Editor’s Note At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, three high-impact studies targeting KRAS G12C-mutant colorectal cancer (CRC) revealed groundbreaking progress in precision oncology. KRAS G12C is a notoriously difficult-to-treat molecular subtype of CRC, historically plagued by limited therapeutic options. However, the presentation of data from the CodeBreaK 101 study, a Phase I/II trial of olomorasib combined with cetuximab, and the KANDLELIT-001 trial has brought new hope to the field.Oncology Frontier invited Professor Xiujuan Qu and Professor Ling Xu from The First Hospital of China Medical University to share their expert perspectives on these landmark studies.
Combination Therapy Shows Its Strength, Survival Benefits Further Improved
In the Phase III CodeBreaK 300 trial (NCT05198934), the KRAS G12C inhibitor sotorasib combined with the anti-EGFR monoclonal antibody panitumumab significantly improved clinical outcomes in chemotherapy-refractory patients with KRAS G12C-mutant metastatic colorectal cancer (mCRC). Building on this, the CodeBreaK 101 trial, a Phase Ib study, explored the addition of FOLFIRI to this combination in previously treated KRAS G12C-mutant mCRC patients. The trial now reports mature data on overall survival (OS) and progression-free survival (PFS), along with updated safety and efficacy outcomes.
The study enrolled patients with KRAS G12C-mutant mCRC who had received at least one prior line of systemic therapy but had not been exposed to a KRAS G12C inhibitor. These patients were included in the expansion cohort of the CodeBreaK 101 Substudy H (NCT04185883). Based on findings from the dose-escalation phase, patients received the recommended Phase II dose (RP2D) of sotorasib (960 mg orally once daily), combined with panitumumab (6 mg/kg IV every two weeks) and standard-dose FOLFIRI (administered IV every two weeks).
The primary endpoint was safety. Secondary endpoints included confirmed response rate, OS, and PFS, all evaluated per RECIST v1.1 criteria by investigators.
As of November 2024, a total of 40 patients had been enrolled (47.5% female; median age 56.0 years; median number of prior systemic treatment lines: 2). Regarding safety, the most common treatment-related adverse events (TRAEs) were acneiform dermatitis and dry skin (67.5%), neutropenia (50.0%), and stomatitis (42.5%). A total of 20 patients (50.0%) experienced grade ≥3 TRAEs. No new safety signals were identified. Discontinuation due to adverse events occurred in 1 patient (2.5%) each for sotorasib and panitumumab, and in 16 patients (40.0%) for any component of FOLFIRI (5-fluorouracil, irinotecan, or folinic acid/leucovorin). At the time of data cutoff, 7 patients remained in the study, 5 of whom had discontinued treatment and entered the follow-up phase.
In terms of efficacy, the updated objective response rate (ORR) was 57.5%, with a disease control rate (DCR) of 92.5%. The median time to response was 1.6 months, and the median duration of response was 6.6 months. After a median follow-up of 29.2 months, median PFS reached 8.2 months and median OS was 17.9 months.
These findings confirm the favorable long-term safety and efficacy of sotorasib combined with panitumumab and FOLFIRI in previously treated KRAS G12C-mutant mCRC. Adverse events were consistent with the known safety profiles of the individual agents. A Phase III study, CodeBreaK 301 (NCT06252649), is currently underway to evaluate this regimen versus standard therapy as first-line treatment in this molecular subtype.
Second-Generation Inhibitor Emerges: Dual Advances in Efficacy and Safety
Olomorasib is a potent and selective second-generation KRAS G12C inhibitor (G12Ci) that has demonstrated promising efficacy and safety in KRAS G12C-mutant cancers. Based on preclinical and early clinical data, combining KRAS G12Ci with cetuximab offers a new therapeutic opportunity for patients with KRAS G12C-mutant colorectal cancer (CRC). This study presents updated results from a Phase I/II trial (NCT04956640), focusing on the safety, tolerability, and optimal dosing of olomorasib in combination with cetuximab.
The trial enrolled patients with advanced KRAS G12C-mutant CRC (confirmed via tissue or blood testing) who had received at least one prior line of oxaliplatin- or irinotecan-based therapy. Patients were assigned to dose-escalation, dose-expansion, or dose-optimization cohorts and received olomorasib at either 100 mg or 150 mg orally twice daily, combined with cetuximab. Dose escalation followed the modified Toxicity Probability Interval-2 (mTPI-2) method. The primary endpoints were safety and the determination of the optimal dose of olomorasib in combination with cetuximab. Antitumor activity was evaluated per RECIST v1.1 in patients who underwent at least one post-baseline assessment or discontinued prior to first evaluation.
As of November 13, 2024, 93 patients had received the combination therapy (49 in the escalation/expansion cohorts and 44 in the optimization cohort). The median age was 58 years, with a median of 3 prior lines of treatment.
Treatment-related adverse events (TRAEs) occurring in ≥20% of patients included acneiform dermatitis (58%), diarrhea (38%), dry skin (31%), paronychia (28%), hypomagnesemia (26%), and rash (26%). Most TRAEs were grade 1–2; 24% of patients experienced grade ≥3 TRAEs. The most common grade ≥3 TRAEs were diarrhea, hypokalemia, and rash—each occurring in two patients. Dose reductions of olomorasib occurred in 2% of patients; 22% required treatment interruptions with olomorasib, and 16% paused cetuximab. Among 61 patients who discontinued treatment, 57 did so due to disease progression. Two patients discontinued cetuximab due to TRAEs but continued olomorasib. The safety profiles across the two dosing groups were similar.
The median duration of combination therapy was 6.5 months, with 32 patients still undergoing treatment at the time of analysis. Efficacy data are summarized in Table 1, while biomarker analyses will be reported separately.
In conclusion, this study confirms that olomorasib combined with cetuximab demonstrates comparable antitumor activity and a favorable safety profile in patients with KRAS G12C-mutant colorectal cancer (CRC). The optimal dose was determined to be olomorasib 100 mg twice daily. These findings further support the potential of combining second-generation KRAS G12C inhibitors with other anticancer therapies to improve outcomes in previously treated patients with KRAS G12C-mutant CRC.
Expanding Clinical Strategies Through Combination Approaches
Preliminary results from the Phase I KANDLELIT-001 trial (NCT05067283) show that MK-1084, a next-generation selective KRAS G12C-GDP covalent inhibitor, demonstrates manageable safety and early signs of antitumor activity in previously treated patients with KRAS G12C-mutant solid tumors, including non-small cell lung cancer and colorectal cancer (CRC). This report presents data on MK-1084 monotherapy, MK-1084 in combination with cetuximab, and MK-1084 combined with cetuximab plus mFOLFOX6 in patients with KRAS G12C-mutant advanced CRC.
Eligible patients had confirmed KRAS G12C mutations, measurable disease per RECIST, and an ECOG performance status of 0–1. Patients with previously treated advanced solid tumors entered Arms 1 and 3 and received MK-1084 monotherapy once or twice daily (total daily dose: 25–800 mg). Patients with advanced CRC who had received 1–2 prior lines of systemic therapy entered Arm 5, receiving MK-1084 once daily (25–200 mg) plus cetuximab (500 mg/m² IV every two weeks). Patients with 0–1 prior lines of therapy were enrolled in Arm 6, receiving MK-1084 (25–100 mg once daily) in combination with cetuximab and mFOLFOX6.
The primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and AEs leading to treatment discontinuation. Secondary endpoints included investigator-assessed objective response rate (ORR) per RECIST v1.1. ORR was evaluated in all patients who had received at least 5 weeks of MK-1084 treatment by the data cutoff (August 12, 2024 for Arms 1 and 3; November 6, 2024 for Arms 5 and 6).
In total, 99 patients were enrolled in Arms 1 and 3, including 53 with CRC (54%). Arm 5 enrolled 34 patients, 68% of whom had received two or more prior lines of therapy. Arm 6 included 20 patients, half of whom were treatment-naïve. The median follow-up durations were 14.8 months (Arms 1+3), 5.3 months (Arm 5), and 1.9 months (Arm 6).
In terms of safety, one patient in Arm 6 experienced grade 3 febrile neutropenia (DLT), while no DLTs occurred in Arms 1, 3, or 5. Treatment-related AEs occurred in 62% (Arms 1+3), 97% (Arm 5), and 90% (Arm 6) of patients, with ≥ grade 3 AEs occurring in 9%, 18%, and 25%, respectively. Treatment discontinuation due to AEs occurred in 1%, 3%, and 15% of patients across the three arms. No treatment-related deaths were reported. The most common treatment-related AEs in each group were: elevated AST (17%) and nausea (17%) in Arms 1+3; acneiform dermatitis (47%) and rash (24%) in Arm 5; nausea (55%) and rash (50%) in Arm 6.
Regarding efficacy in CRC patients, the ORR was 36% (n=53) in Arms 1+3, 50% (n=34) in Arm 5, and 14% (n=14) in Arm 6. All responses were partial responses.
In summary, early data from this study demonstrate that MK-1084 monotherapy, as well as its combinations with cetuximab and mFOLFOX6, exhibit manageable safety profiles and preliminary antitumor activity in patients with KRAS G12C-mutant advanced CRC. Patients remain under follow-up, and enrollment is ongoing.
Expert Commentary
The CodeBreaK 101 study focuses on combination strategies for KRAS G12C-mutant advanced colorectal cancer (CRC), and for the first time, presents long-term data on the triplet regimen of sotorasib plus panitumumab and FOLFIRI. The results are impressive: an objective response rate (ORR) of 57.5%, a disease control rate (DCR) of 92.5%, median progression-free survival (PFS) of 8.2 months, and median overall survival (OS) extended to 17.9 months, all with manageable safety. This study not only validates the synergistic potential between KRAS G12C inhibitors and anti-EGFR therapy but also offers a highly effective and low-toxicity option for patients in later lines of treatment.
The Phase I/II study of the second-generation KRAS G12C inhibitor olomorasib in combination with cetuximab also draws attention. At the optimized dosing schedule (100 mg twice daily), the combination demonstrated antitumor activity comparable to that of first-generation inhibitors, with ORR and PFS outcomes on par, and a grade ≥3 treatment-related adverse event (TRAE) rate of only 24%. Common side effects such as diarrhea and rash were mostly mild to moderate. These findings provide a promising strategy to overcome resistance or insufficient efficacy seen with first-generation inhibitors and support deeper integration of second-generation KRAS G12C inhibitors with anti-EGFR therapies.
The Phase I study of MK-1084 highlights the potential of next-generation KRAS G12C inhibitors both as monotherapy and in combination regimens. Whether as a single agent (ORR 36%), combined with cetuximab (ORR 50%), or part of a triplet regimen including mFOLFOX6 (ORR 14%), the safety profile remained controllable and antitumor activity was observed. Notably, in treatment-naïve patients, the triplet regimen presents a novel approach for conversion or first-line therapy.
Together, these three studies underscore three major emerging trends in the treatment of KRAS G12C-mutant CRC:
1. Enhanced combination strategies: The synergy between KRAS G12C inhibitors, anti-EGFR agents, and chemotherapy continues to gain clinical validation. The upcoming Phase III CodeBreaK 301 trial will further explore this in the first-line setting.
2. Inhibitor evolution and optimization: Second-generation inhibitors like olomorasib are showing improved efficacy and reduced toxicity at lower doses, offering new hope for patients resistant to first-generation therapies.
3. Earlier treatment integration: Moving from late-line use toward first-line, conversion, and even adjuvant therapy, early data from MK-1084 in untreated patients lay the groundwork for this shift.
With the advancement of precision medicine, KRAS G12C-mutant CRC is rapidly evolving from being considered “undruggable” to “treatable,” and now heading toward “personalized optimization.” The data unveiled at this year’s ASCO provide clinicians and patients worldwide with valuable and much-needed new hope.
Expert Profile Professor Xiujuan Qu
Chief Physician, Associate Professor (Second Tier), Doctoral Supervisor Director, Department of Medical Oncology, The First Hospital of China Medical University Deputy Director, Institute of Oncology, China Medical University Director, Liaoning Provincial Key Laboratory of Anticancer Drugs and Biotherapy President, Oncology Branch of the Chinese Medical Doctor Association
Vice Chair, Committee of Medical Oncology, Chinese Anti-Cancer Association Chair, Colorectal Cancer Expert Committee (Internal Medicine Division), Chinese Medical Association Council Member, Chinese Society of Clinical Oncology (CSCO) Vice Chair, CSCO Expert Committee on Precision Medicine and standing member of the Gastric Cancer and Immunotherapy Committees
Chair, Oncology Society, Liaoning Provincial Association for Preventive Medicine Vice Chair, Antitumor Drug Committee, Liaoning Anti-Cancer Association Chair, Oncology Branch, Liaoning Medical Association Vice Chair, Oncology Branch, Liaoning Provincial Society of Basic Medical Sciences
Principal Investigator of 1 Key Technology R&D Program, and 6 National Natural Science Foundation projects Recipient of 1 Second Prize in National Science and Technology Progress, and 3 Provincial Science and Technology Progress Awards
Professor Qu has published over 100 SCI-indexed papers as first or corresponding author in leading journals including JCO, Molecular Cell, and Advanced Science.
Professor Ling Xu
Department of Medical Oncology, The First Hospital of China Medical University
Professor, Chief Physician, Doctoral Supervisor Level-3 Professor of Clinical Technology, China Medical University
Deputy Director, Liaoning Provincial Key Laboratory of Precision Medicine for Tumor Immunotherapy and Biomarkers
Standing Committee Member, Tumor Biomarkers Committee, Chinese Anti-Cancer Association Standing Committee Member, Integrated Tumor Treatment Committee, Liaoning Provincial Medical Association Standing Committee Member, Tumor Immunotherapy and Vaccines Committee, Liaoning Preventive Medicine Association
Principal Investigator of multiple projects funded by the National Natural Science Foundation and provincial key programs Recipient of Liaoning Provincial Science and Technology Progress Award (Second Prize) Recognized as a Leading Talent of Shenyang City
