Immunotherapy-Based Combinations in First-Line Urothelial Cancer: A Systematic Review and Individual Patient Data (IPD) Meta-Analysis
Abstract
:1. Introduction
2. Methods
2.1. Inclusion Criteria
2.2. Search Strategy and Selection Processes
3. Endpoints
3.1. Primary Endpoints
- OS and PFS of Pembrolizumab + EV compared to experimental arms of the other trials of immunotherapy + chemotherapy.
3.2. Secondary Endpoints
- Safety in selected studies.
- OS and PFS in patients enrolled in studies assessing the efficacy of immunochemotherapy combinations in first-line settings compared with chemotherapy arms.
- OS and PFS of the included experimental arms of clinical trials versus avelumab (data from JAVELIN BLADDER 101).
4. Data Extraction
Statistical Analysis
5. Results
5.1. Included Studies
5.2. Pembrolizumab Plus Enfortumab Vedotin vs. Immunotherapy + Chemotherapy
5.3. Secondary Endpoint
5.3.1. Overall Survival
5.3.2. Progression-Free Survival
5.3.3. Comparison with Avelumab Data
6. Safety
7. Discussion
8. Conclusions
Clinical Practice Points
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Bladder Cancer; Version 3. 2023. Available online: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf (accessed on 3 March 2024).
- De Santis, M.; Bellmunt, J.; Mead, G.; Kerst, J.M.; Leahy, M.; Maroto, P.; Gil, T.; Marreaud, S.; Daugaard, G.; Skoneczna, I.; et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J. Clin. Oncol. 2012, 30, 191–199. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Galsky, M.D.; Hahn, N.M.; Rosenberg, J.; Sonpavde, G.; Hutson, T.; Oh, W.K.; Dreicer, R.; Vogelzang, N.; Sternberg, C.N.; Bajorin, D.F.; et al. Treatment of patients with metastatic urothelial cancer “unfit” for Cisplatin-based chemotherapy. J. Clin. Oncol. 2011, 29, 2432–2438. [Google Scholar] [CrossRef] [PubMed]
- Galsky, M.D.; Hahn, N.M.; Rosenberg, J.; Sonpavde, G.; Oh, W.K.; Dreicer, R.; Vogelzang, N.J.; Sternberg, C.N.; Bajorin, D.F.; Bellmunt, J. Defining “cisplatin ineligible” patients with metastatic bladder cancer. J. Clin. Oncol. 2011, 29 (Suppl. 7), 238. [Google Scholar] [CrossRef]
- Martini, A.; Raggi, D.; Fallara, G.; Nocera, L.; Schultz, J.G.; Belladelli, F.; Marandino, L.; Salonia, A.; Briganti, A.; Montorsi, F.; et al. Immunotherapy versus chemotherapy as first-line treatment for advanced urothelial cancer: A systematic review and meta-analysis. Cancer Treat. Rev. 2022, 104, 102360. [Google Scholar] [CrossRef] [PubMed]
- Galsky, M.D.; Arija, J.Á.A.; Bamias, A.; Davis, I.D.; De Santis, M.; Kikuchi, E.; Garcia-Del-Muro, X.; De Giorgi, U.; Mencinger, M.; Izumi, K.; et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2020, 395, 1547–1557. [Google Scholar] [CrossRef] [PubMed]
- Balar, A.V.; Galsky, M.D.; Rosenberg, J.E.; Powles, T.; Petrylak, D.P.; Bellmunt, J.; Loriot, Y.; Necchi, A.; Hoffman-Censits, J.; Perez-Gracia, J.L.; et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet 2017, 389, 67–76, Erratum in Lancet 2017, 390, 848. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Powles, T.; Park, S.H.; Voog, E.; Caserta, C.; Valderrama, B.P.; Gurney, H.; Kalofonos, H.; Radulović, S.; Demey, W.; Ullén, A.; et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N. Engl. J. Med. 2020, 383, 1218–1230. [Google Scholar] [CrossRef] [PubMed]
- Van Der Heijden, M.S.; Sonpavde, G.; Powles, T.; Necchi, A.; Burotto, M.; Schenker, M.; Sade, J.P.; Bamias, A.; Beuzeboc, P.; Bedke, J.; et al. Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. N. Engl. J. Med. 2023, 389, 1778–1789. [Google Scholar] [CrossRef] [PubMed]
- Powles, T.; van der Heijden, M.S.; Castellano, D.; Galsky, M.D.; Loriot, Y.; Petrylak, D.P.; Ogawa, O.; Park, S.H.; Lee, J.L.; De Giorgi, U.; et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): A randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020, 21, 1574–1588, Erratum in Lancet Oncol. 2021, 22, e5. [Google Scholar] [CrossRef] [PubMed]
- Suzman, D.L.; Agrawal, S.; Ning, Y.M.; Maher, V.E.; Fernandes, L.L.; Karuri, S.; Tang, S.; Sridhara, R.; Schroeder, J.; Goldberg, K.B.; et al. FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy. Oncologist 2019, 24, 563–569. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Powles, T.; Csőszi, T.; Özgüroğlu, M.; Matsubara, N.; Géczi, L.; Cheng, S.Y.; Fradet, Y.; Oudard, S.; Vulsteke, C.; Barrera, R.M.; et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): A randomised, open-label, phase 3 trial. Lancet Oncol. 2021, 22, 931–945. [Google Scholar] [CrossRef] [PubMed]
- Powles, T.; Rosenberg, J.E.; Sonpavde, G.P.; Loriot, Y.; Durán, I.; Lee, J.L.; Matsubara, N.; Vulsteke, C.; Castellano, D.; Wu, C.; et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N. Engl. J. Med. 2021, 384, 1125–1135. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Sridhar, S.; O’Donnell, P.H.; Flaig, T.W.; Rosenberg, J.E.; Hoimes, C.J.; Milowsky, M.I.; Srinivas, S.; George, S.; McKay, R.R.; Petrylak, D.P.; et al. 2365MO Study EV-103 cohort L: Perioperative treatment w/enfortumab vedotin (EV) monotherapy in cisplatin (cis)-ineligible patients (pts) w/muscle invasive bladder cancer (MIBC). Ann. Oncol. 2023, 34, S1203. [Google Scholar] [CrossRef]
- Hoimes, C.J.; Flaig, T.W.; Milowsky, M.I.; Friedlander, T.W.; Bilen, M.A.; Gupta, S.; Srinivas, S.; Merchan, J.R.; McKay, R.R.; Petrylak, D.P.; et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J. Clin. Oncol. 2023, 41, 22–31. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Powles, T.; Valderrama, B.P.; Gupta, S.; Bedke, J.; Kikuchi, E.; Hoffman-Censits, J.; Iyer, G.; Vulsteke, C.; Park, S.H.; Shin, S.J.; et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N. Engl. J. Med. 2024, 390, 875–888. [Google Scholar] [CrossRef] [PubMed]
- Van Der Heijden, M.S.; Powles, T.; Gupta, S.; Bedke, J.; Kikuchi, E.; De Wit, R.; Galsky, M.D.; Duran, I.; Necchi, A.; Retz, M.; et al. ASCO GU 2024: Enfortumab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Previously Untreated Locally Advanced Metastatic Urothelial Carcinoma: Subgroup Analyses Results from EV-302, a Phase 3 Global Study. Available online: https://ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.LBA530 (accessed on 15 July 2024).
- Barthelemy, P.; Loriot, Y.; Thibault, C.; Gross-Goupil, M.; Eymard, J.C.; Voog, E.; Abraham Jaillon, C.; Le Moulec, S.; Chasseray, M.; Gobert, A.; et al. ASCO GU 2024: Updated results from AVENANCE: Real-World Effectiveness of Avelumab First-Line Maintenance (1LM) in Patients (pts) with Advanced Urothelial Carcinoma (aUC) and Analysis of Subsequent Treatment. Available online: https://meetings.asco.org/abstracts-presentations/229756 (accessed on 15 July 2024).
Study (Year) | Study Name (NCT Number) | Eligible Patients | Study Drug | No. of Patients | Cisplatin-Eligible Patients | Endpoints |
---|---|---|---|---|---|---|
Michiel S. van der Heijden et al., 2023 [9] | CheckMate-901 NCT03036098 | first-line metastatic urothelial carcinoma | Nivolumab + Gemcitabine–Cisplatin vs. Gemcitabine–Cisplatin | 304 vs. 304 | 608 (100%) | OS: 21.7 vs. 18.9 mo HR 0.78 [0.63–0.96] PFS: 7.9 vs. 7.6 mo OS (PDL1 ≥ 1%): HR 0.75 [0.53–1.06] PFS (PDL1 ≥ 1%): HR 0.60 [0.41–0.81] EORTC QLQ-C30: 40% vs. 66% |
Galsky et al. 2018 [7] | IMVIGOR130 NCT02807636 | first-line metastatic urothelial carcinoma | Atezolizumab + Gemcitabine–Cisplatin/Carboplatin vs. Atezolizumab vs. Placebo + Gemcitabine–Cisplatin/Carboplatin | 451 vs. 362 vs. 400 | 261 (58%) vs. 191 (53%) vs. 224 (56%) | mPFS (A vs. C): 8.2 vs. 6.3 mo HR 0.72 [0.70–0.96] mOS (A vs. C): 16.0 vs. 13.4 mo HR 0.83 [0.69–1.00] OS (B vs. C): 15.7 vs. 13.1 mo HR 1.02 [0.83–1.24] |
Powles et al. 2023 [16] | EV302 NCT-04223856 | first-line metastatic urothelial carcinoma | Enfortumab Vedotin + Pembrolizumab vs. Gemcitabine–Cisplatin/carboplatin | 442 vs. 444 | 240 vs. 242 | PFS (EV + P vs. Chemo): 12.5 vs. 6.3 mo HR 0.45 [0.38–0.54] OS (EV + P vs. Chemo): 31.5 vs. 16.1; HR 0.47 [0.38–0.58] ORR (EV + P vs. Chemo): 67.7 vs. 44.4 |
Powles et al. 2018 [12] | KEYNOTE-361 NCT02853305 | first-line metastatic urothelial carcinoma | Pembrolizumab + Gemcitabine–Cisplatin/Carboplatin vs. Pembrolizumab vs. Gemcitabine–Cisplatin/Carboplatin | 351 vs. 307 vs. 352 | 156 (44%) vs. 137 (45%) vs. 156 (44%) | mPFS (pembro + chemo vs. chemo): 8.3 vs. 7.1 mo HR 0.78 [0.65–0.93] mOS (pembro + chemo vs. chemo): 17.0 vs. 14.3 mo HR 0.86 [0.71–1.02] mOS (pembro vs. chemo): 15.6 vs. 14.3 mo HR 0.92 [0.77–1.11] OS (CPS ≥ 10): 16.1 vs. 15.2 mo HR 1.01 [0.77 vs. 1.32] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Di Civita, M.A.; Torchia, A.; Santini, D.; Marinelli, D.; Magro, V.; Cerro, M.; Pappalardo, L.; Maltese, G.; Santamaria, F.; Zacco, L.; et al. Immunotherapy-Based Combinations in First-Line Urothelial Cancer: A Systematic Review and Individual Patient Data (IPD) Meta-Analysis. Curr. Oncol. 2024, 31, 4713-4727. https://doi.org/10.3390/curroncol31080352
Di Civita MA, Torchia A, Santini D, Marinelli D, Magro V, Cerro M, Pappalardo L, Maltese G, Santamaria F, Zacco L, et al. Immunotherapy-Based Combinations in First-Line Urothelial Cancer: A Systematic Review and Individual Patient Data (IPD) Meta-Analysis. Current Oncology. 2024; 31(8):4713-4727. https://doi.org/10.3390/curroncol31080352
Chicago/Turabian StyleDi Civita, Mattia Alberto, Andrea Torchia, Daniele Santini, Daniele Marinelli, Virginia Magro, Marianna Cerro, Laura Pappalardo, Giulia Maltese, Fiorenza Santamaria, Luca Zacco, and et al. 2024. "Immunotherapy-Based Combinations in First-Line Urothelial Cancer: A Systematic Review and Individual Patient Data (IPD) Meta-Analysis" Current Oncology 31, no. 8: 4713-4727. https://doi.org/10.3390/curroncol31080352