Immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) herald a transformative era in metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) treatment, amid acknowledged sex-based disparities in these cancers. We conducted a systematic review and network meta-analysis (NMA) to identify sex-specific differences in the efficacy of ICI/ADC monotherapy or combination therapies for RCC and TCC survival, in metastatic and adjuvant settings.
A systematic search was conducted up to October 2023 for English articles on ICIs and ADCs as systemic therapies (ICIs in first-line and adjuvant treatment for RCC, ICIs and ADCs in first- and second-line treatment for TCC). Randomised clinical trials were considered. The primary objective was overall survival (OS) of ICIs and ADCs between males and females. The secondary outcomes included progression-free survival, overall response rate, disease-free survival, and recurrence-free survival. Treatment efficacy was evaluated by sex via odds ratios (ORs) and confidence intervals compared with controls. Log ORs were used for creating a frequentist NMA. This meta-analysis was registered on PROSPERO (CRD42023468632).
Eighteen articles met the inclusion criteria. Females had an advantage for RCC-adjuvant treatment for atezolizumab (log OR [SE] = –0.57 ± 0.25, p = 0.024) in OS. Males showed a survival advantage in TCC second-line treatment for ADC-Nectin 4 (log OR [SE] = 0.65 ± 0.28, p = 0.02). No other significant results were shown.
The NMA revealed gender-specific variations in ICI and ADC responses for RCC and TCC, offering insights for personalised cancer care and addressing disparities in cancer care and outcomes.
A systematic review recently published on European Urology Oncology by the European Association of Urology Section of Oncological Urology investigated the impact of sex on the outcomes of immunotherapy and antibody-drug conjugates (ADCs) in patients with urothelial and kidney cancers [1]. A network meta-analysis of randomised clinical trials was included to explore sex-specific differences in treatment efficacy. It focused on overall survival and progression-free survival among other outcomes. The findings highlighted significant sex-based disparities in the response to received therapies, particularly noting advantages in specific contexts for males and females.
While the article addresses both urothelial and kidney cancers, our focus here will be on renal cell carcinoma (RCC).
The study confirms that men are more frequently affected by RCC and typically present with higher tumour stages and grades compared to women. Despite these differences, the response to immunotherapies and ADCs also varies significantly by sex. Immune checkpoint inhibitors such as atezolizumab were found to offer a survival advantage in adjuvant treatment settings for females. This finding is particularly notable as it suggests that women might benefit more from certain immunotherapies post-surgery, potentially leading to better long-term outcomes. The European Association of Urology (EAU) guidelines recommend combination therapies involving immune-oncology drugs and tyrosine kinase inhibitors for treating RCC. The study supports this by demonstrating that these combinations enhance the therapeutic effectiveness. Notably, the combination therapies are suggested to help in better T-cell infiltration and activation, which is crucial for fighting RCC under a medical oncology point of view.
The sex-specific differences in treatment efficacy underscore the importance of personalised medicine. Tailoring treatment strategies based on sex can potentially improve overall survival rates and quality of life for patients with RCC. This approach also highlights the need for further research to optimise therapeutic protocols and address existing disparities.
In summary, the findings from this systematic review and network meta-analysis emphasise the critical role of sex in determining the outcomes of immunotherapy and ADCs in kidney cancer treatment. For RCC, particularly, recognising and leveraging these differences can lead to more effective and personalised therapeutic strategies, ultimately improving patient care and survival outcomes. While the study provides valuable insights, it also acknowledges limitations such as the heterogeneity of the included studies and the lack of direct comparisons between sexes within individual trials. Future research should aim to conduct more granular analyses and explore the underlying biological mechanisms driving these sex-based differences.
Reference
[1] Cerrato C, Crocerossa F, Marchioni M, et al. Effect of sex on the oncological outcomes in response to immunotherapy and antibody-drug conjugates in patients with urothelial and kidney cancer: A systematic review and a network meta-analysis. Eur Urol Oncol. 2024 Apr 20:S2588-9311(24)00096-8. doi: 10.1016/j.euo.2024.03.014. Epub ahead of print.