Pembrolizumab (Keytruda) induced a median overall survival (OS) of 32.7 months versus 15.9 months for ipilimumab (Yervoy) in patients with unresectable stage III-IV melanoma, according to 4-year survival results from the KEYNOTE-006 trial presented at the 2018 ASCO Annual Meeting.
Georgina V. Long, PhD, MBBS
Pembrolizumab (Keytruda) induced a median overall survival (OS) of 32.7 months versus 15.9 months for ipilimumab (Yervoy) in patients with unresectable stage III-IV melanoma, according to 4-year survival results from the KEYNOTE-006 trial presented at the 2018 ASCO Annual Meeting.1
The HR for OS was 0.73 (95% CI, 0.61-0.89). The 4-year landmark OS was 41.7% for pembrolizumab compared with 34.1% for ipilimumab.
Georgina V. Long, PhD, MBBS, conjoint medical director of Melanoma Institute Australia (MIA), and chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, presented the findings. She added that 86% of patients who completed 2 years of pembrolizumab treatment (n = 103) were alive and progression-free at a median follow-up of 20.3 months.
“Pembrolizumab had already established superior survival outcomes versus ipilimumab in advanced melanoma patients, and this is further reinforced with 4 years of data in KEYNOTE-006,” she said in a statement. “Importantly, we’re now seeing ongoing efficacy for patients who complete the protocol-specified 2 years of pembrolizumab treatment, as well as additional antitumor activity for the patients who progress after a first course of treatment and complete a second course of treatment.”
In previous results, the 2-year OS rate was 55% with pembrolizumab versus 43% for those in the ipilimumab arm. The median OS was not reached with pembrolizumab compared with 16 months for ipilumumab.2
In KEYNOTE-006 (NCT01866319), 556 patients were assigned to 10 mg/kg of pembrolizumab for 2 years or 4 doses of 3 mg/kg of ipilimumab every 3 weeks (n = 278). Patients who progressed after achieving and maintaining a response to pembrolizumab were allowed to receive a second course of the anti-PDL1 monoclonal antibody for up to 1 year.
The median patient age in both treatment groups was 62 and men made up about 59% of both cohorts. Thirty-five percent of patients in the pembrolizumab arm were positive forBRAFV600 mutations versus 38% in the ipilimumab group. About one-third of patients in both groups had received prior therapy and roughly 80% in both groups were PD-L1 positive.
Patients were allowed no more than 1 previous therapy and those who had received CTLA­-4, PD-1, or PD-L1 inhibitors were excluded. Eligible patients had an ECOG performance score of 0 to 1, knownBRAFstatus, no central nervous system metastases, and no serious autoimmune disease. Those withBRAFmutations had to have receivedBRAF-directed inhibitor therapy.
Patients continued on trial until progression, intolerability, or withdrawal.
At a median follow-up of 45.9 months, the median OS was 38.7 months versus 17.1 months for treatment-naïve patients (HR, 0.73; 95% CI, 0.57-0.93). The 4-year landmark OS also favored pembrolizumab (44.3% vs 36.4%).
The median progression-free survival (PFS) for all patients was 8.3 months for pembrolizumab versus 3.3 months with ipilimumab (HR, 0.56; 95% CI, 0.47-0.67). For treatment-naïve patients, the median PFS also favored the pembrolizumab arm (11.2 vs 3.7; HR, 0.54; 95% CI, 0.43-0.67).
Pembrolizumab showed a clear advantage in the 3-year landmark PFS rate, both overall (31.1% vs 13.3%) and in treatment-naïve patients (36.2% vs 15.9%).
The overall response rate (ORR) was 42% in the pembrolizumab arm with complete response (CR) in 14% compared with 17% and 3%, respectively, with ipilimumab. The ORR was 47% with 17% achieving CR for treatment-naïve patients assigned to pembrolizumab versus 17% and 3%, respectively, with ipilimumab.
The 3-year landmark duration of response was 65.6% versus 58.7% in favor of pembrolizumab. In treatment-naïve patients, the landmark duration of response was 68.9% for pembrolizumab and 68.3% for ipilimumab. The median duration of response was not reached in either treatment group.
“It's important to note that there were many more responders with pembrolizumab, but the duration of response was similar for pembrolizumab and ipilimumab,” Long said during her presentation. “For treatment-naïve patients, pembrolizumab and ipilimumab have a similar duration of response. Again, noting that there were many more responders in the pembrolizumab arm.”
Among patients who completed 2 years of pembrolizumab, 28 had CR, 65 had partial response and 10 had stable disease. Response is ongoing in 56 patients who had partial response.
“Within those with complete response, 26 patients had an ongoing response and 2 had confirmed progressive disease,” Long said. “The 18-month progression-free survival from completion of pembrolizumab was 95.8% for those with the complete response, 91.3% for those with partial response, and 66.7% for those with stable disease.”
Of the 19 patients who had progression 2 years after completing treatment, 11 discontinued on the study and 8 received a second course of pembrolizumab. Of those 8, Long said 4 have ongoing responses and 3 have stable disease. Only 1 patient progressed.
Four patients had grade 1 adverse events (AEs) during the second course and 1 patient experienced grade 1 rash and grade 2 thyroiditis. Three patients experienced no AEs.
“Retreatment with pembrolizumab upon disease progression can provide additional antitumor activity and acceptable safety,” said Long.