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Pembrolizumab

Classification: C

Drug products: Keytruda, KEYTRUDA

ATC code: L01XC18

Substances: pembrolizumab

Summary

Based on the known sex-related dimorphism in immune system response, the patients' sex is expected to influence the efficacy of immune therapies.

The magnitude of benefit of pembrolizumab treatment of advanced (non-responsive or metastatic) melanoma and head and neck squamous cell carcinoma in term of prolongation of overall survival is sex-dependent in favor of the male patients. Male compared to female patients tended to benefit more from treatment with pembrolizumab among patients with advanced NSCLC and urothelial cancer.

Women are more likely to develop immune checkpoint inhibitor-related adverse events.

Additional information

Generally, women mount stronger innate and adaptive immune responses than men [1]. Since tumors in women have to evade more efficient mechanisms of immune surveillance and undergo a more intensive immuno-editing process to become metastatic [2], advanced tumors in women can be less immunogenic and more resistant to immune therapies [3].Pembrolizumab is an immune checkpoint inhibitor monoclonal antibody that targets the programmed cell death 1 (PD-1) receptor of lymphocytes and blocks its interaction with the ligands PD-L1 and PD-L2 to potentiate an antitumor T-cell response. Pembrolizumab as monotherapy is indicated for the treatment of malign melanoma, metastasized non-small cell lung cancer (NSCLC), refractory primary Hodgkin’s lymphoma, local advanced or metastasized urothelial cancer, and relapsing or metastasized head and neck squamous cell cancer. It’s used either as monotherapy or in combination with platinum-based chemotherapy and pemetrexed is indicated as the first line treatment of metastatic NSCLC of non-squamous type.

Pharmacokinetics and dosing

The product information reports that patient’s sex, age, or race don’t have any clinically important effect on clearance [4].

Effects

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 [3]. The four studies on pembrolizumab included in the meta-analysis showed varying results. While most found a better effect of pembrolizumab compared to control treatment in men [5-6, 10] one study showed similar effect in men and women [3].

The following studies were included in the meta-analysis:

KEYNOTE-006 was a randomized, controlled, phase 3 study assigned 834 patients (497 men, 337 women) with advanced melanoma to receive pembrolizumab (10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (3 mg per kilogram) every 3 weeks. Pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab [5]. The progression-free survival HR for every two weeks treatment with pembrolizumab versus ipilimumab treatment was 0.57 (0.39-0.84) for men and 0.69 (0.46-1.04) for women. The HR for the treatment with pembrolizumab versus ipilimumab treatment were 0.66 (0.45-0.95) for men and 0.78 (0.51-1.21) for women.

In a randomized, open-label, multicenter, phase 3 study, KEYNOTE-040, patients (412 men, 83 women) with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4-9·4) with pembrolizumab and 6·9 months (5·9-8·0) with standard of care (hazard ratio 0·80, 0·65-0·98; nominal p=0·0161). The HR (CI 95%) for men was 0·77 (0·62–0·96), and for women was 0.94 (0·54–1·63) [6].

Another randomized, controlled, phase 3 trial on patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells (187 men, 118 women), KEYNOTE-024, indicated that first-line pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). [7]. A subgroup analysis showed an increased relative benefit with pembrolizumab treatment among men compared to women (hazard ratio for overall survival (95% CI) 0.54 (0.36-0.79) versus 0.96 (0.56-1.62), respectively [8].

An open-label, international, phase 3 trial, randomly assigned 542 patients (402 men, 140 women) with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive either pembrolizumab at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. Pembrolizumab was associated with approximately 3 months longer overall survival and with a lower rate of treatment-related adverse events compared to the chemotherapy group (HR for death 0.73 (95% CI, 0.59–0.91) P=0.002). Subgroup analysis showed the HR for men 0·73 (0·56–0·94). For the women the HR was 0·78 (0·49–1·24) [9].

In contrast to the studies above, a similar effect in men and women was found in KEYNOTE-010. This was a randomized, open-label, phase 2/3 study at 202 academic medical centers in 24 countries that assessed the efficacy of pembrolizumab for patients (634 men, 399 women) with previously treated, advanced NSCLC with PD-L1 expression on at least 1% of tumor cells. The primary endpoints were overall survival. In the total population, the HR for pembrolizumab 2 mg/kg versus docetaxel was 0.71 (95% CI 0.58–0.88; p=0.0008) and the HR for pembrolizumab 10 mg/kg versus docetaxel was 0.61 (0.49–0.75; p<0.0001). Pembrolizumab prolonged overall survival and had a favorable benefit-to-risk profile compared to docetaxel. Subgroup analysis of overall survival showed no difference with  HR 0.65 (0.52–0.81) for men and 0.69 (0.51–0.94) for women [10].

In patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival. The association is mainly seen in men treated with targeted or immune therapy [11].

Adverse effects

In general, 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 [12]. However, no studies with a clinically relevant analysis of differences in adverse effects between men and women have been found.

Reproductive health issues

Data is lacking but pembrolizumab, 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 4 months after use of pembrolizumab. Regarding teratogenic birth defects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Updated: 2019-05-27

Date of litterature search: 2019-02-18

References

  1. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38. PubMed
  2. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565-70. PubMed
  3. 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
  4. KEYTRADA (pembrolizumab). Summary of Product Characteristics. European Medicines Agency (EMA). [updated 2019-02-08, cited 2019-02-18]
  5. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-32. PubMed
  6. Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156-167. PubMed
  7. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-1833. PubMed
  8. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019;1(1):JCO1800149. PubMed
  9. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-1026. PubMed
  10. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50. PubMed
  11. 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
  12. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28(2):368-376. PubMed
  13. Concise. Kalmar: eHälsomyndigheten. 2015 [cited 2018-12-17.] länk

Authors: Alan Fotoohi

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson