Yi-Hsien Yeh

Introduction. Cancer cells evade immune cell recognition via expressing receptor such as PD-L1 on cell surface^1,2. Agents activating immune defense and overcoming immunosuppression have been shown as promising immunotherapeutic strategies against drug resistant cancers, such as melanoma³.  For example, Ipilimumab, an anti–CTLA-4 antibody, has been FDP-approved as a treatment for advanced melanoma based on its effectiveness in improving overall survival. However, despite the survival benefit, Ipilimumab has immune-related adverse events as well as low objective response rate of 11% due to upregulation of immunosuppressive pathways such as PD-L1, IDO, and Tregs⁴. Thus, alternative treatment has been developed.  Pembrolizumab, a PD-L1 inhibitor had been shown to increase 20% patients 6-month survival rate and tripled response rate to 36%^5,6. The effectiveness can also be improved by dual blockade that combing CTLA-4 and PD-1 inhibitor because they function through complementary, non-redundant pathways, for example, Nivolumab, another PD-L1 inhibitor, when combined with Ipilimumab, has been shown to improve objective-response rate and progression-free survival compared to ipilimumab monotherapy⁷.  These new drugs or combination therapy open new doors for future improvement in immunotherapy in treating advanced melanoma. Methods. Randomized, double blind, controlled phase III clinical studies recruited patients with advanced melanoma to receive Pembrolizumab, combination of Nivolumab with Ipilimumab or Ipilimumab monotherapy. Primary end-points were progression-free and overall survival. Outcomes were measured in objective-response rate, progression-free and overall survival rate. Results. Pembrolizumab, as compared with Ipilimumab, significantly prolonged progression-free and overall survival with fewer high-grade adverse events in patients with advanced melanoma. Increased 6 months survival rate from 26.5% to 46.4% and has tripled the response rate compared to Ipilimumab. Combination therapy of Nivolumab and Ipilimumab reports higher confirmed response rate (61%) compared to response rate of nivolumab monotherapy (40%) or pembrolizumab monotherapy (38%) for patients with advanced melanoma.  Conclusion. Studies have shown that pembrolizumab and combination therapy of Nivolumab and Ipilimumab both shows improved efficacy in treating patients with advanced melanoma. These new medication provide alternative therapeutic choice to traditional chemotherapy for patients with drug-resistant melanoma.

1. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39(1):98-106.
2. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
3. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19(19):5300-5309.
4. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5(200):200ra116.
5. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134-144.
6. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532.
7. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(13):1270-1271.