Article Text

Download PDFPDF

312 Female sex independently predicts adjuvant immunotherapeutic benefit from CTLA4 immune checkpoint inhibition
  1. Ahmad Tarhini1,
  2. Ni Kang2,
  3. Sandra Lee3,
  4. F Stephen Hodi4,
  5. Gary Cohen5,
  6. Omid Hamid6,
  7. Laura Hutchins7,
  8. Jeffrey Sosman8,
  9. Harriett Kluger9,
  10. Zeynep Eroglu10,
  11. Henry Koon11,
  12. Donald Lawrence12,
  13. Kari Kendra13,
  14. David Minor14,
  15. Carrie Lee15,
  16. Mark Albertini16,
  17. Lawrence Flaherty17,
  18. Teresa Petrella18,
  19. Howard Striecher19,
  20. Vernon Sondak10 and
  21. John Kirkwood20
  1. 1H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  2. 2Dana Farber Cancer Institute – ECOG-ACRI, Boston, MA, USA
  3. 3Dana Farber Cancer Institute ECOG-ACRIN, Boston, MA, USA
  4. 4Dana Farber Cancer Institute, Boston, MA, USA
  5. 5Greater Baltimore Medical Center, Baltimore, MD, USA
  6. 6Angeles Clinic and Research Institute, Los Angeles, CA, USA
  7. 7University of Arkansas, Little Rock, AR, USA
  8. 8Northwestern University, Chicago, IL, USA
  9. 9Yale University, New Haven, CT, USA
  10. 10H. Lee Moffitt Cancer Center, Tampa, FL, USA
  11. 11Bristol Myers Squibb, Cleveland, OH, USA
  12. 12Massachusetts General Hospital, Boston, MA, USA
  13. 13Ohio State University, Columbus, OH, USA
  14. 14Sutter-California Pacific Medical Center, San Francisco, CA, USA
  15. 15University of North Carolina at Chapel H, Chapel Hill, NC, USA
  16. 16University of Wisconsin, Madison, WI, USA
  17. 17Wayne State University/Karmanos Cancer I, Detroit, MI, USA
  18. 18Odette Cancer Center, Toronto, ON, Canada
  19. 19National Cancer Institute, Rockville, MD, USA
  20. 20University of Pittsburgh, Pittsburgh, PA, USA


Background Sex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. Female sex hormones have been implicated in melanoma development and response to systemic therapy. We hypothesized a gender difference in response to adjuvant immunotherapy with ipilimumab (3 or 10 mg/kg; ipi3 or ipi10) versus high dose IFNα (HDI) as tested in the E1609 trial.

Methods E1609 demonstrated significant overall survival (OS) benefit with ipi3 versus HDI.1 We investigated treatment efficacy between ipi and HDI in the subgroups by sex (female, male), age (< 55 or ≥55), stage at study entry (IIIB, IIIC, M1a/1b), ECOG performance status (PS 0, 1), ulceration (yes, no), primary tumor (known, unknown), number of lymph nodes involved (0, 1, 2–3, 4+). Forest plots were created to compare OS and RFS with ipi3 vs. HDI and ipi10 vs. HDI using the concurrently randomized ITT populations. For the estimated HRs, 95% confidence intervals were created for all subgroups.

Results The subgroups of female, stage IIIC, PS=1, ulcerated, in-transit without lymph node involvement demonstrated significant improvement in overall survival (OS) and/or relapse free survival (RFS) with ipi3 versus HDI as summarized in table 1. Female sex was significant for both OS and RFS and was further explored. In investigating RFS with ipi3 versus HDI, a multivariate Cox regression model including sex, treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.026). Including sex, PS (0 vs. 1), age (<55 vs. 55+), ulceration (yes vs. no), stage (IIIB, IIIC, M1a, M1b), treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.024). While similar trends were seen, no significant interactions between sex and treatment effect were found in the OS multivariate analysis or in the comparison of ipi10 versus HDI. When exploring age, in the univariate analyses in the ipi3 versus HDI comparison older women appeared to drive most of the difference (age ≥55: OS, P=0.02 and RFS, P=0.08; differences non-significant for women <55). Table 1.

Abstract 312 Table 1

Treatment efficacy between ipi3 and HDI by subgroup

Conclusions Female sex was independently associated with RFS adjuvant immunotherapeutic benefit from ipi3, supporting a potentially important role for female related factors in the immune response against melanoma, and these warrant further investigation.

Trial Registration NCT01274338

Ethics Approval The study protocol was approved by the institutional review board (IRB) of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. This study was monitored by the ECOG-ACRIN DataSafety Monitoring Committee and the NCI.

Consent All patients provided IRB-approved written informed consent.


  1. Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567–575. PMID: 31880964.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.