Elsevier

The Lancet Oncology

Volume 18, Issue 9, September 2017, Pages 1182-1191
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(17)30422-9Get rights and content

Summary

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.

Introduction

Colorectal cancer is one of the leading causes of cancer-related death worldwide.1 Standard of care for patients with metastatic colorectal cancer who are not candidates for surgery is palliative fluorouracil-based chemotherapy regimens combined with agents targeting angiogenesis or EGFR.2 Despite a number of available systemic treatments for patients with metastatic disease, 5-year survival is only 13·5%.3

Emerging evidence suggests patients with DNA mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (about 5% of patients) are a distinct biomarker-defined population who benefit less from conventional chemotherapy and have a shorter overall survival than do patients with proficient MMR (pMMR) metastatic colorectal cancer.4, 5, 6, 7 Compared with pMMR/microsatellite-stable tumours, dMMR/MSI-H colorectal cancers are associated with a higher mutational burden and tumour neoantigen load and dense immune cell infiltration.8, 9, 10, 11 In a pooled analysis of four phase 3 studies in the first-line setting,6 patients with dMMR metastatic colorectal cancer had significantly worse outcomes than those with pMMR metastatic colorectal cancer (median overall survival 13·6 vs 16·8 months; hazard ratio [HR] 1·35, 95% CI 1·13–1·61; p=0·001). In this analysis, the presence of a BRAF mutation conferred a poor prognosis, suggesting that the poor prognosis of sporadic dMMR metastatic colorectal cancer might be driven partly by BRAF mutation status.

dMMR/MSI-H metastatic colorectal cancers are currently treated with the same systemic agents used for all metastatic colorectal cancers;2 however, growing evidence supports the use of immune checkpoint inhibitors in this patient population.12, 13, 14 The potential benefit of PD-1 inhibitors in patients with dMMR metastatic tumours was first reported in a phase 1 trial of nivolumab in 39 patients with refractory solid tumours, 14 of whom had metastatic colorectal cancer.13 One patient with dMMR metastatic colorectal cancer received five doses of 3 mg/kg nivolumab and achieved a durable complete response persisting for more than 21 months at the time of publication.13 Long-term follow-up showed clinical and radiological complete response more than 3 years later, at which time the patient had not received any anti-neoplastic treatment for 3 years and had no evidence of disease recurrence. The clinical benefit of PD-1 blockade in dMMR metastatic colorectal cancer has also been reported in a phase 2 study of pembrolizumab.12 Of the 11 patients with dMMR metastatic colorectal cancer in that study, four achieved a partial response, and five had stable disease. On the basis of activity of PD-1 inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer, CheckMate 142 was designed as a phase 2 trial to investigate the activity and safety of nivolumab monotherapy or nivolumab in combination with ipilimumab in patients with MSI-H and non-MSI-H metastatic colorectal cancer. Here we report the activity, safety, and biomarker analyses for nivolumab monotherapy in patients with MSI-H metastatic colorectal cancer.

Research in context

Evidence before this study

We searched PubMed for articles published between Jan 1, 2012, and Jan 1, 2017, with no language restrictions, reporting on the use of a PD-1 immune checkpoint inhibitor for the treatment of patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer using the search terms (“DNA mismatch repair” or “microsatellite instability”) and “programmed cell death receptor-1 inhibitor” and “colorectal cancer”, filtering for articles describing clinical trials.

We also searched abstracts of the annual meeting of the American Society of Clinical Oncology using the search term “DNA mismatch repair” or “microsatellite instability” and “programmed death-1 inhibitor” and “metastatic colorectal cancer”, limiting the results to clinical trials published or presented during the past 2 years. Trials in progress were excluded from the search results.

The search yielded one article and three abstracts that reported the results of a phase 2 study that evaluated the clinical activity of pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, in 35 patients with progressive metastatic carcinoma with or without mismatch repair deficiency. In this study, mismatch repair status was predictive of clinical benefit with pembrolizumab in ten patients with dMMR metastatic colorectal cancer; no responses were noted in patients with proficient MMR metastatic colorectal cancer.

Added value of this study

CheckMate 142 is the largest phase 2 study to our knowledge to assess the activity and safety of PD-1 inhibitor treatment in patients with dMMR/MSI-H metastatic colorectal cancer. Our results show that nivolumab monotherapy was well tolerated, provided durable responses and disease control with all responders alive at the time of analysis, and long-term survival in a population of pre-treated patients with dMMR/MSI-H metastatic colorectal cancer. Responses and disease control were recorded in patients with dMMR/MSI-H metastatic colorectal cancer across all subgroups including patients with tumours that were positive (≥1%) or negative (<1%) for tumour PD-L1 expression, tumours harbouring BRAF or KRAS mutations, and those with and without a clinical history of Lynch syndrome. Additionally, nivolumab was associated with clinically meaningful improvements in patient-reported functioning, symptoms, and global quality of life.

Implications of all the available evidence

Patients with dMMR/MSI-H metastatic colorectal cancer are traditionally given conventional chemotherapy with or without targeted treatments and might have significantly worse outcomes than those with proficient MMR metastatic colorectal cancer. The results from this phase 2 study confirm the clinical benefit of PD-1 inhibitor treatment in dMMR/MSI-H metastatic colorectal cancer and suggest that nivolumab is a new treatment option for patients with previously treated dMMR/MSI-H metastatic colorectal cancer. Ongoing studies are exploring the combination of nivolumab with other immunotherapies in patients with dMMR/MSI-H metastatic colorectal cancer.

Section snippets

Study design and participants

CheckMate 142 is an ongoing, multicentre, open-label, phase 2 trial. We enrolled patients with MSI-H metastatic colorectal cancer at 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA; appendix p 3). Eligible patients had histologically confirmed metastatic or recurrent colorectal cancer with tumours locally assessed as dMMR or MSI-H. Patients were aged 18 years and older with an Eastern Cooperative Oncology Group

Results

Between March 12, 2014, and March 16, 2016, 74 patients with locally determined dMMR/MSI-H metastatic colorectal cancer were recruited and enrolled into stages 1 and 2 of the trial, all of whom were given treatment and included in the analyses. An adequate number of objective responses (n=7) were achieved in the first 19 patients with centrally confirmed dMMR/MSI-H metastatic colorectal cancer given nivolumab in stage 1; therefore, enrolment into stage 2 was initiated and is now complete. As of

Discussion

In this open-label, multicentre, phase 2 study, nivolumab showed encouraging activity in patients with dMMR/MSI-H tumours. Responses were recorded across all patient subgroups, including those with (≥1%) and without (<1%) tumour PD-L1 expression, suggesting that PD-L1 is not a predictive biomarker in these patients. Additionally, responses were reported in patients with and without a clinical history of Lynch syndrome, or KRAS or BRAF mutations. BRAFV600E mutations are associated with sporadic

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