Merck’s calderasib earns FDA Breakthrough Therapy designation with pembrolizumab in KRAS G12C‑mutated NSCLC, supported by Phase 1 data.
Written By: Nalam Karthik, PharmD
Reviewed By: Pharmacally Editorial Team
Merck has received U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation for calderasib (MK-1084) in combination with pembrolizumab (KEYTRUDA) as a first-line treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation and a PD-L1 tumor proportion score (TPS) of at least 1%.
The designation marks the first Breakthrough Therapy recognition for calderasib and was supported by positive data from the Phase 1 KANDLELIT-001 study evaluating the combination in previously untreated KRAS G12C-mutated NSCLC.
Scientific Context
Calderasib is an investigational next-generation KRAS G12C covalent inhibitor that selectively targets one of the most prevalent oncogenic KRAS mutations. KRAS G12C occurs in approximately 14% of lung adenocarcinoma cases and has historically been considered a difficult therapeutic target.
Despite advances in immunotherapy and targeted therapies, durable disease control remains a challenge for many patients with KRAS G12C-mutated NSCLC, highlighting the need for more effective frontline treatment options.
Development Program
The FDA grants Breakthrough Therapy designation to investigational medicines for serious or life-threatening conditions when early clinical evidence suggests substantial improvement over available therapies. The designation provides enhanced regulatory guidance, increased interaction with the agency, rolling review, and potential eligibility for Priority Review.
Merck is advancing calderasib through the broad KANDLELIT clinical development program, which includes five ongoing Phase 3 trials across lung and colorectal cancers.
KANDLELIT-004 (NCT06345729): Evaluating calderasib plus pembrolizumab in newly diagnosed metastatic NSCLC with PD-L1 TPS ≥50%.
KANDLELIT-007 (NCT07190248): Assessing calderasib in combination with subcutaneous pembrolizumab (KEYTRUDA QLEX™) in patients with newly diagnosed advanced or metastatic nonsquamous NSCLC regardless of PD-L1 expression.
Additional Phase 3 studies are evaluating calderasib in locally advanced NSCLC and KRAS G12C-mutated colorectal cancer, reflecting efforts to expand the therapy across multiple disease settings.
Executive Perspective
Dr. Shweta Jain, vice president of global clinical development at Merck Research Laboratories, said the designation underscores the potential of calderasib and highlights the ongoing need for new treatment approaches for patients with KRAS G12C-mutated NSCLC. She noted that advances in precision oncology continue to improve the ability to target key molecular drivers of tumor growth and support the development of more personalized treatment strategies.
Clinical Path Forward
The Breakthrough Therapy designation could accelerate the clinical development and regulatory review of calderasib in lung cancer. Upcoming Phase 3 readouts from the KANDLELIT program will determine whether the calderasib-pembrolizumab combination can improve frontline treatment outcomes and support future regulatory filings in NSCLC and other KRAS G12C-driven cancers.
Reference
About the Writer
Nalam Karthik (LinkedIn) is a healthcare writer and PharmD graduate with interests in pharmacovigilance, drug safety, clinical data analysis, and quality assurance. He is passionate about translating clinical and pharmaceutical knowledge into accessible healthcare content while staying engaged with advancements in drug development and patient safety initiatives.