Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: May 24, 2024
Planned enrollment: 600
MK-1084, now also called calderasib, is an investigational, orally administered targeted therapy from Merck/MSD. It is being developed for advanced solid tumors containing a KRAS G12C mutation, particularly non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). Evidence currently comes primarily from the open-label, nonrandomized phase 1 KANDLELIT-001 trial; randomized phase 3 trials are underway. (annalsofoncology.org)
Calderasib is a selective, covalent inhibitor of the inactive, GDP-bound form of KRAS G12C. Binding is intended to lock mutant KRAS in its inactive state and suppress downstream tumor-promoting signaling. It was designed as an orally bioavailable, low-dose inhibitor. Substantial reductions in circulating KRAS G12C variant allele fraction during treatment provide clinical evidence of target engagement. (pubs.acs.org)
In the latest broadly reported monotherapy analysis of KANDLELIT-001, 123 previously treated patients received calderasib. Confirmed objective response rates were 38% in CRC, 38% in NSCLC, and 34% across other tumor types. Median progression-free survival was 6.2, 8.3, and 5.7 months, respectively. Results in small tumor-specific subgroups, such as hepatobiliary cancer, should be interpreted cautiously. (annalsofoncology.org)
In previously untreated KRAS G12C-mutant NSCLC, earlier phase 1 data showed:
Follow-up was short for the latter two cohorts at the August 12, 2024 cutoff. (ascopubs.org)
Updated CRC data with a January 5, 2026 cutoff continued to show activity with calderasib alone and in combinations with cetuximab with or without mFOLFOX6. The earlier December 2025 analysis reported confirmed response rates of 38% with monotherapy, 46% with calderasib plus cetuximab, and 38% with calderasib, cetuximab and mFOLFOX6. These results remain preliminary because the study was phase 1 and lacked randomized control groups. (annalsofoncology.org)
With monotherapy, treatment-related adverse events occurred in 58% of 123 patients; 10% had grade 3–4 events. The most frequent treatment-related events were elevated ALT, elevated AST, diarrhea and nausea. One patient discontinued calderasib because of nausea, and there were no grade 5 treatment-related events. (annalsofoncology.org)
Combination therapy produced more toxicity. In the updated CRC analysis, grade 3–4 drug-related adverse events occurred in 20% with calderasib plus cetuximab and 42% with calderasib, cetuximab and mFOLFOX6. Reported dose-limiting toxicities included rash, febrile neutropenia, peripheral sensory neuropathy, QT prolongation and alkaline-phosphatase elevation. (annalsofoncology.org)
In the earlier NSCLC analysis, grade 3 or higher drug-related events occurred in 33% with pembrolizumab and 58% with pembrolizumab plus chemotherapy. One treatment-related death from myelosuppression and decreased platelet count was reported in the pembrolizumab cohort. (ascopubs.org)
Calderasib remains investigational. Ongoing phase 3 studies include KANDLELIT-004 and KANDLELIT-007 in first-line KRAS G12C-mutant NSCLC, and KANDLELIT-012 in first-line metastatic CRC. No randomized phase 3 efficacy results have yet been reported. (clinicaltrials.gov)
Last updated: Sep 2026
Goal: Determine whether adding MK-1084 to first-line pembrolizumab improves progression-free and overall survival versus pembrolizumab alone in metastatic KRAS G12C-mutant NSCLC with PD-L1 TPS ≥50%.
Patients: Patients with newly diagnosed stage IV, measurable NSCLC harboring KRAS G12C, PD-L1 TPS ≥50%, ECOG performance status 0–1, and no prior systemic therapy for metastatic disease. Key exclusions include active CNS metastases, clinically significant autoimmune disease or pneumonitis, and substantial immunosuppression.
Design: Randomized, double-blind, multicenter, placebo-controlled phase 3 trial with planned enrollment of 600 patients.
Treatments: Both groups receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles, with either once-daily oral MK-1084 or matching placebo until a discontinuation criterion is met. MK-1084 (calderasib) is an investigational covalent inhibitor that binds GDP-bound KRAS G12C to suppress downstream signaling. Preliminary, nonrandomized phase 1 data in previously untreated KRAS G12C-mutant NSCLC reported response rates of 74% in a pembrolizumab-combination dose-escalation cohort and 40% in an early expansion cohort; these findings require randomized confirmation.
Outcomes: Co-primary endpoints are progression-free survival by blinded independent central review using RECIST 1.1 and overall survival. Secondary endpoints include objective response rate, duration of response, adverse events and treatment discontinuations due to adverse events, and patient-reported quality of life, functioning, dyspnea, cough, and chest pain, including time to deterioration.
Burden on patient: Moderate. Patients take a daily study tablet and attend pembrolizumab infusions every 3 weeks, along with tumor assessments, safety monitoring, and repeated quality-of-life questionnaires. Tumor tissue is required for KRAS G12C and PD-L1 testing. No mandatory serial research biopsies or intensive pharmacokinetic sampling are specified, but the added oral therapy and monitoring extend beyond pembrolizumab alone.
Last updated: Sep 2026
Caution: ClinicalTrials.gov appears to have newer eligibility criteria than the version saved here. Review the current criteria in ClinicalTrials.gov.
The main inclusion and exclusion criteria include but are not limited to the following:
Inclusion Criteria:
* Has a histologically or cytologically confirmed diagnosis of NSCLC
* Has newly diagnosed Stage IV NSCLC by American Joint Committee on Cancer (AJCC) Staging Manual, Version 8
* Has measurable disease based on RECIST 1.1
* Has provided tumor tissue that demonstrates PD-L1 expression in ≥50% of tumor cells
* Has provided tumor tissue that demonstrates presence of KRAS G12C mutation
* Has life expectancy of at least 3 months
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days before randomization
* For participant assigned male sex at birth: If capable of producing sperm, participant must agree to the following during the study treatment period and for at least 10 days after the last dose of oral intervention: Either be abstinent or must agree to use male condom plus additional contraceptive method.
* For participant assigned female sex at birth: Either be a person of nonchildbearing potential (PONCBP) or must agree to follow contraceptive guidance during the study treatment period and for at least 10 days after the last dose of oral intervention and 120 days after the last dose of pembrolizumab. Must abstain from breastfeeding during the study intervention period and for at least 120 days after study intervention.
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART).
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization
Exclusion Criteria:
* Diagnosis of small cell lung cancer
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
* Has a known history of, or active, neurologic paraneoplastic syndrome
* Has an active infection requiring systemic therapy
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QT interval corrected for heart rate by Fridericia's formula (QTcF) interval to \>470 ms, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention
* Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome.
* Has one or more of the following ophthalmological findings/conditions: intraocular diagnosis of central serous retinopathy, retinal vein occlusion, or retinal artery occlusion, diagnosis of retinal degenerative disease pressure \>21 mm Hg and/or any diagnosis of glaucoma
* Is unable to swallow orally administered medication, or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, or malabsorption)
* Received prior systemic anticancer therapy for their metastatic NSCLC
* Received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor within 12 months before diagnosis of metastatic NSCLC
* Has received radiotherapy within 2 weeks of start of study intervention
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
* Active autoimmune disease that has required systemic treatment in the past 2 years
* History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* History of allogeneic tissue/solid organ transplant
* Has not fully recovered from any effects of major surgical procedure. Surgical procedures that required general anesthesia must be completed at least 2 weeks before first study intervention administration.
CABA, Buenos Aires, C1426AGE, Argentina
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Status: Recruiting
Ivano-Frankivsk, Ivano-Frankivsk Oblast, 76018, Ukraine
No email / +380978411455
Status: Recruiting
Kropyvnytskyi, Kirovohrad Oblast, 25011, Ukraine
No email / +380508412400
Status: Recruiting
Kiev, Kyivska Oblast, 03022, Ukraine
No email / +380503858689
Status: Recruiting
Lviv, Lviv Oblast, 79059, Ukraine
No email / +380506749772
Status: Recruiting
Rivne, Rivne Oblast, 33010, Ukraine
No email / +380362633075
Status: Recruiting
Vinnytsia, Vinnytsia Oblast, 21029, Ukraine
No email / +380953105783
Status: Recruiting
Lutsk, Volyn Oblast, 43018, Ukraine
No email / +380503782998
Status: Recruiting
Milton Keynes, Buckinghamshire, MK6 5LD, United Kingdom
No email / 01908 997609
Status: Recruiting
Beverly Hills, California, 90211, United States
No email / 310-432-8955
Status: Recruiting
Bakersfield, California, 93309, United States
No email / 888-577-8839
Status: Recruiting
Miami Beach, Florida, 33140, United States
No email / 888-577-8839
Status: Recruiting
Skokie, Illinois, 60077, United States
No email / 224-534-7580
Status: Recruiting
Springfield, Missouri, 65807, United States
No email / 417-875-3000
Status: Recruiting
Kansas City, Missouri, 64108, United States
No email / 816-404-4093
Status: Recruiting
Billings, Montana, 59102, United States
No email / 888-577-8839
Status: Recruiting
Morristown, New Jersey, 07960, United States
No email / 973-275-7788
Status: Recruiting
Albany, New York, 12206, United States
No email / 888-577-8839
Status: Recruiting
Kettering, Ohio, 45429, United States
No email / 888-577-8839
Status: Recruiting
Cincinnati, Ohio, 45219, United States
No email / 888-577-8839
Status: Recruiting
Lancaster, Pennsylvania, 17601, United States
No email / 717-544-9400
Status: Recruiting
Houston, Texas, 77030, United States
No email / 713-600-0900
Status: Recruiting
Madison, Wisconsin, 53715, United States
No email / 888-577-8839
Status: Recruiting
CABA, Buenos Aires, C1019ABS, Argentina
No email / No phone
Status: Completed
Rivne, Rivne Oblast, 33007, Ukraine
No email / No phone
Status: Completed