the 10 responders had at least one such alteration, and four responders had KRAS G12C amplification, which can contribute to resistance to both ON-only and OFF-state inhibitors. These observations are relevant to the rationale for developing a drug intended to inhibit both active and inactive forms of KRAS G12C. Nevertheless, the cohort is small, and the presence of co-alterations among responders does not by itself demonstrate that FMC-376 overcomes each resistance mechanism. Larger studies will be needed to establish response durability, characterize activity in specific molecular subgroups and determine how the candidate performs after prior KRAS G12C-directed therapy.
Dual ON/OFF Mechanism and Preliminary Safety Findings
FMC-376 is designed to inhibit both the active, or ON, and inactive, or OFF, states of KRAS G12C with comparable potency and high selectivity. According to Frontier, this approach aims to address limitations associated with inhibitors that target only one state of the protein. By suppressing signaling through both states, the candidate is intended to provide more comprehensive inhibition of mutant KRAS G12C and potentially reduce opportunities for continued oncogenic signaling. KRAS G12C mutations occur in several cancers, including NSCLC, colorectal cancer and pancreatic ductal adenocarcinoma. The current clinical evaluation focuses on patients with advanced disease, including those whose tumors have progressed following other treatments. At the 500 mg twice-daily dose, Frontier reported one treatment-related hepatic transaminase elevation, which was Grade 2. No Grade 3 or Grade 4 gastrointestinal toxicities were reported at this dose. Across all monotherapy dose levels, the most frequent treatment-related adverse events were increased blood creatine phosphokinase (CPK), reported in 39% of patients; nausea, 36%; diarrhea, 16%; vomiting, 16%; and fatigue, 15%. Gastrointestinal events were Grade 1 or Grade 2, and the company reported no adverse-event-related treatment discontinuations at 500 mg twice daily or below. These findings are notable because gastrointestinal toxicities and hepatic transaminase elevations have been observed with other KRAS G12C inhibitors. However, the available data are preliminary, and the number of patients exposed at each dose limits the ability to characterize less common or delayed adverse events. Longer follow-up and larger patient cohorts will be necessary to determine whether the observed safety profile is maintained with extended treatment and in combination regimens.
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PROSPER Trial Advances Into Combination and Dose-Optimization Studies
The ongoing Phase 1/2 PROSPER trial is evaluating FMC-376 through multiple clinical development approaches. These include a combination cohort with pembrolizumab, a Phase 1b dose-ranging and dose-optimization cohort in NSCLC patients who are naïve to or previously treated with OFF-state KRAS G12C inhibitors, and a first-line NSCLC monotherapy cohort. The combination study is particularly relevant because combining KRAS G12C inhibitors with immunotherapy can raise concerns about overlapping toxicities, including liver enzyme elevations. As of September 16, 2026, three patients had received FMC-376 at 200 mg twice daily with pembrolizumab. Frontier reported no Grade 3 or higher gastrointestinal or hepatic transaminase adverse events and no treatment-related discontinuations in these three patients. This early safety observation is preliminary and should not be interpreted as establishing the safety of the combination. Additional patients and longer follow-up will be needed to assess tolerability and clinical activity. Frontier is a clinical-stage precision medicines company developing small-molecule therapies using its chemoproteomics-powered Frontier Platform, which combines covalent chemistry and artificial intelligence to pursue targets considered difficult to drug. FMC-376 is one of its investigational oncology candidates. The reported response rates, durability findings and early safety observations provide a rationale for continued investigation, particularly in patients whose disease has progressed after earlier KRAS G12C inhibitors. Future trial results will need to establish the optimal dose, define the benefit-risk profile and determine whether the dual-state approach provides clinically meaningful advantages in first-line or previously treated NSCLC.
Source:Frontier Medicines, ,Press release
