Details of the new results
Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.
So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.
Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.
They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.
Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.
The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.
After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.
Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.
Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.
While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.
During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.
In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.
The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.
Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.
Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.
Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”
As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.
He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.
Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”
There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.
The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.