Calderasib Plus Pembrolizumab Shows Robust Response in KRAS G12C+ Metastatic NSCLC

For oncology nurses caring for patients with KRAS G12C-mutant metastatic non–small cell lung cancer (NSCLC), new data from the phase 1 KANDLELIT-001 trial (NCT05067283) suggest a shifting treatment landscape. Findings presented at the 2026 European Lung Cancer Congress (ELCC) demonstrate that calderasib (MK-1084), both as monotherapy and in combination with pembrolizumab (Keytruda), provides durable antitumor activity and impressive survival rates.¹

Clinical Efficacy: High Response Rates in Combination Therapy

The combination of calderasib and pembrolizumab showed particularly strong efficacy in treatment-naive patients with a tumor proportion score (TPS) of ≥1%.

• Combination ORR: The objective response rate (ORR) reached 72% in the combination arm, climbing to 87% in patients with a TPS ≥50%.
• Disease Control: The disease control rate (DCR) was nearly universal at 95% for the combination and 89% for the triplet therapy (calderasib, pembrolizumab, and chemotherapy).
• Progression-Free Survival: Patients receiving the doublet therapy achieved a median PFS of 28.9 months (95% CI, 20.6-NR).

In the heavily pretreated monotherapy cohort, where 40% of patients were in their third line of therapy or later, calderasib still maintained a respectable ORR of 27% and a median PFS of 8.3 months.^1,2

Nursing Priorities: Monitoring for Hepatic and Immune-Mediated Toxicities

While the investigator team characterized adverse events (AEs) as manageable, the transition from monotherapy to combination therapy requires heightened nursing vigilance for cumulative toxicities.

Hepatic Health

Increased liver enzymes were a recurring theme across all study arms. Nurses should prioritize the monitoring of alanine aminotransferase (ALT) and aspartate aminotransferase (AST):

• Monotherapy: Grade 3 ALT/AST elevations occurred in 3% of patients.
• Doublet Therapy: Elevations rose to 8% with the addition of pembrolizumab.
• Triplet Therapy: Hepatic toxicity reached 11% in the chemo-combination arm.

Symptom Management and Immune Vigilance

Beyond hepatic monitoring, nurses should be prepared to manage a broad range of treatment-related AEs (TRAEs). Common symptoms observed in the combination arms included:

• Dermatologic: Pruritus (32%) and rash (20%).
• Gastrointestinal: Nausea (15%-39%) and diarrhea (13%-20%).
• Hematologic (primarily in triplet therapy): Anemia (46%) and decreased neutrophil counts (37%).

Dose-limiting toxicities (DLTs) were rare but serious, including grade 3 immune-mediated nephritis, colitis, and QT prolongation. It is essential to be adept at differentiating between standard chemotherapy side effects and immune-related adverse events (irAEs), the latter of which would be prompted by the checkpoint inhibitor.

Mechanism of Action: Overcoming the Immunosuppressive Microenvironment

KRAS G12C mutations are unique because they often present with high PD-L1 expression but exist within an immunosuppressive tumor microenvironment.

Calderasib acts as a highly specific KRAS G12C-GDP inhibitor. By locking the KRAS protein in its inactive state, it disrupts the signaling pathways that drive tumor growth. When combined with pembrolizumab, the therapy addresses the "brake" on the immune system while simultaneously targeting the underlying oncogenic driver, leading to the prolonged durability of response (DOR) observed in the trial.

Looking Forward: First-Line Implications

KANDLELIT-007 (NCT07190248) which will evaluate calderasib in combination with a subcutaneous formulation of pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex).

“In KANDLELIT-001, calderasib alone or in combination shows clinically meaningful activity,” said lead author Adrian Sacher, MD, MMSc, FRCPC, in a presentation during the conference. He emphasized that these findings support the continued movement of these combinations into the first-line setting for KRAS G12C-mutated metastatic NSCLC.

References

1. Sacher A, Rottenberg Y, Kwiatkowski M, et al. Updated results for MK-1084 + pembrolizumab in KRAS G12C-mutated metastatic non–small-cell lung cancer enrolled in KANDLELIT-001. Presented at: 2026 ELCC; March 25-28, 2026; Copenhagen, Denmark. Abstract 4MO.
2. Merck initiates phase 3 KANDLELIT-007 trial evaluating calderasib (MK-1084)... News release. Merck. January 7, 2026. Accessed March 27, 2026. https://www.merck.com/news/merck-initiates-phase-3-kandlelit-007-trial-evaluating-calderasib-mk-1084-an-investigational-oral-kras-g12c-inhibitor-in-combination-with-keytruda-qlex-pembrolizumab-and-berahyaluronidas/