Pembrolizumab Elicits Long-Term Survival Benefit in Advanced Melanoma

Pembrolizumab (Keytruda) demonstrated long-term survival benefit compared with ipilimumab (Yervoy) in patients with unresectable stage III/IV melanoma who received up to 1 prior systemic therapy, according to 7-year follow-up data from the phase 3 KEYNOTE-006 (NCT01866319) trial, which included some patients who transitioned to the phase 3 KEYNOTE-587 (NCT03486873) extension study, published in the Journal of Clinical Oncology.¹

At a median follow-up of 85.3 months (range, 0.03-90.8), the median overall survival (OS) among patients who received pembrolizumab (n = 556) was 32.7 months (95% CI, 24.5-41.6) compared with 15.9 months (95% CI, 13.3-22.0) for those treated with ipilimumab (n = 278; HR, 0.70; 95% CI, 0.58-0.83). The 7-year OS rates were 37.8% vs 25.3%, respectively. The median modified progression-free survival (PFS) was 9.4 months (95% CI, 6.7-11.6) in the pembrolizumab arm vs 3.8 months (95% CI, 2.9-4.3) in the ipilimumab arm, with 7-year PFS rates of 23.8% vs 13.3%, respectively.

In the pembrolizumab arm, the complete response (CR), partial response (PR), and stable disease (SD) rates were 16.7%, 34.4%, and 33.1%, respectively, and the 7-year OS rates from the time of best overall response were 85.2%, 61.8%, and 25.9%, respectively.

Following treatment on KEYNOTE-006, 228 patients who received pembrolizumab and 105 patients treated with ipilimumab were eligible to enroll in KEYNOTE-587; 158 patients and 52 patients ultimately enrolled in KEYNOTE-587, respectively. Investigators noted a limitation of the study was the fact that not all eligible patients underwent further follow-up. Patients were eligible to transition to KEYNOTE-587 if they were receiving second-course pembrolizumab or were in survival follow-up per the KEYNOTE-006 study end date of June 3, 2019. Further, those in the survival follow-up phase could receive second-course pembrolizumab for up to a year in KEYNOTE-587.

Patients included in KEYNOTE-006 had received up to 1 prior systemic therapy for advanced disease, excluding CTLA-4, PD-1, or PD-L1 inhibitors. Pembrolizumab was given at a dose of 10 mg/kg once every 2 or 3 weeks for up to 2 years. Patients in the ipilimumab arm were treated at a dose of 3 mg/kg once every 3 weeks for 4 cycles.

Of patients who received second-course pembrolizumab (n = 16), a CR (n = 7), PR (n = 7), or SD (n = 2) was achieved during the first course treatment. During the second course of treatment, the objective response rate was 56% (95% CI, 30%-80%) with patients experiencing a CR (n = 4), PR (n = 5), SD (n = 5), and progressive disease (n = 2). The 2-year PFS rate was 62.5%, and the most common site where progressive disease occurred was the lymph nodes. Although data on these patients were not captured in KEYNOTE-587, response was ongoing for 5 of 7 patients who had a CR/PR, demonstrating that pembrolizumab retreatment may result in benefit for certain patients.

Patients with previously untreated disease who received pembrolizumab (n = 368) experienced a 7-year OS rate of 41.2% compared with 27.6% in the ipilimumab arm (n = 181). The median OS was 38.7 months (95% CI, 27.3-50.9) vs 17.2 months (95% CI, 13.8-26.2), respectively (HR, 0.67; 95% CI, 0.53-0.84). Additionally, the respective 7-year PFS rates were 26.8% vs 15.9% and the median PFS was 12.0 months (95% CI, 8.3-16.6), respectively (HR, 0.62; 95% CI, 0.50-0.76). These findings were consistent with prior analyses.

Previously, improvements in PFS and OS shown in data from KEYNOTE-006 resulted in the FDA expanding the approval of single-agent pembrolizumab to include the frontline treatment of patients with advanced melanoma regardless of BRAF status in December 2015.²

Additional findings from the subgroup analysis demonstrated that pembrolizumab was favorable compared with ipilimumab regardless of BRAF mutation status, lactate dehydrogenase (LDH) level, presence of brain metastases, or tumor size.¹

Those with BRAF wild-type disease treated with pembrolizumab (n = 355) experienced a 7-year OS rate of 36.5% vs 25.7% among those treated with ipilimumab (n = 170), and the median OS was 28.1 months (95% CI, 21.1-42.7) and 13.9 months (95% CI,10.7-24.8), respectively (HR, 0.71; 95% CI, 0.56-0.89). Patients with BRAF-mutant disease who were previously treated with a BRAF/MEK inhibitor experienced 7-year OS rates of 28.3% vs 20.0% in the pembrolizumab (n = 87) and ipilimumab (n = 52) arms respectively. The median OS for pembrolizumab in this subgroup was 20.4 months (95% CI, 12.8-35.6) vs 11.9 months (95% CI, 6.0-17.8) for ipilimumab (HR, 0.72; 95% CI, 0.47-1.08). Those with BRAF-mutant disease who were BRAF/MEK inhibitor naïve achieved 7-year OS rates of 49.7% vs 27.7% in the pembrolizumab (n = 87) and ipilimumab (n = 52) arms, respectively, with a median OS of 78.5 months (95% CI, 36.1-not evaluable) vs 26.2 months (95% CI 16.0-64.0; HR, 0.58; 95% CI, 0.38-0.89).

Patients with normal LDH levels who received pembrolizumab (n = 369) or ipilimumab (n = 179) achieved 7-year OS rates of 42.0% vs 30.5%, respectively (HR, 0.76; 95% CI, 0.60-0.96). Those with elevated LDH in the pembrolizumab (n = 179) and ipilimumab arms (n = 91) experienced 7-year OS rates of 28.9% vs 14.7%, (HR 0.59; 95% CI, 0.44-0.79).

Patients with brain metastases in the pembrolizumab (n = 51) and ipilimumab arms (n = 29) experienced 7-year OS rates of 50.0% vs 27.6%, respectively (HR, 0.49; 95% CI, 0.27-0.87). The 7-year OS rates for those without brain metastases in the pembrolizumab (n = 500) and ipilimumab arms (n = 248) were 36.8% compared with 25.0%, respectively (HR, 0.72; 95% CI, 0.59-0.87).

Finally, patients with tumors 10 cm or greater treated with pembrolizumab (n = 106) or ipilimumab (n = 51) experienced 7-year OS rates of 26.1% vs 15.9%, respectively (HR, 0.67; 95% CI, 0.46-0.99). Those with tumors less than 10 cm in the pembrolizumab (n = 292) and ipilimumab arms (n = 152) achieved 7-year OS rates of 40.7% vs 30.7%, respectively (HR, 0.74; 95% CI, 0.58-0.96).

References

1. Robert C, Carlino MS, McNeil C, et al. Seven-year follow-up of the phase III KEYNOTE-006 study: pembrolizumab versus ipilimumab in advanced melanoma. J Clin Oncol. Published online June 22, 2023. doi:10.1200/JCO.22.01599
2. FDA approves expanded indication for Merck’s Keytruda (pembrolizumab) for the treatment of patients with advanced melanoma. News Release. Merck. December 18, 2015. Accessed July 31, 2023. https://www.merck.com/news/fda-approves-expanded-indication-for-mercks-keytruda-pembrolizumab-for-the-treatment-of-patients-with-advanced-melanoma/