The future of combination therapies in advanced melanoma
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memo https://doi.org/10.1007/s12254-020-00640-x
The future of combination therapies in advanced melanoma Christoph Hoeller
Received: 17 June 2020 / Accepted: 20 July 2020 © The Author(s) 2020
Summary The combination of Cytotoxic T-Lymphozyte Antigen-4 (CTLA-4) and Programmed death1 (PD-1) antibodies and the combination of BRAF and MEK inhibitors are the current clinical standards for combination immune and targeted therapy for melanoma, respectively. The success of these therapies has stimulated research into novel drug combinations for melanoma, of which a large majority are based on combination with PD-1 or PD-Ligand 1 (PD-L1) blocking drugs. Thus, the aim is to provide an overview of the most important combination strategies in late stage clinical development and an outlook on drug combinations in early development that might enter larger clinical trials within the next few years. Keywords Skin cancer · Immunotherapy · BRAF · Intralesional therapy · Vaccine
Introduction The combination of ipilimumab (Ipi) and nivolumab (Nivo) and the combination of BRAF and MEK inhibitors are current standards for combination therapies in immunotherapy and targeted therapy of melanoma [1, 2]. Recent data from pivotal studies have demonstrated that roughly up to 35% (for BRAF/MEK inhibitors) and 50% (for Ipi/Nivo) of firstline patients treated with these combinations are still alive after 5 years. While this is a significant gain over the past standard of chemotherapy, it means that at least half of these patients will not achieve a long-term benefit. Several new combinations that C. Hoeller () Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria [email protected]
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aim to further improve these numbers are currently undergoing late-stage clinical development.
Targeted inhibitors and PD-1/PD-L1 blocking antibodies The clinical rationale for combining targeted and immunotherapy is to utilize the rapid onset of response and high response rate of BRAF/MEK inhibitors and the longer duration of benefit seen in patients responding to checkpoint inhibitors (CPI). In addition, a preclinical rationale is that early during targeted treatment an influx of T-cells into the tumor is observed which could be augmented by adding a CPI [3]. The combination of vemurafenib and cobimetinib with the PD-L1 blocking antibody atezolizumab (NCT02908672, Trilogy) as well as the combination of dabrafenib and trametinib with the PD-1 blocking antibody spartalizumab (NCT02967692, Combi-I) are currently being tested in phase III trials in patients with BRAF mutations and in comparison to the respective BRAF/MEK inhibitor combination. Data from Trilogy presented at AACR showed a median investigator assessed progression-free survival (PFS) of 15.1 vs. 10.6 months (P = 0.0249) in favor of the triplet arm. However, no difference in response rate was seen between the two arms, especially no higher number of complete responses (CRs) was observed with the triplet. Data on overall survival (OS
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