Tan et al. reported clinical outcomes and translational analyses of patients with early-stage DNA mismatch repair-proficient colon cancer from the phase II NICHE trial. Out of 33 patients, 17 received nivolumab and ipilimumab alone and 16 received them in combination with celecoxib. The overall response rate was 26% with 6 MPR and 1 CR. Circulating tumor DNA (ctDNA) was negative in 5/6 responders after neoadjuvant treatment and prior to surgery, while 19/20 non-responders remained ctDNA-positive. Responders showed higher chromosomal genomic instability, increased TCF1 expression, and proliferation of CD8+ T cells, despite a low TMB in all tumors.
Contributed by Shishir Pant
ABSTRACT: Immune checkpoint blockade (ICB) has led to paradigm shifts in the treatment of various tumour types(1-4), yet limited efficacy has been observed in patients with metastatic mismatch-repair proficient (pMMR) colorectal cancer(5). Here we report clinical results and in-depth analysis of patients with early-stage pMMR colon cancer from the phase II NICHE study (ClinicalTrials.gov: NCT03026140). A total of 31 patients received neoadjuvant treatment of nivolumab plus ipilimumab followed by surgery. The response rate was 26% and included six patients with a major pathological response (²10% residual viable tumour). One patient with an ongoing clinical complete response did not undergo surgery. Circulating tumour DNA (ctDNA) was positive in 26/31 patients at baseline, and clearance was observed in 5/6 responders prior to surgery, while 19/20 non-responders remained ctDNA+. Responses were observed despite a low tumour mutational burden in all tumours, while chromosomal genomic instability scores were significantly higher in responders compared to non-responders. Furthermore, responding tumours had significantly higher baseline expression of proliferation signatures and TCF1, and imaging mass cytometry revealed a higher percentage of Ki-67(+) cancer and Ki-67(+) CD8(+) T cells in responders compared to non-responders. These results provide a comprehensive analysis of response to neoadjuvant ICB in early-stage pMMR colon cancers and identify potential biomarkers for patient selection.
Author Info: (1) Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Am
Author Info: (1) Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (3) Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (7) Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Natera, Inc, Austin, TX, USA. (9) Natera, Inc, Austin, TX, USA. (10) Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands. (12) Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (14) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (15) Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands. (16) Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (17) Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. m.chalabi@nki.nl. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. m.chalabi@nki.nl.
