Brief CommunicationOpen Access

Association of Gender with Efficacy of Immunotherapy in Metastatic Melanoma

Varsha Jain1, Sriram Venigalla1, Kevin T. Nead1, Wei-Ting Hwang2, John N. Lukens1, Tara C. Mitchell3, Jacob E. Shabason1*

1Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

2Department of Biostatistics, Epidemiology and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

3Division of Medical Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA


Pre-clinical data from animal models suggest that the anti-tumor efficacy of immune checkpoint blockade agents may be influenced by gender specific sex hormones. However, recent meta-analyses of clinical data aimed at addressing the impact of gender on response to these agents have demonstrated conflicting results. Given the discordant evidence, we sought to evaluate the association of gender with the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. This retrospective cohort study used the National Cancer Database to identify patients who were ≥18 years old with Stage IV melanoma from 2011 to 2015. Patterns of utilization of immunotherapy, including by gender, were assessed using multivariable logistic regression. A multivariable Cox proportional hazards model, including an interaction term between the receipt of immunotherapy and gender, was used to evaluate whether gender modified the association of receipt of immunotherapy with hazards of death. 11,944 patients met study inclusion criteria. Of these, 8,093 (68%) were males and 3,851 (32%) were females. 2,930 (25%) patients received immunotherapy while 9,014 (75%) did not. There was no statistically significant difference in the receipt of immunotherapy between males and females. On multivariable analysis, receipt of immunotherapy was associated with a survival benefit in both males and females. However, a statistically significant difference in efficacy of immunotherapy based on gender was not observed (pinteraction =0.422). Utilizing a real world cohort of patients derived from a national cancer registry, gender was not associated with differences in immunotherapy survival outcomes in patients with metastatic melanoma.


Modern immunotherapy agents targeting cellular immune checkpoint pathways have demonstrated promising survival outcomes in metastatic melanoma, and are now the standard of care1,2. While these drugs hold the promise of offering durable tumor control, only a fraction of treated patients respond. Understanding the clinical and biological factors (such as gender) that may modulate response to these agents is imperative to better select the most efficacious therapies for a particular patient as well as to inform future clinical trials.

Pre-clinical data from animal models does suggest sex hormone based modulation of immune pathways3,4. However, recent meta-analyses evaluating gender-associated differences in response to modern immunotherapies in advanced cancers have shown conflicting results5–7.

Given this area of clinical controversy, we evaluated a real world cohort of patients with metastatic melanoma derived from a national cancer registry to examine the association of gender with the receipt of and survival outcomes with immunotherapy.

This study was exempt from review by our institutional review board as we used a de-identified dataset. We included patients who were ≥18 years, had Stage IV (metastatic) cutaneous melanoma, and were diagnosed from 2011- 2015. This time period was chosen given the approval of Ipilimumab, the first modern immune checkpoint inhibitor (ICI) for metastatic melanoma, in 2011. Patients were excluded if receipt of immunotherapy or the disease stage was unknown or missing (eFigure 1).

Baseline characteristics between patients who did and did not receive immunotherapy were compared using Pearson’s χ2 test. A multivariable logistic regression model was utilized to evaluate the patterns of receipt of immunotherapy.

In order to determine if the association of receipt of immunotherapy with hazards of death was modified by gender, a multivariable Cox proportional hazards model which included an interaction term between receipt of immunotherapy (yes/no) and gender (male/female) was used. The same model as above was used to derive individual hazards of death associated with receipt of immunotherapy for males and females as listed in Table 3.

All baseline covariates (Table 1) were evaluated. Covariates achieving a threshold significance of p<0.1 on univariate analysis were included in multivariable logistic regression and Cox proportional hazards analyses (Table 2 and eTable 1, respectively).

Propensity score (PS) adjustment with robust variance estimation was used to further adjust for potential confounding factors8 and denoted the probability of receiving immunotherapy(matched for all covariates listed in eTable1). A two-tailed p-value <0.05 was considered statistically significant. Statistical analyses were performed using Stata SE, version 15.0 (StataCorp, College Station, TX).

A total of 11,944 patients met study inclusion criteria. Of these, 2,930 (25%) received immunotherapy while 9,014 (75%) did not. There were 8,093 (68%) males and 3,851 (32%) females. The median age of the patient cohort was 66 years (range: 55-76 years). Detailed baseline patient characteristics are listed in Table 1.

Table 1. Baseline patient characteristics
Receipt of Immunotherapy No % Yes % Total % chi2
Total, n 9,014 75 2,930 25 11,944 100  
Gender             0.796
Male 6,102 68 1,991 68 8,093 68  
Female 2,912 32 939 32 3,851 32  
Age             <0.001
18-49 1,187 13 558 19 1,745 15  
50-69 3,921 43 1,473 50 5,394 45  
≥70 3,906 43 899 31 4,805 40  
Race             0.425
Non-Hispanic White 8,490 94 2,767 94 11,257 94  
Non-Hispanic Black 133 1 35 1 168 1  
Hispanic 238 3 70 2 308 3  
Other 153 2 58 2 211 2  
Facility Area             0.001
Metropolitan 7,181 80 2,427 83 9,608 80  
Urban 1,394 15 369 13 1,763 15  
Rural 193 2 50 2 243 2  
Unknown 246 3 84 3 330 3  
Insurance             <0.001
Commercial 2,954 33 1,314 45 4,268 36  
Medicare 4,535 50 1,208 41 5,743 48  
Medicaid 711 8 194 7 905 8  
Uninsured 486 5 105 4 591 5  
Other 328 4 109 4 437 4  
Zip Code Education Level             <0.001
≥21% 1,309 15 300 10 1,609 13  
13%-20.9% 2,250 25 690 24 2,940 25  
7%-12.9% 3,083 34 1,032 35 4,115 34  
<7% 2,345 26 903 31 3,248 27  
Unknown 27 <1 5 <1 32 <1  
Zip Code Median Income             <0.001
<38,000 1,311 15 337 12 1,648 14  
38,000-47,999 2,168 24 612 21 2,780 23  
48,000-62,999 2,512 28 857 29 3,369 28  
≥63,000 2,983 33 1,119 38 4,102 34  
Unknown 40 <1 5 <1 45 <1  
Facility Type             <0.001
East 1,591 18 622 21 2,213 19  
South 3,317 37 880 30 4,197 35  
Central 2,042 23 669 23 2,711 23  
               
West 1,632 18 530 18 2,162 18  
Unknown 432 5 229 8 661 6  
Charlson Deyo Score             <0.001
0 6,662 74 2,410 82 9,072 76  
1 1,608 18 398 14 2,006 17  
2 484 5 91 3 575 5  
3 260 3 31 1 291 2  
Surgery to Metastatic site             0.03
No 6,542 73 2,068 71 8,610 72  
Yes 2,404 27 829 28 3,233 27  
Unknown 68 1 33 1 101 1  
Brain Metastasis             <0.001
None 4,544 50 1,480 51 6,024 50  
Present 2,425 27 632 22 3,057 26  
Unknown 2,045 23 818 28 2,863 24  
Liver Metastasis             <0.001
None 5,441 60 1,605 55 7,046 59  
Present 1,474 16 505 17 1,979 17  
Unknown 2,099 23 820 28 2,919 24  
Lung Metastasis             <0.001
None 4,036 45 1,111 38 5,147 43  
Present 2,893 32 999 34 3,892 33  
Unknown 2,085 23 820 28 2,905 24  
Bone Metastasis             <0.001
None 5,646 63 1,697 58 7,343 61  
Present 1,287 14 416 14 1,703 14  
Unknown 2,081 23 817 28 2,898 24  
Receipt of Chemotherapy             <0.001
No 6,094 68 2,549 87 8,643 72  
Yes 2,620 29 336 11 2,956 25  
Unknown 300 3 45 2 345 3  
Receipt of Radiotherapy             <0.001
No 5,778 64 1,740 59 7,518 63  
Yes 3,166 35 1,184 40 4,350 36  
Unknown 70 1 6 <1 76 1  
Year of Diagnosis             <0.001
2011 1,859 21 341 12 2,200 18  
2012 1,811 20 356 12 2,167 18  
2013 1,881 21 559 19 2,440 20  
2014 1,801 20 707 24 2,508 21  
2015 1,662 18 967 33 2,629 22  

25% of the males and 24% of the females received immunotherapy. On multivariable logistic regression analysis, there was no statistically significant difference in the receipt of immunotherapy between males and females (OR: 0.92, 95% CI: 0.83-1.01, p=0.077). Factors associated with an increased likelihood of receiving immunotherapy included treatment at academic centers, presence of extra-cranial metastatic disease (liver, lung or bone), and a later year of diagnosis. Conversely, factors associated with a decreased likelihood of receiving immunotherapy included having Medicaid and being uninsured (vs. commercial insurance), having a higher Charlson Deyo comorbidity score, receiving chemotherapy, and having brain metastases (Table 2).

Table 2. Adjusted odds associated with the receipt of immunotherapy in patients with metastatic melanoma
  Adjusted Odds ratio 95% Confidence Interval p-value
Gender        
Male [reference]      
Female 0.92 0.83 1.01 0.077
Age 0.96 0.96 0.97 <0.001
Facility Area        
Metropolitan [reference]      
Urban 0.74 0.64 0.87 <0.001
Unknown 0.93 0.71 1.23 0.619
Insurance        
Commercial   [reference]    
Medicare 0.97 0.85 1.11 0.672
Medicaid 0.54 0.45 0.66 <0.001
Uninsured 0.49 0.38 0.62 <0.001
Other 0.79 0.61 1.02 0.075
Zip Code Education Level        
≥21% [reference]      
13%-20.9% 1.31 1.10 1.55 0.002
7%-12.9% 1.30 1.08 1.55 0.005
<7% 1.41 1.15 1.72 0.001
Zip Code Median Income        
<38,000 [reference]      
38,000-47,999 1.00 0.84 1.19 0.989
48,000-62,999 1.07 0.90 1.28 0.457
≥63,000 1.08 0.89 1.32 0.429
Facility Type        
Non-Academic [reference]      
Academic 1.63 1.48 1.81 <0.001
Unknown 0.80 0.62 1.03 0.087
Facility Location        
East [reference]      
South 0.83 0.72 0.95 0.006
Central 0.95 0.82 1.09 0.452
West 0.99 0.85 1.16 0.937
Distance from Treatment Facility        
≤40 miles [reference]      
>40 miles 1.46 1.28 1.66 <0.001
Unknown/Missing 1.25 0.35 4.48 0.729
Charlson Deyo Score        
0 [reference]      
1 0.77 0.68 0.88 <0.001
2 0.57 0.44 0.72 <0.001
3 0.34 0.23 0.50 <0.001
Surgery to Metastatic Site        
No [reference]      
Yes 0.95 0.85 1.05 0.332
Unknown 1.35 0.84 2.18 0.214
Brain Metastasis        
None [reference]      
Present 0.59 0.52 0.67 <0.001
Unknown 1.28 0.80 2.06 0.307
Liver Metastasis        
None [reference]      
Present 1.28 1.12 1.46 <0.001
Unknown 0.87 0.53 1.42 0.577
Lung Metastasis        
None [reference]      
Present 1.58 1.42 1.77 <0.001
Unknown 1.32 0.86 2.01 0.202
Bone Metastasis        
None [reference]      
Present 0.96 0.83 1.11 0.580
Unknown 0.99 0.59 1.65 0.961
Receipt of Chemotherapy        
No [reference]      
Yes 0.22 0.19 0.25 <0.001
Unknown 0.35 0.25 0.49 <0.001
Receipt of Radiation        
No [reference]      
Yes 1.56 1.40 1.74 <0.001
Unknown 0.42 0.17 1.00 0.050
Year of Diagnosis        
2011 [reference]      
2012 1.05 0.88 1.24 0.610
2013 1.62 1.39 1.90 <0.001
2014 2.22 1.91 2.59 <0.001
2015 3.32 2.85 3.85 <0.001

Note: All baseline variables were evaluated. Covariates listed above achieved a threshold significance of p<0.1 on univariable analysis and were included in the multivariable model.

On multivariable survival analysis, receipt of immunotherapy was associated with a survival benefit in both males (HR: 0.56, 95% CI: 0.52-0.61, p<0.0001) and females (HR: 0.62, 95% CI: 0.55-0.70, p<0.001). However, the interaction term testing whether the hazards of death associated with the receipt of immunotherapy is modified by gender was not significant (pinteraction=0.422); highlighting that there was no statistically significant difference in efficacy of immunotherapy based on gender (eTable 1). These findings were consistent on PS matched analysis (Table 3).

Table 3. Overall survival associated with immunotherapy in patients with metastatic melanoma1
  Multivariable   PS analysis
Gender HR [95% CI] p-value Pinteraction   HR[95% CI] p-value Pinteraction
Male 0.56 [0.52, 0.61] <0.001     0.56 [0.51, 0.62] <0.001  
Female 0.62 [0.55, 0.70] <0.001     0.61 [0.53, 0.70] <0.001  
      0.422       0.414

HR= Hazards Ratio, CI = Confidence interval, PS= Propensity Score

1Refer to eTable 1 for a detailed list of covariates included in the multivariable model

We utilized the NCDB to examine the association between gender and receipt and efficacy of modern immunotherapies in a real world cohort of patients with metastatic melanoma. Our results show that there was no difference in the likelihood of receipt of immunotherapy between males and females. Additionally, while immunotherapy was associated with a significant survival benefit in both males and females, we did not observe a statistically significant difference in efficacy based on gender.

Consistent with the trend of increased adoption of ICIs for management of metastatic melanoma, we noted an increased likelihood of receiving immunotherapy in recent years 9. We also observed that patients with brain metastases were less likely to receive immunotherapy as this cohort had been disproportionately excluded from initial melanoma clinical trials 10. Lastly, disparities in adoption of modern therapies between academic vs. community centers has been well documented for other treatments 11 and was also highlighted in our analyses.

Recent research to evaluate if there is a meaningful clinical difference in response to ICIs by gender has resulted in conflicting results. Specifically, Conforti et al6 performed a meta-analysis of 20 prospective studies across numerous disease sites and found that males respond better than females when treated with both cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed death protein-1 (PD-1) inhibitors. However, a recent meta-analysis published by Wallis et al5 failed to find a statistically significant association of gender with the efficacy of ICIs in multiple advanced cancers. Similar to the study by Wallis et al, our findings also suggest that the efficacy of immunotherapy does not differ on the basis of gender. Given the controversy in the aforementioned published meta-analyses of prospective clinical trials, our study contributes additional information regarding the association of gender with the efficacy of immunotherapy. Furthermore, our dataset derives from a large (>10,000) heterogeneous sample of patients treated at more than 1,500 Commission on Cancer accredited facilities 12 across the United States, includes individual level patient data and simulates real life practice patterns.

Our study has several key limitations. First, there is inherent selection bias given the retrospective nature of the analysis. To minimize this bias, we performed PS-weighted analysis to adjust for a range of measured confounders. Second, the NCDB does not specify the type of immunotherapy used and hence definitive conclusions about the agents that were administered such as therapies targeting CTLA-4 and PD-1/PD-L1, Interleukin-2, Interferon-α etc. cannot be drawn. Given the above limitation, we only included patients treated after the approval of the first ICI (ipilumumab) in 2011 for metastatic melanoma. Furthermore, the term immunotherapy as coded by the NCDB can refer to other antibody based therapies, but these are not approved for use in melanoma and therefore if present would only represent a small minority of patients. Lastly, we lacked information about dosage, treatment schedules, duration of treatment, and toxicity which may have contributed to the outcomes.

We demonstrate that in the era of ICIs, there does not appear to be a difference between men and women in the likelihood of receipt of immunotherapy for metastatic melanoma. Additionally, while the receipt of immunotherapy was associated with a survival benefit for both men and women, we did not observe a statistically significant difference in survival outcomes based on gender. These findings further inform the controversy regarding the efficacy of immunotherapy based on gender by contributing real world data from a national cancer registry. Future and ongoing clinical trials utilizing ICIs and other immune modulating agents should further evaluate gender specific responses.

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Article Notes

  • Published on: July 15, 2019

Keywords

  • Melanoma
  • Immunotherapy
  • Immune checkpoint inhibitors
  • Gender

*Correspondence:

Dr. Jacob E. Shabason
Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA; Telephone No: (215) 662-6515; Fax No: (215) 349-5445
Email: jacob.shabason@uphs.upenn.edu.

©2019 Shabason JE. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.