While chemotherapies have historically been the main treatment approach in oncology, the arrival of immunotherapies, which increase the immune system’s anti-tumour ability with fewer side effects, has shifted the treatment paradigm in a variety of cancers. One major strategy in immuno-oncology (IO) development at present is to bring combinations to the market to improve the efficacy of IO products. Immune checkpoint inhibitors (ICIs) have redefined IO treatments, and there is a race to combine novel agents with ICIs. One such mechanism of action in the pipeline with the potential for success as an IO combination partner is the C-C chemokine receptor (CCR4) antagonists.
CCR4 is a receptor that is expressed on regulatory T-cells (Tregs) and is involved in attenuating immune responses to prevent excessively, and potentially fatal, auto-immunity. During carcinogenesis, cancer cells can recruit Tregs in excess to the tumour microenvironment (TME) as an immunosuppressive mechanism. This can interfere with the response of ICIs, which aim to reverse immune suppression. ICIs only interfere with cancer cells’ ability to inactivate effector T-cells via direct pathways, so cancer cells are still able to promote immune suppression via indirect pathways, namely via Treg recruitment. CCR4 antagonists are one strategy being used to target cancer-mediated indirect pathways in immune suppression. Currently, the only marketed CCR4 antagonist in oncology is Kyowa Kirin’s mogamulizumab for the treatment of T-cell lymphomas. Mogamulizumab is currently approved as monotherapy in the US, EU and Japan in two common forms of cutaneous T-cell lymphomas, and is also approved in combination with chemotherapy in other rare hematologic malignancies in Japan. Its most recent Phase IV study showed that mogamulizumab had a response rate of 57.9% and that 38.6% of patients reported adverse drug reactions.
The current pipeline landscape only includes one agent with the same mechanism of action. Hanmi/RAPT Therapeutics’ FLX-475 is a novel CCR4 antagonist involved in a planned registrational Phase III trial to treat multiple oncology indications. Unlike mogamulizumab, FLX-475 is administered orally rather than intravenously, and it is in development to treat both solid and haematological tumours. In a Phase I trial with healthy volunteers, FLX-475 demonstrated outstanding pharmacokinetic properties and no reported dose-limiting adverse events. Since then, Merck & Co. has identified FLX-475 as a potential combination candidate for Keytruda (pembrolizumab). The company has initiated a Phase I/II trial of the combination, which has yielded no dose-limiting toxicities so far and has planned a Phase II combination trial.
GlobalData believes that IO drug combinations are well-positioned to lead the global cancer market, and that ideal combinations for various tumour types are yet to be established. Therefore, GlobalData anticipates an increase in approvals for novel IO combinations over the next several years. FLX-475’s ability to complement ICI treatment without adding toxicity and its involvement with Keytruda in the pipeline make it a likely ideal combination agent for the future.
