Recent Advances in the Treatment of Advanced Urothelial Carcinoma

Please note: the following text was written in 2022 and is an unpublished draft of a publication I wrote for a urologist. It is one example of the type of writing I display on this site as part of my portfolio.

Bladder cancer is the sixth most common cancer in men and the seventeenth most common in women, leading to 150,000 deaths each year worldwide.1 For three decades, the first-line treatment option for advanced or metastatic urothelial carcinoma (mUC) has been cisplatin-based chemotherapy. However, 50% of patients are cisplatin-ineligible, and the alternative, carboplatin plus gemcitabine (GCa), is less effective and more toxic. The need for equally effective, safer treatments has led to the exploration of new therapeutic targets. In the last six years, several drugs have been FDA approved for the treatment of locally advanced or mUC, including PD-1/PD-L1 inhibitors, fibroblast growth factor receptor (FGFR) inhibitors, and antibody-drug conjugates (ADCs).2,3

Immune Checkpoint Inhibitors

For some patients treated with NAC and radical cystectomy (RC) residual cancer remains. The use of chemoimmunotherapeutic agents, known as immune checkpoint inhibitors (ICIs), can optimize cisplatin-based chemotherapy. ICIs are monoclonal antibodies that block the PD1/PD-L1/PD-L2 pathway, an overexpressed pathway in some UCs. Five ICI’s have been approved by the FDA for second-line treatment for locally advanced or mUC without a PD-L1 expression testing requirement. Two of these have also been approved as first line treatment under select criteria.

Pembrolizumab and atezolizumab gained FDA-approval in 2017 as first-line treatment options in cisplatin-ineligible patients with tumors highly expressing PD-L1. Pembrolizumab is a PD-1 inhibitor and is the only ICI which has gained approval via the standard regulatory pathway with Level 1 evidence. In the KEYNOTE-045 phase 3 trial, 542 platinum-refractory patients with advanced UC were placed on either pembrolizumab or the investigator’s choice of chemotherapy (paclitaxel, docetaxel, vinflunine). Pembrolizumab achieved a higher objective response rate and was better tolerated than chemotherapy.4

Atezolizumab blocks PD-L1 and received accelerated FDA approval in May 2016 after a phase 2 trial (IMvigor210) conducted in platinum-refractory and treatment-naïve, cisplatin-ineligible patients. Atezolizumab demonstrated an ORR of 15% in this patient group, with 15% of patients seeing grade 3 or 4 adverse events (AEs).5 Atezolizumab was better tolerated than chemotherapy (docetaxel, paclitaxel, vinflunine) and both treatments performed similarly in the PD-L1 high population in the subsequent phase 3 trial (IMvigor211).6

Durvalumab, nivolumab and avelumab are three additional ICIs which have received accelerated approval for second-line use after demonstrating ORRs in phase 1 and 2 trials between 18% and 24%. Durvalumab (PD-L1 inhibitor) demonstrated an ORR of 17.8% in a phase 1/2 trial in 191 patients who progressed on, were ineligible to, or refused cisplatin-based chemotherapy.7 In patients with high PD-L1 tumors, the ORR observed was 27.6%. The ongoing phase 3 NIAGARA trial is investigating durvalumab as a concurrent treatment with chemotherapy and is expected to be completed by 2025.8

Nivolumab (PD-1 inhibitor), was tested as a second-line treatment in 265 patients after platinum-based chemotherapy, demonstrating an ORR of 19.6% in the entire study population and 28.4% in patients with tumors expressing PD-L1 at greater than 5%.9 It is being investigated in the phase 3 trial ENERGIZE as a concurrent treatment with chemotherapy, which is expected to be completed by 2025.10

Avelumab was similarly evaluated in a second-line setting in 249 patients who received at least one platinum-based chemotherapy treatment, demonstrating an ORR of 17%, with a 28% ORR in high PD-L1-expressing tumors.11 A phase 2 trial (AURA) investigating avelumab as a neoadjuvant therapy with chemotherapy versus chemotherapy alone is expected to be completed by the end of this year.12

FGFR Inhibition

FGFR alterations, especially FGFR3, are present in up to 20% of advanced stage UCs.13,14 Overexpression of FGFR can lead to cell proliferation, survival migration and invasion, and angiogenesis. The most extensively studied FGFR inhibitor is erdafitinib, which was FDA-approved to treat locally advanced or mUC in 2019. Patients must have susceptible FGFR3 or FGFR2 genetic alterations and have progressed within 12 months of platinum-based chemotherapy to be eligible for treatment. Erdafitinib demonstrated a high ORR of 42% in a phase 2 trial in this group of patients.15 Even in those treated previously with ICIs, erdafitinib showed a clinical response in 70% of patients.

Antibody Drug Conjugates

ABDs consist of an FGFR3-specific monoclonal antibody (MoAb), a protease-cleavable linker, and a chemotherapeutic agent. The cytotoxic agent is released inside cells once the ADC is internalized, allowing for more targeted chemotherapy at higher doses. ADCs enter cells through a variety of highly expressed cell surface proteins, including nectin-4, which is overexpressed in mUC.16 Enfortumab veodotin (EV) is an MoAb targeting nectin-4 and is linked to vedotin. In a phase 2, single-arm study, EV was administered to patients with mUC who had been previously treated with PD-1/PD-L1 inhibitors and platinum-based chemotherapy. EV demonstrated an ORR of 44% in 125 patients.17 This study led to accelerated approval for EV in 2019 for patients with locally advanced or mUC. EV has also been explored in a first-line setting combined with pembrolizumab in a phase 1/2 study of 45 patients with mUC, demonstrating a 73% ORR.18

Future Directions

ICIs are being investigated in phase 3 trials in the stand-alone, neoadjuvant, adjuvant, bladder-sparing and post-surgical setting. Current evidence supports their use in neoadjuvant settings, but future research will determine if they will change current standards. Other emerging treatments of advanced or mUC include sequential therapy, the investigation of dual ICI treatment, antiangiogenic therapy, and narrowing of patient selection.

References

1.        Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018;68(6):394-424. doi:10.3322/caac.21492

2.        Patel VG, Oh WK, Galsky MD. Treatment of muscle‐invasive and advanced bladder cancer in 2020. CA: A Cancer Journal for Clinicians. 2020;70(5):404-423. doi:10.3322/caac.21631

3.        Renner A, Burotto M, Valdes JM, Roman JC, Walton-Diaz A. Neoadjuvant immunotherapy for muscle invasive urothelial bladder carcinoma: will it change current standards? Therapeutic Advances in Urology. 2021;13. doi:10.1177/17562872211029779

4.        Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. The New England journal of medicine. 2017;376(11):1015-1026. doi:10.1056/NEJMOA1613683

5.        Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (London, England). 2016;387(10031):1909-1920. doi:10.1016/S0140-6736(16)00561-4

6.        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 (London, England). 2018;391(10122):748-757. doi:10.1016/S0140-6736(17)33297-X

7.        Powles T, O’Donnell PH, Massard C, et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA oncology. 2017;3(9). doi:10.1001/JAMAONCOL.2017.2411

8.        Durvalumab+ Gemcitabine/Cisplatin (Neoadjuvant Treatment) and Durvalumab (Adjuvant Treatment) in Patients With MIBC – Full Text View – ClinicalTrials.gov. Accessed February 13, 2022. https://clinicaltrials.gov/ct2/show/NCT03732677?term=NCT03732677&draw=2&rank=1

9.        Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. The Lancet Oncology. 2017;18(3):312-322. doi:10.1016/S1470-2045(17)30065-7

10.       Sonpavde G, Necchi A, Gupta S, et al. ENERGIZE: A Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. Future Oncology. 2019;16(2):4359-4368. doi:10.2217/FON-2019-0611

11.       Apolo AB, Ellerton JA, Infante JR, et al. Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. Journal for immunotherapy of cancer. 2020;8(2). doi:10.1136/JITC-2020-001246

12.       Martinez Chanza N, Soukane L, Barthelemy P, et al. Avelumab as neoadjuvant therapy in patients with urothelial non-metastatic muscle invasive bladder cancer: a multicenter, randomized, non-comparative, phase II study (Oncodistinct 004 – AURA trial). BMC Cancer. 2021;21(1). doi:10.1186/S12885-021-08990-3

13.       Weinstein JN, Akbani R, Broom BM, et al. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315-322. doi:10.1038/NATURE12965

14.       Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017;171(3):540-556.e25. doi:10.1016/J.CELL.2017.09.007

15.       Siefker-Radtke AO, Necchi A, Park SH, et al. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). https://doi.org/101200/JCO20183615_suppl4503. 2018;36(15_suppl):4503-4503. doi:10.1200/JCO.2018.36.15_SUPPL.4503

16.       Petrylak DP, Perez RP, Zhang J, et al. A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer. https://doi.org/101200/JCO20173515_suppl106. 2017;35(15_suppl):106-106. doi:10.1200/JCO.2017.35.15_SUPPL.106

17.       Rosenberg JE, O’Donnell PH, Balar A v., et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2019;37(29):2592-2600. doi:10.1200/JCO.19.01140

18.       Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. https://doi.org/101200/JCO2020386_suppl441. 2020;38(6_suppl):441-441. doi:10.1200/JCO.2020.38.6_SUPPL.441