Society of Urologic Oncology (SUO) 21st Annual Meeting

SUO 2020: Perioperative Therapy for Muscle-Invasive Bladder Cancer

(UroToday.com) Dr. Kelly Stratton gave a presentation at the 2020 Society of Urologic Oncology (SUO) Annual Virtual Meeting on peri-operative therapy for muscle-invasive bladder cancer (MIBC). He began his talk by demonstrating that the outcomes after radical cystectomy differ significantly according to the pathological results of cystectomy (Figure 1).1 Due to the fact that in some patients, radical cystectomy might not be enough, neoadjuvant chemotherapy (NAC) has been added as a standard of care. Based on level one evidence,2 NAC showed an overall survival benefit of 14% at five years when compared to cystectomy alone (Figure 2).


Bladder cancer outcomes following cystectomy

Figure 1. Bladder cancer outcomes following cystectomy

Benefits of neoadjuvant chemotherapy

Figure 2. Benefits of neoadjuvant chemotherapy

However, there have been various challenges in the use of neoadjuvant chemotherapy over the years. These include variable prescribing patterns, and that some patients are regarded as cisplatin-ineligible patients due to their impaired renal function and hearing loss adverse effects. Lastly, some of the patients simply refuse to be treated with neoadjuvant chemotherapy.

In recent years there have been significant advances made with late-line therapies in metastatic urothelial carcinoma patients, with the approval of several novel drugs in these settings. As a result, there are also many current ongoing Phase I and II trials assessing single agent drugs, combined immunotherapy medications, and a combination of immunotherapy and chemotherapy in the neoadjuvant setting of MIBC. There are also ongoing Phase III studies in this setting (Table 1).

Table 1. Ongoing Phase III trials evaluating neoadjuvant therapy for MIBC

Trial ID Sponsor Primary endpoint (s) Control arm Experimental arm
Cisplatin eligible        
NCT03661320 (ENERGIZE) Bristol-Myers Squibb pCR, EFS GC/split-dose GC
Control + nivolumab + placebo
Control + nivolumab + linrodostat
NCT03732677 (NIAGARA) AstraZeneca pCR, EFS GC/split-dose GC
Control + durvalumab
NCT03924856 (KEYNOTE-866) Merck pCR EFS GC + placebo Control + Pembrolizumab
Cisplatin ineligible        
NCT03924895 Merck pCR EFS -
Pembrolizumab



Recently published trials (Table 2) have shown promising complete response rates ranging between 31% to 46% with single agents, combined immunotherapy treatment, and combined immunotherapy with chemotherapy.

Table 2. Recent trials showing promising results in MIBC

Recent trials showing promising results in MIBC

Dr. Stratton continued by briefly describing these important trials. The PURE-01 trial was a Phase II, single-arm trial of three cycles of pembrolizumab followed by radical cystectomy for T2-4AN0M0 patients, regardless of cisplatin ineligibility. This trial included patients with variant histology as well. The primary endpoint was pathologic complete response (Pt0). A total of 114 patients were enrolled, with 30% having variant histology. The Pt0 rate was 37%.3

Another study assessed and supported the surgical safety of radical cystectomy, and pelvic lymph node dissection in patients enrolled in the PURE-01 trial.4

The ABACUS trial was also a Phase II study investigating two cycles of neoadjuvant atezolizumab in cisplatin-ineligible patients with T2-4AN0M0 urothelial carcinoma.5 The primary endpoint was pathologic complete response, and a total of 88 patients were enrolled. In this trial, eight patients did not receive cystectomy, and the median time from therapy start to cystectomy was 5.6 weeks. A total of 27 patients (31%) achieved Pt0.

Next, the NABUCCO trial was discussed. In this trial, pre-operative ipilimumab and nivolumab were given to patients with locoregionally advanced urothelial cancer. This was a Phase Ib trial with more advanced cisplatin-ineligible patients.6 A total of 23/24 patients underwent radical cystectomy by 12 weeks. Fourteen patients were downstaged with a complete response rate shown by 46%.

The HOG-gu 14-188 trial for cisplatin-ineligible patients was discussed next. This was a Phase Ib/II study assessing the role of gemcitabine+pembrolizumab in cisplatinum-ineligible patients. The primary endpoint was Pt1 or less. The analyzed neoadjuvant therapy had manageable toxicity and had improved pathologic outcomes compared to historic controls.7

The last trial discussed was the BLASST-1 trial, which was a Phase II study of neoadjuvant treatment with nivolumab, gemcitabine, and cisplatin for patients with MIBC.8 The primary outcome was pathologic response (≤PT1N0). The study showed that 66% of patients had non-invasive disease, with 49% demonstrating Pt0.

Next, Dr. Stratton moved on to discuss the role of adjuvant treatment in the setting of MICB. Adjuvant chemotherapy has not been shown to be beneficial in most patients.9


AMBASSADOR trial design

Figure 4. AMBASSADOR trial design

Before concluding his talk, Dr. Stratton mentioned the bladder preservation strategy, with the response to perioperative therapy, possibly providing an opportunity to avoid radical cystectomy. Response/biomarker-driven treatments are currently being considered for bladder preservation. There are also plans to evaluate the addition of immunotherapy to trimodal bladder sparing protocols (Alliance a031701 trial and SWOG/NRG 1806 trial, shown in Figures 5 and 6, respectively).

Concluding his talk, Dr. Stratton reiterated that there are numerous ongoing trials in the peri-operative MIBC setting. Immunotherapy in the neoadjuvant setting has shown promising results, while adjuvant immunotherapy has provided mixed results with additional data pending. Perioperative treatment may include wider adoption of bladder preservation and radiotherapy and with the possible inclusion of immunotherapy. These are exciting times, and we eagerly await the results of ongoing and future trials.

Alliance a031701 bladder preservation trial with the inclusion of immunotherapy

Figure 5. Alliance a031701 bladder preservation trial with the inclusion of immunotherapy

SWOG1806_SUO2020.png

Figure 6. SWOG/NRG 1806 bladder preservation trial with the inclusion of immunotherapy

Presented by: Kelly L. Stratton, MD, FACS, Assistant Professor of Urologic Oncology, University of Oklahoma, Adjunct Assistant Professor of Medical Oncology, Stephenson Cancer Center, Oklahoma City, Oklahoma

Written by: Hanan Goldberg, MD, MSc, Assistant Professor, Urology Department, SUNY Upstate Medical University, Syracuse, New York, Twitter: @GoldbergHanan during at the 21st Annual Meeting of the Society of Urologic Oncology (SUO), December 3-5, Virtual Conference 

References:
1. Stein, John P., Gary Lieskovsky, Richard Cote, Susan Groshen, An-Chen Feng, Stuart Boyd, Eila Skinner et al. "Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients." Journal of clinical oncology 19, no. 3 (2001): 666-675.
2. Grossman, H. Barton, Ronald B. Natale, Catherine M. Tangen, V. O. Speights, Nicholas J. Vogelzang, Donald L. Trump, Ralph W. deVere White et al. "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." New England Journal of Medicine 349, no. 9 (2003): 859-866.
3. Necchi, Andrea, Daniele Raggi, Andrea Gallina, Russell Madison, Maurizio Colecchia, Roberta Lucianò, Rodolfo Montironi et al. "Updated results of PURE-01 with preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma with variant histologies." European urology 77, no. 4 (2020): 439-446.
4. Briganti, Alberto, Giorgio Gandaglia, Simone Scuderi, Andrea Gallina, Renzo Colombo, Nicola Fossati, Francesco Barletta et al. "Surgical safety of radical cystectomy and pelvic lymph node dissection following neoadjuvant pembrolizumab in patients with bladder cancer: prospective assessment of perioperative outcomes from the PURE-01 trial." European Urology (2020).
5. Powles, Thomas, Alejo Rodriguez-Vida, Ignacio Duran, Simon J. Crabb, Michiel Simon Van Der Heijden, Albert Font Pous, Gwenaelle Gravis et al. "A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS)." (2018): 4506-4506.
6. Van der Heijden, M. S., N. Van Dijk, L. Smit, K. Hendricksen, J. M. de Feijter, E. Bekers, E. Hooijberg et al. "904PD Pre-operative ipilimumab and nivolumab in locoregionally advanced, stage III, urothelial cancer (NABUCCO)." Annals of Oncology 30, no. Supplement_5 (2019): mdz249-003.
7. Hoimes, Christopher J., Nabil Adra, Mark T. Fleming, Hristos Z. Kaimakliotis, Joel Picus, Zachary L. Smith, Radhika Walling et al. "Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)-eligible cohort of HCRN GU14-188." (2020): 5047-5047.
8. Gupta, Shilpa, Guru Sonpavde, Christopher J. Weight, Bradley Alexander McGregor, Sumati Gupta, Benjamin Louis Maughan, Xiao X. Wei et al. "Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy." (2020): 439-439.
9. Vale, Claire L. "Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data: Advanced Bladder Cancer (ABC) Meta-analysis Collaboration." European urology 48, no. 2 (2005): 189-201.
10. Hussain, Maha HA, Thomas Powles, Peter Albers, Daniel Castellano, Siamak Daneshmand, Juergen Gschwend, Hiroyuki Nishiyama et al. "IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC)." (2020): 5000-5000.






 

email news signup