CRC is the second leading cause of cancer death among men and women and the third most common cancer diagnosis in the United States, with an estimated 145,600 new cases and 51,020 cancer-related deaths to occur in 2019. The majority of patients with metastatic CRC have incurable disease, with a median overall survival of 30 months at best.
Immune checkpoint inhibitors have demonstrated impressive activity in patients with CRC and other solid tumors that are dMMR. These dMMR tumors exhibit high levels of frameshift mutations detectable as variability in the length of short stretches of DNA (microsatellites). This has been called MSI and has been noted to make these tumors more prone to accumulating mutations, which leads to the generation of neoantigens that can be recognized by the immune system.
Many critical questions remain regarding the most appropriate use of immunotherapy in CRC.
Current Landscape of Immunotherapy in Colon Cancer
Recent discoveries and our better understanding of the complex interactions between cancer cells and the immune system has led to novel and successful immunotherapeutic approaches. Treatment with selective anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 monoclonal antibodies has revolutionized our therapeutic approach to several cancer types. While the highest clinical efficacy of immunotherapy has been observed in melanoma and lung cancer, results in CRC have been less than impressive except in the dMMR–MSI-H group.
What are the currently approved immunotherapeutic treatment options for colorectal cancer?
Currently, there are three FDA-approved immunotherapeutic agents (pembrolizumab, nivolumab plus or minus ipilimumab) for metastatic CRC patients with MSI-H/dMMR.
What are the biomarkers of immune response in CRC?
Several ongoing studies are investigating potential targetable pathways involved in the host immune response to CRC. Correlative studies from clinical trials are essential to identify biomarkers that can serve as immune response surrogates. Patients harboring MSI-H/dMMR tumors appear to benefit most from colon cancer immunotherapy.
What is the role of immunotherapy in MSS/pMMR CRC?
Analyses of MSS/pMMR metastatic CRC cohorts in the checkpoint inhibitor trials has not shown any clinically meaningful benefit with either single-agent PD-1 or the combination of PD-1 and CTLA-4 immunotherapy. This can be explained by the lower antigenicity due to the presence of fewer neoantigens. Clinical trials are testing strategies to improve tumor antigenicity by increasing tumor antigen and major histocompatibility complex class I molecule expression, and to positively alter the tumor microenvironment by vaccination.
When should immunotherapy be utilized in MSI-H/dMMR colon cancer patients?
For metastatic MSI-H/dMMR CRC patients, currently recommended first-line treatment is still combination chemotherapy plus targeted therapy. Nivolumab with or without low-dose ipilimumab and pembrolizumab is approved on progression following first-line treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Although no trials have directly determined whether patients should receive nivolumab alone or in combination with ipilimumab, an indirect comparison suggested that nivolumab plus low-dose ipilimumab provides improved efficacy over nivolumab monotherapy with a favorable risk–benefit profile.
When should immunotherapy be discontinued in responding patients, and what is the outcome of patients who discontinue treatment?
Although outcomes associated with the discontinuation of checkpoint inhibitors have not been rigorously evaluated, subgroup analyses suggest that checkpoint inhibitor therapy may produce long-lasting clinical benefit despite limited treatment duration. Currently, there are no clear data to define exact treatment duration with checkpoint inhibitors. In most cases, treatments are given until true progression or toxicity occurs.
Immunotherapy of cancer is a novel and effective therapeutic strategy. Treatment with selective anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 monoclonal antibodies has brought revolutionary results in MSI-H/dMMR CRC patients. As immune checkpoint inhibitors are integrated into the CRC treatment landscape, their use as single-agent therapy or in combination therapy will evolve and be better defined. Currently, there remain more questions than answers including the timing of treatment initiation, optimal sequencing and optimal duration of treatments and accurate evaluation of response, and management of adverse events. The most difficult challenge of all, however, is to identify those patients with specific tumor and tumor-infiltrating stromal molecular and functional characteristics that could be effectively treated with immunotherapy among the heterogeneous spectrum of CRC patients with MSS/pMMR CRC.