Frontier Medicines Corporation, a clinical-stage precision medicines company unlocking the proteome to develop small molecule oncology and immunology drugs against previously undruggable disease-causing targets, today announced promising preliminary clinical data from the ongoing Phase 1 monotherapy portion of its Phase 1/2 PROSPER trial evaluating FMC-376, a KRAS G12C ON+OFF inhibitor, in patients with advanced KRAS G12C-mutant solid tumors, focused on non-small cell lung cancer (NSCLC). The findings were presented during a rapid oral session at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain.
“These first clinical data for FMC-376 mark an important step for Frontier, demonstrating encouraging responses and durability in a highly G12C-resistant population, as well as a favorable hepatic safety profile that we believe could be particularly important in combination with pembrolizumab in the first-line setting,” said Chris Varma, Ph.D., co-founder, chairperson and chief executive officer of Frontier Medicines. “Designed to inhibit both the ON and OFF states of KRAS G12C with equal potency to address limitations of existing therapies, FMC-376 exemplifies the drug design capabilities of our AI-powered Frontier™ Platform and its potential to deliver differentiated precision medicines against targets long considered undruggable. Due to its equipotent ON and OFF activity, FMC-376 delivered best-in-class efficacy in a heavily pre-treated and highly resistant population, where 90% of responders harbored at least one co-alteration associated with clinical resistance to KRAS inhibitors. We look forward to continuing to advance the PROSPER study across cohorts, with the goal of bringing an impactful treatment option to patients in need.”
Phase 1A Clinical Data Update
- The PROSPER trial initially enrolled patients with advanced KRAS G12C-mutant solid tumors. The findings presented at ESMO focused on patients with NSCLC who were naïve to or previously treated with up to two prior OFF-state KRAS G12C inhibitors. As of April 30, 2026, 62 patients had enrolled in the study across all dose levels/regimens. Twenty-nine NSCLC patients received FMC-376 at 500 mg twice daily (BID).
- The efficacy analysis included 18 response-evaluable NSCLC patients who were treated with prior chemotherapy/immunotherapy in the metastatic setting and treated at 500 mg BID. Confirmation of response and treatment status were updated through July 14, 2026. Patients had received a median of three prior lines of therapy, and nine had previously received and failed up to two prior OFF-state KRAS G12C inhibitors. 83% (15/18) carried at least one clinical resistance co-alteration to KRAS G12C inhibitors.
- Treatment with FMC-376 led to a confirmed overall objective response rate (ORR) of 56% (10/18), including 67% (6/9) in KRAS G12C inhibitor-naïve patients and 44% (4/9) in patients previously treated with an OFF-state KRAS G12C inhibitor.
- Median duration of response was 7.5 months (range 2.7+ to 13.7+ months), with treatment ongoing for six of the 10 responders. Disease control rate was 89% (16/18), including 100% (9/9) in KRAS G12C inhibitor-naïve patients and 78% (7/9) in KRAS G12C inhibitor-pretreated patients.
- Nine of the 10 responders had at least one co-alteration associated with clinical resistance to KRAS inhibitors, including KRAS G12C amplifications in four responders, a known driver of resistance to both ON-only and OFF-state inhibitors.
- Treatment with FMC-376 was well tolerated and demonstrated a favorable safety profile. At the dose of 500 mg BID, there was only a single treatment-related hepatic transaminase elevation, which was Grade 2 (3%). No Grade 3 or 4 gastrointestinal toxicities were reported and no discontinuations due to adverse events were reported at the 500 mg BID dose or below.
- The most frequent treatment-related adverse events (TRAEs) across all monotherapy dose levels were increased blood creatine phosphokinase (CPK) (39%), nausea (36%), diarrhea (16%), vomiting (16%) and fatigue (15%). Gastrointestinal toxicities, including nausea, diarrhea and vomiting, were all Grade 1 or 2 and no adverse events resulted in treatment discontinuation.
The Phase 1/2 PROSPER trial is ongoing, including the dose-escalation cohort evaluating FMC-376 in combination with pembrolizumab. As of September 16, 2026, three patients were enrolled and had received FMC-376 200 mg BID plus pembrolizumab, with no Grade ≥3 gastrointestinal (GI) or hepatic transaminase adverse events (AEs) and no treatment-related discontinuations. The trial also includes a Phase 1b dose-ranging cohort in NSCLC patients naïve to or previously treated with OFF-state KRAS G12C inhibitors, and a first-line NSCLC monotherapy cohort.
“Despite advances in KRAS G12C lung cancer treatment, patients continue to need options that provide higher rates of durable responses, minimize toxicities, and overcome resistance to standard therapies,” said Marcelo V. Negrao, M.D., Associate Professor, UT MD Anderson Cancer Center, the lead investigator who presented the findings at ESMO. “Approaches that target only the ON or OFF state leave opportunities for continued oncogenic signaling. By directly inhibiting both states, FMC-376 has the potential to address these limitations. Additionally, combining KRAS G12C inhibitors with pembrolizumab has historically been challenging because of the potential for overlapping toxicities, including elevated hepatic transaminase levels. FMC-376’s encouraging hepatic safety profile to date suggests it may be particularly well suited for combination treatment in the first-line setting. The confirmed responses and encouraging durability, including in patients previously treated with KRAS G12C off-state inhibitors and those with tumor co-alterations associated with resistance to KRAS inhibitors, support further clinical evaluation of FMC-376.”
About FMC-376
FMC-376 is a dual inhibitor of the ON+OFF states of KRAS G12C, directly targeting both the active and inactive forms of KRAS G12C with equipotency and high selectivity. This differentiated mechanism of action offers the potential to overcome the resistance and lack of response seen with current KRAS G12C single-acting treatments. The KRAS G12C mutation is most prevalent in people with non-small cell lung cancer (NSCLC), colorectal carcinoma (CRC), and pancreatic ductal adenocarcinoma (PDAC). FMC-376 has demonstrated robust anti-tumor activity in preclinical models and is currently being evaluated in the PROSPER Phase 1/2 clinical trial, an open-label, dose-escalation, dose-expansion and cohort-expansion study evaluating the safety, pharmacokinetics and clinical activity of FMC-376 as monotherapy or in combination with pembrolizumab in participants with KRAS G12C-mutated locally advanced unresectable or metastatic solid tumors.
About Frontier Medicines
Frontier Medicines is a clinical-stage precision medicines company pioneering groundbreaking medicines to transform treatment for genetically defined patient populations, starting with oncology and immunology. Our proprietary chemoproteomics-powered drug discovery engine, the Frontier™ Platform, leverages covalent chemistry and artificial intelligence to unlock difficult-to-drug, disease-causing proteins for drug development. Today, we are advancing a diversified pipeline of wholly owned precision medicines against the most critical drivers of cancer and high-value immunology programs. For more information, please visit www.frontiermeds.com. Follow Frontier on LinkedIn.
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