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ESMO 2020 | Updates in 1L urothelial cancer from ESMO 2020

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Thomas Powles

Thomas Powles, MBBS, MCRP, MD, Barts Cancer Institute, London, UK, gives a summary of the data being presented at ESMO 2020 for front-line therapy in urothelial cancer. These include the DANUBE study (NCT02516241) – a randomized, phase III study of first-line durvalumab with or without tremelimumab vs standard of care chemotherapy. A trend towards improved OS was observed but statistical significance was not reached. Prof. Powles also discusses the KEYNOTE-361 study of pembrolizumab combined with chemotherapy vs chemotherapy alone. The progression free survival and overall survival benefit did not reach significance in this study. This interview was recorded via an online conference call with The Video Journal of Oncology (VJOncology).

Transcript (edited for clarity)

Hi, I’m Tom Powles. I’m a medical oncologist from London. I’m giving an update today from ESMO 2020 on frontline urothelial cancer. I’m going to talk about a number of different studies. One is the durvalumab trial where durvalumab plus tremelimumab were compared with chemotherapy. In that trial it was a negative study. What we saw in that study, in the biomarker positive monotherapy durvalumab arm, was hazard ratios in the mid 0...

Hi, I’m Tom Powles. I’m a medical oncologist from London. I’m giving an update today from ESMO 2020 on frontline urothelial cancer. I’m going to talk about a number of different studies. One is the durvalumab trial where durvalumab plus tremelimumab were compared with chemotherapy. In that trial it was a negative study. What we saw in that study, in the biomarker positive monotherapy durvalumab arm, was hazard ratios in the mid 0.85s. It wasn’t enough to be statistically significant. We saw chemotherapy outperforming immune therapy initially and then immune therapy catching up in that biomarker positive population, but it wasn’t enough to take over. We also then saw the durvalumab plus tremelimumab arm which was in an ITT population, not a biomarker positive population. And again, the hazard ratios was within a similar field but actually the response rates for the durva plus treme were higher than that with the durvalumab alone.

What we’re seeing there is tremelimumab actually adding a little bit, maybe 10%, to the activity of durvalumab alone, not enough for a positive trial, but really provocative because it suggests that CTLA-4 inhibition has a role to play. I guess the next steps are upcoming trials with ipilimumab and nivolumab and if we pick the right population in that trial, it might be positive. So in the Danube trial, a negative study, we show long-term durable remissions with immune therapy, but not enough to beat chemotherapy. We saw tremelimumab adding to the activity, which is kind of relevant but it’s not enough for a positive study as things currently stand. Then the really important KEYNOTE-361 trial pembrolizumab versus pembrolizumab plus chemotherapy versus chemotherapy. Another thousand patients, three-arm trial. Again, pembrolizumab and the biomarker positives, as with durvalumab, not enough to get over the line. Chemotherapy, performing best, pembrolizumab catching up in the end, the biomarker not working as well as we’d like.

So a negative arm there and then surprisingly chemotherapy plus pembrolizumab also not beating chemotherapy alone. The hazard ratios again, not dissimilar to the previous IMvigor130 data we saw with PFS hazard ratios and OS hazard ratios. The OS at 0.9, the PFS hazard ratios in the late 0.7s. So, a 20% delay in progression-free survival, which actually wasn’t statistically significant in this trial. Of course, it was in the atezolizumab study. So the InVigor130, chemo plus atezolizumab was statistically significant for PFS. That’s probably because it was a larger trial. I don’t think there’s anything that atezolizumab plus chemotherapy is doing that pembrolizumab plus chemotherapy can’t do. Then of course, the OS signal as with other studies is negative. It’s important to remember the atezolizumab trial doesn’t yet have a final OS signal.

So although at the interim point, it didn’t look statistically significant, it’s possible it may pan out. Remember the current hazard ratio for survival there is 0.83 so I imagine it would have to go a little bit in the right direction to be statistically significant. So the summary of that trial is the chemotherapy plus immune combination doesn’t look synergistic or additive. Wasn’t quite enough to get over the line from either a PFS or an OS perspective. The data somewhat mirrored the data we saw for the IMvigor130 atezolizumab study.  the atezolizumab study was positive and That’s partly because the trial design was slightly different. Is it practice changing? Well, the atezolizumab study is not yet final/has final data but we’d need to have a significant survival advantage and at the moment, 0.83, I’m not sure it will hit that. I think that’s the summary of those two trials.

I guess the third thing that needs to be talked about is the maintenance avelumab study, where you sequence chemotherapy followed by avelumab and that does have a survival advantage of 0.69. We saw some updated data at ESMO today, at this meeting. The reality, I think of the situation is that approach, as it currently stands, appears to be more attractive than either monotherapy and bio-marker positives or the chemotherapy combination approach as things currently stand. I suppose that’s my summary. I hope it was not too confusing. There’s a lot to say. I guess the bottom line is, this frontline chapter with these frontline randomized trials, haven’t been as positive as we would’ve liked. We hoped the chemotherapy combinations would be more active, as was the case in lung cancer, and we hoped that monotherapy with the biomarker would get over the line easily and beat chemotherapy and that wasn’t the case either. Therefore, the maintenance approach with the survival signal is probably the best that we have as things stand.

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