Early Treatment Succeeds in CRC With Next Generation KRAS Inhibitor Calderasib Plus Cetuximab Combo

Median progression-free survival (PFS) was not reached for a group of untreated patients with colorectal cancer (CRC) who received Merck’s investigational KRAS G12C inhibitor calderasib, combined with cetuximab (Erbitux; Eli Lilly) and chemotherapy, according to results being presented today.¹

Updated results from the KANDLELIT-001 trial continue to generate encouraging antitumor activity in patients with KRAS G12C-mutated advanced CRC, with survival taking a leap when calderasib is combined with EGFR-targeting cetuximab and chemotherapy, and when the combination is given earlier in treatment.

Follow-up data from the ongoing phase 1 study are being presented this morning at the European Society for Medical Oncology Gastrointestinal Cancers Congress (ESMO GI) in Munich, Germany.¹

Calderasib (MK-1084) is a next-generation KRAS G12C inhibitor, which is designed with high-affinity binding to allow for improved potency, higher selectivity, and a superior safety profile for use in combinations compared with first-generation KRAS therapies.²

Lead author Rafal Dziadziuszko, MD, PhD, professor at the Medical University of Gdańsk in Poland, spoke with The American Journal of Managed Care® on what these results mean for a population that, despite representing a fraction of CRC patients, still adds up to a sizable group with few treatment options.

A Small Mutation That Translates Into Significant Unmet Need

KRAS G12C mutations occur in roughly 3% to 4% of colorectal cancers,³ but because CRC is so common, that translates into a population of roughly 60,000 just in the United States, based on estimates from the American Cancer Society.⁴ “It's important to note that this is a very common disease, so even 3% to 4% is a big number of patients who have limited treatment options if diagnosed with metastatic disease,” Dziadziuszko said.

KANDLELIT-001 (NCT05067283) is a phase 1, safety-based trial testing calderasib as monotherapy and in combination with agents already central to CRC care—cetuximab, which targets the EGFR pathway, and modified FOLFOX6 chemotherapy.¹ Dziadziuszko explained the rationale for pairing a KRAS inhibitor with an EGFR blocker. “By inhibition of KRAS, you are boosting the activity of the EGFR pathway, which is then inhibited by cetuximab.” That combination, he said, is “known to be more effective from preclinical studies, but also from other trials.”⁵

Long-term Results for Calderasib Seen at ESMO GI

As of the January 5, 2026, data cutoff, the abstract includes 193 patients across the calderasib monotherapy arms (65 with CRC), 77 patients on calderasib plus cetuximab, and 48 on the triplet of calderasib, cetuximab, and mFOLFOX6. Median follow-up ranged from 11.4 months in the cetuximab combination arm to 31.7 months in the CRC monotherapy population.¹ This is long enough, Dziadziuszko said, “to see the long-term outcomes of these patients.”

Results improved as the treatment intensity increased and as patients received therapy earlier in their course of care. Data showed the following:¹

• In the monotherapy arms, the objective response rate (ORR) was 34% and median PFS was 6.2 months.
• Adding cetuximab pushed ORR to 46% and median PFS to 8.5 months overall, with patients on just 1 prior line of therapy reaching a median duration of response of 13.7 months.
• The triplet arm of calderasib, cetuximab, and mFOLFOX6 produced a 77% ORR, and among previously untreated patients specifically, an 87% ORR with median PFS not yet reached.

Biomarker Results Align With Tumor Progression

Notably, the triplet’s 77% ORR came with an important biomarker signal: among 18 patients evaluable for circulating tumor DNA (ctDNA), median KRAS G12C variant allele frequency fell from 21% at baseline to 1% by week 6, and maximum somatic allele frequency dropped from 34% to 2%. These reductions can seen as evidence of target engagement, according to the abstract.¹

Dziadziuszko said the ctDNA data corroborate what investigators are seeing on scans. There might more ctDNA present in those patients who respond in all 3 cohorts, but investigators also see ctDNA levels “in patients treated with cetuximab and calderasib, or cetuximab, chemotherapy, calderasib, corresponding to what we see on the PFS curves,” he said.

This points to broader possibilities for biomarker use. “Monitoring minimal residual disease is something that we are also very keen to use in the clinic,” Dziadzuisko explained. “In this way, we can know better how our patients do before they get progression that's feasible on scans."

Safety Is the Study’s Main Focus

In this phase 1 study, dose-limiting toxicities were reported in 5 patients across the study, and treatment-related adverse events of grade 3-4 rose with combination intensity: 9% in the monotherapy arms, 20% with cetuximab, and 42% with the triplet. Dziadziuszko emphasized that discontinuations due to toxicity remained low.¹ “The best way to [evaluate safety] is to see the number of patients who discontinue the study because of toxicity, and here these are single digits in all 3 cohorts,” he said, adding that most toxicity was gastrointestinal or hepatic and “mainly grade 1 and grade 2.”

Asked whether the data support moving calderasib into frontline treatment rather than reserving it for later lines, Dziadziuszko noted that the question is already being tested. “The phase 3 is ongoing,” he said. “Here we can clearly see that toxicity is on our side with the combination, and efficacy looks very promising... I'm very enthusiastic about it. I think this is the way to proceed.”

More Tumors Being Treated in the KANDLELIT program

KANDLELIT is an umbrella program of clinical trials involving different tumor types at various stages. Calderasib is being codeveloped by Merck with Taiho Pharmaceutical and Astex Pharmaceuticals under a collaboration dating to January 2020, with the program now covering 5 phase 3 trials.⁶

Most of that phase 3 activity is in non-small cell lung cancer (NSCLC), where calderasib is being paired with pembrolizumab (Keytruda) or the subcutaneous formulation Keytruda Qlex across first-line, perioperative, and post-chemoradiation settings (KANDLELIT-004, -007, and -013), and with AstraZeneca's durvalumab (Imfinzi) in a fifth trial (KANDLELIT-015). A phase 2 study, KANDLELIT-014 (NCT07209111), is testing calderasib alone and with cetuximab in select KRAS G12C-mutated solid tumors.

The CRC-specific phase 3, KANDLELIT-012 (NCT06997497), which opened a year ago, tests calderasib plus cetuximab and mFOLFOX6 against mFOLFOX6 with or without bevacizumab in the first line, locally advanced or metastatic setting. It is active and recruiting.

Breakthrough Status in NSCLC Granted in May

FDA granted the calderasib-pembrolizumab combination Breakthrough Therapy Desgination on May 29, 2026, for first-line treatment of KRAS G12C-mutant, PD-L1-expressing (TPS ≥1%) advanced or metastatic NSCLC, based on KANDLELIT-001 data.⁷ In CRC, regulatory filings have not yet been pursued.

For now, Dziadziuszko said, the phase 1 signal in CRC is enough to justify the wait. "When you work in phase 1, you want to deliver your baby to the next level," he said. "And here, it's happening."

References

1. Dziadziuszko R, Moreno Garcia V, Lugowska I, et al. Calderasib (MK-1084) for KRAS G12C-mutated (mut) advanced colorectal cancer (CRC): Results from KANDLELIT-001. Presented at ESMO GI Congress, July 1-4, 2026, Munich Germany. Presentation No. 6RO.
2. Ma X, Sloman DL, Duggal R, et al. Discovery of MK-1084: An orally bioavailable and low-dose KRASG12C inhibitor. J Med Chem. 2024;67(13):11024-11052. doi: 10.1021/acs.jmedchem.4c00572
3. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;389(23):2125-2139. doi: 10.1056/NEJMoa2308795. Erratum in: N Engl J Med. 2025;392(7):728. doi: 10.1056/NEJMx240006.
4. Colorectal cancer is a major public health problem. National Colorectal Cancer Roundtable. American Cancer Society. Updated August 5, 2025. Accessed July 3, 2026. https://nccrt.org/our-impact/data-and-progress/
5. Miyashita H, Hong DS. Combining EGFR and KRAS G12C inhibitors for KRAS G12C mutated advanced colorectal cancer. J Cancer Immunol (Wilmington). 2024;6(2):62-69. doi: 10.33696/cancerimmunol.6.086.
6. 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 July 3, 2026. https://bit.ly/4vMHePr
7. FDA grants Breakthrough Therapy Designation for calderasib (MK-1084), an investigational KRAS G12C inhibitor, for certain patients with newly diagnosed metastatic KRAS G12C-mutant non-small cell lung cancer (NSCLC). News release. Merck. May 29, 2026. Accessed July 3, 2026. https://bit.ly/4wts9Cq