Durable responses in patients with genitourinary cancers following immune checkpoint therapy rechallenge after moderate-to-severe immune-related adverse events

Abstract

Background: Immune checkpoint therapy (ICT) prolongs survival in subsets of patients with cancer but can also trigger immune-related adverse events (irAEs) requiring treatment discontinuation. Recent studies have investigated safety of ICT rechallenge after irAEs, and evidence suggests that rechallenge may be associated with improved antitumor responses. However, data are limited on response duration after ICT rechallenge, particularly after severe irAEs.

Objective: To evaluate safety and efficacy of ICT rechallenge after moderate-to-severe irAEs in patients with renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer.

Methods: In this retrospective cohort study, medical records from September 25, 2013, to June 1, 2020, for patients with genitourinary (GU) cancers at MD Anderson Cancer Center who were rechallenged with the same or different ICT following irAEs were reviewed. Demographics, ICT exposure, irAEs (grade and treatment), ICT discontinuation or rechallenge, rates of subsequent irAEs (new or recurrent) and antitumor activity (objective response rates and response duration) were reviewed.

Results: Sixty-one patients with RCC, UC, and prostate cancer were rechallenged with ICT after experiencing 105 total irAEs. Objective response rates after rechallenge, that is, upgrade in response, were 14% in RCC (4/28), 21% in UC (3/14), and 0% in prostate cancer. All seven patients who achieved upgrade in response had initial grade 2 or 3 irAEs. Responses were durable among these seven patients, with median radiographic progression-free survival not reached (range: 3.7-66.4 months) as of the March 8, 2021, data cut-off (median follow-up 40.9 months (95% CI 35.3 to 46.5)). All achieved complete response except one patient who was lost to follow-up. The rate of subsequent grade 3 or 4 irAEs after rechallenge was 30%, with no fatal irAEs. The rate of recrudescence of the same irAE was 26% (16/61). 54% of patients received corticosteroids (33/61), and 21% received targeted immunosuppression (13/61) for the initial irAEs.

Conclusions and relevance: ICT rechallenge after moderate-to-severe irAEs was associated with deep and durable responses in a subset of patients with RCC and UC, with acceptable safety and no fatal events. Strategies to enable ICT resumption after moderate-to-severe irAEs, such targeted immunosuppression, warrant further study.

Keywords: autoimmunity; immunotherapy; kidney neoplasms; prostatic neoplasms; urinary bladder neoplasms.

Figure 1

Consort diagram. Medical records from patients with prostate cancer, urothelial carcinoma, and renal cell carcinoma were screened for exposure to ICT and experience of irAE using pre-specified search terms. ICT, immune checkpoint therapy; irAE, immune-related adverse event; GU, genitourinary.

Figure 2

Patterns of initial and subsequent irAEs. ‘Arthritis’ includes both arthritis and arthralgia. ‘Colitis’ includes both biopsy proven colitis and suspected. For patients with multiple initial irAEs, the highest grade or most clinically relevant (eg, warranting hospitalization) event is depicted for readability. Pie slices generated for legibility and do not correlate with frequency of irAE. Patients who did not experience a subsequent irAE (n=25) are not included in this diagram. AI, adrenal insufficiency; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Col., colitis; HSR, hypersensitivity reaction; irAEs, immune-related adverse events; MMF=mycophenolate mofetil; Pneumo., pneumonitis; Subs. subsequent; T1DM, type 1 diabetes mellitus.

Figure 3

Outcomes with ICT rechallenge. (A) Progression-free survival (PFS) after first exposure to ICT (ICT1). Initial screening radiographic response assessment obtained per RECIST V.1.1 where available. Radiographic PFS (rPFS) used for patients with prostate cancer. (B) Overall survival (OS) after ICT1. (C) Best radiographic response after irAE. irAEs are annotated for seven patients (four RCC and three UC) with response upgrade. Response upgrades confirmed by two independent radiologists. (D) Swimmer’s plot of PFS after ICT1 (months) in patients with response upgrades. Response upgrades confirmed by two independent radiologists. Yellow arrows indicate ongoing response. CR, complete response; CTLA-4, cytotoxic T lymphocyte-associated protein-4; ICT, immune checkpoint therapy; irAE, immune-related adverse event, PD, progression of disease; PD-1 programmed cell death protein-1; PD-L1, programmed death-ligand 1; PR, partial response; RCC, renal cell carcinoma; SD, stable disease; TKI, tyrosine kinase inhibitor; UC, urothelial carcinoma. *Indicates patient who underwent consolidative surgery.