Paclitaxel and carboplatin after disease progression on immune checkpoint inhibitor for patients with metastatic urothelial carcinoma

Abstract

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice.

Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS).

Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events.

Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.

Keywords

urothelial carcinoma / carboplatin / paclitaxel / immune checkpoint inhibitor / rechallenge

References

[1] Jang A, Adler DM, Rauterkus GP, Bilen MA, Barata PC. Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going? Cancers. 2021; 13: 5065.

[2] Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017; 376: 1015-26.

[3] Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, 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. Lancet Oncol. 2017; 18: 1483-92.

[4] Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020; 383: 1218-30.

[5] Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024; 390: 875-88.

[6] van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, et al. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023; 389: 1778-89.

[7] Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021; 384: 2102-14.

[8] Powles T, Catto JWF, Galsky MD, Al-Ahmadie H, Meeks JJ, Nishiyama H, et al. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. N Engl J Med. 2024; 391: 1773-86.

[9] Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023; 389: 1961-71.

[10] Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, González-Martín A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024; 42: 47-58.

[11] Vaughn D. Paclitaxel and carboplatin in bladder cancer. Eur J Cancer. 2000; 36: 7-12.

[12] Vaishampayan UN, Faulkner JR, Small EJ, Redman BG, Keiser WL, Petrylak DP, et al. Phase II trial of carboplatin and paclitaxel in cisplatin-pretreated advanced transitional cell carcinoma. Cancer. 2005; 104: 1627-32.

[13] Childs DS, Quevedo JF, Costello BA, Pagliaro LC. Chemoimmunotherapy after progression on single-agent pembrolizumab for metastatic urothelial carcinoma: a case series. Anti-Cancer Drugs. 2021; 32: 986-90.

[14] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-47.

[15] Furubayashi N, Hori Y, Morokuma F, Tomoda T, Negishi T, Inoue T, et al. Paclitaxel and carboplatin chemotherapy after platinum-based chemotherapy and pembrolizumab for metastatic urothelial carcinoma. Mol Clin Oncol. 2021; 14: 91.

[16] Chan JK, Brady MF, Penson RT, Huang H, Birrer MJ, Walker JL, et al. Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer. N Engl J Med. 2016; 374: 738-48.

[17] Marchetti C, De Felice F, Musella A, Palaia I, Monti M, Musio D, et al. Weekly versus three weeks chemotherapy for advanced ovarian cancer: a meta-analysis. Oncotarget. 2016; 7: 58709-15.

[18] Safra T, Waissengrin B, Levy T, Leidner E, Merose R, Matceyevsky D, et al. Weekly Carboplatin and Paclitaxel: A Retrospective Comparison with the Three-Weekly Schedule in First-Line Treatment of Ovarian Cancer. Oncologist. 2020; 26: 30-9.

[19] Dessai SB, Chakraborty S, Babu TV, Nayanar S, Bhattacharjee A, Jones J, et al. Tolerance of weekly metronomic paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin. South Asian J Cancer. 2016; 5: 63-6.

[20] Heinhuis KM, Ros W, Kok M, Steeghs N, Beijnen JH, Schellens JHM. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol. 2019; 30: 219-35.

[21] Dwary AD, Master S, Patel A, Cole C, Mansour R, Mills G, et al. Excellent response to chemotherapy post immunotherapy. Oncotarget. 2017; 8: 91795-802.

[22] Vulsteke C, Adra N, Danchaivijitr P, Sabadash M, Rodriguez-Vida A, Zhang Z, et al. Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer. N Engl J Med. 2026; 394: 1257-69.

[23] Galsky MD, Valderrama BP, Maruzzo M, Font A, Ciuleanu T, Chatzkel J, et al. Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer. N Engl J Med. 2026; 395: 338-48.