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

Summary Background Metastatic DNA mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) colorectal cancer (mCRC) has a poor prognosis following conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators, all features that correspond with response to programmed cell death receptor-1 (PD-1) blockade in other tumour types. Thus, nivolumab, a PD-1 immune checkpoint inhibitor, was evaluated in this population. Methods In this is ongoing, multicentre, open-label, nonrandomised, phase 2 trial, adult patients (aged ≥18 years) with histologically confirmed recurrent or mCRC locally assessed as dMMR/MSI-H who had progressed on/after or been intolerant of at least one prior line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan, were enrolled. Patients were given nivolumab 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors v1·1. All patients who received at least one dose of study drug were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02060188. Findings Among the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, most (54·1%) had received ≥3 prior therapies. At a median follow-up of 12·0 months (interquartile range 8·57–18·00 months), 23 of 74 patients (31·1% [95% CI 20·8%–42·9%]) achieved an investigator-assessed objective response; 68·9% (95% CI 57·1%–79·2%) of patients had disease control for ≥12 weeks. Median duration of response was not yet reached; all responders were alive, and 8 (34·8%) had responses of ≥12 months. The most common (≥10% of patients) drug-related adverse events was fatigue (n=16 [21·6%]), diarrhoea (n=15 [20·3%]), pruritus (n=10 [13·5%]) and rash (n=8 [10·8%]). The most common grade 3 or 4 drug-related adverse events were increased lipase (n=6 [8·1%]) and amylase (n=2 [2·7%]) levels. Five patients (6·8%) discontinued treatment because of increased alanine aminotransferase, colitis, duodenal ulcer, acute kidney injury, and stomatitis (n=1 each). Twenty-three patients (31·1%) died during the study; none of these deaths was considered to be treatment related by the investigator. Interpretation Nivolumab provided durable responses and disease control, as well as long-term survival in pre-treated patients with dMMR/MSI-H mCRC, and is a new treatment option for these patients.

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

“…In contrast, previous studies concerning treatment response from PD-1 or PD-L1 blockade in CRC report clinical benefit only for patients with MSI-high tumours, 12 , 13 possibly explained by the fact that MSI-high tumours generally carry a higher mutational load, resulting in a robust T cell response which can be exploited by relieving the negative pressure. Nevertheless, Droeser et al.…”

“…11 In CRC, the clinical benefit of PD-1 or PD-L1 blockade remains uncertain, however, a few studies report a positive effect of anti-PD-1 antibodies in patients with microsatellite instability (MSI) high tumours 12 , 13 and anti-PD-1 therapies were recently approved by the U.S Food and Drug Administration for treatment of any type of advanced MSI-high cancer.…”

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

“…24,25 However, only a small number of patients respond. 7,8 Therefore, it has been urgent to identify the best candidates for this therapy and explore novel targets to develop new treatment strategy. In this study, we found that the B7 and TNFR family genes were mutated, amplified or deleted in CRCs, which is consistent with previous studies in other cancer types, including breast cancer, head and neck cancer.…”

“…6,7 MSI is a consequence of impaired DNA mismatch repair, resulting in mutation accumulations to create a rich source of tumor-specific neoantigens. 13 Some of which will be presented on the major histocompatibility complex (MHC), recognized as foreign by T cells, and thereby might stimulate lymphocytic reaction.…”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…The approval of anti-PD-1 therapy for the treatment of adult and pediatric patients with MSI-H or dMMR solid tumors (pembrolizumab) or colorectal cancer (pembrolizumab and nivolumab) that has progressed, underscores the importance of considering other biomarkers that are not specific to the immune checkpoint pathway when making ICB therapy decisions [13]. Patients with MMR deficiency are associated with a higher mutational burden and tumor neoantigen load than MMR-proficient patients, and these features could be driving clinical benefit of ICBs [33,97,98]. In fact, tumor mutational burden, known to enhance neoantigen formation, has been shown to be associated with increased response to ICBs, and in some cases improved OS as well, across tumor types such as melanoma [99,100], NSCLC [101], and UC [54,56,102].…”