SUO 2015 Designing the next generation of clinical trials - Session Highlights

Washington, DC ( There are currently no trials in support of adjuvant systemic therapy in renal cell carcinoma (RCC). In this session, Dr. Harshman discussed the current therapeutic landscape of advanced RCC and describes techniques for designing the next generation of clinical trials to minimize patient resources and shorten time to completion.

Given that up to 70% of RCCs express PD-L1, PD-1 blockade in kidney cancer has received much excitement over the past several years. Some distinct features of PD-1 blockage in are worthy of mention. Namely, the durability of responses can be long lasting, continued response or disease stabilization is possible even off therapy, and there is good overall tolerability when used as monotherapy. However, there are still a fair number of patients that do not respond by traditional radiologic criteria and the need to markers predictive of response remains. A recent RCT in the metastatic setting demonstrated that patients treated with nivolumab have improved OS relative to patients with everolimus (Motzer et al, NEJM 2015) and led to its recent FDA approval. Moreover, the presence of PD-L1 in renal cell carcinoma is prognostic (patients with high expression do worse) but is not predictive of response to therapy.

Given the positive activity in the metastatic setting, it is reasonable to conjecture about moving the drug forward in the treatment algorithm (i.e. asking what is the best strategy for M0 patients?). Dr. Harshman is a lead investigator for EA8143 which she refers to as a case study of what a modern “adjuvant” trial looks like: many iterations and lots of TEAM WORK! Design considerations included feasibility, efficacy, minimization patient resources, and the ability to get answers quickly. Patients are eligible for EA8143 with ≥T2 or TanyN+ tumors. The protocol includes presurgical priming (i.e. neoadjuvant) with PD-1 blockade followed by complete excision, and augmented by adjuvant PD-1 blockade – a sort of immune checkpoint blockade sandwich. The treatment population is unselected due to a lack of validated selection markers. Primary endpoint is RFS and is powered at 84.9% to detect a 13% absolute benefit at 5 years (55.8 months → 68.8 months). In addition, there is great potential for biomarker discovery and investigation as part of the trial.

In conclusion, it is evident that tumors use complex overlapping mechanisms to evade and suppress the immune system. Thus, the need for combination therapy is real. There are many different possible combinations representing an area ripe for investigation. Such trials should be optimized to minimize patient resources and shorten time to trial completion.

Presented By:

Lauren C. Harshman, MD

Dana Farber Cancer Institute

Reported By:

Benjamin T. Ristau, MD from the Society of Urologic Oncology Meeting - December 2 - 4, 2015 – Washington, DC.

Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA