From the Desk of Evan Yu: “Why Aren’t There More Systemic Therapy Trials for Patients with Muscle-invasive Urothelial Carcinoma of the Bladder?”

Just recently, we discussed neoadjuvant systemic therapy for cisplatin-ineligible patients with muscle-invasive urothelial carcinoma of the bladder.1  For those patients “unfit” for cisplatin with at least one 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 heart failure,2 there are no good options other than cystectomy alone.  Yet, we know the outcomes are not ideal for these patients with cystectomy alone.  Finding systemic therapies that may improve outcomes for these patients is clearly an unmet need in the field.


For patients who are “fit” enough to receive cisplatin-based combination chemotherapy prior to cystectomy, there are still very few clinical trials to accrue patients to.  This is likely due to the acceptance of the randomized control data supporting an overall survival benefit for patients with muscle-invasive disease who receive cisplatin-based combination therapies prior to cystectomy.3  Those patients who are able to achieve a pT0 status at cystectomy clearly have superior survival outcomes.  Therefore, achieving a pT0 status may offer a promising early biomarker to use as a primary clinical trial endpoint for early phase neoadjuvant trials of novel agents.

We need only to look at a couple fascinating presentations at the American Society of Clinical Oncology (ASCO) meeting in June 2018 to see examples of impressive pT0 rates in response to PD-1 or PD-L1 antibody therapy prior to cystectomy.  Specifically, 3 doses of pembrolizumab led to a 39.5% pT0 rate at cystectomy.4  Patients with high PD-L1 expression or DNA repair and/or RB1 genomic alterations also had significantly higher pT0 rates in this trial.  In another trial, 2 doses of atezolizumab led to a 29% pT0 rate at cystectomy, with a 40% pT0 rate at cystectomy for PD-L1 positive patients.5  Toxicities in both these trials were expected and there was no excess in unexpected surgical complications.  These complete response rates to PD-1 or PD-L1 therapy alone are somewhat surprising, given the response rates were seen in patients with the advanced metastatic disease.  The pT0 rates to these agents should excite the field to design more trials with immune-oncology agents in the neoadjuvant setting.

One of the challenges of developing trials for cisplatin-eligible patients compared to cisplatin-ineligible patients is the simple fact that there is a very active comparator for the former.  However, that should not deter us, especially after seeing the complete response rates obtained in the above two trials.  We must recall that complete response rates to cisplatin combination chemotherapy regimens is still low, and those patients who do not achieve a <pT2 status have a grim prognosis.  Therefore, combination trials of newer agents with cisplatin combination chemotherapy should be pursued, especially if the ongoing metastatic disease first-line trials of platinum chemotherapy plus immune-oncology agents offer significantly improved outcomes (NCT02807636, NCT02853305).  Finally, the neoadjuvant setting is quite an ideal setting for biologic exploration, since there is often readily available tissue for translational correlative studies.  And if there is no residual tissue available due to a complete response to systemic therapy, that is a good problem to have.

Below, we highlight a few ongoing trials specifically for patients who are “fit” for cisplatin-based combination chemotherapy.  We need to accrue to these trials and rapidly design more if we hope to move this field forward.

Ongoing neoadjuvant trials for muscle-invasive urothelial cancer patients eligible for cisplatin-based combination chemotherapy

  • Nivolumab + Ipilumumab (NABUCCO) (NCT03387761
  • Nivolumab + TAR-200 (sustained gemcitabine intravesicular release) (NCT03518320) – Requires cisplatin eligible patient to refuse chemotherapy 
  • Pembrolizumab + Gemcitabine/Cisplatin (Hoosier Cancer Research Network) (NCT02365766)

References

  1. Yu, EY. (2017, October 28). From the Desk of Evan Yu: "Options for Cisplatin-ineligible Patients with Muscle-invasive Localized Urothelial Carcinoma" Retrieved from http://www.UroToday.com
  2. Galsky MD et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011 Jun 10;29(17):2432-8. 
  3. Grossman HB et al Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003 Aug 28;349(9):859-66.
  4. Necchi A et al. Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study. Journal of Clinical Oncology 36, no. 15_suppl (May 2018) 4507-4507. 
  5. Powles T et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle-invasive bladder cancer (ABACUS). Journal of Clinical Oncology 36, no. 15_suppl (May 2018) 4506-4506. 


Written by: Evan Yu, MD

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