Merck’s KRAS G12C inhibitor calderasib gains FDA BTD for NSCLC

Edited by Robert McTiernan··3 min read

Merck & Co., Inc. (NYSE: MRK) announced that the US FDA has granted Breakthrough Therapy Designation (BTD) for calderasib (MK-1084), an investigational oral covalent KRAS G12C inhibitor. The award covers the molecule’s use in combination with pembrolizumab (Keytruda) for the first-line treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation and with a PD-L1 tumor proportion score (TPS) ≥1%. This is the first BTD received for calderasib and was supported by data from the Phase I KANDLELIT-001 trial.

BTD provides intensive FDA guidance, organizational commitment from senior review staff, rolling review, and potential eligibility for Priority Review. Calderasib is being co-developed with Japan-based Taiho Pharmaceutical Co. Ltd. and UK-based Astex Pharmaceuticals, a subsidiary of Otsuka Pharmaceutical Co., Ltd., under a collaboration announced in January 2020.

The KANDLELIT-001 trial (NCT05067283) generated the efficacy data supporting this designation. In previously untreated metastatic NSCLC patients with PD-L1 TPS ≥1% receiving calderasib plus pembrolizumab (n=69), the confirmed objective response rate (ORR) was 77% (95% CI: 65–86) at a median follow-up of 12.1 months. In the calderasib monotherapy arm in previously treated NSCLC (n=21), confirmed ORR was 38% (95% CI: 18–62) at a median follow-up of 18.9 months. Across all arms, treatment-related adverse events occurred in 94% of patients in the calderasib plus pembrolizumab arm. These data were presented at the 2025 American Society of Clinical Oncology Annual Meeting.

Merck has since initiated the Phase III KANDLELIT-007 trial (NCT07190248), evaluating calderasib with subcutaneous KEYTRUDA QLEX in newly diagnosed KRAS G12C-mutant nonsquamous NSCLC regardless of PD-L1 expression, enrolling approximately 675 patients with progression-free survival as the primary endpoint. The Phase III KANDLELIT-004 trial (NCT06345729) evaluates calderasib plus pembrolizumab in patients with PD-L1 TPS ≥50%, enrolling approximately 600 patients with co-primary endpoints of progression-free survival and overall survival.

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Research context

The KRAS G12C mutation occurs in approximately 14% of NSCLC adenocarcinoma cases. No KRAS G12C inhibitor has received regulatory approval for first-line NSCLC anywhere globally, creating the competitive context for calderasib’s program. Two approved agents — sotorasib (Lumakras) from Amgen and adagrasib (Krazati) from Bristol Myers Squibb — are indicated only in the previously treated setting.

In the first-line space, calderasib’s principal competitor is olomorasib from Eli Lilly and Company (NYSE: LLY), which received its own BTD in September 2025 for the same indication — first-line KRAS G12C-mutant NSCLC with PD-L1 TPS ≥50% — in combination with pembrolizumab, supported by Phase I/II LOXO-RAS-20001 and Phase III SUNRAY-01 dose optimization data. China-based D3 Bio’s elisrasib (D3S-001) has also reported first-line NSCLC data, with an ORR of 81.3% in combination with pembrolizumab across all PD-L1 expression levels in 48 efficacy-evaluable patients.

Unlike olomorasib, which is positioned primarily in the PD-L1 TPS ≥50% population, calderasib’s BTD covers the broader PD-L1 TPS ≥1% population, and the KANDLELIT-007 trial extends evaluation to a PD-L1-unselected population. The KRAS G12C mutation rate in NSCLC varies geographically — approximately 4% to 14% depending on region — a factor that will influence global trial enrollment and commercial positioning.

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