Cisplatinum-Ineligible Patients with Muscle-Invasive Localized Urothelial Carcinoma Still Do Not Have Good Systemic Therapy Options for Neoadjuvant Treatment

Five years ago, I wrote an article focused on neoadjuvant treatment options in clinical trials for patients with cisplatinum-ineligible, muscle-invasive urothelial carcinoma.¹  The trials highlighted at that time were all focused on exploring immune-oncology agents.  Since that time, we have learned that neoadjuvant pembrolizumab or atezolizumab may contribute significant complete response rates when administered prior to radical cystectomy.^{2, 3}  Yet, the standard of care for patients who are ineligible to receive cisplatinum chemotherapy is the same today as it was 5 years ago and that is to proceed to radical cystectomy without any systemic therapy.

A great unmet need is for efficacious systemic therapy for patients who are “unfit” for cisplatinum combination chemotherapy, including patients who meet one or more of the following criteria: creatinine clearance <60 ml/min, grade ≥2 hearing loss, grade ≥2 neuropathy, ECOG performance status 2, and/or New York Heart Association Class III or IV heart failure.⁴   As there is still nothing in this pre-operative setting that improves outcomes for these patients, agents that are capable of inducing a significant response by shrinking disease and perhaps leading to pathologic complete responses are welcome.

One thing that has changed for metastatic disease, is that we now have available agents that offer high response rates and can be administered to patients “unfit” for cisplatinum.  When it comes to neoadjuvant therapy, it is very clear that response matters, and complete response, with pT0 status at radical cystectomy, has strong correlation with survival outcomes.^{5, 6}  Agents with high response rates for patients with metastatic urothelial carcinoma include antibody drug conjugates, such as enfortumab vedotin or sacituzumab govitecan.^7-10  There are ongoing clinical trial efforts with these antibody drug conjugates in earlier disease states, including neoadjuvant settings.

One interesting combination has been enfortumab vedotin with pembrolizumab.  In a first-line metastatic urothelial carcinoma setting for cisplatinum-ineligible patients, this combination had a confirmed 73.3% objective response rate, with 93% of patients with some level of decrease of measurable tumor.¹¹  The complete response rate was 17.8% for this population.  A more recent presentation of the Cohort K data from the EV-103 trial, presented at the European Society of Medical Oncology Congress, also revealed high objective response rates of 64.5% for this novel combination.  Although non-comparative, Cohort K did include a 1:1 randomization that revealed an objective response rate of 45.2% for an enfortumab vedotin alone arm.¹²  These findings lend much promise to the response rates and pT0 rates if efficacy can be imported to the neoadjuvant setting.  Hence, you will see that many trials outlined below include this promising systemic therapy combination.

The neoadjuvant therapy setting also offers opportunities to perform innovative clinical trials.  For instance, with an early response endpoint of complete pathologic response, it allows the opportunity to test novel agents to assess for efficacy, with ease of performing correlative science studies due to the availability of post-treatment tissue.  Additionally, intravesical administration of agents is utilized regularly for non-muscle invasive bladder cancer.  Novel intravesical agents and/or radiation therapy can be explored with novel combinations in this scenario.  

Below, we highlight some ongoing clinical trials, specifically for patients “unfit” for cisplatinum chemotherapy.  Although most of the trials below are single center efforts, there are some ongoing randomized phase 3 trial attempts to change standard of care for this unmet need population.  

Neoadjuvant Trials for Patients with High-risk, Cisplatin-ineligible Muscle-Invasive Urothelial Cancer

• EV-103 – Phase 1/2 trial of Enfortumab vedotin alone or with pembrolizumab (NCT03288545)
• Phase 2 trial of Enfortumab vedotin and pembrolizumab (NCT05239624)
• EV-303 – Randomized phase 3 trial of perioperative Enfortumab vedotin and Pembrolizumab or pembrolizumab vs. cystectomy alone (NCT03924895)
• VOLGA – Randomized phase 3 trial of Durvalumab and Enfortumab Vedotin with or without Tremelimumab (NCT04960709)
• Phase 2 trial of nivolumab alone or in combination with Ipilumumab (NCT03520491)
• ANTICIPATE – Randomized phase 1/2 trial of Tislelizmab with or without oral APL-1202 (NCT04813107)
• Phase 1 trial of CG0070 combined with nivolumab (NCT04610671)
• OPTIMUS - Phase 2 umbrella study of various monotherapy or combinations including retifanlimab, epacadostat, INCAGN02385, and/or INCAGN02390 (NCT04586244)
• SWOG GAP TRIAL – Randomized phase 2 trial of Gemcitabine and Carboplatin with or without Avelumab (NCT04871529)
• Phase 1/2 intravenous Vitamin C with Gemcitabine and Carboplatin (NCT04046094)
• Phase 1 trial of intravesical measles virotherapy (NCT03171493)
• RAD-VACCINE – Phase 2 trial of Sasanlimab with radiation (NCT05241340)

References:

1. Yu EY. "Options for Cisplatin-ineligible Patients with Muscle-invasive Localized Urothelial Carcinoma." Uro-today. On-line, October 28, 2017.
2. Necchi A, et al. "Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies." Eur Urol 2020; 77:439-46.
3. Szabados B, et al. "Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder." Eur Urol 2022; 82:212-22.
4. Galsky MD, et al. "Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy." J Clin Oncol 2011; 29:2432-8.
5. Grossman HB, et al. "Neoadjuvant Chemotherapy plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer." N Engl J Med 2003; 349:859-66.
6. Martini A, et al. "Tumor downstaging as an intermediate endpoint to assess the activity of neoadjuvant systemic therapy in patients with muscle-invasive bladder cancer." Cancer 2019; 125:3155-63.
7. Rosenberg JE, 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 2019; 37:2592-600.
8. Yu EY, et al. "Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial."Lancet Oncol 2021; 22:872-882.
9. Powles T, et al. "Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma."N Engl J Med 2021; 384:1125-35.
10. Tagawa ST, et al. "TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors."J Clin Oncol 2021; 39:2474-85.
11. Friedlander TW, et al. "Study EV-103: Update on durability results and long term outcome of enfortumab vedotin + pembrolizumab in first line locally advanced or metastatic urothelial carcinoma (la/mUC)."J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4528-4528.
12. Rosenberg JE, 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)."Ann Onc (2022) 33 (suppl_7): S808-869.