Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

Abstract

Background: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer.

Methods: In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188.

Findings: Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator.

Interpretation: Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients.

Funding: Bristol-Myers Squibb.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Plots of change from baseline in target lesion size over time in patients with metastatic or recurrent colorectal cancer locally assessed as dMMR/MSI-H

(A) Percentage change from baseline in the sum of the tumour burden for target lesions over time per investigator assessment for evaluable patients treated with nivolumab. Triangles indicate complete response or partial response per Response Evaluation Criteria In Solid Tumors v1·1; plus signs indicate the first occurrence of a new lesion; solid circle indicate patient who were off treatment; squares indicate percentage change truncated to 100%. (B) Characteristics of response (top panel) or stable disease (bottom panel) evaluated per investigator assessment per Response Evaluation Criteria In Solid Tumors v1·1. The lines represent length of progression-free survival. Triangles indicate censored observations; solid circle indicate the first response; solid black square indicate the last dose when the patient was off treatment; dagger signs indicate death. dMMR/MSI-H=DNA mismatch repair deficient/microsatellite instability–high.

Figure 2:. Plots of progression-free survival per investigator assessment and overall survival in patients with metastatic or recurrent colorectal cancer locally assessed as dMMR/MSI-H

(A) Kaplan-Meier curve for progression-free survival per investigator assessment in patients treated with nivolumab. Triangles indicate censored observations. (B) Kaplan-Meier curve for overall survival in all patients treated with nivolumab. Triangles indicate censored observations. dMMR/MSI-H=DNA mismatch repair deficient/microsatellite instability–high; NE=not estimable.