Medicine Matters oncology

My name is Dr. Moshe Ornstein. I am a genitourinary oncologist at the Cleveland Clinic Taussig Cancer Institute. Our trial revolved around neoadjuvant therapy and adjuvant therapy in patients with kidney cancer.

So it's well known that although treatment for metastatic kidney cancer has improved and we've made tremendous progress over the last couple of years, treatment for patients with localized kidney cancer has lagged behind. And with the exception of sunitinib approved for some patients in the adjuvant setting, there's really no standard of care and no other approved agents in the neoadjuvant or adjuvant setting for localized renal cell carcinoma. Because we know that immunotherapy with checkpoint inhibitors has excellent efficacy in the metastatic setting, we hypothesized that giving these agents in the preoperative and post-operative settings would be feasible and safe. So this trial was a phase 1b trial looking at the use of durvalumab, which is an anti-PD-L1 agent, and tremelimumab, which is an anti-CTLA4 agent, in the neoadjuvant an adjuvant setting for localized renal cell carcinoma.

Because this was a phase 1b trial and we were really looking at safety, there were various cohorts. The first cohort received just durvalumab in the neoadjuvant and adjuvant settings. And the agents were escalated up to the final cohort, which received durvalumab and tremelimumab in combination in the neoadjuvant setting, and then the combination in the adjuvant setting as well.

Ultimately, we enrolled a total of 29 patients into this trial. The trial included patients who had pT2, or I should say clinical T2 or above localized renal cell carcinoma or node positive localized RCC, but had no metastatic disease. Of the 29 patients, the median age was 61. 23 of the 29 patients were male. And it was a typical spread in terms of clinical staging and node staging that one would expect from a localized RCC population.

The key results are as follows. Although in the early cohorts, so the cohorts that just had durvalumab in the neoadjuvant setting, and even the cohorts that had the combination in the neoadjuvant setting and durvalumab monotherapy in the adjuvant setting, the toxicity in those cohorts was acceptable per the study design. Unfortunately, in the later cohorts, where patients were getting durvalumab and tremelimumab both before surgery and getting the combination after surgery as well, we saw higher rates of toxicity than we would have expected, and more importantly, we saw higher rates of therapy discontinuation as a result of toxicity than we expected when designing the trial. And therefore, although we anticipated 33 patients in the trial, we closed the trial early after the enrollment of 29 patients.

So that said, it's fair to say from this trial that the use of durvalumab as monotherapy before surgery and after surgery appears to be safe. When tremelimumab is added to the equation, the toxicity is a little bit more questionable and requires a little bit more investigation before saying with definitive certainty whether it can be used or investigated in further clinical trials.

Being a phase 1b study, what we were most interested in was the toxicity. With regards to efficacy, ongoing follow up is still in process. We are looking at some correlative investigations to determine whether we could find signatures of toxicity which would be helpful as well. But in terms of recurrence free survival or more long term clinical follow up, those investigations are ongoing and will be reported at a later conference.

Although this trial closed a bit early due to toxicity, clinicians and patients should still be encouraged to enroll in clinical trials in the peri-operative setting for localized RCC. It remains an unmet need in the field, and we are in dire need of additional treatment strategies to improve long term outcomes and prevent recurrence of disease and improve overall survival in patients with localized RCC.