September 2016 Edition Vol.11, Issue 9

The Next Wave of Immunotherapies: Costimulators

The Next Wave of Immunotherapies: Costimulators

By Cory Lewis, Ph.D., Manager, Oncology Commercial Development, Kantar Health

Immunotherapies have been in the cancer landscape now for more than 15 years and have made a large impact in the clinic. With over 3,400 cancer therapies in development, immunotherapies have risen to the top of the crowded field. 

Immunotherapies targeting the immune checkpoint in cancer have led to the approval of Keytruda® (pembrolizumab, Merck), Opdivo® (Nivolumab, Bristol-Myers Squibb), Yervoy® (ipilimumab, Bristol-Myers Squibb) and Tecentriq® (atezolizumab, Roche).

Kantar Health’s newly developed CancerLandscapeTM platform identifies 23 immune checkpoint-targeted therapies in 893 trials in development. While initial approaches evaluated immune checkpoint therapies as monotherapies, many current trials evaluate the combination of checkpoint-targeted therapies with many other types of targeted therapies, such as Zydelig, Imbruvica, and Iressa. 

Immune checkpoint therapies are designed to inhibit those molecules that prevent the immune system pathway from acting on cancer cells, while immune costimulators are designed to activate the immune system. 

Immune costimulators work by providing the signal that promotes the expansion and proliferation of killer CD8 and helper CD4 T-cells. While immune checkpoint therapies are “releasing the brakes,” costimulators are “stepping on the gas.” Both mechanisms are required for a robust immune system response. 

Immune checkpoint therapies have changed treatment paradigms and added significant benefit to patient groups with high unmet need, but it cannot be forgotten that only a subset of patients respond to therapy. 

The hope is that by combining checkpoint inhibitors with immune costimulators the immune response will be more robust and response rates will drastically increase. But at what expense? 

Concerns and supporting evidence suggest that side effects can increase along with the substantial immune response. Nevertheless, many combinations are being evaluated to fine tune the immune system response while minimizing side effects.

According to CancerLandscape, 12 immune costimulators are in 41 trials. Targets for immune costimulators include CD40L, GITR, 4-1BB, CD27, TNFRSF25, TMIGD2, ICOS, CD28 and OX40. Of this group, OX40 is the target furthest in development with over 12 clinical trials. 

OX40 is a member of the TNFR super-family, and agonistic OX40 antibodies induce expansion, differentiation and increased survival of CD4 and CD8 T-cells1. Recent data from the 2016 American Society of Clinical Oncology (ASCO) annual meeting showed that OX40 is a viable target as a single agent. 

Pfizer’s PF-8600 (OX40 agonist) in a Phase I trial of 31 patients was well tolerated with no maximum-tolerated dose reached and no Grade 4 adverse events. Efficacy was modest, with one patient with partial response and 14 patients with stable disease out of 25 evaluable patients.2

Phase Ib data of the OX40 agonist, MOXR0916, and the PD-L1 inhibitor atezolizumab were promising in solid tumors. The combination was well-tolerated with no dose-limiting toxicities and no Grade 4 adverse events; however, there was one case of Grade 3 pneumonitis in a non-small cell lung cancer (NSCLC) patient. 

Objective responses were observed with several patients still on treatment after 10 months.3

These data show it is possible to not only take off the brakes but also push on the gas at the same time and have minimal side effects. It is too early to tell whether all drugs targeting OX40 will need to be used in combination to see substantial efficacy data, but it is promising to see that, at least in this combination, the regimen is well-tolerated.

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