Prediction of Benefit from Checkpoint Inhibitors in Mismatch Repair Deficient Metastatic Colorectal Cancer: Role of Tumor Infiltrating Lymphocytes

Author:

Loupakis Fotios1,Depetris Ilaria1,Biason Paola1,Intini Rossana1,Prete Alessandra Anna1,Leone Francesco23,Lombardi Pasquale34,Filippi Roberto34,Spallanzani Andrea5,Cascinu Stefano5,Bonetti Luca Reggiani6,Maddalena Giulia1,Valeri Nicola78,Sottoriva Andrea9,Zapata Luis9,Salmaso Roberta10,Munari Giada1,Rugge Massimo10,Dei Tos Angelo Paolo11,Golovato Justin12,Sanborn John Z.12,Nguyen Andrew12,Schirripa Marta1,Zagonel Vittorina1,Lonardi Sara1,Fassan Matteo10

Affiliation:

1. Department of Clinical and Experimental Oncology, Medical Oncology Unit 1, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy

2. Medical Oncology, ASL Biella, Biella, Italy

3. Medical Oncology, Candiolo Cancer Institute, Fondazione Piemonte per l'Oncologia, IRCCS, Candiolo, Italy

4. Department of Oncology, University of Turin, Turin, Italy

5. Department of Oncology and Haematology, University Hospital of Modena and Reggio Emilia, Modena, Italy

6. Department of Pathology, University Hospital of Modena and Reggio Emilia, Modena, Italy

7. Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom

8. Department of Medicine, The Royal Marsden National Health Service (NHS) Trust, London, United Kingdom

9. Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom

10. Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua University Hospital, Padua, Italy

11. Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy

12. Nantomics, LLC, Santa Cruz, California, USA

Abstract

Abstract Background Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking. Patients and Methods Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of “super” responders and “clearly” refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS). Results In the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463). Conclusion A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy. Implications for Practice Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability–high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer.

Funder

Regione del Veneto

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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