Drug products: YERVOY
ATC code: L01FX04
Due to sex-related dimorphism in immune system response the benefit of ipilimumab treatment of advanced (non-responsive or metastatic) melanoma in terms of prolongation of overall survival is higher in men. Women are more likely to develop immune checkpoint inhibitor-related adverse events.
In our opinion, the described differences do not motivate differentiated dosing or treatment in men and women. However, women will be expected to have a poorer response to treatment.
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 .Ipilimumab is an immune checkpoint inhibitor monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to potentiate an antitumor T-cell response. Ipilimumab either as monotherapy or in combination with nivolumab is indicated for the treatment of advanced (non-responsive or metastatic) melanoma.
Pharmacokinetics and dosing
Pharmacokinetic data do not indicate sex differences .
A meta-analysis including 20 eligible randomized controlled trials (in total 7646 men, 3705 women) of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) showed that the prolongation of overall survival (OS), when achieved, was more significant for men .
In a phase 3 study (401 men, 275 women), ipilimumab 3 mg/kg administered with or without a glycoprotein 100 (gp100) peptide vaccine were compared with gp100 alone in patients with previously treated metastatic melanoma. The median OS was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). HR (95% CI) for men was 0.66 (0.50-0.87), and for women was 0.72 (0.52-0.99). The median OS with ipilimumab alone was 10.1 months (HR for death in the comparison with gp100 alone, 0.66; P=0.003). HR (95% CI) for men was 0.54 (0.37-0.77), and for women was 0.81 (0.55-1.20) . In another phase 3 study, 149 men and 103 women with previously untreated metastatic melanoma were randomized to receive ipilimumab 10 mg/kg plus dacarbazine or dacarbazine plus placebo. OS was significantly longer in the ipilimumab group (11.2 months vs. 9.1 months), with higher survival rates in the ipilimumab-dacarbazine group at different time points up to 3 years (HR for death, 0.72 (0.59-0.87); P<0.001). Men had a better survival (HR 0.70, 95% CI 0.50-0.90). In women no survival benefit was demonstrated (HR 0.86, 95%CI 0.63-1.17) .
A double-blind, multicentre, randomized, controlled, phase 2 trial compared combined nivolumab (an anti-PD-1 antibody) and ipilimumab (63 men, 32 women) versus ipilimumab alone (32 men, 15 women) in patients with advanced melanoma. At a median follow-up of 24.5 months, 2-year OS was 63.8% (95% CI 53.3-72.6) for those assigned to nivolumab plus ipilimumab and 53.6% (95% CI 38.1-66.8) for those assigned to ipilimumab alone. OS rate for the combination arm was 0.74 (0.43-1.26; p=0.26). The HR for men was 0.65 (0.33-1.26), and for women was 0.89 (0.36-2.19), showing a trend but no statistical significant difference between men and women in effect .
In patients with metastatic melanoma, obesity is associated with improved progression-free survival and OS. The association is mainly seen in men treated with targeted or immune therapy .
Ingeneral, women are more susceptible to autoimmune disorders. This could make them more likely to develop immune checkpoint inhibitor-related adverse events, and higher rate of treatment discontinuation .
A prospective study (86 men, 54 women) aimed at analyzing potential clinical and biological markers associated with immune-related toxicity in patients treated with ipilimumab (3 mg/kg, q3w) conducted. Thirty-six of 140 patients experienced a severe adverse event, such as gastrointestinal (n=21), endocrine (n=11) and cutaneous (n=5). Female sex (OR = 1.5, 95% CI 1.06–2.16; p=0.022) and low interleukin-6 serum levels were independent risk factor for immune-related adverse events .
However, ipilimumab induced hypophysitis (IH) has been observed more often among male patients. A retrospective review included 154 adult patients with metastatic melanoma. IH was diagnosed in 17 patients (15 men, 2 women). Male sex and older age were risk factors for IH. As the two female patients were over 65 years, the authors speculate that the presence of higher estrogen levels attenuates the risk of developing IH .
Reproductive health issues
Ipilimumab like most other anti-cancer drugs is not compatible with pregnancy. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2018-11-15
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Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson