Priority Review Granted by FDA for Nivolumab Plus Ipilimumab Combo for MSI-H/dMMR CRC

There has been a supplemental biologics license application (sBLA) granted priority review by the FDA for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cases of metastatic colorectal cancer (mCRC) following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

The sBLA came from the results of a cohort with 119 patients treated with this combination in a phase II trial, the CheckMate-142 study. With a median follow-up of 13.4 months, overall response rate (ORR) in the cohort was 55% (95% CI, 45.2-63.8), with 31% of patients having stable disease, according to an investigator-assessment. There was a disease control rate (DCR) for ≥12 weeks of 80%. Also, 78% demonstrated a reduction in tumor burden from baseline.

Patients treated with nivolumab in the monotherapy cohort had an ORR of 31% and a DCR of 69% at 13 months’ follow-up.

The combination of both drugs, manufactured by Bristol-Myers Squibb (BMS), received a breakthrough designation in this setting previously. Under the Prescription Drug User Fee Act, the FDA has scheduled to make the final decision by July 10, 2018.

“The FDA acceptance of this application with priority review reinforces our belief in the potential of the Opdivo plus Yervoy combination to treat patients with previously treated metastatic colorectal cancer defined by MSI-H or dMMR biomarkers, and is a result of our longstanding commitment to the exploration of I-O/I-O combinations for patient populations with high unmet need,” Ian M. Waxman, MD, development lead, Gastrointestinal Cancers, BMS, said. “We look forward to working with the FDA with the goal of bringing this combination to these colorectal cancer patients.”

In the combination cohort, 119 patients were treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses which was followed up with nivolumab at 3 mg/kg every 2 weeks. There was a median age of 58 in the patients (range, 21-88), while 59% were male, and 92% were white. Also, 45% of patients had an ECOG performance status of 0, while 55% had a status of 1.

Disease stages at diagnoses included II (12%), III (44%), and IV (45%). In these patients, 55% had a tumor in the right colon and 25% had a tumor in the left and sigmoid colon. The mutational status of patients broke down as BRAF/KRAS wild-type in 26% of patients, BRAF-positive in 24%, KRAS-positive in 37%, and unknown in 13%. 

Overall, 76% of the 119 patients had ≥2 prior lines of therapy. Common chemotherapies from prior treatments included fluoropyrimidine (99%), oxaliplatin (93%), and irinotecan (73%). Sixty-three percent of patients continued the treatment; disease progression (19%) was the main reason for discontinuation, followed by toxicity related to a study drug (13%).

Investigators assessing at baseline found 22% of patients had a PD-L1 expression level &ge;1%, 55% had a level <1%, and the level was unknown for 24%. There was also a known clinical history of Lunch syndrome in 29% of patients.

The ORR rate of 55% included 4 (3%) patients with complete responses and 61 (51%) with partial responses. Stable disease was found in 37 paitents while 14 had progressive disease. The best overall response had not yet been determined at the cutoff for 3 patients. The median time to response in those treated with combination therapy was 2.8 months and the responses were durable; median duration of response was not reached while 94% of responders had ongoing responses at the data cutoff.

Irrespective esponses were observed for PD-L1 expression or BRAF/KRAS&nbsp;mutation status. For patients with PD-L1 levels &ge;1, the ORR was 54%, compared to 52% in patients with levels <1. For&nbsp;BRAF-positive,&nbsp;KRAS-positive, and&nbsp;BRAF/KRAS-wild type patients, the ORRs were 55%, 57%, and 55%, respectively. Patients with a clinical history of Lynch syndrome had an ORR of 71%, compared to 48% among patients with no such history.&nbsp;

The 9- and 12-month rates of progression-free survival with combination immune checkpoint inhibitor therapy were 76% and 71%, respectively. In the nivolumab monotherapy cohort, these rates were 54% and 50%. Overall survival at 9 and 12 months was 87% and 85%, respectively, in patients treated with the combination, which was also superior relative to nivolumab monotherapy (78% and 73%, respectively).

There was a total of 41% of patients experiencing a treatment-related adverse event (TRAE). The most common grade 1/2 TRAEs included diarrhea (20%), fatigue (16%), pruritus (15%), pyrexia (15%), hypothyroidism (13%), nausea (12%), rash (9%), hyperthyroidism (11%), increased AST (7%), and increased ALT (5%).

Grade 3/4 TRAEs were experienced by 32% of the patients in the trial. Specifically, grade 3 TRAEs found were increased AST (8%), increased ALT (7%), diarrhea (2%), fatigue (2%), pruritus (2%), rash (2%), hypothyroidism (1%), and nausea (1%).

Thirteen percent of patients discontinued treatment because of TRAEs, all with an ORR (63%) consistent with that of the overall population.

The quality of life (QOL) has been assessed by the EORTC QLQ-C30 global health status/QoL and the EQ-5D visual analog scale. There were some statistically significant and clinically meaningful improvements achieved in key QOL measures, while improvements were maintained for extended periods as well. There were also no new safety signals or treatment-related deaths observed.

The FDA granted an accelerated approval, in August 2017, to single-agent nivolumab for the treatment of adult and pediatric patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

References:

Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi: 10.1200/JCO.2017.76.9901.