Editor's note: Platinum-based chemotherapy remains the cornerstone of treatment for advanced urothelial cancer (UC), but it still does not meet the long-term survival needs of patients; the 39th European Association of Urology Congress held in Paris, France (EAU24) focused on a number of urothelial cancer research hotspots. Dr. Jens Bedke from Klinikum Stuttgart Katharinen Hospital shared the EV-302/KEYNOTE-A39 research results at the conference. " Oncology Frontier " specially invited Dr. Jens Bedke, a well-known expert in the field, to share the current status of immunotherapy and the future treatment of UC.Dr. Jens Bedke
Klinikum Stuttgart Katharinen Hospital
Urology Frontier：Currently, platinum-based combination chemotherapy is still the first-line standard treatment for advanced urothelial carcinoma（UC）. What unmet needs do you think exist for patients with advanced UC?
Dr. Jens Bedke: Thanks a lot for inviting me. So, I think it’s a question of high importance: what are the unmet clinical needs in bladder cancer, especially metastatic bladder cancer? We know that patients are getting older, and the incidence and the general burden of metastatic urothelial cancer is increasing. And the mainstay for treatment is currently platinum-based chemotherapy. What we know about platinum-based chemotherapy is that it’s effective, but we only have long-term survivors on a 5 to 10% level with cisplatin and carboplatinum-based regimens. Even if we have maintenance regimens and concepts after the induction period of platinum-based chemotherapy, response rates are there but they could be higher, and especially, long-term survivors are still missing in this situation. This leads to the question: how can we improve and go beyond platinum-based chemotherapy for the future.
Urology Frontier：Immunotherapy for UC has progressed rapidly in recent years, and NEJM also announced the latest EV-302/KEYNOTE-A39 study results. What breakthroughs did this research achieve?
Dr. Jens Bedke: Well, if you look back, it’s like five to six years since we had the introduction of immune checkpoint inhibitors in the metastatic setting of bladder cancer. Without any doubt, the IO (immunotherapy) agents have definitely improved the outcomes, the survival rates, and also the progression-free survival rates in metastatic bladder cancer patients, either after the induction of platinum-based chemotherapy or if they are platinum-ineligible, or just if there’s a PD-L1 positive fraction of patients receiving checkpoint monotherapy with Pembrolizumab or Atezolizumab. And of course, in the second-line setting, the checkpoint inhibitors. And I think what we have developed over the past is that we have the mainstay of chemotherapy, then we had the addition of the immune checkpoint inhibitors, maybe just as a single agent.
And now, the approach of the EV-302 was a totally new design to combine the IO agents, here the PD-1 antibody Pembrolizumab, with specially designed chemotherapy from the antibody-drug conjugate Enfortumab Vedotin. So, Enfortumab Vedotin is a Nectin-4 targeting antibody, and Nectin-4 is a cell surface protein which is expressed on the cell surface of the tumor cells. And to this antibody, we have a chemotherapeutic agent which is called MMAE, and by the internalization of the Nectin-4 antibody then Enfortumab Vedotin, we have this direct cytotoxic activity of Enfortumab Vedotin, but we also have bystander effects and they have an immunogenic cell death which is provoked by Enfortumab Vedotin. And the rationale was to combine the ADC plus the checkpoint inhibitor in the phase 3 trial EV-302. So, what has been done in EV-302, it was a phase 3, 1-to-1 randomized trial; patients received EV plus Pembrolizumab in three-week cycles. EV was given on day 1 and day 8, and they had the chemotherapy with Gemcitabine/Cisplatin or Gemcitabine/Carboplatin as a comparator. And the trial definitely had a positive outcome. The dual primary endpoints of progression-free survival and overall survival were significantly met.
EV-302 had two dual primary endpoints which were significantly met. So, the progression-free survival of EV plus Pembrolizumab compared to platinum-based chemotherapy was doubled; we had a PFS of around 12 months compared to six months with platinum-based chemotherapy in the EV-302 trial. And in addition, also the overall survival was significantly improved; the second dual primary endpoint, and they had a median overall survival of 32 months observed by EV plus Pembrolizumab in this first-line setting of metastatic bladder carcinoma. And last but not least, the response rate; they had a response rate of 68% with EV plus Pembrolizumab, and 30% of the patients had a complete response.
Now, what was new at this EAU meeting, we presented an update of the upper tract (ureter, renal pelvis) and bladder carcinoma. So, 27% of the patients in EV-302 had an upper tract carcinoma. And what we observed for the PFS and OS as a subgroup analysis, that results for the PFS and OS, but also the response rates were in line with the all-comer cohort for the upper tract. I think this is a very important signal because usually, renal pelvis and ureter, so the upper tract urothelial carcinoma, have a lower response to platinum-based therapy. And this is, let’s say, a location of concern. And the results of EV-302 presented here at the EAU meeting demonstrate that it’s very active and as active as the classical bladder carcinoma.
Urology Frontier：Combined immunotherapy may increase adverse reactions. How do you think it should be managed in clinical practice?
Dr. Jens Bedke: Well, as always, if you have new classes of drugs, we have new side effects of special interest. And what is maybe new or what is of importance, we know that immune checkpoint inhibitors can induce dermatitis. We knew that from EV that dermatitis is of concern, and in the combination, skin reactions are adverse events of special interest. Another special interest is the neuropathy, the sensory or sometimes motor neuropathy which can develop under EV plus Pembrolizumab. How shall we manage that? I think first of all, it’s of importance to have awareness for these side effects and that you have an interdisciplinary management. So, especially if you gain new experience with this combination. So, what can you do? Well, of course, you have the possibility of dose reduction, dose modification, dose interruptions with these agents. Please have an early monitoring for these side effects so that they are tracked and the side effects once they develop are managed promptly. And if you start early treatment of the adverse events, then I think you will have success but they do not run away and aggravate.
Urology Frontier：How should we identify the advantaged groups and thereby improve the clinical benefits for patients?
Dr. Jens Bedke: Well, I mean, with metastatic disease as present, it’s present. So, the question is, how can you prevent the development of metastatic disease? And I think that we have great development in the perioperative setting, new adjuvant treatment either in clinical trials with this combination of EV plus Pembrolizumab or other ADCs, or as we have observed here at the current EAU Congress, the latest update from the CheckMate-274 trial. This is an adjuvant trial of Nivolumab after cystectomy, and we have seen the overall survival data of this trial here at this EAU Congress. Nivolumab in the adjuvant scenario for one year, and the overall survival was a descriptive analysis, but the difference between the Nivolumab-treated arm and the control or the placebo-treated arm was very obvious, so the difference was increasing over time. And we had a 10-month improvement in overall survival, I think, was after three or four years in this trial which was presented. So, start treating early in the adjuvant setting, and I think we can select patients and prevent the development of metastatic disease. On the other hand, this question always relates to biomarkers. The field of biomarkers is very wide, but we had a very interesting presentation here from the IMvigor011 trial, which had a ctDNA approach. If they were positive, they were randomized to adjuvant treatment of Atezolizumab versus observation or placebo, and they had a ctDNA negative fraction which was not trial eligible. And here at the Congress, the ctDNA negative patients and their follow-up were presented, and it was very interesting that if a patient had a ctDNA negative status, the risk of developing a relapse of bladder carcinoma after cystectomy was very low. And the level of ctDNA was measured over time. If they turned positive from negative to positive ctDNA, then the risk of recurrence is there and increases.
