Drug products: OPDIVO
ATC code: L01FF01
Based on the known sex-related dimorphism in immune system response, the patients' sex is expected to influence the efficacy of immune therapies. Some studies indicate better survival in men. A small retrospective study found better survival in men with metastatic melanoma and BMI 25-35 kg/m² but no difference in women.
Generally, women mount stronger innate and adaptive immune responses than men . Since tumors in women have to evade more efficient mechanisms of immune surveillance and undergo a more intensive immuno-editing process to become metastatic , advanced tumors in women can be less immunogenic and more resistant to immune therapies .Nivolumab, an inhibitor of the PD-1 receptor on T-cells, is used in non-small cell lung cancer (NSCLC) unresectable or metastatic melanoma and as adjuvant treatment in metastatic melanoma after total resection [4, 5].
Pharmacokinetics and dosing
Large pharmacokinetic studies have shown men to have a higher clearance of nivolumab compared to women [6, 7]. However, this difference has not been perceived to be clinically relevant as exposure seems to be similar. In the summary of product characteristics, it is reported that patient’s sex, age (29-87 ys), or race don’t have any clinically important effect on clearance [4, 5].
A meta-analysis of randomized trials comparing anti-PD-1/PD-L1 antibody treatment with chemotherapy, including three studies of nivolumab treatment in NSCLC (in all 1788 men, 2083 women, of those 578 men, 817 women were in a nivolumab study) found a survival benefit of immunotherapy, not dependent on patient’s sex .
Another meta-analysis including 20 eligible randomized controlled trials (in all 7646 men, 3705 women of those 1366 men, 852 women were in a nivolumab study) of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) in either melanoma and NSCLC showed that the prolongation of overall survival (OS), when achieved, was more significant for men .
In a meta-analysis including 21 RCTs and 12635 patients, half of them with nivolumab, and not only studies in melanoma and NSCLC patients but also in other type of advanced cancer treated with immune checkpoint inhibitors. OS was similar in men and women for anti-PD-1/PDL-1 while progression free survival (PFS) was longer in men than in women .
In patients with metastatic melanoma obesity is associated with improved PFS and OS . In a retrospective cohort study (79 men, 60 women), the association was mainly seen in men with BMI 25-35 kg/m² and creatinine <0.9 mg/dL treated with targeted or immune therapy .
In a Japanese post-marketing surveillance study (351 men, 329 women) no difference in ADR frequency was found, 56.1% in men and 50.4% in women . Similarly, in a cohort of NSCLC patients treated with nivolumab (56 men, 26 women), 19.5% developed thyroid dysfunction, similarly in men and women .
Reproductive health issues
Data is lacking but nivolumab, like most other anti-cancer drugs, is not considered compatible with pregnancy. It is recommended that women of child bearing potential use contraceptives during and for 5 months after use of nivolumab [4-5]. Regarding teratogenic birth defects, please consult Janusmed Drugs and Birth Defects(in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2019-05-24
- Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38. PubMed
- Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565-70. PubMed
- Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Lancet Oncol. 2018;19(6):737-746. PubMed
- Opdivo (nivolumab). Summary of Product Characteristics. European Medicines Agency (EMA) [updated 2019-04-04, cited 2019-05-24].
- Opdivo (nivolumab). DailyMed [www]. [updated 2019-05-02, cited 2019-05-24]. länk
- Zhang J, Cai J, Bello A, Roy A, Sheng J. Model-Based Population Pharmacokinetic Analysis of Nivolumab in Chinese Patients With Previously Treated Advanced Solid Tumors, Including Non-Small Cell Lung Cancer. J Clin Pharmacol. 2019;1(1):1. PubMed
- Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model-Based Population Pharmacokinetic Analysis of Nivolumab in Patients With Solid Tumors. CPT Pharmacometrics Syst Pharmacol. 2017;6(1):58-66. PubMed
- Huang Q, Zhang H, Hai J, Socinski MA, Lim E, Chen H et al. Impact of PD-L1 expression, driver mutations and clinical characteristics on survival after anti-PD-1/PD-L1 immunotherapy versus chemotherapy in non-small-cell lung cancer: A meta-analysis of randomized trials. Oncoimmunology. 2018;7(12):e1396403. PubMed
- Grassadonia A, Sperduti I, Vici P, Iezzi L, Brocco D, Gamucci T et al. Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials. J Clin Med. 2018;7(12):-. PubMed
- McQuade JL, Daniel CR, Hess KR, Mak C, Wang DY, Rai RR et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 2018;19(3):310-322. PubMed
- Naik GS, Waikar SS, Johnson AEW, Buchbinder EI, Haq R, Hodi FS et al. Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition. J Immunother Cancer. 2019;7(1):89. PubMed
- Kiyohara Y, Uhara H, Ito Y, Matsumoto N, Tsuchida T, Yamazaki N. Safety and efficacy of nivolumab in Japanese patients with malignant melanoma: An interim analysis of a postmarketing surveillance. J Dermatol. 2018;45(4):408-415. PubMed
- Yamazaki H, Iwasaki H, Yamashita T, Yoshida T, Suganuma N, Yamanaka T et al. Potential Risk Factors for Nivolumab-induced Thyroid Dysfunction. In Vivo. 2017;31(6):1225-1228. PubMed
- Concise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2019-03-14.] länk
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson