Efficacy of Immune Checkpoint Inhibitors in Patients with Mismatch Repair-Deficient or Microsatellite Instability-High Metastatic Colorectal Cancer: Analysis of Three Phase-II Trials

Abstract Immunotherapy, especially immune checkpoint inhibitors, has revolutionized the standard-of-care of multiple types of tumors. For colorectal cancer, the clinical development of immune checkpoint inhibitors is mainly separated according to the status of microsatellite instability or mismatch repair in a tumor. High-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer generally has a tumor microenvironment with infiltration of T cells, associated with a favorable response to immune checkpoint inhibitors. Immune checkpoint inhibitors, including pembrolizumab (anti-PD-1 inhibitor) and nivolumab (anti-PD-1 inhibitor) with or without ipilimumab (anti-CTLA-4 inhibitor), have been integrated into the standard-of-care for high-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer. Conversely, limited T-cell infiltration in the tumor microenvironment of microsatellite stable/proficient mismatch repair metastatic colorectal cancer, which constitutes the majority of metastatic colorectal cancer, is assumed to be a major resistant mechanism to immune checkpoint inhibitors. Currently, clinical trials to improve the clinical activity of immune checkpoint inhibitors by immunomodulation are ongoing for metastatic colorectal cancer. Furthermore, immune checkpoint inhibitors are under development in neoadjuvant and/or adjuvant setting. Here, we review the existing clinical data with ongoing trials and discuss the future perspectives with a focus on the immunotherapy of colorectal cancer.

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Immune Checkpoint Inhibitors in Mismatch Repair Proficient/Microsatellite Stable Metastatic Colorectal Cancer Patients: Insights from the AtezoTRIBE and MAYA Trials

Cancers ◽

10.3390/cancers14010052 ◽

2021 ◽

Vol 14 (1) ◽

pp. 52

Author(s):

Marco Maria Germani ◽

Roberto Moretto

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Small Subset ◽

Repair System ◽

Phase Ii Trials ◽

Research Perspectives

In metastatic colorectal cancer (mCRC), remarkable advances have been achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, only in a small subset of tumours (4–5%), harbouring a deficient mismatch repair system (dMMR)/microsatellite instability–high (MSI-H) or mutations in the catalytic subunit of polymerase epsilon (POLE). Within this framework, several combination strategies have been investigated to sensitize proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC to ICIs, with disappointing results so far. However, at the last ESMO meeting, two phase II trials AtezoTRIBE and MAYA provided promising results in this field. In the comparative AtezoTRIBE trial, the addition of atezolizumab to FOLFOXIRI (5-fluoruracil, oxaliplatin and irinotecan) and bevacizumab led to a significant advantage in terms of progression free survival (PFS) in a population of untreated mCRC patients, not selected according to MMR/MSI status. In the single-arm MAYA trial, immune priming with temozolomide in pMMR/MSS chemo-resistant mCRC patients with silencing of O6-methylguanine-DNA methyltransferase (MGMT) allowed reporting signals of sensitivity to the subsequent therapy with nivolumab and a low dose of ipilimumab in some patients. Here, we discuss the rationale, results, criticisms and research perspectives opened by these two studies.

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Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Cancers ◽

10.3390/cancers12082317 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2317 ◽

Cited By ~ 1

Author(s):

Federica Marmorino ◽

Alessandra Boccaccino ◽

Marco Maria Germani ◽

Alfredo Falcone ◽

Chiara Cremolini

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Dna Mismatch Repair ◽

Checkpoint Inhibitors ◽

Favorable Effect ◽

Mutational Load ◽

Dna Mismatch

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.

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Acute Ulceronecrotic Gastritis With Cytomegalovirus Reactivation: Uncommon Toxicity of Immune Checkpoint Inhibitors in Microsatellite Instability–High Metastatic Colorectal Cancer

Clinical Colorectal Cancer ◽

10.1016/j.clcc.2020.04.006 ◽

2020 ◽

Vol 19 (4) ◽

pp. e183-e188

Author(s):

Pauline Hulo ◽

Yann Touchefeu ◽

Estelle Cauchin ◽

Isabelle Archambeaud ◽

Nicolas Chapelle ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cytomegalovirus Reactivation

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Microsatellite instability status in metastatic colorectal cancer and effect of immune checkpoint inhibitors on survival in MSI-high metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15106 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15106-e15106 ◽

Cited By ~ 1

Author(s):

Wataru Okamoto ◽

Yoshiaki Nakamura ◽

Manabu Shiozawa ◽

Yoshito Komatsu ◽

Tadamichi Denda ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Large Scale ◽

Checkpoint Inhibitors ◽

Survival Rates ◽

Gene Mutations ◽

Poorly Differentiated

e15106 Background: Tumor mismatch repair (MMR) predicts benefit of immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). We conducted a large-scale prospective observational trial on microsatellite instability (MSI) status in mCRC: SCRUM-Japan GI-SCREEN CRC-MSI. Methods: mCRC patients (pts) appropriate for systemic chemotherapy were eligible. Paired tumor and normal DNA extracted from FFPE samples were analyzed by the MSI Analysis System, which includes 5 mononucleotide markers. Tumors exhibiting ≥2 unstable markers were defined as MSI-H, while those with ≤1 were labelled MSI-L/MSS. Results: From 2/2016 to 3/2018, 1,711 pts were enrolled, and 1,696 samples were submitted. MSI status was determined in 1,676 pts (98.8%); 51 pts (3.0%) were MSI-H. For MSI-H vs. MSI-L/MSS pts: Median age (years) 64/64; male gender (%) 51.0 vs. 43.8, p=0.31; right-sided primary (%) 70.6 vs. 25.0, p<0.001; and poorly differentiated histology (%) 33.3 vs. 8.9, p<0.001. Of the 864 pts who received parallel NGS testing, median tumor mutation burdens (TMB) in MSI-H and MSI-L/MSS were 32.8 and 12.6 mt/Mb, p<0.001. High TMB, defined as >20 mt/Mb, was observed in 27/29 (93.1%) MSI-H pts. The frequency of representative gene mutations (%) for MSI-H vs. MSI-L/MSS pts were: TP53 17.2 vs. 66.1, p<0.001; PIK3CA 48.3 vs. 13.2, p<0.001; BRAF 34.5 vs. 7.5, p<0.001; MSH2 17.2 vs. 0, p<0.001; CTNNB1 17.2 vs. 0.6, p<0.001; and ERBB2 10.3 vs. 1.4, p<0.001. ERBB2 amplification was detected only in MSI-L/MSS pts (2.3%). Two-year survival rates from first-line systemic therapy in 389 pts with MSI-L/MSS, 5 pts with MSI-H treated with ICI in any-line, and 5 pts with MSI-H not treated with ICI, were 77.7, 100, and 33.3%, respectively. Conclusions: MSI-H mCRC tumors were more frequent in right-sided colon primaries and with poorly differentiated histology. Median TMB was significantly greater in MSI-H pts, and a very high burden was frequently seen. Survival in MSI-H mCRC was poor before ICIs; these agents may improve outcomes for MSI-H pts. Clinical trial #UMIN000020437.

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