Pooled analysis confirms clinical benefit

Source: Healio, April 2016

Pembrolizumab demonstrated favorable long-term safety and antitumor activity in patients with advanced-stage melanoma, according to a pooled analysis of data from the KEYNOTE-001 study.

Pembrolizumab (Keytruda, Merck) is an anti-program death protein-1 antibody that is approved for patients with unresectable or metastatic melanoma who progressed after treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) and a BRAF inhibitor if BRAF V600 mutated, based on data from the randomized cohort of KEYNOTE-001.

The KEYNOTE-001 trial included many cohorts of patients with melanoma, non–small cell lung cancer and other solid tumors.

“Collectively, these data suggest that the majority of patients with melanoma treated with pembrolizumab will experience lasting objective responses," Antoni Ribas, MD, PhD, professor of medicine, surgery, and molecular and medical pharmacology at University of California, Los Angeles and director of the tumor immunology program at Jonsson Comprehensive Cancer Center, and colleagues wrote.

In the current analysis, Ribas and colleagues sought to characterize the long-term antitumor activity and safety associated with pembrolizumab using data pooled from 655 patients (median age, 61 years; 62% men) with advanced melanoma in eight cohorts of the KEYNOTE-001 trial.

These patients were included in nonrandomized cohorts (ipilimumab naive, n = 87; previous ipilimumab treatment, n = 48) and randomized cohorts (ipilimumab naive, n = 226; previous ipilimumab treatment, n = 294). In total, 152 patients were treatment naive.

Patients were treated with one of three exposure protocols: 10mg/kg every 2 weeks, 10 mg/kg every 3 weeks or 2 mg/kg every 3 weeks.

Confirmed objective response served as the primary endpoint. PFS, OS, toxicity and duration of response served as secondary endpoints.

Overall median follow-up was 15 months (range, 8-29), and median follow-up for analyses of antitumor activity was 21 months (range, 14-35).

The final analysis set for the primary analysis of objective response rate comprised 581 patients with measurable disease at baseline.

The objective response rate was 33% (95% CI, 30-37), which included 60 of 133 patients (45%, 95% CI, 36-54) who had not been exposed to ipilimumab. Eight percent (95% CI, 6-11) of patients achieved a complete response and 51% (95% CI, 47-55) achieved disease control.

Seventy-four percent of responses were ongoing at the time of data cutoff in October 2014, and 44% of patients had responses for at least 1 year.

The 12-month PFS rate was 35% (95% CI, 44-53) for the entire population but was 52% (95% CI, 43-60) for treatment-naive patients.

Median OS in the total population was 23 months (95% CI, 20-29). Sixty-six percent (95% CI, 62-69) of patients achieved 12-month OS and 49% (95 CI, 44-53) achieved 24-month OS.

Among treatment-naive patients, median OS was 31 months (95% CI, 24 to not reached), 12-month OS rate was 73% (95% CI, 65-79) and 24-month OS rate was 60% (95% CI, 51-68).

Fourteen percent of patients (n = 92) from the total pooled cohort experienced one or more treatment-related grade 3 or 4 adverse event, the most common of which was fatigue (1.8%).

Four percent (n = 27) of patients discontinued treatment because of a treatment-related adverse event and 9% (n = 59) experienced serious adverse events, the most common of which were colitis (1%), pyrexia (1%) and pneumonitis (1%).

There were no treatment-related deaths reported.

Ribas and colleagues acknowledged that the multi-cohort nature of the population may limit these data. The initial cohorts may have been biased to patients with a higher likelihood of response, whereas later cohorts — which enrolled after the therapy demonstrated efficacy — may have included patients with worse prognostic factors.

Still, these results add to the literature regarding the promise of checkpoint blockades for patients with metastatic melanoma, Shailender Bhatia, MD, and John A. Thompson, MD, both of University of Washington and Fred Hutchinson Cancer Research Center, wrote in an accompanying editorial.

“Although most patients may not experience the ideal outcome of durable complete remission with current regimens, these immune checkpoint-blocking agents provide hope for patients and represent a solid foundation for future research," Bhatia and Thompson wrote. “And as any immunotherapist will enthusiastically declare, this is just the beginning." – by Nick Andrews

Disclosure : Ribas reports stock ownership in Acteris, Arcus, CytomX, Compugen, FLX Bio and Kite Pharma. He also reports consultant roles with Amgen, Genentech, GlaxoSmithKline, Merck, Novartis, Roche and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures. Bhatia reports grants paid to his institution from Abraxis, Amgen, Bionomics, Bristol-Myers Squibb, EMD-Serono, Immune Design, Immunogen, Merck and NantKwest. Thompson reports grants paid to his institution from Merck.