Hans Hammers, MD, PhD
Patients with metastatic renal cell carcinoma had an objective response rate (ORR) of 40% and a 2-year overall survival (OS) rate of nearly 70% with the immune checkpoint combination of ipilimumab (Yervoy) and nivolumab (Opdivo), in phase I results from CheckMate-016 now published online in the Journal of Clinical Oncology.
Investigators observed a 2-year OS rate of 67.3% for patients assigned to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1) and 69.6% for those assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3). ORR was 40.4% in both groups.
Half of patients in the study had metastases that progressed on previous therapy.
“For this group of patients, these are very significant results,” lead author Hans Hammers, MD, PhD, co-leader of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center, said in a press release.
“Both nivolumab plus ipilimumab combination regimens led to favorable OS rates at 2 years for the entire study population, which included both previously treated and treatment-naïve patients,” the investigators wrote. “The preliminary efficacy results of the N1I3 and N3I1 arms along with the encouraging safety results in patients treated with the N3I1 combination regimen support the additional clinical investigation of N3I1 in a phase III study for patients with [metastatic renal cell carcinoma].”
A third group of 6 patients assigned to nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) were censored at the time of analysis, primarily due to progression or dose-limiting toxicity.
A total of 47 patients were assigned to both groups. Twenty-five patients (53.2%) in the N3I1 group and 21 (44.7%) assigned to N1I3 were treatment-naïve. In both groups, patients were assigned to therapy every 3 weeks for four doses, followed by 3 mg/kg nivolumab monotherapy every 2 weeks until progression or toxicity.
At data cutoff, March 16, 2016, median follow-up was 22.3 months for both arms, and minimum follow-up was 22 months. Forty-six (97.9%) patients in the N3I1 arm and 42 (89.4%) in the N1I3 arm received ≥90% of the planned nivolumab and ipilimumab dose intensity during the induction phase.
Although the efficacy outcomes were similar between the two treatment groups, investigators said safety results favored N3I1.
All patients experienced an adverse events (AE) of any grade, and 71.3% experienced a grade 3/4 AE. Investigators recorded treatment-related AEs in 93.6% of all patients, and 50.0% of patients experienced treatment-related AEs classified as grade 3/4.
“Relative to the other arms, patients who received the N3I1 combination regimen had lower rates of treatment-related AEs (all, and grade 3 or 4), lower rates of SAEs, and lower rates of select treatment-related AEs in a majority of categories,” they wrote. “Furthermore, fewer patients in the N3I1 arm discontinued as a result of a treatment-related AE, and fewer patients required an immune-modulating medication to manage AEs.”
In the N3I1 arm, 43 patients (91.5%) had a treatment-related AEs of any grade, and 18 (38.3%) experienced grade 3 or 4 treatment-related AEs. Among patients in the N1I3 arm, 45 (95.7%) experienced treatment-related AEs, with 29 (61.7%) reported grade 3/4 treatment-related AEs.
In the N3I1 arm, 11 patients (23.4%) had a treatment-related serious AE, with nine (19.1%) experiencing a grade 3/4 treatment-related AE. The most common grade 3/4 treatment-related AE were diarrhea and pyrexia.
Sixteen patients (34%) in the N1I3 reported grade 3/4 treatment-related AEs, including 6 with colitis (12.8%), 5 with diarrhea (10.6%), 4 with elevated alanine aminotransferase (8.5%), and 4 with elevated aspartate aminotransferase (8.5%). All treatment-related serious AEs in the N1I3 arm were grade 3 or 4, except for 1 patient with diarrhea.
There were no grade 5 treatment-related AEs observed in either arm.
Treatment-related AEs of any grade that led to discontinuation occurred in five (10.6%) patients in the N3I1 arm and 13 (27.7%) in the N1I3 arms.
Twenty-nine (61.7%) patients in the N3I1 arm and 35 (74.5%) in the N1I3 arm had at least one nivolumab dose delay. Five patients (10.6%) in the N3I1 arm experienced hematologic toxicities that required a dose delay compared with eight (17.0%) in the N1I3 arms.
Of the 12 patients in the N3I1 group who experienced at least one ipilimumab dose delay, 3 (6.4%) were due to hematologic toxicity. Fourteen (29.8%) patients in the N1I3 arm had one or more ipilimumab dose delays, 2 (4.3%) caused by hematologic toxicity.
Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study [published online July 5, 2017]. J Clin Oncol. doi: 10.1200/JCO.2016.72.1985.