Emerging triplet combination treatments are poised to redefine the treatment paradigm in advanced malignancies with high unmet need. The current market is saturated with immuno-oncology (IO) treatments such as checkpoint inhibitors, though these only target co-inhibitory checkpoint receptors in order to reverse cancer-mediated immune suppression. In an effort to potentiate this approach, the first co-stimulatory agonists are being explored in combinations that would allow a low dose of these potent drugs to be used in a triplet combination strategy.

Though checkpoint inhibitors such as Keytruda and Opdivo have re-defined the treatment paradigm in oncology, it is widely believed that the full potential of IO is yet to be achieved. The rationale behind targeting immune receptors is to prevent cancer-mediated immune suppression and thereby allow a normalized immune response against cancer. This strategy is seen when targeting solid tumours and includes a combinatorial agent such as angiogenic inhibitors and other agents. Yet there remains room for improvement. In contrast to targeting co-inhibitory checkpoint inhibitors such as PD-1/PD-L1, the new strategy is to include a co-stimulatory agonist. Therefore, in addition to preventing cancer cells from suppressing the immune system, this strategy would directly, and independently, activate T-cells to target the tumour.

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CD40 has been identified as the leading target to achieve this strategy. As a single-drug treatment, the dose required to get a sufficient effect might be too high and therefore too toxic, but when used in combination, a lower dose can contribute to the potential synergism between drugs targeting different aspects of the immune system against cancer. This strategy is being led by Roche and Bristol-Myers Squibb, which have ongoing Phase I/II trials estimated to be completed by 2020 and 2021, respectively. Roche is looking to combine its blockbusters Tecentriq and Avastin with its pipeline CD40 agonist, selicrelumab. Similarly, BMS is using its blockbuster Opdivo with its pipeline CSF-1 inhibitor cabiralizumab and Apexigen’s CD40 agonist. GlobalData expects that by 2022 triplet combinations will reach the solid tumour markets in indications with high unmet need, namely pancreatic cancer and other advanced metastatic indications.

GlobalData expects that once CD40 agonists become an established part of the treatment paradigm in solid tumours, interest will increase in bringing a similar approach to haematological malignancies. CD40 would equally be a key component in combination treatments for haematological malignancies; however, a three-drug combination for haematological cancers would explore an alternative strategy since there would be no need to target solid tumour characteristics such as the tumour vasculature in the tumour microenvironment. Therefore, GlobalData expects that the novel strategy for haematological malignancies will be the PD-1/PD-L1 combination with a CD40 agonist. Later, a third novel checkpoint inhibitor such as those targeting LAG-3, CD47, or TIM-3 might also be included in triplet combination treatments for haematological malignancies.