Colon cancer and immunotherapy

Colorectal cancer remains the fourth most common cancer diagnosed in the United States despite the rate of diagnosis declining by an average of 1.2% each year since 2012.¹ The incidence of early-onset colorectal cancer, patients diagnosed under the age of 50, has increased over the past several decades with an annual increase of 3.2% between 2012-2021.² With patients being diagnosed at a younger age, it is becoming increasingly important to identify treatment strategies that continue to improve overall survival while also considering long-term side effects of therapy and resulting quality of life. One therapeutic class that has made recent advancements in survival and overall long-term side effect profile for colorectal cancer is immunotherapy. The use of various immunotherapy agents in colorectal cancer has expanded over the past several years to be incorporated in earlier lines of therapy and in new combinations to enhance patient outcomes.

One of the most notable of these advancements in immunotherapy is the utilization of immune checkpoint inhibitors (ICIs) as neoadjuvant therapy. Previous studies have shown that patients with deficient DNA mismatch repair (dMMR) or high-level microsatellite instability (MSI-H) colorectal cancer derive less benefit from adjuvant fluoropyrimidine-based chemotherapy regimens. ICIs have proven to be beneficial for this subset of patients in the metastatic setting, leaving the question of potential use as neoadjuvant therapy to improve outcomes compared to cytotoxic chemotherapy. In the NICHE-2 study, 111 patients with dMMR/MSI-H colon cancer received neoadjuvant treatment with combination ICIs ipilimumab and nivolumab which resulted in an astounding 98% pathologic response rate.³ Importantly, no patients had disease recurrence at the 26-month median follow-up of this study. Similarly impressive results have been shown in the rectal cancer setting. A phase 2 trial by Cerek et al. using the ICI dostarlimab as neoadjuvant therapy for dMMR/MSI-H rectal cancer achieved a 100% complete response rate in the 12 patients enrolled.⁴ Though a small number of patients, this trial shows promise for using ICIs as definitive therapy which would prevent patients from requiring chemotherapy, radiation and surgery, improving quality of life for many patients. Overall, these trials have shifted the treatment paradigm of ICIs to become the preferred therapy choice for neoadjuvant treatment of dMMR/MSI-H colorectal cancer patients.

The practice changing results of ICIs are not limited to the neoadjuvant setting either. Use of ICIs without chemotherapy has become preferred first-line treatment for patients with metastatic dMMR/MSI-H colorectal cancer. Most recently, the phase 3 trial CheckMate 8HW showed that combination ipilimumab plus nivolumab significantly improved progression free survival (PFS) with a 24-month PFS of 72% compared to only 14% with chemotherapy.⁵ Use of ICI-only regimens not only improves PFS but also spares patients from chemotherapy side effects which has been associated with improved quality of life.⁶

Another category of immunotherapy treatments that has expanded in the past year are monoclonal antibodies (mAbs) in new combinations and targeted antibody drug conjugates (ADCs). The use of EGFR targeting mAbs, cetuximab or panitumumab, is being prioritized earlier in metastatic treatment for a variety of new patient groups. Two KRAS targeting therapies, adagrasib and sotorasib, were recently approved for use in combination with an EGFR mAb for metastatic colorectal cancer. The KYRSTAL-1 trial investigating adagrasib plus cetuximab showed a 34% response rate in previously treated patients with a 15.9-month median overall survival (OS).⁷ The CodeBreaK-300 trial compared sotorasib plus panitumumab to investigator’s choice therapy and found an improved overall response rate of 30.2% compared to 1.9%, respectively.⁹ Additionally, OS was not reached in the sotorasib/panitumumab arm while investigator’s choice arm had an OS of 10.3 months. EGFR mAbs have also found new use as first-line treatment in combination with chemotherapy and encorafenib for patients with BRAF V600E mutation. This combination was studied in the BREAKWATER trial compared to chemotherapy alone and showed an improved overall response rate of 61% vs 40%, respectively.⁹ Additionally, the ADC trastuzumab deruxtecan was recently given tumor agnostic approval for solid tumors that are HER2-positive. The ongoing phase 2 trial DESTINY-CRC02 is investigating this drug specifically in colorectal cancer, and it has shown promising initial response rates of up to 37.8%.¹⁰ The large influx of trials utilizing different forms of antibody-based immunotherapy continues to grow. It is becoming a standard addition to treatment regimens or stand-alone treatment option leading to improved outcomes for new groups of patients. While much of the data for antibody therapies and ICIs is still waiting for later phase trials and overall survival data, it is a promising expansion of treatment for the future of colorectal cancer patients. 

References: 

1. National Cancer Institute. SEER Cancer Stat Facts: Colorectal Cancer. Bethesda, MD. Accessed March 7, 2025. https://seer.cancer.gov/statfacts/html/colorect.html.
2. Surveillance Research Program, National Cancer Institute. SEERExplorer: An Interactive Website for SEER Cancer Statistics*. Last updated November 5, 2024. Accessed March 3, 2025. https://seer.cancer.gov/statistics-network/explorer/. Data source(s): SEER Incidence Data, November 2023 Submission (1975-2021), SEER 22 registries.
3. Chalabi, M., Y.L. Verschoor, P.B. Tan, et al. "Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer." New England Journal of Medicine 390, no. 21 (2024): 1949-1958. https://doi.org/10.1056/NEJMoa2400634.
4. Cercek, Andrea, et al. "Durable Complete Responses to PD-1 Blockade Alone in Mismatch Repair Deficient Locally Advanced Rectal Cancer." Journal of Clinical Oncology 42 (2024): LBA3512-LBA3512.
5. Andre, T., E. Elez, E. Van Cutsem, et al. "Nivolumab Plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer." New England Journal of Medicine 391, no. 21 (2024): 2014-2026. https://doi.org/10.1056/NEJMoa2402141.
6. Andre, T., M. Amonkar, J.M. Norquist, et al. "Health-Related Quality of Life in Patients with Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer Treated with First-Line Pembrolizumab versus Chemotherapy (KEYNOTE-177): An Open-Label, Randomised, Phase 3 Trial." Lancet Oncology 22, no. 5 (2021): 665-677. https://doi.org/10.1016/S1470-2045(21)00064-4.
7. Yaeger, R., N.V. Uboha, M.S. Pelster, et al. "Efficacy and Safety of Adagrasib Plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer." Cancer Discovery 14, no. 6 (2024): 982-993. https://doi.org/10.1158/2159-8290.CD-24-0217.
8. Fakih, Marwan, et al. "Overall Survival (OS) of Phase 3 CodeBreaK 300 Study of Sotorasib Plus Panitumumab (Soto+Pani) versus Investigator’s Choice of Therapy for KRAS G12C-Mutated Metastatic Colorectal Cancer (mCRC)." Journal of Clinical Oncology 42 (2024): LBA3510-LBA3510.
9. Kopetz, S., T. Yoshino, E. Van Cutsem, et al. "Encorafenib, Cetuximab, and Chemotherapy in BRAF-Mutant Colorectal Cancer: A Randomized Phase 3 Trial." Nature Medicine, published online January 25, 2025. https://doi.org/10.1038/s41591-024-03443-3.
10. Raghav, K., S. Siena, A. Takashima, et al. "Trastuzumab Deruxtecan in Patients with HER2-Positive Advanced Colorectal Cancer (DESTINY-CRC02): Primary Results from a Multicenter, Randomized, Phase 2 Trial." Lancet Oncology 25, no. 9 (2024): 1147-1162. https://doi.org/10.1016/S1470-2045(24)00380-2.