Merck’s Investigational KRAS Inhibitor Calderasib Receives FDA Breakthrough Therapy Designation for First-Line KRAS G12C-Mutated Lung Cancer
Merck, known as MSD outside the United States and Canada, has announced a significant regulatory milestone for its oncology pipeline with the U.S. Food and Drug Administration (FDA) granting Breakthrough Therapy designation to calderasib (MK-1084), an investigational oral KRAS G12C inhibitor. The designation applies to the use of calderasib in combination with KEYTRUDA® (pembrolizumab), Merck’s blockbuster anti-PD-1 immunotherapy, 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) of at least 1%.
The regulatory recognition marks the first Breakthrough Therapy designation awarded to calderasib and highlights the growing interest in precision oncology approaches designed to target specific genetic drivers of cancer. The FDA’s decision was supported by encouraging clinical findings from the ongoing Phase 1 KANDLELIT-001 study, which is evaluating the combination of calderasib and KEYTRUDA in patients with KRAS G12C-mutated NSCLC.
The designation represents an important step forward for Merck’s efforts to expand its oncology portfolio beyond immunotherapy and into targeted cancer treatments aimed at addressing unmet medical needs in genetically defined patient populations.
Expanding Precision Medicine in Lung Cancer
Non-small cell lung cancer remains the most common type of lung cancer and is responsible for a significant proportion of cancer-related deaths worldwide. Advances in molecular profiling have transformed the treatment landscape in recent years, allowing physicians to identify specific genetic mutations that drive tumor growth and tailor treatments accordingly.
Among these genetic alterations, KRAS mutations are among the most frequently observed oncogenic drivers. Historically, KRAS was considered one of the most challenging cancer targets due to the difficulty of directly inhibiting the protein. However, recent scientific breakthroughs have enabled the development of therapies that specifically target certain KRAS mutations, opening new treatment possibilities for patients.
The KRAS G12C mutation is the most common KRAS alteration identified in non-small cell lung cancer, particularly in adenocarcinoma. It is estimated to occur in approximately 14% of patients with this subtype of lung cancer. Because the mutation acts as a key driver of tumor growth and survival, therapies designed to inhibit KRAS G12C have become an important area of oncology research.
Calderasib is being developed as a highly specific oral inhibitor of the KRAS G12C mutation. By selectively targeting the altered KRAS protein, the investigational therapy aims to disrupt cancer cell signaling pathways and inhibit tumor growth while minimizing effects on healthy cells.
FDA Recognition Highlights Potential Clinical Impact
The FDA’s Breakthrough Therapy designation is reserved for investigational treatments that show the potential to provide substantial improvements over currently available therapies for serious or life-threatening diseases.
To qualify for the designation, a drug must demonstrate promising preliminary clinical evidence suggesting meaningful benefits on clinically significant endpoints. The designation is intended to accelerate the development and review of therapies that may offer important advances for patients facing limited treatment options.
Receiving Breakthrough Therapy designation provides several advantages during the regulatory process. Companies gain access to increased interaction with FDA experts, including guidance on efficient clinical development strategies and opportunities for more frequent communication with senior agency officials.
In addition, therapies granted the designation may benefit from rolling submission of regulatory applications and potential eligibility for Priority Review, both of which can help shorten review timelines if clinical development remains successful.
For Merck, the designation underscores growing confidence in the potential of calderasib as a targeted treatment option for patients with KRAS G12C-mutated lung cancer.
Merck Sees Opportunity to Address an Unmet Need
Merck executives highlighted the significance of the designation as part of the company’s broader commitment to advancing precision oncology.
Dr. Shweta Jain, Vice President of Global Clinical Development at Merck Research Laboratories, emphasized the importance of understanding the biological mechanisms that drive cancer growth and leveraging those insights to develop more effective therapies.
According to Jain, advances in cancer biology and precision medicine continue to create opportunities for innovative treatment approaches that directly target the molecular drivers of disease. She noted that the Breakthrough Therapy designation reflects both the promise of calderasib and the ongoing need for additional treatment options for patients with KRAS G12C-mutated non-small cell lung cancer.
The designation also demonstrates Merck’s strategy of combining targeted therapies with immuno-oncology agents such as KEYTRUDA to potentially enhance treatment outcomes.
Positive Findings from the KANDLELIT-001 Trial
The FDA’s decision was based on preliminary clinical evidence generated from the Phase 1 KANDLELIT-001 study.
Although detailed results have not yet been fully disclosed in the announcement, the trial provided sufficient evidence for regulators to determine that the combination of calderasib and KEYTRUDA may offer meaningful clinical benefit in the first-line treatment setting.
The rationale behind the combination is based on the complementary mechanisms of action of the two therapies. Calderasib directly targets the KRAS G12C mutation, while KEYTRUDA enhances the body’s immune response against cancer by blocking the PD-1 pathway.
Researchers believe that combining targeted inhibition of a key cancer driver with immune checkpoint blockade could potentially produce deeper and more durable responses than either approach alone.
The ongoing clinical program will continue to evaluate the safety, efficacy, and long-term outcomes associated with the combination across multiple patient populations.
Broad Phase 3 Development Program Underway
Merck is pursuing an ambitious development strategy for calderasib through its global KANDLELIT clinical program, which currently includes five Phase 3 studies spanning various stages of disease and multiple tumor types.
One of the most advanced studies, KANDLELIT-004, is evaluating calderasib in combination with KEYTRUDA as a first-line treatment for patients with newly diagnosed metastatic NSCLC harboring KRAS G12C mutations and high PD-L1 expression, defined as a tumor proportion score of 50% or greater.
Another study, KANDLELIT-007, is investigating calderasib alongside KEYTRUDA QLEX, a combination of pembrolizumab and berahyaluronidase alfa-pmph, in patients with newly diagnosed advanced or metastatic nonsquamous NSCLC regardless of PD-L1 expression levels.
Beyond lung cancer, Merck is also exploring calderasib’s potential in colorectal cancer. The Phase 3 KANDLELIT-012 trial is evaluating the investigational agent in combination with cetuximab and mFOLFOX6 chemotherapy as a first-line treatment for certain patients with locally advanced unresectable or metastatic colorectal cancer carrying KRAS G12C mutations.
Additional studies are examining the use of calderasib in earlier stages of lung cancer treatment. KANDLELIT-013 is evaluating the therapy in combination with KEYTRUDA QLEX for patients with locally advanced KRAS G12C-mutated NSCLC who have previously received neoadjuvant or adjuvant therapy.
Meanwhile, KANDLELIT-015 is investigating calderasib in combination with durvalumab for patients with locally advanced KRAS G12C-mutated NSCLC following chemotherapy and radiation treatment.
Collectively, these studies reflect Merck’s strategy of evaluating calderasib across the entire continuum of care, from early-stage disease to advanced metastatic settings.
Strategic Collaboration Supports Development
The development of calderasib is being conducted through a strategic collaboration involving Merck, Taiho Pharmaceutical Co., Ltd., and Astex Pharmaceuticals, a United Kingdom-based subsidiary wholly owned by Otsuka Pharmaceutical Co., Ltd.
The partnership, announced in January 2020, combined the scientific expertise and development capabilities of the participating organizations to advance novel therapies targeting KRAS-driven cancers.
The collaboration has enabled the rapid progression of calderasib through clinical development and has positioned the program as one of the most closely watched efforts in the competitive KRAS inhibitor landscape.
The FDA’s Breakthrough Therapy designation for calderasib represents an important validation of the investigational therapy’s potential and highlights the continued momentum behind targeted treatments for genetically defined cancers.
As Merck advances the extensive KANDLELIT development program, the company aims to determine whether calderasib, particularly when combined with KEYTRUDA, can establish a new treatment option for patients with KRAS G12C-mutated non-small cell lung cancer and potentially other KRAS-driven malignancies.
If future studies confirm the promising early results observed to date, calderasib could become a significant addition to the expanding arsenal of precision oncology therapies, offering new hope for patients whose cancers are driven by one of the most common oncogenic mutations in lung cancer.
About calderasib
Calderasib (MK-1084) is an investigational, highly potent and specific next-generation KRAS G12C covalent inhibitor. Mutations in KRAS are among the most prevalent mutations found in cancer, occurring with high frequency in non-small cell lung cancer (NSCLC), pancreatic, urogenital and colorectal cancers. The KRAS G12C mutation is the most frequently observed KRAS mutation in patients, occurring in approximately 14% of patients with NSCLC (adenocarcinoma). Despite decades of research and recognition of the therapeutic importance of targeting KRAS, the development of small molecule inhibitors targeting KRAS mutations has been challenging.
About lung cancer
Lung cancer is the leading cause of cancer death worldwide. In 2022 alone, there were approximately 2.4 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer is the most common type of lung cancer, accounting for about 80% of all cases. In 2025, the overall five-year survival rate for patients diagnosed with lung cancer was nearly 30% in the United States.
Improved survival rates are due, in part, to earlier detection and screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. Early detection and screening remain an important unmet need, as 43% of lung cancer cases are not found until they are advanced.
About KEYTRUDA® (pembrolizumab) injection for intravenous use, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 2,800 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
About KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use, 165 mg + 2,000 units/mL
KEYTRUDA QLEX is a fixed-combination drug product of pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody and berahyaluronidase alfa enhances dispersion and permeability to enable subcutaneous administration of pembrolizumab. KEYTRUDA QLEX is administered as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel, over one minute every three weeks (2.4 mL) or over two minutes every six weeks (4.8 mL).
