Recent data indicate a role of immunotherapy for tumours with high levels of microsatellite instability, especially in the neoadjuvant setting
Colorectal cancer (CRC), one of the most prevalent cancers globally, can be classified into two groups based on its ability to repair DNA microsatellite damage. Tumours that are mismatch repair-deficient and have high levels of microsatellite instability (MSI) have shown remarkable responses to immunotherapy, particularly checkpoint inhibitors. This is exemplified by the recently published NICHE-2 study in patients with MSI colon cancer, which reported a pathological response to neoadjuvant nivolumab plus ipilimumab in almost all patients (N Engl J Med. 2024;390:1949–1958). Conversely, tumours that are mismatch repair-proficient and microsatellite stable (MSS) have a lower mutational burden and have historically been less responsive to immunotherapeutic strategies. These patients, who constitute around 85% of CRC cases, represent a significant unmet need in CRC (Front Immunol. 2020;11:369).
MSS CRC tumours have long been thought to be resistant to immunotherapy due to the lack of neoantigens expressed on the tumour surface. However, recent advances have indicated that these barriers can be overcome and that immunotherapy still has the potential to play an important role in the treatment of MSS CRC. For example, a phase Ia/Ib trial combining the anti-CTLA-4 antibody botensilimab and the PD-1 inhibitor balstilimab has reported durable responses in patients with MSS metastatic CRC (mCRC) without liver metastases (J Clin Oncol. 2023;41(Suppl 4):LBA8). Similarly, in a phase I/II study, the EGFRxCD28 costimulatory bispecific antibody recently demonstrated promising anti-tumour activity in patients with MSS CRC (J Clin Oncol. 2024;42(Suppl 16):2503). The AtezoTRIBE phase II study also showed that the combination of chemotherapy with the VEGF inhibitor bevacizumab and the PD-L1 inhibitor atezolizumab improved progression-free survival in patients with MSS mCRC (Lancet Oncol. 2022;23:876–887). Particularly significant results were observed in patients with a high Immunoscore-IC result, indicating the potential predictive value of Immunoscore-IC in selecting patients with MSS CRC who are most likely to benefit from immunotherapy.
One of the most exciting recent developments is the application of immunotherapy for MSS CRC in the neoadjuvant setting. The NICHE trial marked the beginning of neoadjuvant immunotherapy for these patients, demonstrating strong pathological responses with PD-1 plus CTLA-4 blockade prior to surgery (Nat Med. 2020;26:566–576). This trial is ongoing and different combinations of agents are being evaluated to determine the most promising treatment strategies in this setting. Further evidence supporting neoadjuvant immunotherapy for MSS CRC comes from the NEST-1 trial, which met its primary endpoint and demonstrated robust responses to neoadjuvant botensilimab and balstilimab in patients with MSS CRC (J Clin Oncol. 2024;42(Suppl 3):117). An update on the NEST-1 study will be presented at the ESMO Gastrointestinal Cancers Congress 2024 (Munich, 26–29 June 2024; Abstract 8MO). Additionally, the TARZAN study has shown that a large proportion of patients with MSS rectal cancer achieved organ preservation following a short course of neoadjuvant radiotherapy combined with atezolizumab and bevacizumab. Findings from this study will also be presented at the ESMO Gastrointestinal Cancers Congress (Abstract 247P).
Beyond clinical trials, there is growing interest in translational studies aimed at identifying the factors that make certain MSS tumours responsive to immunotherapy. By analysing genomic data and employing advanced techniques, such as single-cell analysis and imaging mass cytometry, we hope to identify biomarkers that can predict treatment responses. Although still in its early stages, there are high hopes that this work could pave the way for more personalised and effective treatment strategies.
Looking to the future, the focus remains on refining patient selection and exploring new combinations of immunotherapy agents. The ultimate goal is to identify effective treatments for patients with MSS disease, who represent the majority of cases of CRC. The progress made so far marks a promising step towards overcoming the challenges associated with MSS tumours and extending the benefits of immunotherapy to a broader population of patients with CRC.
