Novel Therapy Yields Anti-Tumor Activity in KRAS G12C–Mutated CRC

As a single agent or in combination, MK-1084 showed promising efficacy and safety results for patients with KRAS G12C–mutated CRC.

Whether as a single agent or in combination, MK-1084 showed promise regarding anti-tumor activity and safety for patients with KRAS G12C–mutated advanced colorectal cancer (CRC), according to results from the phase 1 KANDLELIT-001 (NCT05067283) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

At a median follow-up of 23.2 months (range, 0.2-37.7) the confirmed objective response rate (ORR) in patients receiving MK-1084 monotherapy was 38% (95% CI, 25%-52%) and the disease control rate was 83% (95% CI, 70%-92%). The time to response (TTR) was 1.5 months (range, 1.2-12.4) and the median duration of response (DOR) was 7.1 months (range, 2.5-21.3).

In patients receiving MK-1084 plus cetuximab (Erbitux), the confirmed ORR and DCR were 46% (95% CI, 30%-63%) and 92% (95%, 79%-98%), respectively, at a median follow-up of 9.2 months (range, 0.5-15.6). The median TTR and DOR were 1.5 months (range, 1.2-8.1) and 10.8 months (range, 2.7-11.1+), respectively. Among patients who received the triplet of MK-1084 plus cetuximab and chemotherapy, the confirmed ORR was 38% (95% CI, 21%-58%) and DCR was 93% (95% CI, 77%-99%) at a median follow-up of 4.6 months (range, 0.1-9.5). The median TTR and DOR were 1.4 months (range 1.2-4.4) and not reached (range, 1.3+ to 7.2+), respectively.

Safety data for the monotherapy arms included patients enrolled in KANDLELIT-001 with various solid tumors, not just CRC. In this population, there were 11 grade 3 treatment-related adverse events (TRAEs) and 1 grade 4 TRAE. The corresponding numbers were 7 and 0, respectively, in the doublet arm, and 4 and 5 in the triplet arm. There were 3 dose-limiting toxicities (DLTs) overall: 1 DLT in the monotherapy arm (grade 3 electrocardiogram QT prolonged) and 2 DLTs in the triplet arm (grade 3 febrile neutropenia and grade 2 peripheral sensory neuropathy). There were no TRAE-related deaths in any of the arms. At the data cutoff date of March 12, 2025, 24% of the CRC patients in the monotherapy arms, 59% of patients in the doublet arm, and 97% of patients in the triplet arm remained on study treatment.

“Data support further evaluation of MK-1084-based combinations for the treatment of KRAS G12C–mutant colorectal cancer,” Iwona Lugowska, MD, PhD, Maria Sklodowska-Curie National Research Institute and Oncology Centre, Warsaw, Poland, said when presenting the findings.

KANDLELIT-001 Background

Overall, the ongoing KANDLELIT-001 study has 6 arms, 4 of which included patients with CRC (the other 2 arms were all patients with lung cancer). Arms 1 and 3 were the MK-1084 monotherapy arms and included patients with various locally advanced unresectable or metastatic solid tumor types who had received at least 1 prior systemic treatment for advanced disease. Patient in arm 5 had locally advanced unresectable or metastatic CRC and 1 or 2 previous lines of systemic therapy in the advanced disease setting. The arm 5 group received MK-1084 plus cetuximab. Arm 6 also included patients with locally advanced unresectable or metastatic CRC; however, these patients had received 0 or 1 prior systemic lines for advanced disease. Patients in this cohort received MK-1084 plus cetuximab and chemotherapy.

Across the 2 monotherapy groups combined (arms 1+3), there were 58 patients with CRC. The median age of these patients was 58 (range, 27-81), 48% were female, 81% were White, and 17% were Asian. The ECOG performance status was 1 for 66% of patients and 0 for 34% of patients. Over 80% of patients received at least 2 prior lines of therapy with nearly 20% having received at least 4 lines.

There were 41 patients in the doublet group (arm 5) and 33 patients in the triplet group (arm 6), with the median age being 58 years in both arms. The 2 arms were 51% vs 52% female, 51% vs 30% Asian, and 49% vs 70% White, respectively. The ECOG performance status in the doublet arm was 1 for 49% and 0 for 51%, and two-thirds (66%) of patients had received 2 prior lines of therapy. In the triplet arm, the ECOG performances status was 1 for 36% and 0 for 64%. Forty-two percent of patients were treatment-naïve and 58% had received 1 prior line of systemic therapy.

Regarding dosing, patients in the monotherapy arms (arms 1+3) received oral MK-1084 once or twice daily for a total daily dose of 25 to 800 mg. In the doublet group (arm 5), patients were treated with oral MK-1084 once or twice daily for a total daily dose of 25 to 200 mg plus cetuximab IV per label. In arm 6, patients received oral MK-1084 once or twice daily for a total daily dose of 25 to 100 mg plus cetuximab IV per label and the mFOLFOX6 chemotherapy regimen (oxaliplatin, leucovorin, and 5-fluorouracil) per label.

The primary end points were DLTs, AEs, and AEs resulting in treatment discontinuation. The key secondary end points were investigator-reviewed ORR and DOR per RECIST v1.1.

Looking ahead, Lugowska said the open-label phase 3 KANDLELIT-012 trial is comparing MK-1084 plus cetuximab and mFOFOX6 against bevacizumab (Avastin) plus mFOLFOX6 in the first-line setting for patients with locally advanced unresectable or metastatic CRC.

Of note, data for the lung cancer arms of the KANDLELIT-001 study were presented in a separate abstract (8605) at the 2025 ASCO Annual Meeting.

Reference

Lugowska I, Simonelli M, Xue J, et al. The KRAS G12C inhibitor MK-1084 for KRAS G12C–mutated advanced colorectal cancer (CRC): Results from KANDLELIT-001. J Clin Oncol. 2025;43(suppl 17):3508. doi:10.1200/JCO.2025.43.16_suppl.3508