Phase III study: Pembrolizumab demonstrates superior survival, progression free survival and overall response rate compared to Ipilimumab

MSD (known as Merck & Co Inc. in the United States and Canada) has announced results from the randomised, pivotal Phase 3 study, KEYNOTE-006 which compared pembrolizumab to ipilimumab in patients with advanced melanoma. In the study, pembrolizumab was statistically superior to ipilimumab for progression-free survival (PFS), overall survival (OS), and overall response rate (ORR).¹

The results were presented today at the American Association for Cancer Research (AACR) Annual Meeting by Dr. Antoni Ribas of Jonsson Comprehensive Cancer Center, University of California, Los Angeles (abstract # CT101), included in the AACR press program, and were also published online in the New England Journal of Medicine.¹

Dr James Larkin, Consultant Medical Oncologist at The Royal Marsden said, "This is an important set of results because it is the first time that one of the newer anti-PD1 immunotherapy drugs, in this case pembrolizumab, has been compared head to head with an established immunotherapy drug. This trial has shown significant prolongation of disease control and increased survival for those treated with pembrolizumab in comparison with ipilimumab, so is another major step forward for patients with advanced melanoma."

KEYNOTE-006 Results in the Treatment of Advanced Melanoma

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase 3 study (ClinicalTrials.gov, NCT01866319) of 834 patients from 16 countries with unresectable stage III or IV advanced melanoma with no more than one prior systemic therapy. Patients received pembrolizumab 10 mg/kg every two weeks (n=279), pembrolizumab 10 mg/kg every three weeks (n=277), or four cycles of ipilimumab 3 mg/kg every three weeks (n=278).1 The co-primary endpoints were PFS and OS; secondary endpoints were ORR, duration of response, and safety. Tumour response was assessed at week 12, then every six weeks thereafter by independent central review per RECIST 1.1. This first presentation of data from KEYNOTE-006 is based on interim analyses conducted for PFS with a data cut-off of September 3, 2014 (median follow-up, 7.9 months) and for OS with a data cut off of March 3, 2015 (median follow-up, 13.8 months).¹

Data Showed pembrolizumab was Statistically Superior to Ipilimumab for PFS, OS and ORR

The median PFS for pembrolizumab was 5.5 months (95% CI, 3.4 - 6.9 [2 week regimen]) and 4.1 months (95% CI, 2.9 - 6.9 [3 week regimen]) compared to 2.8 months for ipilimumab (95% CI, 2.8 - 2.9)). The hazard ratios for disease progression for pembrolizumab versus ipilimumab were 0.58 (95% CI, 0.46 to 0.72; P<0.001) for the 2-week regimen and 0.58 (95% CI, 0.47 to 0.72;P<0.001) for the 3-week regimen. The estimated 6-month progression-free survival 47.3% for patients receiving pembrolizumab every 2 weeks, 46.4% for those receiving pembrolizumab every 3 weeks, and 26.5% for those receivingipilimumab.1 One-year OS for pembrolizumab was 74.1 percent (2-week group) and 68.4 percent (3 week regimen) compared to 58.2 percent for ipilimumab (HR 0.63 [95% CI, 0.47-0.83, P=0.00052] for the 2 week regimen and 0.69 [95% CI, 0.52-0.90, P=0.00358] for the 3 week regimen as compared with ipilimumab). At the time of analysis, median overall survival was not reached in any treatment group.¹

Response rates were 33.7% for pembrolizumab every 2 weeks (P<0.001 vs. ipilimumab), 32.9% for pembrolizumab every 3 weeks (P<0.001), and 11.9% for ipilimumab; complete response rates were 5.0 percent, 6.1 percent, and 1.4 percent, respectively. Responses were ongoing in 89.4 percent (2 week regimen) and 96.7 percent (3 week regimen) of pembrolizumab -treated patients and in 87.9 percent of ipilimumab-treated patients.1 Median duration of response was not reached for pembrolizumab 3-week group (42+ to 246+) and ipilimumab (33+ to 239+). Median duration of response for the 2 week regimen was not reached and add the ranges.¹

The efficacy and safety profiles were similar between the two pembrolizumab schedules evaluated in the study. Two previous studies, KEYNOTE-001 and KEYNOTE-002, demonstrated that the efficacy and safety were similar among the pembrolizumab doses and schedules evaluated; 10 mg/kg every two weeks, 10 mg/kg every three weeks, and 2 mg/kg every three weeks.¹

Safety Findings from KEYNOTE-006

The safety profile of pembrolizumab in this study was generally consistent with that reported previously in patients with advanced melanoma.2,3 The most common treatment-related adverse events of any grade occurring in the pembrolizumab groups were fatigue, diarrhoea, rash and pruritis (20.9%, 16.9%, 14.7% and 14.4% respectively for the 2 week regimen and 19.1%, 14.4%,

13.4% and 14.1% for the 3 week regimen). For ipilimumab, the most frequent treatment-related adverse events were pruritis, diarrhoea, fatigue and rash (25.4%, 22.7%, 15.2% and 14.5% respectively).1 Grade 3 to 5 treatment-related adverse events occurred in 13.3 percent (2 week regimen) and 10.1 percent (3 week regimen) of patients treated with pembrolizumab and in 19.9 percent for ipilimumab.1 Discontinuation due to treatment-related adverse events was less frequent with pembrolizumab (2 week regimen and 3 week regimen) than with ipilimumab (4.0%, 6.9%, and 9.4%, respectively). One death in the ipilimumab group was attributed to study treatment.¹

Treatment-related adverse events of an autoimmune or immune-related nature most frequently observed with pembrolizumab (2 week and 3 week regimen) were hypothyroidism (10.1% and 8.7%) and hyperthyroidism (6.5% and 3.2%). With ipilimumab, colitis occurred in 8.2 percent of patients.1 Grade 3 to 4 inflammatory or immune-mediated treatment events reported in more than 1 percent of pembrolizumab -treated patients (2 week and 3 week regimen) were colitis (1.4% and 2.5%) and hepatitis (1.1% and 1.8%), and in ipilimumab-treated patients were colitis (7.0%) and hypophysitis (1.6%).¹

About pembrolizumab

Pembrolizumab works by making the cancer cell 'visible' to the immune system so it can be attacked by the body's natural defence mechanisms.² Clinical trials have shown improvement in the prognosis for patients with advanced melanoma treated with pembrolizumab, and for those patients who respond to treatment the responses are durable.³

Pembrolizumab is being investigated in more than 30 types of cancers, involving an estimated 8,000 patients worldwide.

About KEYNOTE-006

KEYNOTE-006 is a multicentre, international, randomised, controlled, three-arm, phase III study evaluating the safety and efficacy of two dosing schedules of pembrolizumab compared to ipilimumab in patients with unresectable stage III or IV advanced melanoma who have received no more than one prior systemic therapy. The study randomised 834 patients to receive pembrolizumab 10 mg/kg every three weeks, pembrolizumab 10 mg/kg every two weeks, or four cycles of ipilimumab 3 mg/kg every three weeks. The co-primary endpoints of the study were progression-free survival (PFS) and overall survival (OS); secondary endpoints were overall response rate (ORR), duration of response, and safety, with an exploratory analysis for health-related quality of life (QoL). Tumour response was assessed at week 12, then every 6 weeks thereafter per RECIST 1.1 (Response Evaluation Criteria in Solid Tumours) by independent, central, blinded radiographic review and investigator-assessed, immune-related response criteria. The trial was stopped early in March 2015 based on the recommendation of the study's independent Data Monitoring Committee.