With the discovery of molecular targets and the development of corresponding targeted inhibitors, the treatment of metastatic colorectal cancer (mCRC) is becoming increasingly precise and personalized. At the recent 9th Annual Meeting of the Chinese Medical Doctor Association Colorectal Oncology Committee, Dr. Xiujuan Qu from The First Hospital of China Medical University shared the latest advancements in precision treatment for advanced colorectal cancer, including novel therapeutic strategies and the promising role of KRAS G12C inhibitors.

Optimizing Treatment Outcomes for RAS Wild-Type mCRC

Numerous studies have confirmed that EGFR monoclonal antibodies (EGFR mAbs) combined with doublet chemotherapy represent the standard treatment strategy for RAS/RAF wild-type advanced colorectal cancer, particularly for left-sided colon cancer. However, the challenge remains how to further improve treatment efficacy.

The PARADIGM study compared panitumumab plus mFOLFOX6 with bevacizumab plus mFOLFOX6 in first-line treatment of RAS wild-type mCRC. Conducted across 197 research centers between May 2015 and June 2017, the study enrolled 823 patients, with outcomes stratified based on ctDNA analysis.

Among wild-type mCRC patients, the median overall survival (mOS) was 41.3 months in the panitumumab group versus 34.4 months in the bevacizumab group (HR: 0.75; 95% CI: 0.62–0.92). Among mutant mCRC patients, the mOS was 19 months in the panitumumab group versus 22.2 months in the bevacizumab group (HR: 1.14; 95% CI: 0.84–1.54).

With wild-type mCRC patients responding differently to maintenance therapy, 2024 ESMO presented a study investigating the optimal maintenance therapy strategy.

This study included 348 patients (≥18 years old) diagnosed with RAS/BRAF wild-type mCRC via histology or cytology, who had achieved CR, PR, or SD after nine cycles of FOLFOX plus cetuximab induction therapy. Patients were randomized 1:1 to receive cetuximab plus capecitabine or cetuximab monotherapy, with PFS as the primary endpoint.

As of December 31, 2023, a total of 80 patients were enrolled, with 42 in group A and 38 in group B. Notably, 92.5% of patients had left-sided colorectal cancer, and 81.3% achieved PR or CR after induction therapy.

The results demonstrated superior PFS (7.3 months vs. 5.3 months) and OS (30.5 months vs. 22.5 months) in the cetuximab plus capecitabine group, indicating that combination maintenance therapy offers better survival benefits than cetuximab monotherapy.

KRAS Mutations: KRAS G12C Inhibitors Opening the Door to Precision Treatment

KRAS mutations occur in 40–50% of colorectal cancer cases and are associated with poor prognosis. In recent years, the development of KRAS G12C inhibitors for colorectal cancer has gained considerable momentum.

Adagrasib, a KRAS G12C inhibitor, has demonstrated initial efficacy in phase I/II clinical trials, with a median progression-free survival (PFS) of 5.6 months, a disease control rate (DCR) of 86%, and an objective response rate (ORR) of 19%.

The Code-100 phase I/II trial evaluating sotorasib monotherapy in KRAS-mutated colorectal cancer reported a PFS of 4 months and a median OS of 10 months.

However, KRAS G12C inhibitors appear less effective in colorectal cancer than in lung cancer, prompting the need for strategies to enhance therapeutic efficacy.

A major challenge is both primary and acquired resistance to KRAS G12C inhibitors, which stems from the complexity of signaling networks and the heterogeneity of KRAS-mutated alleles. Resistance mechanisms include:

• Amplification or mutation of upstream receptor tyrosine kinases (RTKs)
• Secondary activation mutations in the KRAS G12C codon
• KRAS gene amplification
• Activating mutations in downstream signaling pathways such as PIK3CA, BRAF, or MEK

To overcome resistance, future research will focus on combination therapy strategies involving KRAS G12C inhibitors.

The KRYSTAL-10 trial is the first phase III clinical study in the CRC field evaluating adagrasib plus cetuximab versus FOLFIRI/mFOLFOX6 as second-line treatment for KRAS G12C-mutated CRC patients. The study’s results are highly anticipated and could pave the way for a major breakthrough in KRAS-mutant colorectal cancer treatment.

Additionally, emerging data suggest that KRAS G12C inhibitors may reshape the immunosuppressive tumor microenvironment, making them promising candidates for combination with PD-1 inhibitors. Future research will explore how KRAS G12C inhibitors can synergize with immunotherapy to further enhance treatment outcomes.

Evolving Treatment Approaches for BRAFV600E-Mutant Colorectal Cancer

The treatment paradigm for BRAFV600E-mutant metastatic colorectal cancer (mCRC) has evolved from single-agent targeted therapy to dual-target and triple-target combinations. The BEACON trial demonstrated that both triple therapy (BRAF inhibitor + MEK inhibitor + EGFR inhibitor) and dual therapy (BRAF inhibitor + EGFR inhibitor) significantly improved objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) compared to standard therapy. However, no significant difference was observed between the triple and dual therapy groups in terms of survival benefits.

Based on the BEACON trial findings, BRAF inhibitors combined with EGFR inhibitors have become the standard second-line treatment for BRAFV600E-mutant mCRC. Despite this progress, BRAF-mutant colorectal cancer remains associated with poor prognosis, underscoring the need for further therapeutic advancements to improve clinical outcomes.

The NAUTICAL CRC trial, an ongoing phase II, multicenter, randomized, open-label study, is evaluating dual-target therapy versus standard chemotherapy (Irinotecan/cetuximab or FOLFIRI/cetuximab) in Chinese patients with BRAFV600E-mutant mCRC who have progressed after one or two lines of prior therapy. Early data suggest that dual-target therapy provides a survival advantage, with an ORR of 24.6% versus 6.3% and a median duration of response (DOR) of 8.2 months versus 4.2 months, compared to chemotherapy alone.

Targeted Therapy and Immunotherapy in BRAFV600E-Mutant Colorectal Cancer

Studies have shown that PD-L1 expression is elevated in BRAF-mutant colorectal cancer, prompting investigations into the potential benefits of combining targeted therapy with immunotherapy.

A phase I/II trial evaluating encorafenib, cetuximab, and nivolumab in microsatellite-stable (MSS) BRAFV600E-mutant mCRC reported encouraging efficacy. Among 22 evaluable patients, the ORR was 50%, the disease control rate (DCR) was 96%, and the median DOR was 7.7 months. After a median follow-up of 11.4 months, the mPFS was 7.4 months, and the mOS reached 15.1 months. These findings suggest that adding PD-1 inhibitors to dual-target therapy may enhance outcomes in BRAFV600E-mutant mCRC.

Case Study: Combination Therapy for BRAFV600E-Mutant pMMR Colorectal Cancer

During the conference, Dr. Xiujuan Qu presented a clinical case highlighting the efficacy of late-line combination therapy in a BRAFV600E-mutant, pMMR mCRC patient.

The case involved a 32-year-old female patient diagnosed with BRAFV600E-mutant, pMMR colorectal cancer with low tumor mutational burden (TMB-L) and PD-L1 (22C3) expression. The patient had high tumor burden (CA199 >1000) and multiple metastatic sites, including the ovary, lung, and retroperitoneal lymph nodes.

A first-line triplet regimen (bevacizumab + chemotherapy) was administered, successfully controlling tumor progression and reducing tumor burden. Systemic therapy combined with localized surgery extended first-line PFS.

For second-line therapy, bevacizumab plus chemotherapy maintained disease control, allowing interventional treatment for a solitary lung metastasis.

During third-line treatment, the patient received regorafenib plus a PD-1 inhibitor, achieving a meaningful survival benefit, demonstrating the potential of integrating anti-angiogenic therapy with immunotherapy in BRAF-mutant colorectal cancer.

Future Directions in Precision Therapy for Colorectal Cancer

In the era of precision oncology, molecular profiling is critical for guiding individualized treatment strategies based on tumor-specific mutations.

For KRAS-mutant colorectal cancer, KRASG12C inhibitors represent a promising breakthrough, addressing a previously untargetable oncogenic driver. The KRYSTAL-10 trial, which is evaluating KRASG12C inhibitors in combination with cetuximab, is currently underway worldwide, with China actively participating. Moving forward, KRASG12C inhibitors in combination therapy strategies will be a key area of research and clinical development.

For BRAFV600E-mutant colorectal cancer, BRAF inhibitors (BRAFi) combined with EGFR inhibitors (EGFRi) in dual-target therapy have been established as the standard second-line treatment. However, the optimal first-line strategy remains under investigation, with ongoing studies exploring dual-target therapy combined with either immunotherapy or chemotherapy as potential front-line options.

As research progresses, advancing combination strategies—particularly targeted therapy with immunotherapy and chemotherapy—will play a crucial role in improving survival outcomes for patients with BRAFV600E- and KRAS-mutant colorectal cancer.

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Dr. Xiujuan Qu

• Chief Physician, Second-Level Professor, PhD Supervisor
• Director, Department of Oncology, The First Hospital of China Medical University
• Deputy Director, Department of Oncology Research and Education
• Director, Liaoning Provincial Key Laboratory of Tumor Drugs and Biotherapy
• Vice President, Chinese Medical Doctor Association Oncology Branch
• Standing Member and Head of Internal Medicine Group, Colorectal Cancer Committee, Chinese Medical Doctor Association
• Board Member, Chinese Society of Clinical Oncology (CSCO)
• Vice Chair, CSCO Smart Healthcare Expert Committee; Standing Member, CSCO Gastric Cancer and Immunotherapy Committees
• Chair, Liaoning Provincial Preventive Medicine Association Oncology Division
• President-elect, Liaoning Medical Association Oncology Division
• President-elect, Liaoning Anti-Cancer Association Tumor Biomarkers Committee
• President-elect, Liaoning Immunology Society Oncology Division
• Principal Investigator of one national key scientific and technological project and six National Natural Science Foundation projects
• Recipient of the National Science and Technology Progress Award (Second Prize) and three Provincial Science and Technology Progress First Prizes
• Published over 100 SCI-indexed articles in journals including JCO, Molecular Cell, and Advanced Science