Sex and Survival Outcomes in Patients with Renal Cell Carcinoma Receiving First-line Immune-based Combinations

Background: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking.

Method: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy.

Results: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008).

Conclusions: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.

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References

Choueiri T, Powles T, Burotto M, Escudier B, Bourlon M, Zurawski B . Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021; 384(9):829-841. PMC: 8436591. DOI: 10.1056/NEJMoa2026982. View

Ning K, Peng Y, Jiang Y, Li Z, Luo X, Lin L . Sex differences in renal cell carcinoma: a single-cell analysis reveals exhausted CD8 T-cells highly infiltrated in males. Biol Sex Differ. 2023; 14(1):58. PMC: 10503187. DOI: 10.1186/s13293-023-00540-9. View

Perera N, Bellomo T, Schmidt W, Litt H, Shyu M, Stavins M . Analysis of Female Participant Representation in Registered Oncology Clinical Trials in the United States from 2008 to 2020. Oncologist. 2023; 28(6):510-519. PMC: 10243778. DOI: 10.1093/oncolo/oyad009. View

Marchioni M, Martel T, Bandini M, Pompe R, Tian Z, Kapoor A . Marital status and gender affect stage, tumor grade, treatment type and cancer specific mortality in T N M renal cell carcinoma. World J Urol. 2017; 35(12):1899-1905. DOI: 10.1007/s00345-017-2082-9. View

Diaz-Montero C, Rini B, Finke J . The immunology of renal cell carcinoma. Nat Rev Nephrol. 2020; 16(12):721-735. DOI: 10.1038/s41581-020-0316-3. View

Irelli A, Sirufo M, DUgo C, Ginaldi L, De Martinis M . Sex and Gender Influences on Cancer Immunotherapy Response. Biomedicines. 2020; 8(7). PMC: 7400663. DOI: 10.3390/biomedicines8070232. View

Wallis C, Butaney M, Satkunasivam R, Freedland S, Patel S, Hamid O . Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers: A Systematic Review and Meta-analysis. JAMA Oncol. 2019; 5(4):529-536. PMC: 6459215. DOI: 10.1001/jamaoncol.2018.5904. View

Haslam A, Prasad V . Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs. JAMA Netw Open. 2019; 2(5):e192535. PMC: 6503493. DOI: 10.1001/jamanetworkopen.2019.2535. View

Ricketts C, Linehan W . Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC). PLoS One. 2015; 10(10):e0140257. PMC: 4618848. DOI: 10.1371/journal.pone.0140257. View

10.

Santoni M, Massari F, Myint Z, Iacovelli R, Pichler M, Basso U . Clinico-Pathological Features Influencing the Prognostic Role of Body Mass Index in Patients With Advanced Renal Cell Carcinoma Treated by Immuno-Oncology Combinations (ARON-1). Clin Genitourin Cancer. 2023; 21(5):e309-e319.e1. DOI: 10.1016/j.clgc.2023.03.006. View

11.

Santoni M, Massari F, Grande E, Procopio G, Matrana M, Rizzo M . Cabozantinib in Pretreated Patients with Metastatic Renal Cell Carcinoma with Sarcomatoid Differentiation: A Real-World Study. Target Oncol. 2021; 16(5):625-632. DOI: 10.1007/s11523-021-00828-z. View

12.

Libert C, Dejager L, Pinheiro I . The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol. 2010; 10(8):594-604. DOI: 10.1038/nri2815. View

13.

Ma J, Yao Y, Tian Y, Chen K, Liu B . Advances in sex disparities for cancer immunotherapy: unveiling the dilemma of Yin and Yang. Biol Sex Differ. 2022; 13(1):58. PMC: 9587634. DOI: 10.1186/s13293-022-00469-5. View

14.

Conforti F, Pala L, Pagan E, Bagnardi V, De Pas T, Queirolo P . Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion. Clin Cancer Res. 2021; 27(15):4311-4324. PMC: 7611463. DOI: 10.1158/1078-0432.CCR-21-0136. View

15.

Oertelt-Prigione S . The influence of sex and gender on the immune response. Autoimmun Rev. 2011; 11(6-7):A479-85. DOI: 10.1016/j.autrev.2011.11.022. View

16.

Graham J, Abdel-Rahman O, Choueiri T, Heng D . Re: Fabio Conforti, Laura Pala, Vincenzo Bagnardi, et al. Cancer Immunotherapy Efficacy and Patients' Sex: A Systematic Review and Meta-analysis. Lancet Oncol 2018;19:737-46: Outcomes of Metastatic Renal Cell Carcinoma by Gender: Contrasting Results.... Eur Urol. 2018; 74(6):e139-e140. DOI: 10.1016/j.eururo.2018.07.004. View

17.

Santoni M, Massari F, Matrana M, Basso U, De Giorgi U, Aurilio G . Statin use improves the efficacy of nivolumab in patients with advanced renal cell carcinoma. Eur J Cancer. 2022; 172:191-198. DOI: 10.1016/j.ejca.2022.04.035. View

18.

Santoni M, Rizzo A, Mollica V, Matrana M, Rosellini M, Faloppi L . The impact of gender on The efficacy of immune checkpoint inhibitors in cancer patients: The MOUSEION-01 study. Crit Rev Oncol Hematol. 2022; 170:103596. DOI: 10.1016/j.critrevonc.2022.103596. View

19.

Tulchiner G, Pichler R, Ulmer H, Staudacher N, Lindner A, Brunner A . Sex-specific hormone changes during immunotherapy and its influence on survival in metastatic renal cell carcinoma. Cancer Immunol Immunother. 2021; 70(10):2805-2817. PMC: 8423679. DOI: 10.1007/s00262-021-02882-y. View

20.

Motzer R, Alekseev B, Rha S, Porta C, Eto M, Powles T . Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021; 384(14):1289-1300. DOI: 10.1056/NEJMoa2035716. View