Risk of bowel obstruction in patients with colon cancer responding to immunotherapy: an international case series.

BACKGROUND: Immunotherapy is used routinely for treating deficient mismatch repair (dMMR) colon cancer (CC). This case series highlights an emerging safety issue, where patients develop bowel obstruction associated with immunotherapy response. PATIENTS AND METHODS: Patients with dMMR CC who developed bowel obstruction while responding to immunotherapy were retrospectively identified. Data on patient, disease, treatment, and response-specific factors were explored for potential risk factors. Overall treatment numbers were used to estimate incidence. RESULTS: Nine patients from eight European centres were included. Common features were hepatic flexure location (5/9), T4 radiological staging (6/9), annular shape (8/9), radiological stricturing (5/9), and endoscopic obstruction (6/9). All received pembrolizumab and obstructed between 45 and 652 days after starting treatment. Seven patients underwent surgical resection; one was managed with a defunctioning stoma; and one was managed conservatively. One patient died from obstruction. Radiological response was seen in eight patients, including two complete responses. Pathological response was seen in all seven who underwent resection, including four complete responses. The overall incidence of immunotherapy response-related obstruction in these centres was 1.51%. CONCLUSIONS: Bowel obstruction associated with immunotherapy response may represent a rare treatment-related complication in dMMR CC. Clinicians must recognise this safety signal and share experience to maintain patient safety.

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

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.