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Induction Avelumab Followed by Chemoimmunotherapy and Maintenance Versus Chemotherapy Alone as First-Line Therapy in Cis-Ineligible Metastatic Urothelial Carcinoma (INDUCOMAIN): A Randomized Phase II Study

Background:
Platinum-based chemotherapy (ChT) has been the standard first-line treatment for metastatic urothelial carcinoma (mUC). The purpose of this study was to evaluate the use of induction avelumab followed by avelumab in combination with carboplatin-gemcitabine (carbo/gem) followed by avelumab maintenance. We tested the hypothesis that induction immunotherapy (IO) could enhance the response to ChT and prevent its detrimental effect on immune cells.

Materials and Methods:
INDUCOMAIN is a multicenter, randomized, investigator-initiated, open-label phase II study evaluating the safety and efficacy of induction avelumab before carboplatin-gemcitabine-avelumab, followed by avelumab maintenance (arm A), compared to carbo/gem (arm B). Eligibility criteria included patients with mUC, no prior systemic therapy, and ineligibility for cisplatin by Galsky criteria. Patients were stratified by the presence/absence of visceral metastasis and Eastern Cooperative Oncology Group performance status 0-1 versus 2. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Results:
Eighty-five patients were included and randomized to arm A (n = 42) and arm B (n = 43), respectively. ORR was similar between treatment arms: 59.5% in arm A and 53.5% in arm B (P = 0.57). Fourteen patients (33%) in arm A early progressed/died before or at first response assessment, compared to three patients (7%) in arm B. Median OS was 11.1 months in arm A and 13.2 months in arm B [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.57-1.46, P = 0.69]. Median PFS was 6.9 months in arm A versus 7.4 months in arm B (HR 0.99, 95% CI 0.61-1.60, P = 0.95). Treatment-related adverse events of grade 3-4 occurred in 70.7% of patients in arm A and in 72.1% in arm B. No predictive role of programmed death-ligand 1 expression was found.

Conclusions:
The hypothesis that induction avelumab could enhance the efficacy of subsequent ChT was not proven. Administering IO alone as induction before ChT is not an adequate strategy.
A Rodriguez-Vida,1 B P Valderrama,2 D Castellano,3 A Pinto,4 B Mellado,5 J Puente,6 M A Climent,7 M Domenech,8 F Vazquez,9 J L Perez-Gracia,10 T Bonfill,11 R Morales-Barrera,12 E Gonzalez-Billalabeitia,13 X Garcia-Del-Muro,14 P Maroto,15 N Navarro-Gorro,1 N Juanpere,16 O Juan,17 J Bellmunt18

  1. Medical Oncology Department, Hospital del Mar, CIBERONC, Barcelona.
  2. Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla.
  3. Medical Oncology Department, Hospital 12 de Octubre, Madrid.
  4. Medical Oncology Department, Hospital La Paz, Madrid.
  5. Medical Oncology Department, Hospital Clínic, Laboratory of Traslational Genomics in Solid Tumors, IDIBAPS, University of Barcelona, Barcelona.
  6. Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONC, Madrid.
  7. Medical Oncology Department, Instituto Valenciano de Oncología, Valencia.
  8. Medical Oncology Department, Hospital Althaia, Manresa.
  9. Medical Oncology Department, Hospital General Universitario de Elche, Alicante.
  10. Oncology Department, Clínica Universidad de Navarra, Pamplona.
  11. Medical Oncology Department, Hospital Universitario Parc Taulí, Sabadell.
  12. Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona.
  13. Medical Oncology Department, Hospital 12 de Octubre, Madrid; Medical Oncology Department, Hospital Morales Meseguer, Murcia.
  14. Medical Oncology Department, Institut Català d'Oncologia IDIBELL Research Institute, University of Barcelona, Barcelona.
  15. Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona.
  16. Pathology Department, Hospital del Mar, IMIM Research Institute, Barcelona.
  17. Medical Oncology, Pivotal S.L.U., Clinical Research Organisation, Madrid, Spain.
  18. Medical Oncology Department, Hospital del Mar, CIBERONC, Barcelona; Dana Farber Cancer Center, Harvard Medical School, Boston, USA.
Source: Rodriguez-Vida A, Valderrama BP, Castellano D, Pinto A, Mellado B, Puente J, Climent MA, Domenech M, Vazquez F, Perez-Gracia JL, Bonfill T, Morales-Barrera R, Gonzalez-Billalabeitia E, Garcia-Del-Muro X, Maroto P, Navarro-Gorro N, Juanpere N, Juan O, Bellmunt J. Induction avelumab followed by chemoimmunotherapy and maintenance versus chemotherapy alone as first-line therapy in cis-ineligible metastatic urothelial carcinoma (INDUCOMAIN): a randomized phase II study. ESMO Open. 2024 Sep;9(9):103690. doi: 10.1016/j.esmoop.2024.103690. Epub 2024 Aug 29. PMID: 39214051; PMCID: PMC11402049. 

Read an Expert Commentary by Bishoy Faltas, MD