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Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis

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Abstract

Background

Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab.

Materials and methods

This retrospective study included patients who received nivolumab plus ipilimumab at six centres, institutions, or hospitals between September 2018 and February 2022. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used.

Results

This study included 129 patients with a median follow-up of 12.3 months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165–0.648, p = 0.001; HR 0.334, 95% CI 0.151–0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235–1.097, p = 0.085 or HR 0.245, 95% CI 0.110–0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316–1.036, p = 0.085 or HR 0.267, 95% CI 0.113–0.628, p = 0.002) compared with those who experienced single or zero irAE.

Conclusions

Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab.

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Acknowledgements

We thank Yoshiko Yonejima and Keiko Yamamoto for their support with the data collection at Toranomon Hospital and Dokkyo Medical University Saitama Medical Centre.

Funding

None of the authors of this manuscript received any type of support, benefits, or funding from a commercial party related directly or indirectly to the subject of this article.

Author information

Authors and Affiliations

  1. Department of Urology, Jichi Medical University Saitama Medical Center, 1-847, Amanuma-cho, Omiya-ku, Saitama, Saitama, 330-8503, Japan

    Satoshi Washino & Tomoaki Miyagawa

  2. Department of Uro-Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan

    Suguru Shirotake & Masafumi Oyama

  3. Department of Urology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama, 350-8550, Japan

    Hideki Takeshita, Makoto Kagawa & Satoru Kawakami

  4. Department of Urology, Saitama Cancer Center, 818, Ina-machi, Kitaadati-gun, Komuro, Saitama, 362-0806, Japan

    Masaharu Inoue, Keita Izumi & Yoh Matsuoka

  5. Department of Medical Oncology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Yuji Miura

  6. Department of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Saitama, 343-0845, Japan

    Yoji Hyodo & Kazutaka Saito

  7. Musashino Study Group, Saitama, Japan

    Satoshi Washino, Suguru Shirotake, Hideki Takeshita, Masaharu Inoue, Yuji Miura, Yoji Hyodo, Makoto Kagawa & Keita Izumi

  8. Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, Osaka, 545-8585, Japan

    Satsuki Taniuchi & Ayumi Shintani

Authors
  1. Satoshi Washino
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  2. Suguru Shirotake
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  3. Hideki Takeshita
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  4. Masaharu Inoue
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  15. Tomoaki Miyagawa
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Contributions

SW had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: SW. Acquisition of data: SW, SS, YM,YH, MK, KI. Analysis and interpretation of data: SW, ST, AS. Drafting of the manuscript: SW. Critical revision of the manuscript for important intellectual content: SS, HT, MI, YM. Statistical analysis: SW, ST, AS. Obtaining funding: none. Administrative, technical, or material support: None. Supervision: MO, SK, KS, YM, TM. Other: none.

Corresponding author

Correspondence to Satoshi Washino.

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Conflict of interest

This study was approved by the institutional review board of each study institution and carried out according to the Declaration of Helsinki and its amendments. Informed consent was obtained from all patients via posters and/or websites using the opt-out method. Sugure Shirotake received lecture fees from Bristol Meyers Squibb and Ono Pharmaceutical. Yuji Miura received lecture fees from Takeda Pharmaceutical, Bristol Meyers Squibb and Eisai, and research grants from MSD and Ono Pharmaceutical. Kazutaka Saito received lecture fees from Takeda Pharmaceutical and Merck Biopharma. The other authors have no conflicts of interest to declare.

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Washino, S., Shirotake, S., Takeshita, H. et al. Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. Int J Clin Oncol 28, 1651–1658 (2023). https://doi.org/10.1007/s10147-023-02406-x

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  • DOI: https://doi.org/10.1007/s10147-023-02406-x

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