Complete pathological response after chemotherapy or immune checkpoint inhibitors in deficient MMR metastatic colorectal cancer: Results of a retrospective multicenter study

Abstract

About 5% of the patients with metastatic colorectal cancers (mCRC) present microsatellite instability (MSI)/deficient mismatch repair system (dMMR). While metastasectomy is known to improve overall and progression‐free survival in mCRC, specific results in selected patients with dMMR/MSI mCRC are lacking. Our study aimed to describe metastasectomy results, characterize histological response and evaluate pathological complete response (pCR) rate in patients with dMMR/MSI mCRC. We retrospectively reviewed data from all consecutive patients with dMMR/MSI mCRC who underwent surgical metastasectomy between January 2010 and June 2021 in 17 French centers. Primary outcome was to assess the pCR rate defined by tumor regression grade (TRG) 0. Secondary endpoints included relapse‐free survival (RFS) and overall survival (OS), and explored TRG as predictive factor for RFS and OS. Among the 88 patients operated, 109 metastasectomies were performed in 81 patients after neoadjuvant treatment [chemotherapy ± targeted therapy (CTT): 69, 85.2%; immunotherapy (ICI): 12, 14.8%], and pCR was achieved in 13 (16.1%) patients. Among the latter, pCR rate were 10.2% in the patients having received CTT (N = 7) and 50.0% in the patients treated with ICI (N = 6). Radiological response did not predict TRG. With a median follow‐up of 57.9 (IQR 34.2‐81.6) months, median RFS was 20.2 (15.4‐not reached) months, median OS was not reached. Major pathological responses (TRG0 + TRG1) were significantly associated with longer RFS (HR 0.12, 95% CI 0.03‐0.55; P = .006). The pCR rate of 16.1% achieved with neoadjuvant treatment in patients with dMMR/MSI mCRC is consistent with previously reported rates in pMMR/MSS mCRC. Immunotherapy showed better pCR rate than chemotherapy ± targeted therapy. Further prospective trials are needed to validate immunotherapy as neoadjuvant treatment in resectable/potentially resectable dMMR/MSI mCRC and identify predictive factors for pCR.

Clinical significance of metastasectomy and pathological response to pembrolizumab in mismatch repair-deficient metastatic colorectal cancer: A retrospective multi-institutional study

“…Another previous study examined the pCR rate after pembrolizumab in patients with dMMR mCRC. Marolleau et al investigated 88 patients with dMMR mCRC who underwent metastasectomy between 2010 and 2021 at 17 centers in France [4]. The study included 81 patients who underwent metastasectomy after neoadjuvant treatment (69 patients received chemotherapy with/without targeted therapy, and 12 patients received immunotherapy).…”

“…In colorectal cancer (CRC), the overall percentage of microsatellite instability-high (MSI-H)/dMMR is 12%-16% in Western studies, and 6%-7% in Japanese studies [3]. In addition, dMMR CRCs are more commonly observed in localized disease and the incidence of dMMR in metastatic CRC (mCRC) is about 3%-8% of mCRC, which is lower than that in localized CRC [4].…”

“…In recent years, the remarkable e cacy and high clinical/pathological complete response (c/pCR) rate of neoadjuvant immunotherapy for localized CRC has been reported [20][21][22][23][24][25]. However, to the best of our knowledge, to date there has been only one report on the pCR rate after pembrolizumab in mCRC [4].…”

“…However, we have not studied either the signi cance of metastasectomy or the pCR rate after pembrolizumab treatment in patients with dMMR mCRC. With only a small number of mCRC patients identi ed as dMMR, clinical studies in this selected group are particularly challenging [4]. Hence, we conducted a retrospective multi-institutional study to describe the signi cance of metastasectomy in patients with dMMR mCRC, and the pCR rate of the patients treated with pembrolizumab.…”

Case report: Fatal overwhelming post-splenectomy infection in a patient with metastatic angiosarcoma treated with immunotherapy

“…Physicians should assess and discuss with the patients the risks and benefits associated with continuation of immunotherapy if no active tumor is present. This is particularly important because the use of anti-PD1 and anti-CTLA4 has been associated with eradication of tumor in patients with various tumor types, including melanoma ( 29 ), renal cancer ( 30 ), microsatellite-instable colorectal cancer ( 31 ), high-grade neuroendocrine carcinoma ( 32 ) and prostate cancer ( 33 ) (and personal experience). Guidelines should be developed for immunotherapy trials to include PET/CT imaging and biopsies for individual patients who respond to treatment to determine whether further immunotherapy is indicated.…”