New emerging treatment options and targeted therapies for bladder cancer

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Published: 4 Jun 2020
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Dr Arlene Siefker-Radtke and Dr Yohann Loriot

Dr Arlene Siefker-Radtke (MD Anderson Cancer Center, Houston, USA) and Dr Yohann Loriot (Institut Gustave Roussy, Villejuif, France) discuss the latest emerging treatment options, including targeted therapies from ASCO 2020.

The experts begin the session, by discussing the results from the practice-changing JAVELIN Bladder 100 trial. Dr Loriot notes that these results are exciting and provide a new treatment strategy for advanced urothelial carcinoma patients in the first-line.

Dr Siefker-Radtke and Dr Loriot go onto to discuss the emerging use of targeted therapies in bladder cancer, especially FGFR inhibitors and the latest data presented at the meeting.

Dr Siefker-Radtke outlines the main results from the BLC2001 trial, which is investigating the use of erdafitinib in locally advanced or metastatic urothelial carcinoma.

She also describes the phase Ib/II FORT-2 study, which evaluated the safety and efficacy of another FGFR inhibitor, rogaratinib in combination with atezolizumab. Dr Loriot comments that the strategy used in this trial, which identified FGFR mRNA over-expression could broaden the patient population eligible for this treatment. However, he also warns that the response rate in these patients could be lower.

Dr Siefker-Radtke concludes and states there are various treatment combinations being explored for bladder cancer currently, involving immunotherapy, chemotherapy and targeted agents. 
 

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

ASR:       Hello, I am Arlene Siefker-Radtke, a Professor of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center where I do all bladder all the time. I’m here today with ecancer and my colleague, Dr Yohann Loriot, who is the Director of Bladder Cancer at Gustave Roussy in Paris, France. We’re here today to discuss some of the ASCO abstracts that have presented, or been presented, in a virtual fashion for those of us who had to attend remotely. So, welcome Yohann.

YL:         Hello Arlene.

ASR:       I wanted to ask you, with the excitement in bladder cancer at ASCO, what did you think of the plenary session and having a bladder abstract there?

YL:         Yes, it was very incredible because I think it is the first time that an abstract was presented during the plenary session at ASCO for bladder cancer. So it was very great news for physicians but also for the patients because now we can discuss bladder outside the hospital or in the media as well. So it’s very important, first, for the patients. Obviously this study was very great because we have now data supporting that we can change the way we are treating patients as first line. So it was a great, great moment.

ASR:       It certainly was and for those who haven’t yet viewed the abstracts there was a trial of gemcitabine platinum plus or minus avelumab in the first response or maintenance setting. In this clinical trial it took patients who had stable disease or better as response to their first line chemotherapy and they were randomised to either avelumab or best supportive care. As Yohann has indicated, we saw a significant p-value, suggesting giving immunotherapy with avelumab in that front line maintenance setting was associated with an improvement in survival from 14 to 21 months. But avelumab has now entered the ranks of one other checkpoint inhibitor for bladder cancer, pembrolizumab, which also showed a significant p-value in a large randomised trial. What do you think about the options of giving immunotherapy? Is it better to give it in the maintenance setting or is it better to give it second line at progression?

YL:         It is, I think, the most relevant question we can have from this study, the JAVELIN study. It’s still a case by case discussion we should have. For example, a patient who achieves a complete response after 4-6 cycles of chemotherapy will maybe want to have a break because he is fed up with the side effects of the chemotherapy. For this patient it’s fine to give a break and maybe to give subsequent immunotherapy like pembrolizumab as second line. But for a patient who achieved only stable disease with bone mets, liver mets, I would prefer to give maintenance immunotherapy with avelumab in this patient. So overall we have level 1 evidence with avelumab but still we have maybe to discuss case by case with the patient which strategy is the better for the patient.

ASR:       That’s a really good point because, as Yohann mentioned, patients who have a high disease burden, we do know from the pembrolizumab data they did not do as well, especially in the setting of liver metastases. So it does seem that there is a cohort of patients who would benefit from receiving immunotherapy right away before their disease is as explosive. But we also have to consider there’s risk as well, both the risk of toxicity if patients do not yet require treatment or possibly the cost to their pocketbook going on treatment that maybe would not benefit them. So I think it is a very exciting time and seeing another agent show a significant p-value impacting survival really tells us that immunotherapy is here to stay for the treatment of urothelial cancer. I know there are several other abstracts of novel agents that have shown a lot of interest and especially the work with erdafitinib. I know that you’re a definite collaborator on this trial as well, Yohann.

YL:         Yes, there is a huge interest in targeted therapy in bladder cancer and, of course, the FGFR inhibitors are maybe the top leaders in the field of targeted therapy in bladder cancer. So you are lucky in the US because you have access to erdafitinib in second line. It’s not the case in Europe because we have to wait for the phase III trial which enrols still patients. But we had data here at ASCO trying to combine an FGFR inhibitor with immunotherapy, that is something we are willing to look at. There are many phase I and phase II trials like the NORSE combining erdafitinib with cetrelimab and at ASCO we got some data from a different FGFR inhibitor, regorafenib, combined with atezolizumab as well.

ASR:       That’s a really good point. We’re seeing FGF inhibitors working well in bladder cancer. The long-term follow-up data from the erdafitinib trial suggests that there’s a median overall survival of around 11 months with a median two years of follow-up and still seeing that 40% objective response rate that was confirmed on a second study. Building on that backbone of FGF targeted therapy we saw other combinations being presented, specifically the erdafitinib with cetrelimab combination which is showing response rates of around 50% in the phase I portion and other FGF inhibitors as well such as rogaratinib plus immunotherapy which was showing an objective response rate around 60% in the small phase I portion of the trial. So we have several FGF combinations that are coming in to play. I know the rogaratinib strategy was still looking at mRNA or amplification, what do you think about that strategy in general, Yohann?

YL:         It’s still unclear if an amplification or an over-expression of FGFR3 is a very good target in bladder cancer. We don’t have very strong data to support that, we are sure that fusion and mutation are oncogenic but for the over-expression we are not sure. So the strategic use in the trial can broaden the number of patients that could be treated with an FGFR inhibitor but maybe the response rate could be lower because, once again, an amplification or an over-expression is not as oncogenic as a mutation or a fusion.

ASR:       That’s a good point as well. When we saw the randomised data from single agent rogaratinib the response rate looking at amplification was lower, around 20%, compared to the response rate we saw with erdafitinib which focussed more on those FGFR3 mutations and fusions. There are other targeted agents as well, such as infigratinib and we saw some data presented at ASCO as well suggesting a response rate maybe as high as 40% but a median survival of seven months. Do you think that accounts for any differences in the drug or differences in trial, Yohann?

YL:         I think there is a different reason. The specificity of the inhibitor could be different between infigratinib and erdafitinib, for example, and maybe the trial and the way that we personalise the dose with erdafitinib because it’s been shown that the phosphate level was correlated with the response. So that’s something that could explain the difference in terms of response.

ASR:       So that’s definitely a good point, achieving the relevant dose could play an impact on response. When you also look at the two drugs the infigratinib is given on an intermittent schedule, three weeks out of four, compared to erdafitinib which is given on a continuous schedule. So I don’t think we can declare any definitive evidence that one is definitely better than the other without a randomised trial design and it will take more time to see how many of the other FGF inhibitors pan out as single agents. But with the combination strategies with immunotherapy the hope is that we will soon have these options that provide more long-term durable benefit because while erdafitinib and other FGF inhibitors work, they are like tyrosine kinase inhibitors and the benefit does appear to be more limited to time while you were on treatment rather than durable responses off therapy, or at least that has been my impression. Is that yours as well, Yohann?

YL:         Yes, I think that the most important endpoint when we combine FGFR inhibitors with the immunotherapy is the durability of the response and if we look at the melanoma field when you combine targeted therapy and immunotherapy you can increase the response rate but the feeling is that maybe the durability is longer. So that’s something we want to show in bladder cancer as well.

ASR:       Yes, that’s definitely going to be more important as the field develops, showing that durability of response which we’ve seen with immunotherapy options creating durability even in patients off treatment. So building to those better combinations or building on that backbone of immune checkpoint inhibition seems like a very reasonable strategy to help enhance the field. What do you think about other combination strategies that are being developed in urothelial cancer?

YL:         So there are many different combinations ongoing, one reported at this ASCO was to combine cabozantinib with immunotherapy, so atezolizumab. There is a rationale to that because we know that angiogenesis is one of the mechanisms of resistance to immunotherapy and we have, with the example from the renal cancer when we combined angiogenesis inhibitors and immunotherapy you can expect a very good outcome. But there was a phase I trial combining cabozantinib and atezolizumab and I think the data is quite encouraging. In this data we had patients previously treated with chemotherapy and the response rates were around 25% so it’s quite good but we need now to provide more data to know if the combinations are excellent combinations.

ASR:       So it sounds like combinations of immunotherapy either sequenced with chemotherapy or possibly combined with chemotherapy, combining immunotherapy with other targeted agents like FGF inhibitors, that we’re seeing a rationale for combinations with MET and VEGF inhibitors, with the cabozantinib data. So it really does appear that we’re using immunotherapy as that backbone and trying to build upon the immune response to enhance the long-term benefit for our patients. So I’d like to take this time to thank you, Yohann, for your insights on the treatment of urothelial cancer. I’d like to thank all of our listeners who are listening today and I hope that everyone is remaining appropriately socially distant during these coronavirus times as we work towards getting back together and continuing to find better treatments for urothelial cancer. Thank you.

YL:         Thank you, Arlene.