The U.S. Food and Drug Administration has approved nivolumab (Opdivo?; Bristol-Myers Squibb Company | BMS) injection for intravenous use for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body?s digestive or gastrointestinal system. In the United States, CRC is the third most common cancer, in 2017 it is estimated that there will be approximately 135,000 new cases of the disease and that it will be the second leading cause of cancer-related deaths among men and women combined.
Approximately 5% of metastatic CRC patients have mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors.
Mismatch repair deficiency occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, which leads to MSI-H tumors in certain types of cancer, including CRC. Patients with dMMR or MSI-H metastatic CRC are less likely to benefit from conventional chemotherapy and typically have a poor prognosis.
Routine testing to confirm dMMR or MSI-H status should be conducted for all metastatic CRC patients.
Approval of nivolumab was based on CheckMate-142, in which nivolumab demonstrated an objective response rate of 28% (95% CI: 17-42; 15/53) among patients who received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan 
CheckMate -142 is a Phase II, multicenter, open-label, single-arm study evaluating Opdivo in patients with locally determined dMMR or MSI-H mCRC whose disease had progressed during, after, or were intolerant to, prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy.
In this study, 74 patients received nivolumab 3 mg/kg administered intravenously every two weeks.2 The recommended dose is 240 mg administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity. Across the 74 patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Efficacy outcome measures included independent radiographic review committee-assessed confirmed ORR per RECIST 1.1, and duration of response. More than half of patients (51%) had a BRAF (16%) or KRAS (35%) mutation.
In this trial, Opdivo demonstrated an ORR of 28% (95% CI: 17-42; 15/53) in patients who received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, including a 1.9% complete response rate (1/53) and a 26% partial response rate (14/53). Median duration of response in these patients was not reached (range: 2.8+-22.1+ months).
Among all enrolled patients, 32% (95% CI: 22-44; 24/74) responded to treatment with Opdivo, including a 2.7% complete response rate (2/74) and a 30% partial response rate (22/74). The median duration of response was not reached (range: 1.4+-26.5+ months). Data from CheckMate -142 were published in The Lancet Oncology in July.
For this indication, the approval was has been granted under accelerated approval based on overall response rate (ORR) and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The recommended dose is 240 milligrams administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.
In the CheckMate -142 trial, among patients (53/74) who received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, 28% (95% CI: 17-42; 15/53) responded to treatment with nivolumab. The percentage of patients with a complete response was 1.9% (1/53) and the percentage of patients with a partial response was 26% (14/53). Among these responders, the median duration of response was not reached (range: 2.8+-22.1+ months).
Among all enrolled patients, 32% (95% CI: 22-44; 24/74) responded to treatment with nivolumab; 2.7% (2/74) experienced a complete response, 30% (22/74) experienced a partial response.
Nivolumab is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity.
?As part of our commitment to address hard-to-treat cancers, with today?s approval, nivolumab provides a new treatment option for these patients who have historically faced a poor prognosis,? noted Chris Boerner, president, U.S. Commercial, Bristol-Myers Squibb.
?This approval is one example of how our commitment to translational medicine and investigating predictive biomarkers may help us discover treatment approaches to address different patients? unique needs.?
?Patients with metastatic colorectal cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy,? explained said Heinz-Josef Lenz, M.D., FACP, J. Terrence Lanni Chair in Gastrointestinal Cancer Research, University of Southern California.
?While the challenges of treating these patients have been significant, tumors characterized by these biomarkers are immunogenic. Therefore, advances in immunotherapy research are encouraging in presenting new treatment options for appropriate patients with MSI-H metastatic colorectal cancer.?
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines?) recommend universal MMR or MSI testing for all patients with a personal history of colon or rectal cancer to inform use of immunotherapy in patients with metastatic disease.
The National Comprehensive Cancer Network? (NCCN?) panel recommends nivolumab as a category 2A treatment option in patients with metastatic deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer in second- or third-line therapy.
?As the third most common type of cancer in the United States, our view is that colorectal cancer ? particularly for those with dMMR or MSI-H metastatic disease ? has been in need of new research and treatments. The approval of nivolumab for appropriate patients with this disease gives the community more hope,? noted Michael Sapienza, chief executive officer of the Colon Cancer Alliance.
Last editorial review: August 1, 2017
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