KEYMAKER-U01 Substudy 01J: A Randomized Phase 2 Umbrella Study With Rolling Arms of Investigational Agents for First-line Treatment of Participants With Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With KRAS G12C Mutations

Overview

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)

Mechanism of action

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)

Efficacy

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:

• Calderasib plus pembrolizumab, dose-escalation cohort: 74% response rate, 91% disease-control rate and median progression-free survival of 25 months.
• Calderasib plus pembrolizumab, early expansion cohort: 40% response rate.
• Calderasib plus pembrolizumab and chemotherapy: 41% response rate.

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)

Safety

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)

Development status

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)

Further reading

• KANDLELIT-001 monotherapy results — Annals of Oncology
• Updated colorectal-cancer results — Annals of Oncology
• NSCLC results — Journal of Clinical Oncology
• Discovery and medicinal chemistry of MK-1084 — Journal of Medicinal Chemistry
• KANDLELIT-007 phase 3 registry record — ClinicalTrials.gov

Last updated: Sep 2026

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Has histologically or cytologically confirmed diagnosis of advanced or metastatic nonsquamous Non-Small Cell Lung Cancer (NSCLC)

* Has tumor tissue or circulating tumor deoxyribonucleic acid (ctDNA) that demonstrates the presence of Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutations

* Can provide an archival tumor tissue sample or newly obtained core, incisional, excisional biopsy of a tumor lesion not previously irradiated

* Has recovered to ≤Grade 1 or baseline from any Adverse events (AEs) due to previous anticancer therapies and/or ≤Grade 2 neuropathy and/or endocrine-related AEs adequately treated with hormone replacement

* Has well controlled human immunodeficiency virus (HIV) on antiretroviral therapy (ART) if HIV-infected

* Has undetectable hepatitis B (HBV) viral load and have received HBV antiviral therapy for at least 4 weeks if hepatitis B surface antigen (HBsAg) positive

* Has undetectable hepatitis C (HCV) viral load if HCV-infected

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Has a diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements

* Has HIV-infection with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease

* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease

* Has uncontrolled, clinically 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 corrected 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

* Has received prior systemic anticancer therapy for advanced or metastatic NSCLC

* Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) (except endocrine disorders that can be treated with replacement therapy) or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis

* Has received previous treatment with an agent targeting KRAS

* Has received prior systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) and has not recovered to grade ≤ 1 or baseline from AE associated with anticancer therapy before allocation/randomization

* Has received radiation therapy to the lung that is \>30 Gray within 6 months of start of study intervention

* Has a 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

* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years

* Has a known active central nervous system (CNS) metastases and/or carcinomatous meningitis

* Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed

* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

* Has a history of stem cell/solid organ transplant

* Has not adequately recovered from major surgery or has ongoing surgical complications