Authors: Yongchao Wang, Ting Han, Xiaolin Lin, Xiuying Xiao
Colorectal cancer (CRC) is the third most common malignancy worldwide and the second leading cause of cancer-related deaths. In China, CRC ranks second in incidence and fourth in mortality among all cancers, accounting for approximately 30% of global new cases and over 75% of cases in East Asia. Although the age-standardized incidence rate of CRC in China is moderate globally, the significantly higher age-standardized mortality rate underscores the severe disease burden. The rising incidence has imposed substantial socioeconomic pressure, highlighting the urgent need to explore and optimize treatment strategies for CRC.In 2024, the field of CRC treatment achieved numerous innovative breakthroughs, particularly in perioperative management and immunotherapy and targeted therapy for metastatic CRC. To provide a comprehensive summary of these advancements, Oncology Frontier invited Dr. Xiuying Xiao’s team from Renji Hospital, to write this review. The article focuses on new perioperative treatment strategies and the latest achievements in immunotherapy and targeted therapies based on KRAS and EGFR.I. New Strategies and Modalities in Perioperative Treatment
The perioperative treatment of CRC witnessed the emergence of multiple innovative strategies in 2024. These approaches aim to improve surgical success rates and patient survival through preoperative and postoperative therapies. They are based on a deeper understanding of CRC biology and supported by positive clinical trial outcomes, offering patients more precise and personalized treatment options.
1. TNT: A Superior Approach
In 2024, Total Neoadjuvant Therapy (TNT) emerged as a promising alternative to conventional neoadjuvant chemoradiotherapy (CRT) for treating high-risk locally advanced rectal cancer. The TNTCRT trial, a multicenter, randomized, open-label phase III study, enrolled rectal cancer patients with high-risk recurrence factors, such as T4 or T3 tumors with extramural venous invasion, N2-positive status, mesorectal fascia involvement, or enlarged lateral lymph nodes.
The results demonstrated that the 3-year disease-free survival (DFS) rate was 76.8% in the TNT group compared to 67.9% in the CRT group. Pathological complete response (pCR) rates were significantly higher in the TNT group (27.51%) compared to the CRT group (9.84%). However, the 3-year overall survival (OS) rates were similar between the groups (89.8% vs. 88.2%). This study confirmed that TNT improves pCR rates and extends DFS in preoperative settings. Moving forward, efforts will focus on optimizing neoadjuvant treatment models for locally advanced rectal cancer, tailoring treatments to individual risk factors to enhance survival outcomes and quality of life.
2. Single-Agent and Dual Immunotherapy Options
2.1 Immune Monotherapy
At the 2024 ASCO meeting, a multicenter phase II study presented findings on pembrolizumab as neoadjuvant therapy for high-risk stage II or III dMMR/MSI-H CRC patients. The median tumor mutational burden (TMB) was 42 mutations/Mb (range: 4–82), with only one patient having a low TMB (≤5 mutations/Mb), while the rest had high TMB (≥20 mutations/Mb).
Among 32 patients, 17 (53%) achieved pCR, and the evaluable tumor pCR rate was 58% (19/33). Importantly, no grade 3 or higher immune-related adverse events (irAEs) were reported. These results highlight the remarkable efficacy and safety of pembrolizumab in treating high-risk CRC patients with dMMR/MSI-H and high TMB.
Another PD-1 inhibitor, toripalimab, showed equally promising results in a phase II trial for dMMR locally advanced rectal cancer. Among 42 patients who completed toripalimab treatment, all achieved clinical complete response (cCR), with the response duration exceeding two years. Remarkably, none of the patients required chemotherapy, radiotherapy, or surgery. Although the sample size was small, the exceptional clinical outcomes suggest that toripalimab offers a new possibility for dMMR/MSI-H patients to avoid surgery and preserve organ function.
2.2 Dual Immunotherapy
The NICHE-1 study previously demonstrated that the combination of nivolumab and ipilimumab achieved a pathological response rate of 100% and a pathological complete response (pCR) rate of 60% in non-metastatic dMMR/MSI-H colorectal cancer (CRC) patients. However, nearly half of the participants were in the early stages of the disease, and the sample size was limited. This led to the NICHE-2 study, a phase II trial involving untreated, locally advanced dMMR CRC patients.
In this study, 111 patients were included in the efficacy analysis. Pathological response was observed in 109 patients (98%), with 105 (95%) achieving major pathological response (MPR) and 75 (68%) achieving pCR. With a median follow-up of 36.6 months, the 3-year disease-free survival (DFS) rate reached 100%. For high-risk patients with locally advanced dMMR rectal cancer, preoperative treatment with one dose of ipilimumab combined with two doses of nivolumab yielded remarkable results. For dMMR/MSI-H rectal cancer patients strongly wishing to preserve anal function, dual immunotherapy has become an increasingly viable treatment strategy.
Additionally, a phase Ib randomized, open-label study evaluated IBI310 (anti-CTLA-4 antibody) combined with sintilimab for neoadjuvant therapy in MSI-H/dMMR CRC patients. Results showed that dual immunotherapy achieved an 80% pCR rate after just two treatment cycles, while single-agent immunotherapy achieved a pCR rate below 50%, highlighting the significant advantages of dual immunotherapy in the neoadjuvant setting. All patients who underwent surgery achieved R0 resection, and both treatment regimens demonstrated comparable and manageable safety profiles. Moving forward, dual immunotherapy is likely to become the preferred neoadjuvant treatment strategy to improve radical resection rates.
Beyond CTLA-4 antibodies, other immune checkpoint-related antibodies are under clinical investigation. Lymphocyte-activation gene 3 (LAG-3), an immune checkpoint receptor protein, is expressed on T cells after prolonged antigen stimulation and serves as a marker of T cell exhaustion. By binding to major histocompatibility complex class II molecules, LAG-3 downregulates T cell activity while enhancing the suppressive activity of regulatory T cells, making it a potential therapeutic target.
At the 2024 ESMO conference, the NICHE-3 study was presented, evaluating nivolumab combined with relatlimab (anti-LAG-3 antibody) for neoadjuvant treatment of locally advanced (≥T3 and/or N+) dMMR CRC. Among 59 patients, 57 (97%) achieved the primary endpoint, with 92% achieving MPR and 68% achieving pCR. After a median follow-up of 8 months, all patients were alive, and 98% had no disease recurrence. However, 15 patients (25%) experienced endocrine-related immune adverse events requiring long-term hormone replacement, including hypothyroidism (17%), adrenal insufficiency (7%), and both conditions in 2% of patients. These findings demonstrate that nivolumab combined with relatlimab provides a high pathological response rate in locally advanced dMMR CRC patients.
Across the NICHE studies, whether PD-1 inhibitors are combined with CTLA-4 or LAG-3 antibodies, dual immunotherapy in dMMR CRC consistently demonstrates outstanding efficacy, with pathological response rates ranging from 97% to 100% and pCR rates from 60% to 68%. Current domestic and international guidelines recommend MMR testing for all CRC patients at diagnosis, regardless of disease stage, as determining MMR status is essential for optimizing treatment strategies and maximizing therapeutic benefits.
While the overall toxicity of dual immunotherapy is manageable, the combination of nivolumab and relatlimab showed a higher incidence of long-term endocrine disorders, warranting further large-scale studies to confirm the safety profile. Nevertheless, with pCR rates exceeding 60%, dual immunotherapy offers strong clinical evidence to support surgery-free treatment strategies in CRC.
2.3 Immunotherapy Combined with Anti-Angiogenesis
The Sun Yat-sen University Cancer Center reported the first prospective study evaluating PD-1 antibodies combined with VEGFR inhibitors as neoadjuvant therapy in dMMR/MSI-H CRC patients—the NEOCAP study. Results showed that 54% of patients achieved cCR and 61% achieved pCR. However, treatment-related adverse events led to discontinuation in 25% and 51% of patients treated with camrelizumab and apatinib, respectively. Despite safety concerns, the study demonstrated the feasibility of organ preservation in MSI-H/dMMR CRC patients who achieve cCR with this combination therapy, potentially avoiding postoperative complications and improving quality of life.
II. Dual Immunotherapy: A New Era in First-Line Treatment
In metastatic CRC (mCRC), significant advances have been made in immunotherapy. By activating or enhancing the patient’s immune system to attack cancer cells, immunotherapy has offered new hope for patients with advanced CRC.
For MSI-H/dMMR mCRC patients, the phase III randomized controlled trial Keynote 177 confirmed the efficacy of pembrolizumab as a first-line treatment. Further progress was reported at the 2024 ASCO conference, where the CheckMate 8HW trial evaluated dual immunotherapy with nivolumab and ipilimumab. In this study, patients with unresectable or metastatic MSI-H/dMMR CRC were enrolled. After a median follow-up of 31.5 months, the progression-free survival (PFS) rate was significantly higher in the dual therapy group compared to the chemotherapy group (P < 0.001). At 24 months, the PFS rate was 72% for the dual therapy group compared to 14% for the chemotherapy group, with a mean survival time extended by 10.6 months.
Furthermore, only 23% of patients in the dual therapy group experienced grade ≥3 treatment-related adverse events, compared to 48% in the chemotherapy group. With lower toxicity and superior PFS, dual immunotherapy is poised to replace chemotherapy as the standard first-line treatment for MSI-H/dMMR mCRC patients.
However, the question of whether dual immunotherapy is superior to single-agent immunotherapy remains unresolved. The CheckMate 8HW trial’s other endpoint—PFS comparison between the dual and single-agent groups—has yet to be published. Data from the CheckMate 142 cohort study suggest that nivolumab combined with ipilimumab is more effective than nivolumab monotherapy.
In clinical practice, some patients achieve good outcomes with PD-1 inhibitors alone, while others do not benefit from monotherapy. According to the CheckMate 8HW study, dual therapy provides significant PFS benefits for these patients. Identifying appropriate patient groups through biomarker-driven precision screening will be crucial to further clarify the indications for monotherapy and dual therapy.
III. A New Chapter in Precision Medicine: Multidrug Combinations in Later-Line Treatment
At the 2024 ESMO conference, the IKF-AIO-RAMTAS phase III trial reported results comparing ramucirumab combined with TAS-102 (Group A) versus TAS-102 monotherapy (Group B) in metastatic colorectal cancer (mCRC) patients who had undergone multiple prior lines of therapy. While the trial did not achieve its primary endpoint of overall survival (OS), the progression-free survival (PFS) results showed a statistically significant improvement: 2.37 months for Group A versus 2.07 months for Group B (P = 0.011). The disease control rate (DCR) was higher in the combination therapy group. Interestingly, subgroup analyses revealed that female patients and those with left-sided tumors experienced improved OS with the combination treatment. Although the trial did not meet the OS endpoint in the intention-to-treat (ITT) population, the addition of ramucirumab to TAS-102 selectively improved outcomes in difficult-to-treat female and left-sided mCRC patients, supporting individualized treatment decisions for patients who fail standard therapies.
Advances in Targeted Therapy for Specific Mutations
KRAS G12C Mutation
Several targeted therapies for KRAS G12C-mutated mCRC have emerged as promising options.
- CodeBreaK101 (Phase Ib Study): This study evaluated the efficacy and safety of sotorasib combined with panitumumab in chemotherapy-resistant KRAS G12C-mutant mCRC patients. Results showed an objective response rate (ORR) of 30.0%, with a median PFS of 5.7 months and a median OS of 15.2 months in the sotorasib 960 mg plus panitumumab group.
- CodeBreaK300 (Phase III Study): Updated data presented at the 2024 ASCO conference demonstrated statistically significant PFS improvements for KRAS G12C-mutant mCRC patients treated with sotorasib 960 mg plus panitumumab (median PFS: 5.6 months) or sotorasib 240 mg plus panitumumab (median PFS: 3.9 months), compared to investigator’s choice therapy (median PFS: 2.2 months). The sotorasib 960 mg group provided greater clinical benefits without significantly increasing toxicity, suggesting this combination as a potential new standard for KRAS G12C-mutant advanced CRC.
- Divarasib Combination Therapy: A phase Ib clinical trial published in Nature Medicine evaluated divarasib combined with cetuximab in previously untreated KRAS G12C-mutant mCRC patients. The study reported an ORR of 62.5%, with a median duration of response of 6.9 months and a median PFS of 8.1 months. The exploratory analysis revealed a reduction in KRAS G12C mutation frequency and the emergence of resistance-related genetic alterations upon disease progression. These findings suggest that combining divarasib with EGFR inhibitors may offer a novel therapeutic strategy for KRAS G12C-positive CRC.
- Adagrasib Combination Therapy: Adagrasib combined with cetuximab achieved an ORR of 34.0%, a DCR of 85.1%, a median response duration of 5.8 months, a median PFS of 6.9 months, and a median OS of 15.9 months in KRAS G12C-mutant mCRC patients, further highlighting the potential of combination therapies in this subgroup.
HER2-Positive mCRC
For HER2-positive mCRC, surgery, chemotherapy, and radiotherapy have limited efficacy, necessitating deeper exploration of targeted treatments.
- MOUNTAINEER Study: This global phase II study evaluated the efficacy and safety of tucatinib combined with trastuzumab in chemotherapy-refractory HER2-positive, RAS wild-type mCRC patients. The combination achieved a median PFS of 8.2 months and a median OS of 24.1 months, demonstrating significant clinical benefit and manageable safety. This study supports the use of tucatinib plus trastuzumab as a new therapeutic option for HER2-positive mCRC, potentially reshaping treatment standards for this subgroup.
Progress in MSS/pMMR CRC
While immunotherapy has significantly improved outcomes for MSI-H/dMMR patients, the majority of CRC cases (95%) are microsatellite stable (MSS) or mismatch repair proficient (pMMR), which do not benefit from immune monotherapy.
- CAPability-01 (Phase II Study): This study explored the combination of chidamide (a histone deacetylase inhibitor) plus sintilimab (PD-1 inhibitor) ± bevacizumab (VEGF inhibitor) as third-line or later therapy for MSS/pMMR mCRC patients. Results showed an 18-week PFS rate of 64.0%, an ORR of 44.0%, and a median PFS of 7.3 months, highlighting the promise of this triple therapy. Based on these findings, the 2024 CSCO Colorectal Cancer Guidelines encourage MSS/pMMR patients to participate in clinical trials involving this combination therapy, which leverages epigenetic and immune synergy to improve outcomes.
Conclusion
In 2024, significant advances were made in neoadjuvant immunotherapy, particularly for dMMR/MSI-H CRC patients, where single-agent and dual immunotherapy markedly improved response rates, even achieving surgery-free and organ-preservation outcomes. For MSS/pMMR patients, progress has focused on optimizing combination therapies to overcome the limitations of single-agent targeted treatments.
These research breakthroughs have not only deepened our understanding of CRC mechanisms but also expanded therapeutic options for patients. As these new therapies continue to be refined and implemented, we can anticipate notable improvements in the quality of life and prognosis for CRC patients.
