Merck, known as MSD outside of the United States and Canada, announced the initiation of KANDLELIT-007, a phase 3 clinical trial evaluating calderasib (MK-1084), an investigational oral selective KRAS G12C inhibitor, in combination with Keytruda QLEX (pembrolizumab and berahyaluronidase alfa-pmph) for the first-line treatment of patients with KRAS G12C-mutant, advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC).
This randomized, unblinded open-label, multicenter clinical trial (NCT07190248) will evaluate calderasib given orally once daily in combination with Keytruda QLEX administered subcutaneously, compared with subcutaneous Keytruda QLEX in combination with intravenous pemetrexed and chemotherapy (carboplatin or cisplatin), in newly diagnosed patients with KRAS G12C-mutant advanced or metastatic nonsquamous NSCLC. In both treatment arms, Keytruda QLEX will be administered once every six weeks; in the comparator arm, pemetrexed will be given on days 1 and 22 of every three-week cycle and carboplatin or cisplatin will be given on days 1 and 22 for up to two three-week cycles.
“While outcomes for patients with NSCLC have significantly improved over the last decade, we know there is more work to do. KRAS is the most frequently mutated oncogene in cancer, and the KRAS G12C mutation occurs in approximately 4% to 14% of all patients with lung cancer globally,” said Dr. Gregory Lubiniecki, vice president, global clinical development, Merck Research Laboratories. “By pairing our oral calderasib candidate with subcutaneously administered Keytruda QLEX in this trial, we will evaluate whether this chemotherapy-free combination that requires no intravenous access may help improve outcomes for patients with KRAS G12C-mutant NSCLC.”
The trial will enroll approximately 675 patients globally. The primary endpoint of the study is progression-free survival (PFS) in patients whose tumours express PD-L1 (tumour proportion score [TPS] =1%). Secondary endpoints include PFS in all study participants and overall survival, overall response rate, duration of response and safety in both the PD-L1 (TPS =1%) expressor patient population and all comers.
In addition to KANDLELIT-007, calderasib is being investigated in the phase 3 KANDLELIT-012 study (NCT06997497), which is evaluating calderasib in combination with cetuximab and mFOLFOX6 for the first-line treatment of certain patients with KRAS G12C-mutant locally advanced unresectable or metastatic colorectal cancer, and the phase 3 KANDLELIT-004 study (NCT06345729), which is investigating calderasib in combination with Keytruda (pembrolizumab) for the first-line treatment of certain patients with KRAS G12C-mutant locally advanced or metastatic NSCLC whose tumours express PD-L1 (TPS =50%). Calderasib is also currently being evaluated in the phase 1 KANDLELIT-001 trial (NCT05067283) to assess safety, tolerability, pharmacokinetics and efficacy of calderasib as monotherapy and as part of various combination therapies in patients with KRAS G12C-mutant advanced solid tumours and in the Phase 2 KANDLELIT-014 study (NCT07209111) evaluating calderasib as monotherapy and in combination with cetuximab for certain patients with KRAS G12C-mutant advanced solid tumours. As announced, data from KANDLELIT-001 were presented at the 2025 European Society for Medical Oncology Congress.
Calderasib is being developed through a collaboration with Taiho Pharmaceutical Co. Ltd. and Astex Pharmaceuticals (UK), a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd. This collaboration was announced in January 2020.
Calderasib (MK-1084) is an investigational, potent and specific 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, pancreatic, urogenital and colorectal cancers. The KRAS G12C mutation is the most frequently observed KRAS mutation in patients, occurring in approximately 4% to 14% of patients with non-small cell lung cancer (adenocarcinoma) depending on their geographic location. 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.
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. Early detection and screening remain an important unmet need, as 43% of lung cancer cases are not found until they are advanced.
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 1,600 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.
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).
Keytruda and Keytruda QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with metastatic nonsquamous non–small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumour aberrations.
Keytruda and Keytruda QLEX are each indicated, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, for the first-line treatment of adult patients with metastatic squamous NSCLC.
Keytruda and Keytruda QLEX, as single agents, are each indicated for the first-line treatment of adult patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) =1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
• stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
• metastatic.
• Keytruda and Keytruda QLEX, as single agents, are each indicated for the treatment of adult patients with metastatic NSCLC whose tumours express PD-L1 (TPS =1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda or Keytruda QLEX.
Keytruda and Keytruda QLEX are each indicated for the treatment of adult patients with resectable (tumours =4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
Keytruda and Keytruda QLEX, as single agents, are each indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a =4 cm), II, or IIIA NSCLC.
Merck is advancing research aimed at transforming the way lung cancer is treated, with a goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients around the world, Merck is at the forefront of lung cancer research. In NSCLC, Keytruda has six approved U.S. indications (see indications above) and is approved for advanced disease in more than 95 countries. Among Merck’s research efforts are trials focused on evaluating Keytruda in earlier stages of lung cancer as well as identifying new combinations and coformulations with Keytruda.
Every day, Merck follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, the company are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumour types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. |