Adjuvant vs Neoadjuvant Immunotherapy in RCC

The use of immune checkpoint inhibitors as adjuvant or neoadjuvant therapy in kidney cancer could offer important new treatment options. Questions remain, though, on the timing and sequence of therapy. Experts discussed some of the new trials with these agents and their rationales at the 15^th International Kidney Cancer Symposium, held November 4–5 in Miami, Florida.

“We have an embarrassment of riches,” said Robert G. Uzzo, MD, of Fox Chase Cancer in Philadelphia, who spoke during the session. “[We have] two trials that are tremendously important, and I don’t know that any of us know which is the best trial or the right trial.” The two trials in question involve nivolumab, a PD-1 inhibitor, in one case, and atezolizumab, a PD-L1 inhibitor, in the other, and differ in the timing of treatment.

Lauren C. Harshman, MD, of the Dana-Farber Cancer Institute in Boston, spoke about the PROSPER renal cell carcinoma (RCC) trial, involving neoadjuvant nivolumab. “Our rationale for pre-nephrectomy anti-PD-1 priming is that there is an ongoing but unsuccessful anti-tumor T-cell response in the primary tumor,” she said, as well as in the tumor microenvironment and draining lymph nodes. PD-1 blockade may enhance the T-cell response, with potential to eradicate micrometastases; doing so after nephrectomy, however, could mean there are fewer effector cells and cytokines and thus a less potent response.

The PROSPER RCC trial has received National Cancer Institute and US Food and Drug Administration approval to proceed, and Harshman said it will likely activate soon. It will randomize patients with non-metastatic stage II or greater RCC to either neoadjuvant nivolumab followed by resection and further nivolumab, or to resection followed by observation.

“One of the most exciting aspects of this trial design is the major opportunity to move the field forward with biomarker discovery and science,” Harshman said. All patients will undergo biopsy prior to randomization, and treatment with nivolumab prior to resection will allow analysis of tissues and serum after that treatment that otherwise is not possible. Among the questions to be answered are whether priming increases trafficking and proliferation of CD8+ T cells to the tumor, whether tumor PD-L1 expression adaptively increase after nivolumab therapy, and others.

Harshman noted that the neoadjuvant approach does require a change in workflow that urologists and medical oncologists are not used to, and will thus require substantial collaboration between these groups of clinicians.

Sumanta Kumar Pal, MD, of City of Hope Cancer Center in Duarte, California, spoke about using an adjuvant rather than neoadjuvant approach, using atezolizumab (the IMmotion trial). He noted that an adjuvant approach, following nephrectomy may be logistically more feasible, and that certain factors associated with enrolling patients to trials could make conclusions about the neoadjuvant approach very difficult.

“We’re going to face a very practical issue when it comes to enrolling patients on these studies,” he said. He noted that in the EVEREST trial-which tested everolimus in kidney cancer patients-a very small proportion of patients were referred to the trial prior to undergoing nephrectomy, often at outside institutions. This suggests it may be very difficult to find enough patients to sufficiently power a neoadjuvant trial in this malignancy.

Uzzo noted another potential limitation inherent to PROSPER and other neoadjuvant trials. “We know that these [agents] are very immunologically active, but how quickly do immune-related adverse events occur?” he asked. In immunotherapy trials with other malignancies, immune-related adverse events can happen rapidly or take weeks to develop. This means that patients and clinicians must be prepared to delay surgery in certain cases if such effects are present.

“Both trials are necessary in this space, and none of us know which is better,” Uzzo concluded.