By Will Boggs MD
NEW YORK (Reuters Health) - 30/8/2019
Nivolumab plus ipilimumab is more effective than sunitinib as first-line treatment for patients with advanced renal-cell carcinoma (RCC), according to an extended follow-up of the ongoing CheckMate 214 trial.
"The overall survival benefit was maintained for nivolumab/ipilimumab over longer follow-up in intermediate-/poor-risk patients and the entire intent-to-treat population," said Dr. Robert J. Motzer from Memorial Sloan Kettering Cancer Center, in New York City.
"With longer follow-up, progression-free survival is looking better for nivolumab/ipilimumab," he told Reuters Health by email. "The complete response proportion and durability of response are impressive."
The immunotherapy combination of the PD-1 immune-checkpoint inhibitor antibody nivolumab and the anti-CTLA-4 antibody ipilimumab provided longer overall survival and a higher proportion of patients achieving an objective response, compared with sunitinib, in earlier analyses of the CheckMate 214 phase 3 trial.
In the current study, Dr. Motzer and colleagues assessed the efficacy and safety of this combination (versus sunitinib) over a median follow-up of 32.4 months in 847 patients with intermediate- or poor-risk RCC and 249 patients with favorable-risk RCC.
At follow-up, 43% of patients in the intermediate-/poor-risk nivolumab/ipilimumab group had died, versus 54% in the sunitinib group. Median overall survival was not reached with the combination and was 26.6 months with sunitinib (hazard ratio, 0.66; P<0.0001). The 30-month overall survival was 60% versus 47%, respectively.
In the favorable-risk group, 30-month overall survival was not significantly different between the nivolumab/ipilimumab group (80%) and the sunitinib group (85%), the researchers report in The Lancet Oncology, online August 16.
Among intermediate/poor-risk patients, the progression-free survival (PFS) curves for the two treatment groups began to separate after around nine months, such that the 30-month PFS probability was higher with nivolumab/ipilimumab (28%) than with sunitinib (12%).
PFS among favorable-risk patients did not differ significantly between the treatment groups.
Significant independent baseline predictors of worse overall survival included lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions.
Treatment-related adverse events leading to discontinuation were more common in the nivolumab/ipilimumab group (22%) than in the sunitinib group (12%). But potentially immune-mediated adverse events occurred with similar frequency within 30 days of the last dose in both groups (81% vs. 83%, respectively).
There were no new safety signals at longer follow-up.
"Immune-related side effects are relatively common, particularly during the induction part, when both nivolumab and ipilimumab are given, but in most instances they can be successfully managed with steroids," Dr. Motzer said. "The treatment program avoids chronic toxicities associated with tyrosine kinase inhibitors, like sunitinib and axitinib, including hypertension and skin toxicity (hand-foot skin reaction)."
"The quality of life measures showed an advantage for nivolumab/ipilimumab over sunitinib," he said.
"The FDA approval of the three combinations, nivolumab plus ipilimumab (in 2018), avelumab plus axitinib (in 2019), and pembrolizumab plus axitinib (in 2019), opened the door to a shift from monotherapy towards combination therapy for first-line treatment for patients with advanced renal cell carcinoma," write Dr. Giuseppe Procopio and colleagues at Fondazione IRCSS Istituto Nazionale dei Tumori di Milano, in Milan, Italy, in a linked editorial.
"Practical caveats remain unsolved," they note, "including the optimal duration of treatment exposure, the need to continue treatment with both drugs until progressive disease, the timing of the assessment of response, and the criteria used to improve the identification of responses and disease status."
"The evolution of this dynamic scenario could change after the release of results of two other clinical trials (CLEAR and CheckMate 9ER), which are testing other combinations, such as lenvatinib plus pembrolizumab and lenvatinib plus everolimus, and nivolumab plus cabozantinib, respectively," the editorial concludes.
Dr. Manuela Schmidinger of the Medical University Vienna, who has studied various aspects of advanced RCC and its treatment, told Reuters Health by email, "The results represent a breakthrough in RCC treatment: never before has the former standard of care sunitinib been beaten by another agent. Moreover, no other agent has ever proven superiority in terms of overall survival."
"Chances for patients with metastatic RCC have never been better than today," she said. "We see long-term responders and sometimes quite dramatic remissions."
"Future research needs to focus on predictive factors to identify the best treatment for the individual patient," said Dr. Schmidinger, who was not involved in the treatment.
Bristol-Myers Squibb and ONO Pharmaceutical funded the study, employed two of the authors and had various relationships with several others, including Dr. Motzer and three of the editorialists.
Lancet Oncol 2019.
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