For decades, the KRAS gene was the most famous undruggable target in cancer. KRAS mutations drive a large fraction of lung, colorectal, and pancreatic tumors, yet the protein's smooth surface gave drug designers nothing to grab. That changed when chemists found a way to wedge inhibitors into a specific mutated form called KRAS G12C. Merck's KANDLELIT-004 trial (ClinicalTrials.gov identifier NCT06345729) is the company's bid to take its own KRAS G12C inhibitor, calderasib (development code MK-1084), and combine it with the immunotherapy that anchors modern lung-cancer care, pembrolizumab, sold as Keytruda. The study was last updated on June 15, 2026, and is actively recruiting.
Here is the question the trial is built to answer, stated plainly: in patients whose lung tumors carry the KRAS G12C mutation and express high levels of the immune marker PD-L1, does adding calderasib to pembrolizumab work better as a first treatment than pembrolizumab plus a placebo? The full title pins down the population precisely: a Phase 3, randomized, double-blind, multicenter study of MK-1084 in combination with pembrolizumab compared with pembrolizumab plus placebo as first-line treatment of participants with KRAS G12C-mutant, locally advanced or metastatic non-small cell lung cancer with PD-L1 tumor proportion score of 50% or higher.
How the trial is structured
KANDLELIT-004 enrolls 600 participants and randomizes them into two arms. In the experimental arm, patients receive pembrolizumab 200 mg by intravenous infusion on day 1 of each 21-day cycle, for up to 35 cycles, plus oral calderasib. In the comparator arm, patients receive the identical pembrolizumab regimen plus an oral placebo tablet. The trial is described as triple-masked, meaning the blinding extends across multiple parties to protect the integrity of the result, and the placebo arm is an active comparator because everyone receives real pembrolizumab. That design is the ethical and scientific backbone of the study: no patient is denied the standard immunotherapy, and the only variable being tested is whether the added KRAS pill provides benefit on top of it.
There are two co-primary endpoints, and both are the outcomes that genuinely matter in oncology. The first is progression-free survival (PFS), the time until the cancer grows or spreads, assessed over roughly 42 months. The second is overall survival (OS), plainly how long patients live, assessed over roughly 56 months. Merck states two formal hypotheses: that calderasib plus pembrolizumab is superior to placebo plus pembrolizumab on progression-free survival per standard RECIST tumor-response criteria, and, by extension, on overall survival.
Why high PD-L1, KRAS G12C lung cancer is a deliberate target
The eligibility criteria are doing strategic work. By requiring a PD-L1 tumor proportion score of 50% or higher, Merck is selecting the patients who already respond best to pembrolizumab monotherapy, which is the established standard of care in that group. That raises the bar: the trial is not asking whether the combination beats nothing, but whether calderasib can squeeze additional benefit out of patients who already do relatively well on Keytruda alone. By also requiring the KRAS G12C mutation, the trial confines itself to the exact tumors calderasib is designed to hit. The result is a tightly defined, biomarker-selected population, which is how modern lung-cancer trials are built and how a positive result becomes a clean, prescribable indication.
There is a scientific rationale for pairing the two mechanisms. KRAS G12C inhibitors shut down a core growth signal inside the tumor, while pembrolizumab releases the brakes on the immune system so it can attack the cancer. There is preclinical and translational thinking that blocking KRAS signaling can make tumors more visible and vulnerable to immune attack, so the two drugs may be more than additive. KANDLELIT-004 is the rigorous test of whether that synergy shows up as longer survival in actual patients.
The choice of a 21-day cycle and up to 35 cycles of pembrolizumab is not incidental detail; it mirrors the established standard dosing of the immunotherapy backbone, which keeps the comparator arm faithful to real-world first-line care. That fidelity is what makes the trial interpretable. If the experimental arm wins, the only thing that differs between the two groups is the addition of oral calderasib, so any survival benefit can be attributed to the KRAS inhibitor rather than to some difference in how the immunotherapy itself was given. This is the kind of disciplined, single-variable design that regulators expect before they will expand a label, and it is why the placebo tablet in the comparator arm matters as much as the active drug in the experimental one.
What a win would mean, and the caveats
The study started on May 24, 2024, and its estimated primary completion date is February 19, 2029. The long timeline reflects the dual survival endpoints; you cannot measure how much longer patients live without following them for years. A clear positive readout would show calderasib plus pembrolizumab significantly extending progression-free survival and, ideally, overall survival versus pembrolizumab plus placebo. That would establish a new first-line standard for this genetically defined subgroup and put a Merck-owned KRAS inhibitor at the center of a combination regimen built on Merck's own immunotherapy franchise, a vertically integrated win.
The caveats are real. First-generation KRAS G12C inhibitors have shown meaningful but sometimes durability-limited responses, and combining a targeted oral agent with immunotherapy raises the stakes on tolerability; overlapping toxicities can blunt the benefit if patients cannot stay on treatment. Setting the comparator as pembrolizumab, an already-effective regimen in this high-PD-L1 group, makes a statistically convincing improvement harder to achieve. And because the overall-survival readout trails the progression-free analysis, an early PFS signal would still need the survival data to confirm it before the case is closed. Until then, KANDLELIT-004 is one of the more consequential lung-cancer questions in the clinic, and February 2029 is when the first decisive answer is due.