Calderasib Regimen Shows Meaningful Responses in Frontline KRAS G12C+ NSCLC

First-line calderasib (MK-1084) plus pembrolizumab (Keytruda) produced meaningful responses and prolonged progression-free survival (PFS) in patients with KRAS G12C-mutated metastatic non–small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of 1% or higher, according to updated results from the phase 1 KANDLELIT-001 study (NCT05067283) presented at the 2026 European Society for Medical Oncology (ESMO) Congress.¹

What were the outcomes with the first-line combination?

Among 122 response-evaluable patients treated with first-line calderasib plus pembrolizumab (TPS of at least 1%), the combination produced an ORR of 71% (95% CI, 62%-78%), a disease control rate (DCR) of 93% (95% CI, 87%-97%), and a median duration of response (DOR) of 33.0 months (range, 1.2+ to 45.3+). The median PFS was 28.8 months (95% CI, 20.6-not reached [NR]). The median time to response was 1.4 months.

Activity was greatest in patients with high PD-L1 expression; among those with a TPS of 50% or higher (n = 64), the ORR was 84% (95% CI, 73%-92%), the DCR was 94% (95% CI, 85%-98%), and the median DOR was not reached. Among those with a TPS of 1% to 49% (n = 58), the ORR was 55% (95% CI, 42%-68%), and the median DOR was 26.2 months. The median PFS was 34.4 months (95% CI, 21.8-NR) in the TPS 50% or higher subgroup and 25.1 months (95% CI, 10.5-NR) in the TPS 1% to 49% subgroup, with 12-month PFS rates of 76% and 65%, respectively.

How did calderasib monotherapy and the triplet regimen perform?

In the pooled calderasib monotherapy arms (arms 1 and 3), which enrolled patients with advanced NSCLC who had received at least 1 prior systemic therapy, the ORR was 35% (95% CI, 26%-45%), and the DCR was 78% (95% CI, 68%-85%) among 103 response-evaluable patients, with a median DOR of 16.8 months (range, 1.2+ to 36.1+) and a median PFS of 8.3 months (95% CI, 6.0-16.4). In the first-line triplet arm of calderasib plus pembrolizumab and platinum-based chemotherapy (arm 4; any TPS; n = 46), the ORR was 65% (95% CI, 50%-79%), the DCR was 89% (95% CI, 76%-96%), the median DOR was 19.4 months (range, 1.9+ to 27.4+), and the median PFS was 17.6 months (95% CI, 10.5-26.3). Reductions in KRAS G12C variant allele frequency (from a median of 0.73% to 0%) and maximum somatic allele frequency (from 4.76% to 1.91%) in circulating tumor DNA by cycle 3, day 1 were interpreted as evidence of robust target engagement.

What was the safety profile?

Any-grade treatment-related adverse events (TRAEs) occurred in 61% of patients in the calderasib monotherapy arms (which included all solid tumors; n = 271), 89% in the calderasib plus pembrolizumab arm (n = 136), and 98% in the triplet arm (n = 46); grade 3 TRAEs occurred in 7%, 25%, and 59% of patients, respectively. TRAEs led to discontinuation of calderasib in 1% of patients in the monotherapy arms, 4% in the combination arm, and 7% in the triplet arm.

Grade 5 TRAEs were reported in 1 patient in the combination arm (myelosuppression and decreased platelet count) and 1 patient in the triplet arm (immune-mediated myositis). The most common TRAEs with calderasib monotherapy were increased aspartate aminotransferase (12%), increased alanine aminotransferase (11%), nausea (10%), and diarrhea (10%). Hepatic transaminase elevations and immune-related events were more frequent with the combination and triplet regimens, consistent with the addition of pembrolizumab and chemotherapy.

“In KANDLELIT-001, calderasib alone or in combination with pembrolizumab [with or without] platinum-based chemotherapy show[ed] clinically meaningful activity in [patients] with KRAS G12C-mutated metastatic NSCLC,” presenting study investigator Mehmet Ali Nahit Şendur, MD, from Ankara Yıldırım Beyazıt University and Ankara Bilkent City Hospital in Ankara, Turkiye, concluded with coinvestigators.

What is the trial design, and what comes next?

Calderasib is a next-generation, highly potent and selective oral KRAS G12C-GDP inhibitor. KANDLELIT-001 is an ongoing, open-label phase 1 study evaluating calderasib as monotherapy or in combination in patients with KRAS G12C-mutated advanced solid tumors, including the NSCLC arms reported here. Eligible patients had histologic or blood-based confirmation of a KRAS G12C mutation, an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria.

The primary end points were the incidence of dose-limiting toxicities, AEs, and AEs leading to discontinuation. Secondary end points included ORR and DOR per RECIST v1.1 guidelines by investigator assessment and pharmacokinetics, with PFS and ctDNA clearance assessed as exploratory end points.

The investigators concluded that the findings support enrollment in the phase 3 KANDLELIT-004 (NCT06345729) and KANDLELIT-007 (NCT07190248) studies of calderasib plus pembrolizumab as first-line therapy.

Reference

Gray JE, Peled N, Liu L, et al. Calderasib (MK-1084), alone or in combination, for KRAS G12C-mutant metastatic non-small cell lung cancer. Presented at: European Society for Medical Oncology (ESMO) Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract 2680RO.