Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: July 16, 2025
Planned enrollment: 477
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 and cetuximab to first-line mFOLFOX6 improves progression-free survival compared with mFOLFOX6 with or without bevacizumab, while characterizing safety and tolerability.
Patients: Patients have histologically confirmed, locally advanced unresectable or metastatic colorectal adenocarcinoma with a tumor KRAS G12C mutation. Participants in Part 2 must not have received systemic therapy for unresectable or metastatic disease. Key exclusions include active CNS metastases, significant uncontrolled cardiovascular disease, inflammatory bowel disease, and known DPD deficiency.
Design: Two-part, randomized, open-label, multicenter study comparing an investigational combination with an active-control regimen. Treatment continues until discontinuation criteria are met.
Treatments: The experimental arm receives oral MK-1084 (calderasib), cetuximab, and mFOLFOX6; the comparator receives mFOLFOX6 with optional bevacizumab at investigator discretion. MK-1084 is an investigational covalent inhibitor of GDP-bound KRAS G12C, intended to keep mutant KRAS inactive and suppress downstream signaling. In a nonrandomized phase 1 colorectal cancer analysis, confirmed response rates were 38% with MK-1084 alone, 46% with MK-1084 plus cetuximab, and 38% with MK-1084, cetuximab, and mFOLFOX6; these preliminary results do not establish comparative benefit. mFOLFOX6 comprises oxaliplatin, leucovorin or levofolinate, and fluorouracil given every 2 weeks; bevacizumab may be added in the control arm.
Outcomes: Primary measures include dose-limiting toxicity during approximately the first 28 days, Part 1 adverse events and treatment discontinuations due to adverse events, and progression-free survival. Secondary measures include centrally reviewed objective response and duration of response, overall survival, Part 2 safety, and patient-reported quality of life, functioning, appetite loss, and bloating, including time to deterioration.
Burden on patient: Estimated moderate burden. Every-2-week infusion visits for chemotherapy and cetuximab or optional bevacizumab, plus oral MK-1084 in the experimental arm, require ongoing travel and treatment time. Tumor mutation confirmation, safety monitoring, response assessments, and repeated quality-of-life questionnaires add demands; the provided details do not specify mandatory research biopsies or intensive pharmacokinetic sampling.
Last updated: Sep 2026
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has a histologically confirmed diagnosis of locally advanced unresectable or metastatic (unresectable Stage III or Stage IV as defined by American Joint Committee on Cancer \[AJCC\] eighth edition) colorectal adenocarcinoma
* Part 2 only: Has not received systemic anticancer therapy for locally advanced unresectable or metastatic colorectal cancer
* Tumor tissue demonstrates presence of a Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation
* 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 and have undetectable HBV viral load
* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, chronic diarrhea)
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
* Has known dihydropyrimidine dehydrogenase (DPD) deficiency
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization
* Has 1 or more conditions that, in the opinion of the investigator, make the participant ineligible for treatment with bevacizumab
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease
* Has active infection requiring systemic therapy
* Has not adequately recovered from major surgery or have ongoing surgical complications
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
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