Safety, Antitumor Activity of Modified Ipilimumab/Nivolumab Regimen Reinforces Approved Dosing in RCC

Johanna Bendell, MD

Investigators of the CheckMate 920 trial (NCT02982954) found no differences in safety signals or responses with modified dosing of nivolumab (Opdivo) and ipilimumab (Yervoy) compared with the standard dose in patients with advanced renal cell carcinoma (aRCC) treated in the frontline.¹

CheckMate 920 is a phase 3b/4, nonrandomized, community-based trial. When compared against results from the CheckMate 214 study (NCT02231749),² a randomized phase 3 trial conducted in an academic setting that confirmed the long-term efficacy and tolerability of the combination in patients with intermediate- or poor-risk aRCC in the first line, no significant differences were observed in efficacy despite the trials employing different dosing strategies.

CheckMate 920, cohort 1 examined nivolumab 6 mg/kg plus ipilimumab 1 mg/kg every 8 weeks alternating with 480 mg nivolumab every 8 weeks, with administration staggered every 4 weeks, in patients with clear cell aRCC. The standard dose from CheckMate 214 was 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses then nivolumab alone every 2 weeks.

“Antitumor responses showed no evidence of improvement relative to those with standard combination dosing in CheckMate 214 after similar follow-up,” Johanna Bendell, MD, lead study author, said in her presentation at the International Kidney Cancer Symposium 2020.

The primary end point of CheckMate 920 looked at the incidence of high-grade immune-mediated adverse events (AEs) that occurred in more than 1 patient with aRCC as of the last dose of therapy. Patients in this trial had a median age of 64.5 years and 81.1% were male. Most fell into the intermediate-risk group (61.3%) and all patients had predominant clear cell histology with a baseline Karnofsky performance status of 70% or more. No patients were continuing in the treatment period, mostly due to disease progression (58.5%) or study drug toxicity (18.9%).

In the 106 evaluable patients, the most common immune-mediated AEs of any grade and grade 3/4, respectively, were rash (23.6% and 4.7%), diarrhea/colitis (14.2% and 7.5%), adrenal insufficiency (6.6% and 1.9%), and hepatitis (5.7% and 2.8%). There were no grade 5 immune-mediated AEs reported. In 36.8% of patients, corticosteroid treatment of 40 mg or more of prednisone or equivalent was initiated to manage these AEs. Of those receiving corticosteroids, 24.5% were treated for 14 days or more and 7.5% were treated for 30 days or more.

Grade 3/4 treatment-related AEs (TRAEs) occurred in 43.4% of patients. The most common any-grade TRAEs were fatigue and diarrhea at 46.2% and 29.2%, respectively. The most common grade 3/4 TRAE was lipase increase at 14.2%. There were no grade 5 TRAEs reported.

Any-grade AEs leading to discontinuation were observed in 28.3% of patients and grade 3/4 events in 19.8%. Colitis, malignant neoplasm progression, pneumonitis, and diarrhea were the most common any-grade AEs, all occurring in 3.8% of patients. The most common grade 3/4 AEs leading to discontinuation were colitis (3.8%) and malignant neoplasm progression (3.8%).

Secondary end points of the trial included progression-free survival (PFS), objective response rate (ORR) by RECIST 1.1, time to response, and duration of response. Overall survival (OS) was an exploratory end point.

In the 96 response-evaluable patients, the investigator-assessed ORR was 34.4% (95% CI; 25.0%-44.8%), including 5 complete responses, 28 partial responses; there were 28 patients with stable disease, 31 with progressive disease, and 4 had indeterminable response. Bendall pointed out that the ORR in CheckMate 214 was similar, at 41%. The median time to response was 2.9 months (range, 2.5-36.9), with a median duration of response of 9.2 months.

There was a median PFS of 4.8 months (95% CI, 3.0-8.3) per investigator assessment. The rates of PFS at 12 and 24 months were 28.7% and 15.9%, respectively. Median OS was not reached (95% CI, 24.8 to not evaluable) and the rates of OS at 12 and 24 months were 78.1% and 62.2%, respectively. In CheckMate 214, the median PFS was 9.7 months and the median OS was also not reached.

“With similar follow-up, efficacy measures with modified nivolumab plus ipilimumab dosing in CheckMate 920 showed no evidence of improvement relative to those seen with standard combination dosing in CheckMate 214,” said Bendell, who is chief development officer and director of the Gastrointestinal Cancer Research Program at Sarah Cannon in Nashville, Tennessee, during her presentation of the data.

Bendall concluded that although these results favor the standard dose of the immunotherapy combination, caution must be taken when cross comparing trials.

“CheckMate 920 and CheckMate 214 differ in their design and setting, and direct comparisons cannot be made,” Bendall said. “The antitumor activity observed in CheckMate 920 therefore reinforces the use of the standard combination dosing employed in the pivotal CheckMate 214 trial and currently recommended for aRCC.”

_REFERENCES:

_{1. Bendell J, Hutson T, Gordan L, et al. Nivolumab 6 mg/kg plus ipilimumab 1 mg/kg (N6I1) every 8 weeks (Q8W) alternating with nivolumab 480 mg Q8W for first-line (1L) advanced renal cell carcinoma (aRCC): safety and efficacy from CheckMate 920. Presented at: International Kidney Cancer Symposium 2020; November 6-7, 2020; Virtual.}

_{2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126}