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2020 Bladder Cancer Review with Dr. Petros Grivas: What Every Physician Should Know

Op-Med is a collection of original articles contributed by Doximity members.

On December 5, 2020, the Society of Urologic Oncology completed their annual three-day meeting. During this virtual meeting, there was a discussion that 2020 has been the best year in history for new bladder cancer treatments for our patients. In fact, this year we have had four new FDA-approved medications that are considered practice-changing treatments for bladder cancer. 

Along that line, I had an opportunity to interview Dr. Petros Grivas, an international thought leader in urothelial cancer to discuss the cutting edge new treatments to help our patients with bladder cancer.

The following is an interview between Dr. Chandler Park, President of the Kentucky Society of Clinical Oncology, and American Society of Clinical Oncology (ASCO) Education Faculty; and Dr. Petros Grivas, Director of University of Washington Genitourinary Cancers Program, and Associate Professor at the University of Washington School of Medicine.

Dr. Park: Dr. Grivas, great to catch up with you again. I always enjoy our lively discussions at national clinical trial and bladder cancer expert roundtable meetings. Thank you for joining us for this Doximity interview.

Dr. Grivas: You are welcome. Dr. Park, great to catch up with you as well.

Dr. Park: Congratulations to you and your Javelin 100 Bladder Cancer study team for the landmark clinical study for patients with metastatic bladder cancer. As one of the leading researchers for this landmark paper, can you discuss this clinical practice-changing study for our Doximity audience?

Dr. Grivas: Thank you Dr. Park. Javelin Bladder 100 trial is a randomized phase 3 trial that randomized patients who had response or stable disease to/after 4-6 cycles of "induction" Gemcitabine/Cisplatin or Gemcitabine/Carboplatin chemotherapy in the 1L setting of advanced / metastatic urothelial cancer to either avelumab (anti-PDL1) plus best supportive care vs best supportive care alone. Patients were stratified based on best response to prior induction chemotherapy and metastatic site (visceral vs non-visceral); the time window was 4–10 weeks from end of prior chemotherapy.

Primary endpoint was OS in "all comers" regardless of PD-L1 expression and in the subset of patients with PDL1-positive tumors (based on SP263 assay). The primary endpoint of overall survival was met in both populations with a very significant difference (HR 0.69 and 0.56, respectively) and a median OS difference of 7.1 months in "all comers." Avelumab was relatively well tolerated with 7% treatment related G3 adverse events and 12% discontinuation rate due to treatment emergent (any cause) events. Progression-free survival also significantly favored the avelumab group in both populations. Results were presented at the 2020 ASCO Plenary session on 5/31/20 and published at NEJM on 9/18/20.

Based on these data, avelumab received FDA approval as switch maintenance therapy in patients with response or stable disease to induction platinum-based chemotherapy and represents the new standard of care in this setting. In July, both NCCN & European guidelines changed to reflect this new standard practice.

Dr. Park: Agree. This is a game changer for our patients with metastatic bladder cancer. Every patient should be treated with chemotherapy than maintenance avelumab. It is the new standard of care. Interestingly, when we last spoke in July at our bladder cancer expert round table we both discussed adding Dose dense MVAC as an option before maintenance Avelumab. One week later, our recommendations were updated in the NCCN Bladder Cancer guidelines, Version 6.2020. Which patients would you consider Dose Dense MVAC over Cisplatin and Gemcitabine?

Dr. Grivas: Only very few patients receive dose dense/ accelerated MVAC in the 1L setting of advanced / metastatic urothelial cancer, maybe a few young fit patients with excellent ECOG PS. Although the Javelin Bladder 100 trial did not include patients with prior dose dense/ accelerated MVAC, it is reasonable to extrapolate the results in those patients in practice in the context of platinum-based chemotherapy.

Dr. Park: Also, the NCCN guidelines updated treatment recommendations to include patients that are considered Cisplatin ineligible. These patients can receive Carboplatin and Gemcitabine with maintenance Avelumab. 

Dr. Grivas: Yes, subgroup analyses presented at the 2020 ESMO meeting showed that the OS and PFS benefit appears across different subset of patients, e.g. regardless of which induction chemotherapy regimen was given or the best response to that chemotherapy.

Dr. Park: Let’s talk about the next lines of treatment in Bladder Cancer. In December 2019, we had an FDA approval for Enfortumab Vedotin (EV) for treatment after immunotherapy. What are your thoughts on the updated EV-201: Long-term results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and PD-1/PD-L1 presented at: ESMO Virtual Congress 2020; September 19-21, 2020 — Abstract 746P?

Dr. Grivas: Very impressive data confirming durability of clinical benefit in a proportion of patients, with no new major safety signals, reiterating that Enfortumab Vedotin is a great therapy option (accelerated FDA approval) for patients who had tumor progression on prior platinum-based chemotherapy and anti-PD1/PD-L1 agents. The data from ESMO came timely along with a press release from the EV-301 phase III trial showing significant OS (HR 0.70; 95%CI 0.56-0.89; P = .001) and PFS benefit (HR 0.61; 95%CI 0.50-0.75; P < .00001) with EV vs (taxane or vinflunine) chemotherapy. Moreover, another recent press release showed impressive ORR 52% (95%CI 40.8-62.4) with EV from the cohort 2 of the EV-201 trial in patients previously treated with PD-1/L1 inhibitor, but not platinum-containing chemotherapy for advanced disease. EV is being combined with pembrolizumab with a very promising overall response rate in the phase Ib EV-103 trial; it is also being tested in the phase III EV-302 trial versus platinum-based chemotherapy; however, that phase III trial does not include switch maintenance avelumab for the patients in the chemotherapy control arm who have no progression on chemotherapy.

Dr. Park: Agree, EV is a great option for patients after they progress on immunotherapy. EV combines the specificity of an antibody to target specific cancer receptor known as Nectin-4 on bladder cancers. This medication alone demonstrated a 44% response rate in patients that progressed on platinum doublet treatment and immunotherapy. About 12% of the patients experienced a complete response. In terms of the first line setting for metastatic urothelial cancer patients that are cisplatin ineligible, I am very excited about the EV-103 trial that was presented at ASCO GU. In this study, patients with The ORR in patients with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19). This combination is very promising for first line setting for cisplatin ineligible patients. Lastly, any other thoughts on promising studies from our recent conferences such as ESMO and SUO Meetings?

Dr. Grivas: Very important data were presented from DANUBE & Keynote-361 trials in the front line setting of advanced urothelial cancer. Both are excellent, very important, large, randomized phase III trials with proper follow up; however, neither met any of the primary endpoints, therefore they will not impact practice. On the contrary, data regarding the overall response rate, response duration, and toxicity profile from Sacituzumab Govitecan (IMMU-132) in the cohort 1 of the phase II TROPHY-U-01 trial, generated significant attention and promise that this antibody drug conjugate (against Trop-2) has the potential to impact practice in the future, especially in patients with progression after prior standard therapies in this very challenging advanced urothelial cancer setting. There is a launched phase III trial (TROPiCS-04) comparing Sacituzumab Govitecan to taxane or vinflunine chemotherapy (NCT04527991). Overall, there is a lot of progress in this disease, including numerous clinical trials and emerging data on putative biomarkers.

Dr. Park: Thank you Dr. Grivas for the outstanding interview. Looking forward to catching up at future meetings. 

My personal thoughts-after reviewing all of the current data in bladder cancer.

1. Patients with newly diagnosed metastatic bladder cancers should be treated with 4–6 cycles of Gemcitabine/Cisplatin, Gemcitabine/Carboplatin, or Dose Dense MVAC chemotherapy in the first line setting. If patients have response or stable disease after platinum-based chemotherapy, patients should receive maintenance Avelumab. This is the new standard of care that all oncologists should incorporate into their practice. 

2. Enfortumab vedotin is making a big splash in metastatic bladder cancer. At the ASCO GU meeting in February 2020, Enfortumab with Pembrolizumab for first line metastatic urothelial cancer patients not eligible for cisplatin ineligible patients demonstrated an incredible 73.3% response rate. This has the potential to be the standard of care for cisplatin ineligible metastatic bladder cancer patients if the data remains strong in the Phase III trials. 

3. If a metastatic bladder cancer patient progresses on immunotherapy, patient should be treated with Enfortumab Vedotin. On the other hand, if a patient has a FGFR mutation or FGFR 2/3 fusion, they should be considered for erdafitinib based on the NEJM paperI would evaluate the side effect profile to guide treatment between Enfortumab Vedotin versus Erdafitinib if a patient has an activating mutation or fusion in FGFR2 or FGFR3.

4. I am very intrigued by CheckMate 274 trial. In October 2020, there was an early announcement for CheckMate-274, a phase III trial involving patients treated with adjuvant nivolumab after radical cystectomy in patients with high-risk, muscle-invasive urothelial carcinoma met its primary endpoint of improving disease-free survival in patients whose tumor cells expressed PD-L1 ≥1%. Although the standard of care is for patients to receive neoadjuvant chemotherapy before radical cystectomy, there are times when a radical cystectomy is done first. The data read out on this study will be very interesting to review. The data will be released in 2021. 

5. Lastly, in earlier stage of bladder cancer there was an FDA-approved treatment for BCG unresponsive, high risk non muscle invasive bladder cancer in January 2020. This is a very tough patient population for urologists. Many of these patients progress to muscle invasive bladder cancer. Treatment recommendations include cystectomy. Now, based on the FDA approval, patients can be treated with immunotherapy. 41% of the patients in the study experienced a complete response. Therefore, based on this study, immunotherapy is considered a new standard of care treatment for patients who are ineligible for cystectomy or have elected not to undergo cystectomy.

Illustration by April Brust

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