Clinical benefit with immune checkpoint inhibitors in advanced melanoma
Data from trials presented at the European Society for Medical Oncology (ESMO) Congress 2016 showed clinically significant overall survival (OS) benefit with CTLA-4 and PD-1 inhibitors in patients with advanced melanoma.
“CA184-169 is the first phase III study directly comparing the benefit-risk profile of ipilimumab 10 mg/kg vs 3 mg/kg in patients [n=727] with untreated or previously treated unresectable stage III/IV melanoma who had not received prior BRAF or immune checkpoint inhibitors. Results showed improved OS with higher-dose ipilimumab,” reported lead investigator Dr Paolo Ascierto of the Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. [ESMO 2016, abstract 1106O]
At a minimum follow-up of 43 months, median OS (primary endpoint) was 15.7 months in the 10 mg/kg arm vs 11.5 months in the 3 mg/kg arm (hazard ratio [HR], 0.84; p=0.04). However, patients who received higher-dose ipilimumab experienced higher rates of treatment-related grade 3–5 adverse events (AEs) (34.3 vs 18.5 percent), AEs leading to discontinuation, and treatment- and immune-related AEs.
“Although the treatment landscape has evolved for first-line melanoma treatment, the clinical utility of ipilimumab in refractory patients warrants further evaluation,” Ascierto concluded.
“These results suggest that there is more to gain from CTLA-4 blockade at 3 mg/kg [than 10 mg/kg]. However, first-line ipilimumab is no longer a standard in treating melanoma and has been replaced by PD-1 or PD-1/CTLA-4 blockade,” said discussant Dr Oliver Michelin of the Swiss Institute of Bioinformatics, Lausanne, Switzerland.
The KEYNOTE-002 trial demonstrated superior progression-free survival with the PD-1 inhibitor pembrolizumab vs investigator-choice chemotherapy in patients with advanced, ipilimumab-refractory melanoma. However, OS was not significant different between the two arms. [ESMO 2016, abstract 1107O]
“Nevertheless, PD-1 inhibitors are effective and well tolerated in first-, second- and subsequent lines of treatment, and are therefore an important component of our armament,” said Michelin. “Results from the CA184-169 study also suggest that we should keep a close eye on CTLA-4 blockade and long-term benefit when designing the next-generation combination therapy.”