Association Between the Occurrence and Spectrum of Immune-Related Adverse Events and Efficacy of Pembrolizumab in Asian Patients With Advanced Urothelial Cancer: Multicenter Retrospective Analyses and Systematic Literature Review

Kijima, Toshiki; Fukushima, Hiroshi; Kusuhara, Shota; Tanaka, Hajime; Yoshida, Soichiro; Yokoyama, Minato; Ishioka, Junichiro; Matsuoka, Yoh; Numao, Noboru; Sakai, Yasuyuki; Saito, Kazutaka; Matsubara, Nobuaki; Yuasa, Takeshi; Masuda, Hitoshi; Yonese, Junji; Kageyama, Yukio; Fujii, Yasuhisa

doi:10.1016/j.clgc.2020.07.003

Cited by 20 publications

(25 citation statements)

References 43 publications

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“…4 5 Several previous studies have reported that the incidence of irAEs is associated with a good therapeutic response to ICIs in malignancies, 6 7 including melanoma, 8 non-small cell lung cancer, 9 10 gastric cancer, 11 12 and UC. [13][14][15] However, immortal time bias has not always been fully addressed in these studies. We previously reported the correlation between irAEs and favorable efficacy of pembrolizumab in patients with UC using single-center preliminary data 13 ; however, immortal time bias was not eliminated.…”

Section: Introductionmentioning

confidence: 99%

Impact of immune-related adverse events on the therapeutic efficacy of pembrolizumab in urothelial carcinoma: a multicenter retrospective study using time-dependent analysis

Kawai

Taguchi

Nakagawa

et al. 2022

J Immunother Cancer

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BackgroundSeveral studies have reported the incidence of immune-related adverse events (irAEs) as a predictor of the efficacy of anti-programmed cell death protein 1 antibodies in patients with cancer. However, immortal time bias has not always been fully addressed in these studies. In this retrospective multicenter study, we assessed the association between the incidence of irAEs and the efficacy of pembrolizumab in urothelial carcinoma (UC) using time-dependent analysis, an established statistical method to minimize immortal time bias.MethodsThe study included 176 patients with advanced UC who underwent pembrolizumab treatment at seven affiliated institutions between January 2018 and July 2020. Patients with irAEs were compared with those without irAEs in terms of overall survival (OS) and cancer-specific survival (CSS). Immortal time bias was eliminated by using time-dependent analysis.ResultsOf the 176 patients, irAEs occurred in 77 patients (43.8%), with a median of 60 days. The irAEs (+) cohort showed significantly favorable OS and CSS compared with the irAEs (−) cohort (p=0.018 and p=0.005, respectively), especially in the cohort with grade 1–2 irAEs (OS and CSS; p=0.003 and p=0.002, respectively). Multivariate analyses identified any irAEs and grade 1–2 irAEs as independent favorable prognostic factors for OS and CSS.ConclusionEven after minimizing immortal time bias by time-dependent analysis, the incidence of irAEs, especially grade 1–2 irAEs, could be a significant predictor of favorable prognoses in patients with UC who have undergone pembrolizumab treatment.

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Section: Introductionmentioning

confidence: 99%

Impact of immune-related adverse events on the therapeutic efficacy of pembrolizumab in urothelial carcinoma: a multicenter retrospective study using time-dependent analysis

Kawai

Taguchi

Nakagawa

et al. 2022

J Immunother Cancer

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“…A growing body of systematic reviews and meta-analyses [ 115 , 116 , 117 , 118 , 119 ] suggest that irAEs, including endocrine irAEs [ 116 , 119 ], could be designated as a predictive factor for the therapeutic efficacy of ICPi, being related to the improvement of the overall response [ 115 , 117 , 118 ], overall survival (OS) [ 115 , 116 , 117 , 118 ], and progression-free survival (PFS) [ 116 , 117 , 118 ] compared to the absence of irAEs. A stronger association of irAEs with response to anti-PD-1/anti-PD-L1 mAbs compared to the response to anti-CTLA-4 mAbs has been observed, likely due to intraclass differences in the indications, mechanisms, and time course of the treatments.…”

Section: The Association Of Ir Thyroid Disorders With Icpi Efficacymentioning

confidence: 99%

The Continuum of Thyroid Disorders Related to Immune Checkpoint Inhibitors: Still Many Pending Queries

Deligiorgi

Sagredou

Vakkas

et al. 2021

Cancers

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Background: Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors. Methods: The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1). Results: With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies. Conclusions: Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care.

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“…7,[9][10][11][12] Interestingly, there are data suggesting that immune-mediated adverse events may be associated with responses to therapy in mUC, as well as in other solid tumors. [33][34][35][36] Again, as in mRCC, some of these responses persist despite discontinuation of therapy. Thus, patients with a response to immune checkpoint inhibitors who require discontinuation of therapy should be monitored for evidence of clinical or radiographic progression prior to initiating further treatment.…”

Section: Responses In Metastatic Urothelial Carcinomamentioning

confidence: 99%

Immune Checkpoint Inhibition in Advanced Bladder and Kidney Cancer: Responses and Further Management

Parikh

Powles

2021

American Society of Clinical Oncology Educational Book

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Immune checkpoint inhibitors have an established role in the treatment of newly diagnosed metastatic kidney cancer. Treatment regimens combining nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib have demonstrated superior overall survival compared with sunitinib in randomized studies. Response rates vary from 42% to 71.1% with these combinations. Atezolizumab and pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with metastatic bladder cancer. These and other checkpoint inhibitors have been studied in metastatic bladder cancer and are routinely used after progression on platinum-based chemotherapy. Durable responses are observed in bladder and kidney cancer. Although some patients may experience immune-related adverse events requiring treatment discontinuation, a portion of these patients will continue to experience a response off-therapy. At the time of progression, patients with metastatic kidney cancer may be treated with antiangiogenesis agents, and there are data suggesting that they may also be treated with a rechallenge of immunotherapy. In patients with metastatic bladder cancer who have progression after immune checkpoint inhibition, there are considerable data supporting the use of enfortumab vedotin. Ongoing studies are evaluating novel combinations of immune checkpoint inhibitors with other agents; thus, the treatment landscape of metastatic bladder and kidney cancer is expected to continue to evolve rapidly.

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Association Between the Occurrence and Spectrum of Immune-Related Adverse Events and Efficacy of Pembrolizumab in Asian Patients With Advanced Urothelial Cancer: Multicenter Retrospective Analyses and Systematic Literature Review

Cited by 20 publications

References 43 publications

Impact of immune-related adverse events on the therapeutic efficacy of pembrolizumab in urothelial carcinoma: a multicenter retrospective study using time-dependent analysis

Impact of immune-related adverse events on the therapeutic efficacy of pembrolizumab in urothelial carcinoma: a multicenter retrospective study using time-dependent analysis

The Continuum of Thyroid Disorders Related to Immune Checkpoint Inhibitors: Still Many Pending Queries

Immune Checkpoint Inhibition in Advanced Bladder and Kidney Cancer: Responses and Further Management

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