FDA Approves Nivolumab for MSI-H or dMMR Colorectal Cancer

The FDA has granted an accelerated approval to nivolumab (Opdivo) for the treatment of adult and pediatric 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.

The approval is based on results from the phase II CheckMate-142 trial, in which the overall response rate (ORR) was 28% in mCRC patients who received prior fluoropyrimidine, oxaliplatin, and irinotecan, including 1 complete response (CR) and 14 partial responses (PRs).

The FDA-recommended dose for the PD-1 inhibitor in this setting is 240 mg IV every 2 weeks until disease progression or unacceptable toxicity. The accelerated approval of nivolumab for this indication is contingent upon the outcomes of confirmatory trials.

“Patients with metastatic colorectal cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy,” Heinz-Josef Lenz, MD, J. Terrence Lanni Chair in Gastrointestinal Cancer Research, University of Southern California, said in a statement. “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.”

The open-label, international, phase II CheckMate-142 study enrolled patients with recurrent or mCRC, including MSI-H patients and microsatellite stable patients. Patients were randomized to receive either single-agent nivolumab or nivolumab combined with ipilimumab (Yervoy). The FDA reviewed a cohort of 74 MSI-H or dMMR patients from the study who received 3 mg/kg of nivolumab every 2 weeks. The primary endpoint was ORR, with additional outcome measures including progression-free survival, overall survival, and safety.

For the 74-patient cohort, the median age was 52.5 years (range, 26-79), 59.5% of patients were male, and 87.8% of patients were white. All patients had an ECOG performance status of 0 or 1.

The majority of patients (54.1%) had at least 3 prior lines of therapy. Seventy-two percent of patients had prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Mutations in BRAF (16%) or KRAS (35%) were reported for over half of the patients.

Across the entire study population, the overall response rate was 32% (24/74; 95% CI, 22-44), with 2 CRs and 22 PRs. The median duration of response had not been reached (range, 1.4+ to 26.5+ months).

Fifty-three patients had received prior fluoropyrimidine, oxaliplatin, and irinotecan. The 28% (n = 15; 95% CI, 17-42) ORR in this group included a 1.9% CR rate and a 26% PR rate. The median duration of response was not reached (range, 2.8 to 22.1 months).

Data for these 74 patients presented at the he 2017 Gastrointestinal (GI) Cancers Symposium suggested that there was a response and clinical benefit regardless of PD-L1 expression, BRAF mutation status, KRAS mutation status, and clinical history of Lynch Syndrome.

Safety data presented at the meeting showed that the rate of all-grade adverse events (AEs) was 68.9%, with the most common being fatigue (23%), diarrhea (21.6%), pruritus (13.5%), lipase increased (12.2%), and rash (10.8%). Grade 3/4 AEs occurred in 20.3% of patients, including lipase increased (8.1%), fatigue (1.4%), and diarrhea (1.4%).

Among the 45.9% of patients who discontinued treatment, the reasons included disease progression (36.5%), treatment-related toxicity (5.4%), maximum clinical benefit (1.4%), patient decision (1.4%) and withdrawn consent (1.4%). The were no deaths associated with treatment-related toxicity.

“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.8 The approval of Opdivo for appropriate patients with this disease gives the community more hope,” Michael Sapienza, chief executive officer of the Colon Cancer Alliance, said in a statement.

Overman MJ, Lonardi S, Leone F, et al. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: update from CheckMate 142. J Clin Oncol 35, 2017 (suppl 4S; abstract 519).