Immunotherapy promise for gynaecologic extra-renal clear cell carcinomas

Prof Don Dizon - Lifespan Cancer Institute, Providence, USA

I am fortunate to be presenting BrUOG 354 which is a phase II randomised non-comparative clinical trial that looked at two regimens of immunotherapy for people with non-renal clear cell cancers. The immunotherapy regimens that we tried were nivolumab monotherapy and then nivolumab in combination with ipilimumab. Ultimately this was done in people with gynaecological clear cell cancers, 85% of the volunteers had ovarian cancer. It was designed as a two-stage clinical trial, meaning we enrolled a limited number of people in the first stage and then stopped the trial to see which arm, if either or both, had enough activity to warrant continuation of the trial. When we enrolled enough people in the first stage and looked at the results, we decided that although there was activity with nivolumab alone it didn’t warrant to continue to treat people on that arm and in the second stage everybody got the combination of nivolumab with ipilimumab.

The results I’m presenting today are the overall response rates which with nivolumab was 14% and with the combination was 33%. Now, complete responses were only seen in the treatment using combination therapy; there were no complete responders in the people who got nivolumab alone. The median progression free survival was 2.2 months with nivolumab and the median overall survival with single agent was about 6 months. When you look at the combination, the median progression free survival was 17 months and median overall survival was 24 months. It’s important with the combination that there are still people who are receiving therapy, so the upper limit of that confidence interval around overall survival hasn’t been reached.

Also importantly, we looked at safety and we saw no new safety signals beyond what we already know around treatments with immunotherapy. So encouragingly we didn’t find this particular patient population at risk for any new or worrisome side effects. In fact, the most common of them was hypothyroidism, a well-known side effect of immune checkpoint inhibitors.

So, in conclusion, what we can say is that a common combination immunotherapy regimen and a commonly available single agent regimen using nivolumab or nivolumab with ipilimumab represents a very important combination for people with clear cell cancers which, by the way, is a) a rare malignancy of the gynaecological tract, representing around 10% of those cancers; b) tends to portend a worse prognosis in general because they do not respond as well to standard chemotherapy and if you do get a response it tends not to last; and c) this is a group of patients who if the disease recurs face a very worrisome prognosis in terms of staying disease free but also living through that diagnosis. Showing that immunotherapy has important activity is a really important step in our personalisation of therapies for ovarian cancer and it is my hope that this regimen becomes more available to people who have clear cell cancers.

What could be the impact of this research?

The impact of this trial is severalfold. One, we were able to do this trail during COVID19 and it really required a process of decentralisation, meaning we were able to ship these drugs on trial to where the patients lived rather than requiring the patients to come to Brown for treatment. We were only able to do that because the United States FDA allowed it and our sponsor, Bristol Myers, also agreed to do it. But where there is a will, you can decentralise clinical trials with drugs that everyone has developed comfort around. So that’s number one, a very important signal.

The second is we can now extend the option of immunotherapy to people who have a clear cell cancer based on this data which represents the largest group of people with clear cell treated with immunotherapy on study.

Anything else you would like to add?

The other thing I would add is in a time where we want to make sure that our trials represent the diversity of the United States population, for example, we are able to show it is possible to enrol a diverse population. Indeed, we actually under-sampled white patients in this trial if you look at the proportion of patients with clear cell who get this, and we enrolled over 11% were from a non-white background. The only reason that we are able to do that, and it’s what we know about clinical trials and diversity, everyone who saw us for consideration of the trial were actually offered the trial.