An accelerated approval has been granted by the FDA for the combination of nivolumab plus ipilimumab for the treatment of both adult and pediatric patients, over the age of 12 years, with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, following progression on treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
An accelerated approval has been granted by the FDA for the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of both adult and pediatric patients, over the age of 12 years, with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC), following progression on treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
The approval is based on findings from the phase II CheckMate-142 trial. In this study, a cohort of 119 patients with MSI-H or dMMR mCRC were treated with the combination. Eighty-two patients had a prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The overall response rate (ORR) was 46% (95% CI, 35%-58%) among these patients.1Among the 38 responders, there were 3 complete responses (CRs) and 35 partial responses (PRs), while median duration of response (DOR) was not reached (range, 1.9-23.2+ months). Overall, 89% of the responders had a response of ≥6 months, with 21% having a response ≥12 months.
ORR was 49% (95% CI, 39%-58%) among all patients in the study. Among the 58 responders, there were 5 CRs and 53 PRs. The median DOR was not reached (range, 1.9-23.2+ months), with 83% of responders having a response ≥6 months and 19% having a response ≥12 months. Fifty-one of the 58 responses were ongoing at the data cutoff.
“Metastatic colorectal cancers with dMMR or MSI-H biomarkers can be difficult to treat and some patients may need additional options,” Heinz-Josef Lenz, MD, L. Terrence Lanni Chair in Gastrointestinal Cancer Research, Keck School of Medicine of University of Southern California and principal investigator of the study at USC Norris Comprehensive Cancer Center, said in a statement.
“The FDA’s approval of an I-O/I-O combination provides us with an encouraging approach to address this challenging disease in patients who have progressed following treatment with three standard chemotherapy options,” added Lenz.
Data from the trial were published in theJournal of Clinical Oncologyin March 2018.2The 119 patients in the combination cohort were treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab at 3 mg/kg every 2 weeks. The median patient age was 58 (range, 21-88), 59% of patients were male, and 92% were white. Forty-five percent of patients had an ECOG performance status of 0, with the remaining 55% having a status of 1.
At diagnosis, the disease stages were II (12%), III (44%), and IV (45%). Fifty-five percent had a tumor in the right colon and 25% had a tumor in the left and sigmoid colon. Mutational status includedBRAF/KRASwild-type (26%),BRAF-positive (24%),KRAS-positive (37%), and unknown (13%).
Of the 119 treated patients, 76% had ≥2 prior lines of therapy. The most common prior chemotherapies were fluoropyrimidine (99%), oxaliplatin (93%), and irinotecan (73%). Sixty-three percent continue on treatment; disease progression (19%) was the main reason for discontinuation, followed by toxicity related to a study drug (13%). At baseline, 22% of patients had a PD-L1 expression level ≥1%, 55% had a level <1%, and the level was unknown for 24%. Twenty-nine percent of patients had a known clinical history of Lynch syndrome.
Forty-one percent of patients experienced a treatment-related adverse event (TRAE). The most common grade 1/2 TRAEs were 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 occurred in 32% of patients. Grade 3 TRAEs specifically included increased AST (8%), increased ALT (7%), diarrhea (2%), fatigue (2%), pruritus (2%), rash (2%), hypothyroidism (1%), and nausea (1%).
Quality of life (QOL) was assessed by the EORTC QLQ-C30 global health status/QoL and the EQ-5D visual analog scale. Statistically significant and clinically meaningful improvements were achieved in key QOL measures, and improvements were maintained for extended periods. No new safety signals or treatment-related deaths were observed.
The accelerated approval of this combination is contingent upon results from a confirmatory trial.
In August 2017, the FDA granted an accelerated approval 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.