Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Immune checkpoint inhibitors have led to unprecedented prolongation of overall survival (OS) for patients with advanced melanoma. Five-year follow-up of KEYNOTE-006 showed pembrolizumab prolonged survival versus ipilimumab. Efficacy results with 7-year follow-up are presented. At data cutoff (April 19, 2021), median follow-up was 85.3 months (range, 0.03-90.8 months). Median OS was 32.7 months for pembrolizumab versus 15.9 months for ipilimumab (hazard ratio [HR], 0.70; 95% CI, 0.58 to 0.83); 7-year OS was 37.8% and 25.3%, respectively. OS HRs favored pembrolizumab regardless of BRAF status or prior BRAF/MEK-inhibitor treatment and prognostic characteristics (elevated lactate dehydrogenase, large tumor size, and brain metastasis). Median modified progression-free survival (mPFS) was 9.4 months for pembrolizumab versus 3.8 months for ipilimumab; 7-year mPFS was 23.8% and 13.3%, respectively. In patients who completed ≥94 weeks of pembrolizumab, the 5-year OS was 92.9% and the 5-year mPFS was 70.1%. The objective response rate with second-course pembrolizumab (n = 16) was 56% (95% CI, 30 to 80) and the 2-year mPFS was 62.5%. These findings confirm that pembrolizumab provides long-term survival benefit in advanced melanoma.

Long‐term survival with systemic therapy in the last decade: Can melanoma be cured?

“…Pembrolizumab was compared with ipilimumab in patients with advanced melanoma who had received no more than one previous systemic therapy. [11][12][13][14] The 5-year PFS and OS of the KEYNOTE-006 trial in the pembrolizumab group were 25% and 40% respectively, and the 7-year PFS and OS were 24% and 38%, respectively. The little difference between the 5-year and 7-year outcomes indicates a sustained response of pembrolizumab over time 14 (Table 1).…”

“…Pembrolizumab was compared with ipilimumab in patients with advanced melanoma who had received no more than one previous systemic therapy 11–14 . The 5‐year PFS and OS of the KEYNOTE‐006 trial in the pembrolizumab group were 25% and 40% respectively, and the 7‐year PFS and OS were 24% and 38%, respectively.…”

“…The 5‐year PFS and OS of the KEYNOTE‐006 trial in the pembrolizumab group were 25% and 40% respectively, and the 7‐year PFS and OS were 24% and 38%, respectively. The little difference between the 5‐year and 7‐year outcomes indicates a sustained response of pembrolizumab over time 14 (Table 1). Notably, patients in the KEYNOTE‐006 trial received pembrolizumab for up to 2 years, whereas in other trials, treatment was continued until progressive disease or unacceptable toxicity was observed.…”

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs

“…The recent success of immune checkpoint inhibitors has ushered in a new era to treat advanced cancers through rational engagement of the immune system 1–3 . Remarkable objective responses have been observed at primary tumors across a multitude of cancer immunotherapy strategies, although achievement of objective responses at metastatic sites remains an elusive clinical outcome for the majority of patients 4–6 .…”

Optimal strategy in managing advanced melanoma

“…Long-term survival was also observed with anti-PD-1 Abs as well as ipilimumab, with 6.5-year OS of 42% reported with nivolumab in first-line treatment 36 and 7-year OS of 37.8% reported with pembrolizumab in first-line treatment. 37 Since anti-PD-1 Abs are significantly more effective and have a lower incidence of serious irAEs than ipilimumab, [31][32][33] anti-PD-1 Abs are now the mainstay of advanced melanoma treatment in guidelines. 38,39 Since the anti-CTLA-4 Ab acts in the priming phase and the anti-PD-1 Ab acts in the effector phase, the combination of these two was expected to enhance efficacy.…”