Perioperative nivolumab did not improve RFS in RCC patients at high risk for recurrence

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Published: 10 Sep 2022
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Dr Mohamad Allaf - The Johns Hopkins Hospital, Baltimore, USA

Dr Mohamad Allaf, speaks to ecancer about his phase 3 randomised open label trial comparing perioperative nivolumab versus observation in patients with RCC undergoing nephrectomy.

In the investigational arm, nivolumab was administered (480mg IV q4 weeks) with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm was surgery followed by surveillance without a placebo. Baseline tumour biopsy was required only in the nivolumab arm.

The results demonstrated perioperative nivolumab did not improve RFS in RCC patients at high risk for recurrence. OS data remains immature but is not statistically different between arms.  

Subset analyses including risk stratification by pathologic stage are ongoing.

I was here proudly presenting the ECOG-ACRIN 8143, the PROSPER RCC trial. This is a trial that compared neoadjuvant plus adjuvant nivolumab in the treatment arm versus a standard of care observation arm in patients with high risk kidney cancer undergoing surgery who were at risk for recurrence. The primary endpoint was recurrence free survival.

With the success of nivolumab in the treatment of metastatic kidney cancer patients there is increased enthusiasm for using it in earlier stage patients, those who have what looks like localised cancer that then is destined to recur. We designed the trial with a neoadjuvant component with the idea of priming the immune system before surgery. This is an idea that comes from good data preclinically that shows that priming the immune system before surgery while the primary tumour is in place elicits stronger immune responses. Then also to maximise the effect of the therapy we gave adjuvant nivolumab as well to maximally engage the immune system after the primary tumour is removed. So that’s the biological basis of the study. The idea was to give this therapy to see if we could decrease recurrence free survival in patients.

The study, after 16 months of follow-up, met the futility endpoints and unfortunately this was a negative study. So if you look at the Kaplan-Meier curves there was no separation and the conclusion was that perioperative nivolumab given as we did in the study did not decrease recurrence free survival. There’s a lot of data that we still have yet to analyse in this study and, because of its unique design of giving therapy before surgery and enrolling patients based on clinical stage, that we will have to do to discern if there are some subpopulations that benefitted from this. 

There’s a lot to be done in terms of analysing subpopulations and also one of the study secondary endpoints is a lot of correlative science. Patients who underwent the treatment arm, who received systemic nivolumab, also underwent a biopsy prior to surgery. So we have tissue before surgery and we have tissue after the treatment with nivolumab and surgery and that’s going to give us a wealth of information to study the effect of the therapy on patients and biomarker discovery and analysis.

Some of the summaries from the study are, number one, it’s premature to conclude that giving neoadjuvant or adjuvant nivolumab to patients at high risk for recurrence is something we should do minus additional data. The other take-home message is that neoadjuvant trials are hard to do and this is a unique trial that brought together the urologic and the oncology communities and in a tour de force we were able to actually complete the trial, increasing my personal enthusiasm and, I think, our communities’ enthusiasm for running additional trials that have a neoadjuvant component to study the strategy further.