Betting Combos on Biomarkers

Pharmacodynamic biomarkers are driving IO combos in absence of monotherapy responses

Despite lackluster monotherapy data at SITC from the latest tranche of immunotherapy candidates, drug developers are moving into combination trials with PD-1 and PD-L1 inhibitors based on biomarkers of pharmacodynamic activity. Results from the next randomized controlled trials putting that rationale to the test could be another year away.

The annual Society for Immunotherapy of Cancer (SITC) meeting yielded a deluge of Phase I data from single-agent and combination studies of immunotherapy agents against new targets. The goal is to find the next combination partner for PD-1 or PD-L1 inhibitors that can augment the average 30% response rate of the now standard-of-care agents in solid tumors.

In oral sessions, companies presented monotherapy data from at least seven programs addressing six targets. Four of those therapies double down on the mechanism of PD-1/PD-L1 inhibitors by inhibiting a second checkpoint protein. Three others either relieve a different type of immunosuppression or stimulate T cell proliferation (see “Figure: Brakes vs. Gas”).

Figure: Brakes vs. Gas

A selection of oral presentations at the Society for Immunotherapy of Cancer Conference (SITC) highlighted monotherapy data for next-generation immunotherapy candidates that aim to either take the brakes off the immune system or step on the gas.

1) Several of the therapies double down on the mechanism of PD-1/PD-L1 inhibition by targeting a different checkpoint protein, including the adenosine A2A receptor (ADORA2A); T cell immunoreceptor with Ig and ITIM domains (TIGIT); and lymphocyte-activation gene 3 (LAG3; CD223).

2) Two of the candidates inhibit immune suppressors that aren’t considered checkpoints. One targeted transforming growth factor β produced by regulatory T cells (Tregs); the other targeted all CD4+ T cells in tumors, which trial sponsor IDAC Theranostics Inc. believes dampen intratumoral CD8+ T cell activity.

3) One of the compounds stimulates T cell proliferation via stimulation of the innate immune activator transmembrane protein 173 (STING; TMEM173) in dendritic cells (DCs).

Six of the candidates led to one or two partial responses. None produced a complete response, and one produced no responses at all. Nevertheless, companies are moving forward with expanded Phase I cohorts or Phase II trials testing the

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