Calderasib

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. 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. This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/ Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.

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. 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. 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. The content above comes from the network. if any infringement, please contact us to modify.