Melanoma pipeline: In search of the next-generation CTLA-4


The launch of Bristol-Myers Squibb’s (BMS) Yervoy (ipilimumab) in 2011 marked the first new branded treatment for metastatic melanoma in 13 years and the first immuno-oncology product approved for any indication.

Yervoy is a monoclonal antibody (mAb) directed against the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and its activity boosts the immune system's ability to fight tumours. The drug is heralded as a scientific breakthrough and it helped extend survival in patients with advanced melanoma.

Yervoy’s four-dose treatment costs roughly $140,000. Yervoy ran into a series of reimbursement blocks in markets such as the UK and Australia that resulted in delayed approvals, with discounts being offered by the company to appease cost-effectiveness watchdogs such as the UK’s National Institute for Health and Care Excellence (NICE). In subsequent years, programmed death-1 (PD-1) drugs Opdivo (nivolumab) and Keytruda (pembrolizumab) were approved in melanoma, which were both deemed to be safer and more efficacious than Yervoy. The advent of PD-1-based regimens, together with the notoriety of Yervoy for having substantial toxicity levels, resulted in the drug being progressively side-lined.

BMS is pursuing a next-generation anti-CTLA-4 agent devoid of the unfavourable toxicity profile of Yervoy. New patents were filed by BMS in 2014 regarding the design or modification of anti-CTLA-4 antibodies, to enhance their activity and reduce toxicity. This move alludes to the company’s interest in securing a position for anti-CTLA-4 antibodies within the future treatment paradigm.

A Phase I/IIa trial has recently been registered by BMS for BMS-986218, which involves 452 patients. This is a  high number for a first-in-human study. According to the National Cancer Institute, BMS-986218 is an engineered version of Yervoy. Notably, the study design compares Yervoy and BMS-986218 monotherapy, as well as BMS-986218 combined with Opdivo.

Success of BMS’ Phase I/IIa trial has the potential to invigorate BMS’ position as a leader in anti-CTLA-4 drugs and to fend off competitor AstraZeneca’s tremelimumab, which is an anti-CTLA-4 mAb. BMS-986218 has an edge over tremelimumab with respect to clinical development in melanoma, as BMS has established its presence in that setting. Notably, tremelimumab is a drug that has previously been shown to be ineffective as first-line treatment in patients with advanced melanoma. It is is currently in Phase III development for other cancer indications besides.

BMS’ strategy to develop a second anti-CTLA-4 mAb offers an avenue to improve upon the currently available PD-1/CTLA-4 combinatorial treatments, such as BMS’ Opdivo + Yervoy. The race for developing the next-generation anti-CTLA-4 drug is heating up, and the readout from the BMS trial is thereby eagerly awaited.