Immunotherapy in Metastatic Colorectal Cancer: More Than Just MSI-H?

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In an era of genomics, proteomics, and immunology a biomarker as simple as anatomy may be useful in terms of predicting responses in patients with colorectal cancer.

Jason Henry, MD

Jason Henry, MD

For many patients, there is no greater sense of promise than cancer immunotherapy and it is often the first inquiry we receive. Of course, the concept of cancer immunotherapy is not new, dating back 150 years when William B. Coley observed tumor regressions following injection of bacterial broths.1,2

These early observations were followed by years of struggle and marginal success. In 2011, regulatory approval of the immune checkpoint inhibitor (ICI) ipilimumab (Yervoy), a monoclonal antibody targeting CTLA-4, prompted significant enthusiasm for treatments that can provide durable clinical benefits—often with limited side effects.3 Another ICI, nivolumab (Opdivo), followed in 2014, fully ushering in a new age of cancer immunotherapeutics.

Unfortunately, a majority of our patients with gastrointestinal (GI) malignancies, including those with colorectal cancer (CRC), were not included in early celebrations. CRC is a heterogenous disease driven by genomic instability with mutations in genes including RAS, RAF, and mismatch repair (MMR) proteins representing the most common.

One of the earliest studies completed by Bert H. O’Neil, MD, and team investigated the antitumor activity of the PD-L1 inhibitor pembrolizumab (Keytruda) in patients with CRC. A total of 138 patients were screened for tumor PD-L1 expression with 23 patients treated. The overall response rate (ORR) was 4%, and the lone patient with a partial response had a microsatellite instability-high (MSI-H) tumor.4 A subsequent study, CheckMate-142 led by Michael Overman, MD, et al, investigated nivolumab plus or minus ipilimumab in both microsatellite stable (MSS) and MSI-H metastatic CRC and demonstrated similar findings with non–MSI-H patients, harboring a median PFS of 1.4 months.5 Emerging from these data was a sense that CRC is a cold tumor and responses with ICI are only expected for patients with MSI-H tumors.

Of course, these wins should not be dismissed, as they represent meaningful progress for a select group of patients. Mutations in MMR resulting in MMR deficiency and MSI-H account for approximately 15% of all CRCs, and are enriched in early-stage cancer.6 For patients with metastatic disease, MSI-H CRC represents about 5% of all patients and some combination of immune checkpoint blockade is expected in the first-line metastatic setting. Encouragingly, the phase 3 KEYNOTE 177 trial comparing pembrolizumab with chemotherapy demonstrated an improved PFS of 16.5 vs 8.2 months and an ORR of 43.8%.7

Equally, the phase 2 Checkmate-142 trial evaluated the role of nivolumab in combination with ipilimumab, and showed an ORR of 69% with a complete response (CR) rate of 13%.8 More recently, a phase 2 study, in which single-agent dostarlimab (Jemperli) was administered to patients with MSI-H stage 2 or 3 rectal cancer, demonstrated complete clinical responses in 12/12 (100%) patients.9 This represents significant progress with lifechanging results—even if only for a select cohort of patients.

For patients with MSS CRC, renewed enthusiasm emerged when a phase 1b trial of regorafenib (Stivarga) plus nivolumab in patients with MSS CRC demonstrated a 36% ORR (n = 9/25). This exceeded historical norms for regorafenib alone and suggests a potential synergistic effect.10 In this study, the authors observed that only 2 of 13 patients with liver metastases enjoyed an objective response. While a follow-up phase 2 study demonstrated an ORR of only 7.1%, it was noted that patients without liver metastases had an ORR of 21.7%. Treatment of liver metastases with immunotherapy is challenging due to an immunosuppressive environment, local immune tolerance, and a possible metabolism effect.11

What emerged was site of metastasis as a predictor of response to ICI in MSS CRC. At the 2023 Gastrointestinal Cancers Symposium, Anthony El-Khoueiry, MD, presented 1a/1b data for patients with MSS metastatic CRC treated with botensilimab (anti–CTLA-4 antibody) and balstilimab (anti–PD-1 antibody). Seventy patients were evaluated; the ORR was 23%, 11 of 16 of which were ongoing at time of presentation. All responses were seen in patients without liver metastasis. Importantly, 81% of patients without liver metastases were alive at 12 months validating our eagerness to provide patients with durable responses.12 Similarly, a recent study in JAMA Oncology led by Marwan Fakih, MD, et al studying a combination of regorafenib, ipilimumab, and nivolumab demonstrated differential response based on sites of disease. In their study, 39 total patients were enrolled. For the 22 patients without liver metastases, the ORR was 36.4%, while no responses were seen in patients with active liver metastases.13

This is an exciting time. In an era of genomics, proteomics, and immunology a biomarker as simple as anatomy may be useful in terms of predicting responses. As we encounter patients, it is often humbling to recognize our inability to predict therapeutic benefit. While innovative therapies are essential, we must continue to examine predictive biomarkers and acknowledge that progress is not always a novel therapy, but rather novel application of an old one.


  1. Adams JL, Smothers J, Srinivasan R, and Hoos A. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 2015;14:603-622. doi:10.1038/nrd4596
  2. Hoos A, Britten C. The immuno-oncology framework: enabling a new era of cancer therapy. Oncoimmunology. 2012;1(3):334-339. doi:10.4161/onci.19268
  3. Decker WK, da Silva RF, Sanabria MH, Angelo LS, Guimarães F, Burt BM, et al. Cancer immunotherapy: historical perspective of a clinical revolution and emerging preclinical animal models. Front Immunol. 2017;8:829. doi:10.3389/ fimmu.2017.00829
  4. O’Neil BH, Wallmark JM, Lorente D, Elez E, Raimbourg J, Gomez-Roca C, et al. Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLOS ONE. 2017;12(12):e0189848. doi:10.1371/journal.pone.0189848
  5. Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer(mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. J Clin Oncol. 2016;34(15 suppl):3501. doi:10.1200/JCO.2016.34.15_suppl.3501
  6. Kocarnik JM, Shiovitz S, Phipps AI. Molecular phenotypes of colorectal cancer and potential clinical applications. Gastroenterol Rep (Oxford). 2015;3(4):269-276. doi:10.1093/gastro/gov046.
  7. Andre T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383(23):2207-2218 doi:10.1056/NEJMoa2017699
  8. Lenz H-J, Lonardi S, Zagonel V, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Two-year clinical update [abstract]. J Clin Oncol. 2020;38:4040-4040. doi:10.1200/JCO.2020.38.15_suppl.4040
  9. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi: 10.1056/NEJMoa2201445
  10. Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2020;38(18):2053-2061. doi:10.1200/JCO.19.03296
  11. Yu, J, Green, MD, Li, S, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021;27;152-164. doi:10.1038/s41591-020-1131-x
  12. El-Khoueiry A, Fakih M, Gordon MS, et al. Results from a phase 1a/1b study of botensilimab (BOT), a novel innate/adaptive immune activator, plus balstilimab (BAL; anti-PD-1 antibody) in metastatic heavily pretreated microsatellite stable colorectal cancer (MSS CRC). J Clin Oncol. 2023;41(suppl 4):LBA8. doi:10.1200/JCO.2023.41.4_suppl.LBA8
  13. Fakih M, Sandhu J, Lim D, Li X, Li S, Wang C. Regorafenib, ipilimumab, and nivolumab for patients with microsatellite stable colorectal cancer and disease progression with prior chemotherapy: a phase 1 nonrandomized clinical trial. JAMA Oncol. Published online March 09, 2023. doi:10.1001/jamaoncol.2022.7845
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