By: Arnold DuBell, Ph.D., M.B.A, Consultant, Clinical and Scientific Assessment, Kantar Health and Greg Wolfe, Ph.D., Senior Consultant, Clinical and Scientific Assessment, Kantar Health
Recent progress in the development of novel therapeutic agents to combat melanoma has been tremendous. Immune checkpoint inhibition and targeted inhibition of BRAF and MEK are two therapeutic approaches that have significantly improved survival for patients with advanced melanoma. Since 2011, the Food and Drug Administration (FDA) has approved three checkpoint inhibitors: starting with the CTLA4 inhibitor Yervoy® (ipilimumab, Bristol-Myers Squibb), with subsequent approvals of PD-1 inhibitors Keytruda® (pembrolizumab, Merck & Co.) and Opdivo® (nivolumab, Ono/Bristol-Myers Squibb).
Immune checkpoints play critical roles in balancing co-stimulatory and co-inhibitory signals that regulate human self-tolerance and control the amplitude and duration of T-cell responses. PD-1 is a key immune checkpoint receptor expressed on activated T-cells. Binding of PD-1 to its ligand (PD-L1) results in suppression of the immune response, and tumor cells can manipulate this critical pathway to elude attack by tumor-infiltrating T-cells.
Opdivo holds the title of the first PD-1 inhibitor to gain global regulatory approval when it was approved in Japan in July 2014 for melanoma. In September 2014, Keytruda became the first PD-1 inhibitor to gain approval in the U.S. when the FDA awarded Keytruda accelerated approval for treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. However, the race to the U.S. market was tight as Opdivo received accelerated approval from the FDA in December 2014 for a similar indication. Although both Keytruda and Opdivo were approved for previously treated melanoma, the National Comprehensive Cancer Network (NCCN) was sufficiently convinced by these agents’ activity in pretreated patients that the latest guidelines (v3.2015) recommend consideration of use of both Opdivo and Keytruda instead of Yervoy in the first-line setting. With the battle now shifting to treatment-naïve advanced melanoma, these agents need to prove their superiority to Yervoy, which has ruled as the only approved checkpoint inhibitor in the U.S. since 2011.
Results from the Phase III KEYNOTE-006 trial (NCT01866319) were presented Sunday at the AACR (American Association of Cancer Research) Annual Meeting in Philadelphia.1 Merck initiated this pivotal, three-arm trial in August 2013 to evaluate the safety and efficacy of two dosing schedules of Keytruda compared to Yervoy for the treatment of Yervoy-naïve patients with unresectable or metastatic melanoma. In this study 834 unresectable, Stage III/IV patients were randomized (1:1:1) to receive Keytruda (10 mg IV) either once every two weeks (Q2W) or once every three weeks (Q3W) for up to two years or Yervoy (3 mg/kg IV) once Q3W for a total of four doses (the approved Yervoy dose regimen). Eligible patients may have received one or fewer prior therapy excluding anti-CTLA4, PD-1 and PD-L1 agents; one-third of enrolled patients had received prior therapy, typically chemotherapy or a BRAF inhibitor (one-third of enrolled patients had BRAF mutations). Progression-free survival (PFS) and overall survival (OS) were co-primary endpoints.
Keytruda was superior to Yervoy in all key study endpoints. Median PFS was 5.5 months for Keytruda (Q2W), 4.1 months for Keytruda (Q3W), and 2.8 months for Yervoy; PFS rates at six months were 47.3% for Keytruda (Q2W) (HR= 0.58; p<0.00001), 46.4% for Keytruda (Q3W) (0.58; p=0.00001), and 26.5% for Yervoy. Median OS data was immature for all study arms, while the OS rates at 12 months were 74.1% for Keytruda (Q2W) (HR= 0.63; p<0.00052), 68.4% for Keytruda (Q3W) (0.69; p=0.00358), and 58.2% for Yervoy. Overall response rates (ORR) were 33.7% for Keytruda (Q2W) and 32.9% for Keytruda (Q3W), versus 11.9% for Yervoy. Keytruda also demonstrated a superior safety profile compared with Yervoy. Grade 3 to 5 adverse events attributable to study drugs were reported in 13.2% (Keytruda Q2W), 10.1% (Keytruda Q3W), and 19.9% (Yervoy) of patients with events similar to what is characteristic of the class but with individual adverse events occurring rarely; rates of treatment discontinuation due to treatment-related adverse events were 4.0%, 6.9%, and 9.4%, respectively. As OS results at the second interim analysis crossed the prespecified efficacy boundary, the KEYNOTE-006 trial was halted early and results were unblinded; however, the study is ongoing for safety and survival follow-up until the final analysis.
Compared with patients randomized to Yervoy, patients randomized to Keytruda experienced a 1.8-fold improvement in the six-month PFS rate, a reduction in risk of death of 31% to 37%, and a 2.8-fold increase in ORR. With such strongly positive results from KEYNOTE-006 in hand, Merck will move toward regulatory filing of Keytruda in the first-line setting as quickly as possible. As Keytruda demonstrated significant improvement in both PFS and OS compared with Yervoy, it is evident that Yervoy’s dominance as front-line standard of care for BRAF-wildtype patients will soon fade away as PD-1 checkpoint inhibitors assume this role.
The question remains as to which PD-1 inhibitor will win the battle for the front-line setting. Although the results from KEYNOTE-006 are outstanding, one must not forget that in June 2014 Bristol-Myers Squibb announced preliminary results of their Phase III CheckMate-066 trial (NCT01721772) that evaluated Opdivo versus dacarbazine as first-line therapy in 418 patients with unresectable Stage III or Stage IV melanoma. CheckMate-066 was prematurely terminated because the independent data-monitoring committee confirmed a significant OS benefit was achieved (BMS press release, June 25, 2014). Median OS was not reached for the Opdivo arm and was 10.8 months for the dacarbazine arm (p=<0.001). One-year survival was 73% for Opdivo-treated patients versus 42% for dacarbazine (p<0.0001); median PFS was 5.1 months for the Opdivo arm versus 2.2 months for dacarbazine; and objective response rates were 40.0% versus 13.9% for Opdivo and dacarbazine, respectively.2 Drug-related Grade 3/4 adverse events occurred in 12% of patients treated with Opdivo and 18% of patients treated with dacarbazine, with only 2% and 3% of patients, respectively, discontinuing due to adverse event. If one indulges in a cross-trial comparison (with all of the usual caveats) with regard to PFS, OS and ORR, Keytruda and Opdivo appear to have quite similar efficacies and safety profiles as front-line agents for advanced/metastatic melanoma. With the activity of Keytruda and Opdivo appearing so similar, how will physicians choose between two highly active agents? Although Opdivo was the first to report results of the first-line randomized trial, it was in comparison with a now-defunct standard of care (dacarbazine). Keytruda may be at an advantage in having shown clear superiority against the current standard of care, Yervoy. That could propel physicians to preferentially utilize Keytruda. However, it should not be overlooked that the dose of Keytruda utilized in the KEYNOTE-006 trial (10 mg/kg Q2W or Q3W) is significantly higher than the dose at which it is currently approved (and priced) in the relapsed/refractory setting (2 mg/kg Q2W). At the currently approved dose, Keytruda costs $12,500 per month; at the dose tested in the KEYNOTE-006 trial, the monthly price for Keytruda would presumably be in excess of $60,000 per month. Clearly this is not sustainable, so cost of therapy could become a major decision factor when choosing between Keytruda and Opdivo (at the dose tested in CheckMate-066 and -067, the cost per month is $12,500), unless the pricing of the higher dose of Keytruda is creatively managed.
Bristol-Myers Squibb is not far behind with its own trial comparing Opdivo with Yervoy. The company is conducting the Phase III CheckMate-067 trial (NCT01844505) to determine whether Opdivo alone or Opdivo in combination with Yervoy will extend survival compared with Yervoy alone in patients with previously untreated metastatic melanoma. OS and PFS are co-primary endpoints. Given the results of KEYNOTE-006, one would expect that Opdivo also will be able to best Yervoy when comparing the two monotherapies. CheckMate-067 will confirm these expectations, but perhaps more importantly will inform how efficacy of the combination of inhibition of PD-1 and CTLA4 checkpoint pathways compares to a PD-1 inhibitor alone. What level of gain in survival can be expected with this dual-blockade? Will toxicity of the combined agents be insurmountable?
Between the CheckMate-066 results first reported at the Society of Melanoma Research in November 2014, the KEYNOTE-006 results reported at AACR in April 2015, and looking ahead to the widely anticipated CheckMate-067 trial readout, a heated battle is playing out among the checkpoint inhibitors in advanced melanoma. With both PD-1 inhibitors showing one-year overall survival in excess of 70%, compared with less than 40% one-year survival historically,3 this battle is turning into a win-win for patients and physicians.
1. Ribas A, Schachter J, Long GV et al. Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma. AACT Abstract CT101, 2015.
2. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Eng J Med. 2014;372:320-330.
3. Kantar Health, CancerMPact® Patient Metrics U.S., accessed April 19, 2015.