Merck’s calderasib KRAS G12C inhibitor gains FDA Breakthrough Therapy designation for metastatic NSCLC

Merck (NYSE: MRK) announced receipt of US FDA Breakthrough Therapy Designation (BTD) for calderasib (MK-1084), an oral next-generation KRAS G12C covalent inhibitor. The BTD 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 expressing PD-L1 with a tumor proportion score (TPS) ≥1%. The designation, the first awarded to calderasib, was supported by data from the Phase I KANDLELIT-001 trial.

BTD confers rolling review eligibility, intensive FDA guidance, and potential access to Priority Review — procedural advantages that become material when a Phase III program of the scale Merck has assembled is already underway. The company has five Phase III KANDLELIT trials running across NSCLC and colorectal cancer settings.

Calderasib is being developed in collaboration with Taiho Pharmaceutical and Astex Pharmaceuticals, a subsidiary of Otsuka Pharmaceutical, under an arrangement announced in January 2020.

KANDLELIT-001 data

The designation rests on efficacy data from KANDLELIT-001 presented at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting and published in the Journal of Clinical Oncology (Abstract 8605). In the first-line NSCLC cohort receiving calderasib plus pembrolizumab in patients with PD-L1 TPS ≥1%, the objective response rate (ORR) reached 77% at a median follow-up of 12.1 months. That figure compares to the approximately 45% ORR reported for pembrolizumab monotherapy in PD-L1–high NSCLC in KEYNOTE-024, providing the basis for the FDA’s determination that preliminary evidence suggests substantial improvement over available therapy — the threshold required for BTD.

The Phase III program pivoting on this signal includes KANDLELIT-004, which evaluates calderasib plus pembrolizumab in newly diagnosed metastatic NSCLC with KRAS G12C mutation and PD-L1 TPS ≥50%, and KANDLELIT-007, which tests calderasib with subcutaneous KEYTRUDA QLEX in nonsquamous NSCLC regardless of PD-L1 expression. Two additional trials — KANDLELIT-013 and KANDLELIT-015 — address locally advanced KRAS G12C-mutant NSCLC in post-neoadjuvant and post-chemoradiation settings, respectively. KANDLELIT-012 extends the program to first-line colorectal cancer in combination with cetuximab and mFOLFOX6.

Research context

KRAS G12C occurs in approximately 14% of NSCLC adenocarcinoma cases, making it the most prevalent individual KRAS variant in the disease. The mutation was long considered intractable to small molecule inhibition until the identification of a cryptic switch-II pocket in the GDP-bound, inactive conformation of the protein, which covalent inhibitors exploit by forming an irreversible bond with the mutant cysteine at position 12.

Two KRAS G12C inhibitors are currently approved in the US: sotorasib (Lumakras, Amgen), granted accelerated approval in May 2021 and converted to full approval in January 2023 for previously treated KRAS G12C-mutant NSCLC, and adagrasib (Krazati, Mirati/Bristol Myers Squibb), approved in December 2022 for the same second-line indication. Both approvals are in the previously treated setting; no KRAS G12C inhibitor holds a first-line approval in NSCLC.

Calderasib’s “next-generation” positioning implies potential differentiation from sotorasib and adagrasib, though Merck has not released head-to-head comparative data. The first-generation agents share the covalent GDP-state binding mechanism but differ in potency, selectivity, and resistance profiles. Adagrasib has demonstrated central nervous system penetration and activity against certain acquired resistance mutations — characteristics Merck has not yet disclosed for calderasib in public-domain data.

The pembrolizumab combination strategy also distinguishes calderasib’s development path from the approved agents, which are both indicated as monotherapies in the second-line setting. Combining KRAS G12C inhibition with PD-1 blockade carries mechanistic rationale: KRAS pathway suppression can modulate the tumor immune microenvironment, potentially enhancing responsiveness to checkpoint inhibition.

The broader competitive landscape includes divarasib (Roche/Genentech), another next-generation KRAS G12C inhibitor in Phase III development, and a range of earlier-stage programs targeting KRAS G12C through non-covalent, pan-KRAS, or bifunctional degrader mechanisms. Amgen is also evaluating sotorasib in first-line combinations.