Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

Abstract

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

“…Generally speaking, there are two kinds of therapy strategies, namely conventional chemotherapy with or without targeted therapy and rechallenge of anti-PD1/PD-L1 with the aid of other therapy. In a retrospective study investigating the efficacy of chemotherapy with or without targeted therapy in MSI/dMMR mCRC patients after progression on anti-PD1/PD-L1 monotherapy [ 18 ], the ORR and DCR were 13% and 45%, and the mPFS and mOS were 2.9 months and 7.4 months, respectively, which were consistent with the results in our study. The mOS was 6.5 months in the chemo-targeted group in our study when excluding patients who received anti-PD1/PD-L1 plus other therapy after progression on chemotherapy with or without targeted therapy.…”

“…Thus far, limited open literature has reported the therapy strategy in MSI/dMMR gastrointestinal patients who have received prior ICI monotherapy. There are only two studies prospectively exploring the efficacy of anti-PD1/PD-L1 plus inhibitors of some emerging targets, including TGF (15 patients) [ 16 ] and TIM3 (22 patients) [ 17 ], and a retrospective study analyzing the efficacy of conventional chemotherapy with or without targeted therapy (31 patients) [ 18 ]. Regrettably, they all failed.…”

PD-L1 Expression in High-Risk Early-Stage Colorectal Cancer—Its Clinical and Biological Significance in Immune Microenvironment

“…In addition to prognostic significance, this evidence may suggest a potential therapeutic approach to CRC through the combination of ICIs and CXCL9-based therapy. The efficacy of anti-PD-1/PD-L1 antibodies has been well demonstrated in various types of cancer, including MSI-H CRC [ 64 , 65 ]. However, dMMR/MSI-H CRC comprises approximately 5% of metastatic CRC, and the efficacy of ICIs has been unsatisfactory in the majority of CRC which is mismatch repair proficient (pMMR) or microsatellite stable (MSS) [ 66 , 67 ].…”

The emerging era of personalized medicine in advanced colorectal cancer

“…It should be noted however, that despite the high response rates and durable clinical benefit seen with ICIs, up to 50% of MSI‐H/dMMR mCRC tumors have been reported to display primary or secondary resistance to immunotherapy and will eventually progress. This resistance is gradual, suggesting that changes in the TME and the tumor genome are occurring, which result in this acquired ICI resistance (9, 21, 24) 140,144,158 …”

“…This resistance is gradual, suggesting that changes in the TME and the tumor genome are occurring, which result in this acquired ICI resistance (9,21,24). 140,144,158 MSI-H tumors carry a high and variable tumor mutational burden (TMB), which has recently been shown to be a predictor of ICI treatment response. This may be responsible for the observed heterogeneous responses to anti-PD-1 therapies, thus highlighting a role for TMB scoring when making decisions regarding the best choice of treatment.…”