Thomas Powles, MD, MRCP
There is an urgent need to develop new drugs for the treatment of urothelial cancer. Chemotherapy was the only approved treatment in advanced disease for 40 years, which was associated with response rates of between 30% and 50% in the front-line setting.1-3 However, durable remissions were infrequent, and cross resistance with subsequent chemotherapy occurred.4,5 Chemotherapy in platinum-refractory diseases is largely ineffective.
The introduction of immune checkpoint inhibition a few years ago made a huge impact for approximately one-fifth of patients with platinum-refractory urothelial disease. Treatment resulted in long-term durable remissions for some.4,5 Sadly, we have not been able to predict which patients benefit, and the programmed cell death ligand 1 (PD-L1) biomarker has been inconsistent.
Randomized data in this setting show an overall survival benefit for pembrolizumab compared with chemotherapy (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.59–0.91) in unselected patients, which remains the gold standard. However, this is compared with largely ineffective chemotherapy, so the bar was low. Recent randomized front-line data with the combination of atezolizumab and chemotherapy hold much promise.12 Immune checkpoint inhibitors appear to have better efficacy earlier in the disease, when activated T cells are more prominent.6,7 Many trials are ongoing in the front-line setting as well as the muscle-invasive arena, and results are eagerly anticipated.
Fibroblast growth factor receptor (FGFR) inhibitors such as erdafitinib have also shown activity in treatment-refractory urothelial carcinoma.8 A total of 40% of tumors with DNA alterations to FGF respond to erdafitinib in this population. However, only about one-fifth of patients harbor these alterations, reducing the impact of this cavalry charge. Also, more data on duration of response are required, as it may not be as impressive as that seen with immune therapy. Further studies, earlier in the disease and with combinations, will be needed to be transformative; such studies, including the NORSE trial, are ongoing.
‘Eye-Catching’ Data on Enfortumab Vedotin
So, although there has been recent progress in advanced platinum-refractory urothelial carcinoma, there is still a lot to do. The phase II EV-201 study of enfortumab vedotin, reported by Rosenberg et al and highlighted in this issue of The ASCO Post, is a significant step in the right direction.9 Enfortumab vedotin is an antibody-drug conjugate targeting Nectin, which is expressed in the vast majority of urothelial carcinomas.
The study population consisted of patients with tumors exposed to both platinum-based therapy and immune checkpoint inhibition. Further chemotherapy, which is a current standard of care, would be expected to be associated with response rates in the region of 10% to 15%. The confirmed response rate of 44%, the duration of response of 7.7 months, and the median overall survival of approximately 1 year in the trial of enfortumab vedotin are eye-catching data. However, enfortumab vedotin is associated with toxicity, particularly peripheral sensory neuropathy and hyperglycemia, which requires
consideration. Guidelines have already changed to support the use of enfortumab vedotin in this setting.10 A confirmatory randomized phase III study is ongoing. It is likely that patients will want this therapy prior to the availability of data from this randomized trial.
There are alternatives to enfortumab vedotin in this setting, such as erdafitinib. Comparing phase II data is futile. However, the FGF approach requires molecular testing, which delays treatment and selects out patients.
Where Is Enfortumab Vedotin Headed Next?
Where does enfortumab vedotin go next? Phase I/II data for enfortumab vedotin in combination with pembrolizumab were presented in June 2019.11 The study was performed in the front-line cisplatin-ineligible setting. Response rates were more than 70%. These results seem groundbreaking, when one considers carboplatin and gemcitabine are associated with much lower response rates.1 If these data were repeated in front-line randomized trials, enfortumab vedotin plus immune checkpoint inhibition could supersede chemotherapy altogether.
When one looks forward, replacing front-line chemotherapy and neoadjuvant chemotherapy may be possible for enfortumab vedotin.— Thomas Powles, MD, MRCP
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However, the efficacy results with enfortumab vedotin plus pembrolizumab need to be taken into context with other ongoing front-line trials. The IMvigor130 trial, which is comparing chemotherapy with or without atezolizumab, recently reported a progression-free survival advantage for chemotherapy plus immune therapy (HR = 0.82, 95% CI = 0.70–0.96), and the response rate for the combination was 47%.12 Comparing phase II and III trials is also futile, but enfortumab vedotin plus pembrolizumab looks competitive.
When one considers the past 5 years of drug development in urothelial carcinoma, it could be argued that immune therapy did not reach the heady heights seen in melanoma and renal cancer. Other agents with a novel mechanism of action such as enfortumab vedotin could help fulfill these expectations. When one looks forward, replacing front-line chemotherapy and neoadjuvant chemotherapy may be possible for enfortumab vedotin. This is likely to be in combination with other agents. There is a bright light at the end of the tunnel in urothelial carcinoma, and I don’t think it’s a train. ■
Dr. Powles is Professor of Urology Cancer and Director of Barts Cancer Centre, London.
DISCLOSURE: Dr. Powles reported financial relationships with AstraZeneca, Roche, Exelixis, Bristol-Myers Squibb, Novartis, Pfizer, Merck Sharp & Dohme, and Ipsen.
REFERENCES
1. De Santis M, Bellmunt J, Mead G, et al: Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer ‘unfit’ for cisplatin-based chemotherapy: Phase II results of EORTC study 30986. J Clin Oncol 27:5634-5639, 2009.
2. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068-3077, 2000.
3. Sternberg CN, de Mulder P, Schornagel JH, et al: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42:50-54, 2006.
4. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017.
5. Powles T, Durán I, van der Heijden MS, et al: Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial. Lancet 391:748-757, 2018.
6. Powles T, Kockx M, Rodriguez-Vida A, et al: Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 25:1706-1714, 2019.
8. Loriot Y, Necchi A, Park SH, et al: Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 381:338-348, 2019.
9. Rosenberg JE, O’Donnell PH, Balar AV, et al: Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 37:2592-2600, 2019.
10. Univadis: ESMO update on bladder cancer guidelines. Available at https://www.univadis.co.uk/viewarticle/esmo-update-on-bladder-cancer-guidelines-689008. Accessed November 25, 2019.
11. Hoimes CJ, Rosenberg JE, Srinivas S, et al: EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. ESMO Congress 2019. Abstract 901O. Presented September 28, 2019.
12. Grande E, Fabre P, Galsky M, et al: IMvigor130: Efficacy and safety from a phase III study of atezolizumab as monotherapy or combined with platinum-based chemotherapy vs placebo in previously untreated locally advanced or metastatic urothelial carcinoma. ESMO Congress 2019. Abstract LBA14_PR. Presented September 30, 2019.
