Is Adjuvant Therapy a New Standard for Urothelial Carcinoma?

Adjuvant therapy trials for urothelial carcinoma have traditionally been challenging to perform.  Radical cystectomy is a significantly morbid procedure that leads to high complication and readmission rates.   Hence, many patients are not fit to receive any adjuvant therapy after definitive local therapy due to a compromised health situation. At this time, neoadjuvant chemotherapy is still the definitive standard.1 However, not all patients receive neoadjuvant therapy for a multitude of reasons.  For those who did not receive neoadjuvant cisplatin combination chemotherapy, common sense warrants strong consideration of adjuvant therapy as long as a patient is fit and interested.

However, we have extremely limited evidence on what to do if a patient has residual muscle invasive disease after prior receipt of neoadjuvant combination cisplatin-based chemotherapy.  This is clearly an unmet need population due to the very poor prognosis.

Early hints that adjuvant therapy might offer benefit came from the Advanced Bladder Cancer (ABC) collaborative meta-analysis.2  Six small trials were combined to demonstrate a hazard ratio (HR) of 0.75 in favor of adjuvant cisplatin chemotherapy, but the trials were fraught with many issues, including statistical underpowering, methodological flaws, early cessation of accrual, and confusing statistical analyses.  This meta-analysis was followed by 3 attempts at definitive, randomized phase 3 adjuvant trials using cisplatin combination chemotherapy, none of which were fully accrued.  The Italian trial of adjuvant gemcitabine/cisplatin vs. gemcitabine/cisplatin at relapse was completely negative, however, less than 1/3 of the planned accrual was achieved.3   The Spanish trial was positive with adjuvant gemcitabine/cisplatin/paclitaxel over observation with less than half the planned patients enrolled.4  Finally, the EORTC 30994 trial of “dealer’s choice” combination adjuvant cisplatin-based chemotherapy regimen vs. delay of receipt at metastatic recurrence was also negative, however, again, less than half of the trial accrual was accomplished.5

Ultimately, the Peri-Operative chemotherapy versus surveillance in upper Tract urothelial cancer (POUT) trial was performed with positive results.6  This was a randomized phase 3 trial for upper tract urothelial carcinoma staged operatively as either pT2-4N0-3M0 or pTanyN1-3M0.  Patients either received surveillance or adjuvant chemotherapy with gemcitabine/cisplatin or gemcitabine/carboplatin.  Of the 132 patients randomly assigned to chemotherapy, approximately 2/3 received cisplatin and 1/3 received carboplatin.  The primary endpoint was disease free survival (DFS), and this was positive in favor of the adjuvant chemotherapy arm with a HR of 0.45, 95% CI 0.30-0.68, p=0.0001.  Overall survival data is still pending.  Although this represents a new standard for the use of adjuvant platinum chemotherapy for high-risk upper tract urothelial carcinoma, my personal preference is still to use neoadjuvant cisplatin combination chemotherapy when possible.  This, however, is just an extrapolation from the neoadjuvant lower urinary tract trials, with strong personal preference since in with neoadjuvant therapy the patient has twice as many nephrons in this pre-operative scenario.

Naturally, adjuvant therapy trials have since evolved to an evaluation of immuno-oncology agents.  Unfortunately, the first to read out was the IMvigor010 trial, and the results were negative.7  This was a randomized phase 3 trial for patients with urothelial bladder or upper tract ypT2-4a or ypN+ if patients had received prior neoadjuvant chemotherapy or pT3-4a or pN+ if patients did not receive prior neoadjuvant chemotherapy.  Patients were randomly assigned 1:1 to atezolizumab, an inhibitor of PD-L1, vs. observation with DFS as the primary endpoint.  Of the 809 patients accrued, almost half had received neoadjuvant chemotherapy and almost half had lymph node-positive disease.  Median DFS was 19.4 (95% CI 15.9-24.8) vs. 16.6 (95% CI 11.2-24.8) months with a HR of 0.89 (95% CI 0.74-1.08), p=0.2446.

Just weeks ago, the CheckMate 274 adjuvant nivolumab PD-1 inhibitor trial was presented at the 2021 Genitourinary Cancers Symposium.8  This was another randomized phase 3 adjuvant trial for high-risk muscle invasive urothelial carcinoma of the bladder or upper tract, similar in design to the IMvigor010 trial above, although blinding and a placebo-control strategy was employed.  Of the 709 patients randomized to the trial, the primary endpoint of DFS was met by nivolumab with median DFS of 21.0 (95% CI 17.1-33.4) vs. placebo 10.9 (95% CI 8.3-13.9) months, HR 0.70 (95% CI 0.54-0.89), p=0.0006.  The population with PD-L1 expression > or = 1% had a median DFS that was not reached (95% CI 22.0-NE) vs. 10.8 (95% CI 5.7-21.2) months, HR 0.53 (95% CI 0.34-0.84), p=0.0004.

We now have an interesting dilemma.  Although it will be nice to eventually see mature overall survival data, there is no question that the CheckMate 274 trial is impressively positive.  Although it is too early to comment on regulatory approval status for nivolumab, we have a situation where we have multiple checkpoint inhibitors, felt by many to be similar in overall efficacy, with opposite results.  Differences in clinical trial design strategy, with the IMvigor010 trial lacking placebo control and blinding, leading to higher drop-out rates in the control arm, may have contributed, in some degree, to the negative results.  Personally, I would like to see the results of the randomized phase 3 AMBASSADOR trial (NCT NCT03244384) with pembrolizumab, being run by the ALLIANCE cooperative group.  However, there are certain subgroups of patients that it might be worth acting on as soon as regulatory agencies provide a label for nivolumab.  For instance, those who received prior neoadjuvant cisplatin combination chemotherapy and are left with residual ypT2 disease or greater at surgery seemed to derive very significant benefit from nivolumab.  This specific population has an extremely poor prognosis and represents a clear unmet need population.

There are other niches still to be explored in greater depth for adjuvant therapy trials.  Specifically, radiation for patients with residual poor histopathologic features after cystectomy and fibroblast growth factor receptor (FGFR)-directed therapy for those with FGFR alterations, are both potentially fruitful areas for trial development and accrual.  As we learn more about clinically impactful biologic subgrouping, other molecular niches will emerge for both adjuvant and/or neoadjuvant therapy trials.  For the time being, the below trials are available for patients with the above clinical and molecular situations and remain a priority for the field.

Adjuvant Therapy Trials for Patients with High-risk Urothelial Cancer
  • AMBASSADOR phase 3 trial with pembrolizumab vs. observation (NCT03244384)
  • Randomized intensity modulated radiation therapy (IMRT) to bladder bed and nodes vs. observation for pT3 or pT4a (prior neoadjuvant chemotherapy allowed) (NCT04740866)
  • BART randomized trial of cystectomy +/- adjuvant chemotherapy +/- adjuvant IMRT for lymph node-positive and/or pT3/4 and/or cut margin positive (NCT02951325)
  • Phase 2 trial of 3D conformal radiation for patients with urothelial or squamous with pT3/4 and/or positive nodes (NCT01954173)
  • Phase 3 trial of gemcitabine/cisplatin vs. placebo for upper tract TanyN0M0 with lymphovascular invasion (NCR04255771)
  • PEGASUS Phase 2 trial of Pemigatinib for FGFR altered T3-4 and/or N1-3 urothelial carcinoma (NCT04294277)
  • PROOF 302 Randomized Phase 3 trial of Infigratinib vs. placebo for FGFR3 altered urothelial carcinoma (NCT04197986)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

  1. Grossman H, Natale R, Tangen C, et al. "Neoadjuvant Chemotherapy plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer." N Engl J Med. 2003; 349:859-66.
  2. ABC Meta-analysis Collaboration. Eur Urol 2005; 48:289-301.
  3. Cognetti F, Ruggeri E, Felici A, et al. "Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial." Ann Oncol. 2012; 23:695-700.
  4. Paz Ares LG, Solsona E, Esteban E, et al. "Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study." J Clin Oncol. 28, no. 18_suppl (LBA4518).
  5. Sternberg CN, Skoneczna I, Kerst JM, et al. "Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial." Lancet Oncol. 2015; 16:76-86.
  6. Birtle A, Johnson M, Chester J, et al. "Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial." Lancet. 2020; 395:1268-77.
  7. Hussain MHA, Powles T, Albers P, 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)." J Clin Oncol. 38, no. 15_suppl (May 20, 2020) 5000-5000.
  8. Bajorin DF, et al. "CheckMate 274: Adjuvant Nivolumab May Improve Disease-Free Survival in Patients With Muscle-Invasive Urothelial Carcinoma." J Clin Oncol. 39, 2021 (suppl 6, abstr 391).

Related Content:

ASCO GU 2021: First Results from the Phase 3 CheckMate 274 Trial of Adjuvant Nivolumab vs Placebo in Patients Who Underwent Radical Surgery for High-Risk Muscle-Invasive Urothelial Carcinoma

ASCO GU 2021: Updated Outcomes of POUT: A Phase III Randomized Trial of Peri-Operative Chemotherapy Versus Surveillance in Upper Tract Urothelial Cancer
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