Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer

POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes...

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Published in:	Annals of oncology Vol. 35; no. 7; p. 643
Main Authors:	Ambrosini, M, Rousseau, B, Manca, P, Artz, O, Marabelle, A, André, T, Maddalena, G, Mazzoli, G, Intini, R, Cohen, R, Cercek, A, Segal, N H, Saltz, L, Varghese, A M, Yaeger, R, Nusrat, M, Goldberg, Z, Ku, G Y, El Dika, I, Margalit, O, Grinshpun, A, Murtaza Kasi, P, Schilsky, R, Lutfi, A, Shacham-Shmueli, E, Khan Afghan, M, Weiss, L, Westphalen, C B, Conca, V, Decker, B, Randon, G, Elez, E, Fakih, M, Schrock, A B, Cremolini, C, Jayachandran, P, Overman, M J, Lonardi, S, Pietrantonio, F
Format:	Journal Article
Language:	English
Published:	England 01-07-2024
Subjects:	Adult Aged Aged, 80 and over Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology DNA Mismatch Repair DNA Polymerase II - genetics DNA Polymerase III - genetics Female Humans Immune Checkpoint Inhibitors - therapeutic use Male Microsatellite Instability Middle Aged Mutation Poly-ADP-Ribose Binding Proteins - genetics metastatic colorectal cancer proofreading deficiency POLD1 mutations immune checkpoint inhibitors POLE mutations
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Summary:	POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.
ISSN:	1569-8041
DOI:	10.1016/j.annonc.2024.03.009