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Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma

Background: Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC.

Patients and Methods: We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors.

Results: We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months.

Conclusion: Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.

Rafee Talukder,1 Dimitrios Makrakis,1 Genevieve Ihsiu Lin,2 Leonidas N Diamantopoulos,3 Scott Dawsey,4 Shilpa Gupta,4 Lucia Carril-Ajuria,5 Daniel Castellano,5 Ivan de Kouchkovsky,6 Tanya Jindal,6 Vadim S Koshkin,6 Joseph J Park,7 Ajjai Alva,7 Mehmet A Bilen,8 Tyler F Stewart,9 Rana R McKay,9 Nishita Tripathi,10 Neeraj Agarwal,10 Naomi Vather-Wu,11 Yousef Zakharia,12 Rafael Morales-Barrera,13 Michael E Devitt,14 Alessio Cortellini,15 Claudia Angela Maria Fulgenzi,15 David J Pinato,15 Ariel Nelson,16 Christopher J Hoimes,17 Kavita Gupta,18 Benjamin A Gartrell,18 Alex Sankin,18 Abhishek Tripathi,19 Roubini Zakopoulou,20 Aristotelis Bamias,21 Jure Murgic,22 Ana Fröbe,23 Alejo Rodriguez-Vida,24 Alexandra Drakaki,25 Sandy Liu,25 Eric Lu,25 Vivek Kumar,26 Giuseppe Di Lorenzo,27 Monika Joshi,28 Pedro Isaacsson-Velho,29 Lucia Alonso Buznego,30 Ignacio Duran,30 Marcus Moses,31 Pedro Barata,31 Guru Sonpavde,32 Jonathan L Wright,33 Evan Y Yu,34 Robert Bruce Montgomery,34 Andrew C Hsieh,34 Petros Grivas,35 Ali Raza Khaki36

  1. Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
  2. Department of Epidemiology, University of Washington, Seattle, WA
  3. Department of Medicine, University of Pittsburgh, Pittsburgh, PA
  4. Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
  5. Department of Medical Oncology, Hospital Universitario, Madrid, Spain
  6. Division of Oncology, Department of Medicine, University of California, San Francisco, CA
  7. Division of Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI
  8. Winship Cancer Institute of Emory University, Atlanta, GA
  9. Division of Hematology/Oncology, Department of Medicine, University of California San Diego, La Jolla, CA
  10. Division of Oncology, Department of Medicine, University of Utah, Salt Lake City, UT
  11. Department of Medicine, University of Iowa, Iowa City, IA
  12. Division of Oncology, Department of Medicine, University of Iowa, Iowa City, IA
  13. Vall d'Hebron Institute of Oncology, Vall d’ Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
  14. Division of Hematology/Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
  15. Department of Surgery and Cancer, Imperial College London, London
  16. Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
  17. Division of Medical Oncology, Seidman Cancer Center at Case Comprehensive Cancer Center, Cleveland, OH
  18. Division of Medical Oncology, Duke University, Durham, NC
  19. Departments of Medical Oncology and Urology, Montefiore Medical Center, Bronx, NY
  20. Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
  21. Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
  22. 2nd Propaedeutic Department of Internal Medicine, ATTIKON University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
  23. Department of Oncology and Nuclear Medicine, University Hospital Center Sestre Milosrdnice, Zagreb
  24. School of Dental Medicine, Zagreb, Croatia
  25. Medical Oncology Department, Hospital del Mar Research Institute, Barcelona, Spain
  26. Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA
  27. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
  28. Oncology University of Molise and ASL, Salerno, Italy
  29. Division of Hematology/Oncology, Department of Medicine, Penn State Cancer Institute, Hershey, PA
  30. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
  31. Division of Oncology, Hospital Moinhos de Vento, Porto Alegre, Brazil
  32. Hospital Universitario Marques de Valdecilla. IDIVAL. Santander, Spain
  33. Deming Department of Medicine, Section of Hematology/Oncology, Tulane University, New Orleans, LA
  34. Genitourinary Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
  35. Fred Hutchinson Cancer Center, Seattle, WA
  36. Department of Urology, University of Washington, Seattle, WA
  37. Division of Oncology, Department of Medicine, Stanford University, Palo Alto, CA

Source: Talukder R., Makrakis D., Lin G. et al. "Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma." Clinical Genitourinary Cancer. 2022. ISSN 1558-7673.