VJToday

Managing urothelial carcinoma with targeted therapies 

VJOncology is excited to present the latest data and developments in the bladder cancer field, with comments from Yohann Loriot, Jonathan Rosenberg, Petros Grivas and more.

In the last four years, FDA approval of several targeted agents have extended the treatment options for patients with locally advanced or metastatic urothelial cancer (la/mUC), the most common type of bladder cancer.1

Platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) have become the backbone of therapy regimens, with ICIs including atezolizumab and pembrolizumab given in first-line in patients who are cisplatin-ineligible.2-5 In the Phase III KEYNOTE-045 (NCT02256436) and IMvigor211 (NCT02302807) trials of pembrolizumab and atezolizumab, objective response rates (ORR) were 21.1% and 23%, respectively.4,5 As a result of the low ORR, new therapeutic approaches are required for patients with mUC.6

Three targeted therapies have been developed and approved in the second line by the FDA for patients with la/mUC: erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor (TKI),7 and the antibody-drug conjugates (ADCs) enfortumab vedotin (EV),8 targeting nectin-4, and sacituzumab govitecan (SG),9 targeting Trop-2. Of these three targeted agents, the EMA has only approved EV for mUC.10

Key developments in 2022

Safety and efficacy of erdafitinib at two years

In February, the long-term efficacy and safety data for the Phase II BLC2001 trial (NCT02365597) of erdafitinib in mUC patients harboring FGFR mutations were reported.11 At median 24.0 months follow up, the regimen of continuous once daily 8 mg/day oral erdafitinib in 28-day cycles achieved an ORR of 40% (40 of 101 patients; 95% CI 30–49).11 No new safety signals were reported. Grade 3–4 treatment-emergent adverse events (TRAEs) of any causality occurred in 71% of patients, with the most common of any cause being stomatitis (14%) and hyponatraemia (11%). There were no treatment-related deaths. 11

In this video, Yohann Loriot, MD, PhD, Gustave Roussy, Villejuif, France, and University of Paris-Saclay, Gif-sur-Yvette, France, comments on the consistent activity and manageable safety profile of erdafitinib in the BLC2001 study.

30% two-year survival rate for third-line mUC patients with EV

In June, long-term outcomes from the Phase III EV-301 (NCT03474107) trial of enfortumab vedotin (EV) versus standard chemotherapy in patients with la/mUC were presented during the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting.12 At 23.75 months of follow up, median overall survival (OS) was significantly longer with EV compared with chemotherapy (median OS: 12.91 versus 8.94 months, respectively; HR = 0.704 [95% CI: 0.581-0.852], 1-sided P= 0.00015).12 Median progression free survival (PFS) was also improved with EV; 5.55 months EV versus 3.71 months chemotherapy (HR = 0.632 [95% CI: 0.525-0.762]; 1-sided P< 0.00001). Rates of TRAEs (93.9% vs 91.8%), including serious TRAEs (22.6% vs 23.4%), were comparable between the groups.12

“There was a 10% increase in two-year survival to just shy of 30% for EV, compared to just under 20% for patients treated with standard-of-care chemotherapy.  While that’s not a spectacular number, we have not been thinking of 30% of patients being alive two-years after third line therapy in the past,” comments Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center, New York City, NY, as he discusses the results of the final analysis for this trial in this video.

ORR of almost 65% with combination of EV and pembrolizumab 

Highly anticipated results of Cohort K of the EV-103 study (NCT03288545) were also presented in September.13 The trial aimed to evaluate the antitumor activity of EV monotherapy or in combination with pembrolizumab as first-line therapy in previously untreated cisplatin-ineligible patients with la/mUC. Confirmed ORR for EV plus pembrolizumab was 64.5% (95%CI: 52.7-75.1), and 45.2% (95%CI: 33.5-57.3) for EV monotherapy.13 Median duration of response (DOR) was not reached for the combination and 13.2 months (95%CI: 6.1-16.0) for monotherapy.13 TRAEs of special interest included skin reactions, peripheral neuropathy, ocular disorders, and hyperglycemia, most of which occurred at higher rates with the combination and were Grade ≤2.13

In this interview, Dr Rosenberg comments on the efficacy and safety data, including the increase in skin reactions observed with the combination, presented in the abstract.

TROPHY-U-01 Cohort 3: combining ICIs and ADCs

Interim efficacy and safety results of Cohort 3 of the Phase II TROPHY-U-01 (NCT03547973) trial evaluating SG in combination with pembrolizumab as second-line therapy in mUC that has progressed after platinum-based chemotherapy have also been reported.14 At a median follow-up of 5.8 months ORR was 34% (95% CI: 20.1–50.6; 1 CR; 13 PR); six-month PFS rate was 47%.14 Treatment-emergent adverse events (TEAEs) grade ≥3 occurred in 59% of patients; key TEAEs of any cause included diarrhea (24%), anemia (20%), febrile neutropenia (10%), fatigue (7%), and asthenia (5%).14 Two patients discontinued treatment due to TRAEs and no treatment-related deaths reported.14 

During the 2022 ASCO Genitourinary Cancers Symposium, Petros Grivas, MD, PhD, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, discusses the wider TROPHY-U-01 trial, as well as the results from Cohort 3.

Challenges and unmet needs

Discussing one of the key challenges in daily practice, Enrique Grande, MD, PhD, MSc, MD Anderson Cancer Center Madrid, Madrid, Spain, explains the complexities of treatment sequencing for mUC patients who are platinum-based chemotherapy ineligible and have not responded or relapsed following immune checkpoint inhibitor (ICI) therapy.

He notes that EV has the highest level of evidence in this setting: “EV has demonstrated to be superior, improving the overall survival, response rate, progression-free survival and also the quality of life when compared in the EV-301 study to chemotherapy.” Dr Grande also discusses the FGFR inhibitor erdafitnib, which is yet to gain EMA approval, before commenting on patient selection, noting that if patients are fit enough and there is a balance between toxicity and benefit, EV should be given, and that, once erdafitnib garners approval, FGFR molecular testing should be routinely applied to identify those who would benefit from it.

A further challenge with ADCs is a lack of understanding surrounding resistance mechanisms to these drugs, for EV Dr Rosenberg has discussed potential mechanisms for this including downregulation of NECTIN4 and potential involvement of drug efflux pumps. Additionally, their toxicity has become a key area that clinicians should be educated around,15 both in the long and short term, as ADCs’ ability to extend survival creates long-term survivorship challenges. In this video, Dr Rosenberg discusses such concerns across a range of treatments for UC, highlighting that having such a challenge for patients treated for metastatic disease is a new but exciting challenge.

Conclusions

The introduction of targeted agents has provided la/mUC patients with a wider range of treatment options able to increase survival, and improve quality of life. While these are exciting developments, to fully capitalize on their potential, research continues into the optimal sequencing of targeted therapies, their  use in combinations, as well as the development of new agents with novel targets such as HER2.

Written by Blanka Awtani

References: 

  1. Szklener K, Chmiel P, Michalski A, Mańdziuk S. New Directions and challenges in targeted therapies of advanced bladder cancer: The role of FGFR inhibitors. Cancers. 2022Mar10;14(6):1416.  
  1. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. The Lancet. 2017Jan7;389(10064):67–76.  
  1. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (Keynote-052): A Multicentre, single-arm, phase 2 study. The Lancet Oncology. 2017Nov;18(11):1483–92.  
  1. Fradet Y, Bellmunt J, Vaughn DJ, et al. Randomized phase III keynote-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: Results of >2 years of follow-up. Annals of Oncology. 2019Jun;30(6):970–6.  
  1. 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. The Lancet. 2018Feb24;391(10122):748–57.  
  1. Ungaro A, Tucci M, Audisio A, et al. Antibody-drug conjugates in urothelial carcinoma: A new therapeutic opportunity moves from bench to bedside. Cells. 2022Feb25;11(5):803.  
  1. Center for Drug Evaluation and Research. FDA grants accelerated approval to Erdafitinib for metastatic urothelial carcinoma [Internet]. U.S. Food and Drug Administration. FDA; 2019 [cited 2023Jan17]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma  
  1. FDA grants accelerated approval to enfortumab vedotin-ejfv for Metasta [Internet]. U.S. Food and Drug Administration. FDA; 2019 [cited 2023Jan17]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-metastatic-urothelial-cancer  
  1. Center for Drug Evaluation and Research. FDA grants accelerated approval for Sacituzumab Govitecan [Internet]. U.S. Food and Drug Administration. FDA; 2021 [cited 2023Jan23]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer  
  1. EMA. Meeting highlights from the Committee for Medicinal Products Human Use (CHMP) 13-16 December 2021 [Internet]. European Medicines Agency. 2022 [cited 2023Jan18]. Available from: https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-13-16-december-2021  
  1. Siefker-Radtke AO, Necchi A, Park SH, et al. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: Long-term follow-up of a phase 2 study. The Lancet Oncology. 2022Jan11;23(2):248–58.   
  1. Rosenberg JE, Powles T, Sonpavde GP, et al. Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab Vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Journal of Clinical Oncology. 2022Jun2;40(16_suppl):4516–.   
  1. Rosenberg JE, Milowsky M, Ramamurthy C, et al. LBA73 study EV-103 cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (p) in previously untreated cisplatin-ineligible patients (PTS) with locally advanced or metastatic urothelial cancer (LA/MUC). Annals of Oncology. 2022Sep;33.   
  1. Grivas P, Pouessel D, Park CH, et al. Trophy-U-01 Cohort 3: Sacituzumab Govitecan (SG) in combination with pembrolizumab (Pembro) in patients (PTS) with metastatic urothelial cancer (MUC) who progressed after Platinum (plt)-based regimens. Journal of Clinical Oncology. 2022Feb16;40(6_suppl):434–.   
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