Calderasib showed strong efficacy, with ORRs up to 72% in combination with pembrolizumab in patients with KRAS G12C–mutant metastatic NSCLC.
Calderasib (MK-1084) alone or in combination with pembrolizumab (Keytruda) demonstrated clinically meaningful and durable antitumor activity across multiple treatment settings in patients with KRAS G12C–mutated metastatic non–small cell lung cancer (NSCLC), with particularly high response rates and prolonged progression-free survival (PFS) observed when combined with pembrolizumab, according to findings from the ongoing phase 1 KANDLELIT-001 trial (NCT05067283).1
Findings that were shared during the
Among patients with a tumor proportion score (TPS) of at least 1% who received calderasib plus pembrolizumab (n = 98), the ORR was 72% (95% CI, 63%-81%) and the DCR was 95% (95% CI, 88%-98%). The median TTR and DOR were 1.4 months (range, 1.2-10.3) and not reached ([NR] range, 1.4+ to 37.1+). Responses were further evaluated in patients with a TPS between 1% and 49% (n = 44) and at least 50% (n = 54). In the former category, the ORR and DCR were 55% (95% CI, 39%-70%) and 93% (95% CI, 81%-99%), respectively. The median TTR and DOR were 1.4 months (range, 1.2-4.2) and NR (range, 1.4+ to 37.1+), respectively. In the latter category, the ORR was 87% (95% CI, 75%-95%) and the DCR was 96% (95% CI, 87%-100%). The median TTR and DOR were 1.4 months (range, 1.2-10.3) and 27.8 months (range, 1.5+ to 30.6+), respectively.
Among patients who received calderasib in combination with pembrolizumab and chemotherapy (n = 46), the ORR was 65% (95% CI, 50%-79%) and the DCR was 89% (95% CI, 76%-96%). The median TTR and DOR were 1.5 months (range, 1.2-18.1) and NR (1.9+ to 21.1+), respectively.
“In KANDLELIT-001, calderasib alone or in combination shows clinically meaningful activity in participants with KRAS G12C–mutated metastatic NSCLC,” Adrian Sacher, MD, MMSc, FRCPC, lead study author and staff medical oncologist at Princess Margaret Hospital and an assistant professor in the Departments of Medicine & Immunology at the University of Toronto in Canada, said in a presentation of the data.
KRAS genes are commonly mutated across cancers, and as the most commonly mutated gene in NSCLC, occurring in 11% to 16% of lung cancers, inhibition of the target is of high interest. KRAS G12C mutations also have a preponderance for PD-L1 positivity and an immunosuppressive tumor microenvironment, making combined KRAS G12C and checkpoint inhibition a potentially sound strategy.
Calderasib is a highly potent and specific KRAS G12C-GDP inhibitor that served as the KRAS G12C inhibitor of interest in the KANDLELIT-001 trial. The study enrolled patients at least 18 years of age with histologic or blood-based confirmation of a KRAS G12C mutations, an ECOG performance status of 0 or 1, and measurable disease per RECIST 1.1.
The study was designed with 4 arms: arms 1 and 3 enrolled 193 patients with locally advanced, unresectable, or metastatic solid tumors (NSCLC, n = 68) who had received at least 1 prior systemic therapy for advanced disease to receive between 25 mg and 800 mg of oral calderasib monotherapy per day; arm 2 enrolled 107 patients with PD-L1–positive (TPS ≥1%), metastatic NSCLC with no indication for EGFR, ALK, or ROS1 TKI therapy nor prior therapy for metastatic disease to receive between 25 mg and 400 mg of oral calderasib per day plus pembrolizumab; arm 4 enrolled 46 patients with metastatic NSCLC with no indication for EGFR, ALK, or ROS1 TKI therapy nor prior therapy for metastatic disease to receive the same dose and schedule of calderasib plus pembrolizumab, in addition to chemotherapy.
The primary end points were the incidence of dose-limiting toxicities (DLTs), adverse effects (AEs), and AEs that led to discontinuation. Secondary end points were ORR and DOR per RECIST 1.1 criteria by investigator assessment and pharmacokinetic measures of calderasib administered as monotherapy or as part of combination therapy.
The patient characteristics were “as expected,” Sacher explained, pointing out that patients in the calderasib monotherapy arm were generally heavily pretreated with 40% of those with NSCLC receiving therapy in the third line or later.
The median PFS in arms 1+3 (NSCLC only), 2, and 4 was 8.3 months (95% CI, 4.2-18.1), 28.9 months (95% CI, 20.6-NR), and 15.1 months (95% CI, 10.5-NR), respectively. The 6- and 12-month PFS rates were 60% and 41% in arms 1+3, respectively, 90% and 75% in arm 2, and 82% and 64% in arm 4.
In arm 2, among patients with a TPS between 1% and 49% and 50% or greater, the median PFS was 25.1 months (95% CI, 9.5-NR) and NR (95% CI, 20.6-NR), respectively. The 6- and 12-month PFS rates in the former population were 84% and 66%, respectively; these rates in the latter population were 94% and 81%.
“The AEs were manageable,” Sacher said. “The rate of grade 3 increased alanine aminotransferase [ALT] level or increased aspartate aminotransferase [AST] level was 3% with calderasib monotherapy, 8% with calderasib plus pembrolizumab, and 11% with the triplet,” he added.
Treatment-related AEs (TRAEs) occurred in 61% (n = 117), 89% (n = 95), and 98% (n = 45) of patients in arms 1+3, 2, and 4, respectively.
In all patients enrolled in arms 1+3 (n = 193), TRAEs included AST increase (12%), ALT increase (12%), nausea (12%), and diarrhea (11%).
In arm 2, TRAEs included increased AST levels(36%), increase ALT levels (34%), pruritus (32%), rash (20%), diarrhea (20%), nausea (15%), anemia (11%), fatigue (11%), and increased alkaline phosphatase levels (11%).
In arm 4, TRAEs included anemia (46%), increased ALT levels (43%), increased AST levels (43%), nausea (39%), decreased neutrophil count (37%), fatigue (35%), decreased white blood cell count (30%), decreased platelet counts (24%), decreased appetite (24%), decreased lymphocyte count (22%), neutropenia (17%), pruritus (17%), increased creatinine (15%), rash (15%), diarrhea (13%), thrombocytopenia (13%), increased gamma-glutamyltransferase levels (13%), and constipation (13%).
TRAEs led to calderasib discontinuation across arms 1+3 (n = 1), 2 (n = 5), and 4 (n = 3), and 1 treatment-related fatality each occurred in arms 2 and 4.
DLTs were evaluated in the DLT-evaluable populations across arms 1+3 (n = 183), 2 (n = 102), and 4 (n = 46) and occurred across arms 1+3 (n = 2), 2 (n = 2), and 4 (n = 5). DLTs included increased blood alkaline phosphate leves (n = 1) and grade 3 QT prolongation on ECG (n = 1) in arms 1+3, grade 3 increased ALT (n = 1), grade 3 increased AST levels (n = 1), and grade 3 immune-mediated nephritis (n = 1) in arm 2, and grade 3 increased ALT levels (n = 2), grade 3 increased AST levels (n = 1), grade 3 colitis (n = 1), grade 3 diarrhea (n = 1), and grade 3 nausea (n = 1) in arm 4.
“Our findings support enrollment in the phase 3 KANDLELIT-004 [NCT06345729] and KANDLELIT-007 [NCT07190248] studies of calderasib and pembrolizumab as first-line therapy in KRAS G12C–mutated metastatic NSCLC,” Sacher said. In January 2026, Merck announced the launch of KANDLELIT-007, which will employ pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) as the immunotherapy component.2
Disclosures: Sacher disclosed institutional research and clinical trial involvement as a primary investigator with AstraZeneca, Amgen, Genentech, Merck Sharp and Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA (MSD), Lilly, Pfizer, BMS, Spectrum, GSK, Iovance, CRISPR Therapeutics, BridgeBio, and Hotspot Therapeutics; advisory board participation without personal fees for Genentech-Roche, Amgen, MSD, and AstraZeneca; and travel expenses for trial investigator meetings from Amgen, Genentech-Roche, and MSD.
