Investigators Launch Phase 3 Trial of Calderasib Combo in Advanced NSCLC

Investigators have launched the phase 3 KANDLELIT-007 trial (NCT07190248) evaluating calderasib (MK-1084) plus subcutaneous pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) as frontline treatment for patients with advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring KRAS G12C mutations, according to a press release from the developer, Merck.¹

As part of the unblinded, open-label, multicenter trial, approximately 675 patients will be assigned to receive calderasib given orally once daily plus subcutaneous pembrolizumab or subcutaneous pembrolizumab in combination with intravenous pemetrexed and chemotherapy. All patients will receive subcutaneous pembrolizumab once every 3 weeks. Those in the comparator arm will receive pemetrexed on days 1 and 22 of each 3-week cycle plus carboplatin or cisplatin on days 1 and 22 for a maximum of 2 cycles.

The trial’s primary end point will be progression-free survival (PFS) among patients with a PD-L1 tumor proportion score (TPS) of at least 1%. Secondary end points include PFS among all patients, overall survival (OS), overall response rate (ORR), duration of response, and safety.

“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,” Gregory Lubiniecki, MD, vice president of global clinical development at Merck Research Laboratories, stated in the press release.¹ “By pairing our oral calderasib candidate with subcutaneously administered [pembrolizumab] 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.”

Developers designed calderasib as a potent and specific KRAS G12C covalent inhibitor. The press release noted that developing small molecule inhibitors directed towards KRAS mutations has been “challenging” despite decades of research on therapeutically targeting this marker.

Patients 18 years and older with nonsquamous stage IIIB or IIIC NSCLC not eligible for curative resection or chemoradiation or those with stage IV disease are eligible for enrollment on the KANDLELIT-007 trial.² If patients have HIV-positive status, they must have well-controlled disease on antiretroviral therapy to be eligible for enrollment.

Those with small cell lung cancer, active inflammatory bowel disease requiring immunosuppressive medication, significant cardiovascular disease or cerebrovascular disease, or a gastrointestinal disorder impacting absorption are ineligible for study entry. Patients are also unable to enroll on the study if they have received prior systemic anticancer therapy for advanced or metastatic NSCLC, known active central nervous system metastases and/or carcinomatous meningitis, or active autoimmune disease requiring systemic treatment within 2 years of entering the study.

Assessment of calderasib is currently underway in several other clinical trials, including the phase 1 KANDLELIT-001 trial (NCT05067283), which is evaluating the agent’s safety, tolerability, pharmacokinetics, and efficacy among patients with KRAS G12C-mutated advanced solid tumors. Investigators previously presented data from the KANDLELIT-001 trial at the European Society for Medical Oncology (ESMO) Congress 2025.³

Data from KANDLELIT-001 revealed an ORR of 38% among patients with colorectal cancer, 38% among those with NSCLC, and 34% among those with other types of solid tumors. In each respective population, the median PFS was 6.2 months (95% CI, 5.1-8.1), 8.3 months (95% CI, 4.2-not reached), and 5.7 months (95% CI, 4.0-14.4). Overall, findings supported the conclusion that calderasib demonstrated manageable safety and promising activity in a range of KRAS G12C-mutated solid tumors.

References

1. Merck initiates phase 3 KANDLELIT-007 trial evaluating calderasib (MK-1084), an investigational oral KRAS G12C inhibitor, in combination with KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) in certain patients with advanced NSCLC. News release. Merck. January 7, 2026. Accessed January 7, 2026. https://tinyurl.com/3z59s8ua
2. A clinical study of MK-1084 and other treatments for participants with non-small cell lung cancer (MK-1084-007/​KANDLELIT-007). ClinicalTrials.gov. Updated January 5, 2026. Accessed January 7, 2026. https://tinyurl.com/2s4e87t6
3. MK-1084 monotherapy in participants (Pts) with KRAS G12C–mutated advanced solid tumors: activity and safety in the phase I KANDLELIT-001 study. Ann Oncol. 2025;36(suppl 2):S606-S607. doi:10.1016/j.annonc.2025.08.1495