Honghong Zhou

Pembrolizumab versus Ipilimumab in Advanced Melanoma

BACKGROUND The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)

BACKGROUND Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING Merck & Co.

Abstract CT101: Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma

Background: Ipilimumab (IPI; anti-CTLA4) and pembrolizumab (PEMBRO; anti-PD-1) are checkpoint inhibitors that stimulate immune responses to cancer. In KEYNOTE-001, PEMBRO showed durable antitumor activity in melanoma patients (pts), regardless of prior IPI treatment. KEYNOTE-006 (NCT01866319) is a pivotal phase III study comparing IPI with 2 PEMBRO dosing regimens in IPI-naive (IPI-N) advanced melanoma pts. Methods: Pts were randomized 1:1:1 to PEMBRO 10 mg/kg Q2W, PEMBRO 10 mg/kg Q3W, or 4 doses of IPI 3 mg/kg Q3W. Randomization was stratified by ECOG PS (0 vs 1), line of therapy (first vs second), and PD-L1 expression (positive [staining in ≥1% of tumor cells] vs negative). BRAFV600-mutant pts naive to BRAF inhibitors were eligible if LDH was normal and there was no evidence of tumor-related symptoms or rapidly progressing disease. PEMBRO was continued until progression, intolerable toxicity, or 24 months. Response was assessed at wk 12 and every 6 wk thereafter per RECIST v1.1 by central review (primary for efficacy) and per immune-related response criteria by investigator review (primary for therapy management). Primary end points are PFS and OS. Secondary end points include ORR and safety. Primary objective of the first interim analysis (IA1), which occurred after completion of enrollment, was to evaluate the superiority of either PEMBRO schedule over IPI for PFS at a 1-sided α = 0.002. IA1 was to be performed when ≥260 PFS events occurred across all arms and all pts had ≥6 mo of follow-up. Differences in PFS and OS were assessed by a stratified log-rank test. Data cutoff date was Sep 3, 2014. The final OS analysis will be performed as the data matures. Results: 834 pts from 16 countries were enrolled between Sep 2013 and Mar 2014; 66% were treatment naive, 80% were PD-L1+, 36% were BRAFV600 mutant, and 69% had ECOG PS 0. Based on 502 PFS events (central RECIST v1.1), both PEMBRO doses demonstrated superiority over IPI (HR 0.58, P Citation Format: Antoni Ribas, Jacob Schachter, Georgina V. Long, Ana Arance, Jean Jacques Grob, Laurent Mortier, Adil Daud, Matteo S. Carlino, Catriona McNeil, Michal Lotem, James Larkin, Paul Lorigan, Bart Neyns, Christian U. Blank, Omid Hamid, Michele Kosh, Honghong Zhou, Nageatte Ibrahim, Scot Ebbinghaus, Caroline Robert. Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2015-CT101

Abstract CT004: KEYNOTE-006: PD-L1 expression and efficacy in patients (Pts) treated with pembrolizumab (pembro) vs ipilimumab (IPI) for advanced melanoma

Background: The anti-PD-1 antibody pembro and the anti-CTLA-4 antibody IPI have shown efficacy in advanced melanoma. In KEYNOTE-006 (NCT01866319), pembro significantly improved PFS, ORR, and OS compared with IPI. Here, we present data on PD-L1 expression and efficacy at the second interim analysis. Methods: IPI-naive pts were randomly assigned in a 1:1:1 ratio to pembro 10 mg/kg Q2W or Q3W or 4 cycles of IPI. Randomization was stratified by PD-L1 expression using Dako9s PD-L1 IHC 22C3 pharmDx assay (positive [membranous PD-L1 staining in ?1% of tumor and adjacent immune cells] vs negative), ECOG PS (0 vs 1), and line of therapy (1st vs 2nd). IHC scores of 0 (0% staining), 1 ( Results: Overall, 834 pts enrolled. Of the 821 PD-L1 evaluable pts, 671 (82%) were PD-L1 positive. Pembro significantly improved PFS (P Conclusions: PD-L1 positivity is associated with improved efficacy with pembro compared with IPI. Higher degree of PD-L1 positivity correlated with greater improvement in PFS, OS, and ORR. As evidenced by treatment effect in all groups, pembro monotherapy is appropriate in pts regardless of PD-L1 status. Citation Format: Matteo Carlino, Antoni Ribas, Rene Gonzalez, Christoph Hoeller, Gil Bar-Sela, Catherine Barrow, David Chao, Pascal Wolter, Carola Berking, Oddbjorn Straume, Alfonso Berrocal, Esther Holgado, Tara C. Gangadhar, Geoffrey Weiss, Honghong Zhou, Kenneth Emancipator, Nageatte Ibrahim, Dirk Schadendorf. KEYNOTE-006: PD-L1 expression and efficacy in patients (Pts) treated with pembrolizumab (pembro) vs ipilimumab (IPI) for advanced melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT004.