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

Abstract

Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy. Methods: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group). Results: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers. Conclusions: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials.

Opportunities and challenges of immunotherapy for dMMR/MSI-H colorectal cancer

“…The second strategy involves use of ICI in combination with other therapies, such as targeted therapy and chemotherapy or dual immunotherapy. A retrospective study showed that combining ICI with other treatments (e.g., anti-angiogenesis therapy in 15 patients and chemotherapy in 9 patients) resulted in better clinical outcomes compared to chemotherapy with or without targeted therapy for patients with MSI-H GI cancer who had progressed on ICIs 20 . Prospective studies have shown limited clinical benefit when combining anti-PD-L1 with TGF-β bifunctional fusion protein inhibitor (0% ORR) and anti-TIM3 (4.5% ORR) in patients with ICI-resistant MSI-H CRC 21 , 22 .…”

PD-1/PD-L1 Inhibitor Plus Chemotherapy Versus PD-1/PD-L1 Inhibitor in Microsatellite Instability Gastrointestinal Cancers: A Multicenter Retrospective Study

“… 10 It was reported in a retrospective study that patients with MSI/dMMR gastrointestinal cancer who had progressed on PD-1/PD-L1 inhibitors could still benefit from anti–PD-1/PD-L1 plus chemotherapy. 11 Recently, the combination strategy of anti–PD-1/PD-L1 and chemotherapy has been proven to be more effective than chemotherapy and as the standard of care in many cancers, including lung cancer, GC, and esophagus cancer. 12 - 15 Notably, in non–small-cell lung cancer (NSCLC), the PFS and OS curves of anti–PD-1/PD-L1 versus chemotherapy were always crossed in prior studies.…”