Clinical Overview of Immunotherapy in Oncology
Scott K. Pruitt
MSD, Oncology-Early Development, Rahway, NJ, USA
Overview/Description of presentation:
The concept of harnessing the immune system to fight cancer is not new, but only recently have immunomodulatory pharmaceutical agents been developed that show clear clinical benefit for the treatment of cancer. Following studies of anti-CTLA4 mAb monotherapy and cell-based Provenge, in melanoma and prostate cancer, respectively, which demonstrated that immunotherapy was clinically efficacious, attention has turned to multiple different strategies to stimulate anti-tumor immunity.
Clinically approved approaches to cancer immunotherapy currently include CART-T cell therapy and oncolytic virus injection, but arguably the most important approach is blockade of the PD-1/PD-L1 immuno-inhibitory pathway. Anti-PD1 mAbs pembrolizumab and nivolumab, as wells as other, have been approved as monotherapy in multiple indications, in many cases based on objective response rate (ORR) results from single arm trials.
While tumor expression of PD-L1, assessed by immunohistochemical staining, is predictive of response to PD-1/PD-L1 blockade in a variety of tumor types, also under active exploration are multiple other potentially predictive biomarkers, including tumor microsatellite instability-high (MSI-H). Pembrolizumab recently received the first tumor type agnostic biomarker-based approval for the treatment of any tumor found to be MSI-H. This unique USFDA approval was based on data from multiple single arm trials, including a rare tumor basket trial, and local biomarker testing.
Anti-PD-1/PD-L1 mAb monotherapy continues to be evaluated in multiple indications and remains the foundation for cancer immunotherapy, but many current trials are evaluating the additional of second agents in combination with PD-1/PD-L1 blockade. The combination of nivolumab + anti-CTLA4 mAb, for example, remains under active investigation, while the combination of pembrolizumab + chemotherapy is showing clinical promise in multiple indications. In contrast, results from studies evaluating the combination of pembrolizumab + the IDO1 inhibitor epacadostat have begun to be reported, with no additive benefit of the combination over pembrolizumab monotherapy recently reported in melanoma, despite early phase clinical studies that suggested promising clinical anti-tumor activity with this combination. Triple combination therapies, again with PD-1/PD-L1 blockade as the common foundation, are being evaluated in clinical trials, some of which are utilizing an umbrella trial design approach to potentially allow efficient signal finding for multiple different combination therapies within a specific tumor indication.
A major challenge remains over how, in Phase 1b/2 studies, to identify promising combinations that have enhanced efficacy over PD-1/PD-L1 blockage alone and therefore warrant further clinical investigation. It is also not clear if the unique paradigm of accelerated approval based on single arm trial data with a subsequent confirmatory pivotal study will be acceptable for such combinations of multiple agents or whether the “combination rule” will require larger multiple arm studies that in turn would delay access of dying cancer patients to potentially effective immunotherapy combination regimens.
Conclusions/Take home message:
The field of tumor immunotherapy is rapidly evolving, necessitating novel approaches to regulatory approvals, signal finding studies, and potentially predictive biomarkers.