Ipilimumab-induced hypophysitis, a single academic center experience
Immune checkpoint inhibitors, single or in combination, have recently become a cornerstone for the treatment of many malignancies. Ipilimumab, a CTLA-4 inhibitor, was initially FDA approved for treatment of unresectable or metastatic melanoma and subsequently in combination therapy for other cancers. Ipilimumab-induced hypophysitis (IH) risk of development varies in different studies between 0 and 17%. Furthermore, little is known on how to predict which patients will develop IH and its impact on efficacy of Ipilimumab and survival for these patients. Here we reviewed IH and its impact on progression-free survival (PFS) and overall survival (OS).
Retrospective, IRB- approved review of consecutive 117 melanoma patients who received ipilimumab between 2011 and 2016 was undertaken. Demographic and clinical characteristics, treatment timing and doses, time to progression after therapy, and survival data were reviewed. Patients were predefined in two groups: patients with and without IH. Descriptive statistics were used to summarize the demographic and clinical characteristics of the study sample. All values are shown as means and standard deviation [mean (SD)] unless indicated otherwise. P < 0.05 was considered to be statistically significant.
Of the 117 patients, 15 (12.8%) with a median age of 62.1 years developed IH. In the IH cohort, 10 (66.7%) were male and were significantly older than females (median 67.7 vs. 50.8; P = 0.009). This difference was not seen in non-IH group. Male patients with IH were significantly older than males without IH (67.7 vs. 56.4 years, P = 0.020), however this difference was not observed in females. No patient who received prior cancer systemic therapy (0/30) developed IH vs. 17.2% (15/72) without prior therapy developed IH (OR 0.00; 95% CI 0.00 to 0.73, P = 0.011). Between IH and non-IH patients, there was no difference in gender, race, ethnicity, BMI, diabetes or autoimmune disease at baseline, number of administered ipilimumab cycles, presence of primary melanoma lesion, or BRAF status. IH and non-IH patients had a similar median PFS (8.1 vs. 6.8 months, HR = 0.51, 95% CI 0.24 to 1.05 P = 0.062) and OS (53.3 vs. 29.5 months; HR 0.66, 95% CI 0.30 to 1.46; P = 0.307).
In this study of melanoma patients treated with Ipilimumab, risk of developing IH was high (almost 13%). Older age in men and no prior cancer therapy were associated with IH higher risk. Development of IH was not associated with PFS or OS. Increased use of immune checkpoint inhibitors in the future will impact IH overall risk, thus awareness is needed. Given the lack of reliable identifiable risk factors, close monitoring of signs and symptoms after each therapy cycle is critical for early detection and treatment of hypophysitis.
KeywordsMalignant melanoma Ipilimumab Hypophysitis Immunotherapy Immune related adverse side effects
Biostatics support was provided by the Biostatistics Shared Resource, Knight Cancer Institute [NCI P30CA069533] (EL, YC).
Compliance with ethical standards
Conflict of interest
Travis Snyders declares that he has no conflict of interest. Daniel Chakos declares that he has no conflict of interest. Umang Swami declares that he has no conflict of interest. Emile Latour declares that he has no conflict of interest. Yiyi Chen declares that she has no conflicts of interest. Maria Fleseriu declares that she has no conflict of interest. Mohammed Milhem is a member of advisory boards for Amgen, Trieza, Biontech, Blueprint medicines corporation, Immunocore, and Array BioPharma, Inc. Yousef Zakharia is a member of advisory boards for Amgen, Roche diagnostics, Novartis, Jansen, Eisai, Exelixis, Castle Bioscience, Array, and Bayer. Roula Zahr declares that she has no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
The Institutional Review Board at the University of Iowa Hospitals and Clinics approved this study. As this was a retrospective review of patient data, individual informed consent was exempted by the Institutional review board.
- 1.Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723Google Scholar
- 2.YERVOY® (ipilimumab) product information. https://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed Apr 5 2019
- 3.Caturegli P et al (2016) Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am J Pathol 186(12):3225–3235Google Scholar
- 4.Joshi MN et al (2016) Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review. Clin Endocrinol (Oxf) 85(3):331–339Google Scholar
- 5.Cukier P et al (2017) Endocrine side effects of cancer immunotherapy. Endocr Relat Cancer 24(12):T331–T347Google Scholar
- 6.Dillard T et al (2010) Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 13(1):29–38Google Scholar
- 7.National Comprehensive Cancer Network. Management of immunotherapy-related toxicities. Version 2. 2019–April 8, 2019. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf Accessed Apr 10 2019
- 8.Corsello SM et al (2013) Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 98(4):1361–1375Google Scholar
- 9.Min L et al (2015) Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. Clin Cancer Res 21(4):749–755Google Scholar
- 10.Faje AT et al (2018) High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 124:3706–3714Google Scholar
- 11.Faje AT et al (2014) Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 99(11):4078–4085Google Scholar
- 12.Faje A (2016) Hypophysitis: evaluation and management. Clin Diabetes Endocrinol 2:15Google Scholar
- 13.Caturegli P et al (2005) Autoimmune hypophysitis. Endocr Rev 26(5):599–614Google Scholar
- 14.Faje A (2016) Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 19(1):82–92Google Scholar
- 15.Barroso-Sousa R et al (2018) Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 4(2):173–182Google Scholar
- 16.Albarel F et al (2015) Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol 172(2):195–204Google Scholar
- 17.Fleseriu M et al (2016) Hormonal replacement in hypopituitarism in adults: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 101(11):3888–3921Google Scholar
- 18.Maker AV et al (2006) Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 29(4):455–463Google Scholar
- 19.Ascierto PA et al (2017) Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 18(5):611–622Google Scholar
- 20.Prete A, Salvatori R (2000) Hypophysitis. In: Feingold KR (ed) Endotext. MDText com Inc, South Dartmouth (MA)Google Scholar
- 21.Luther C et al (2019) Advanced stage melanoma therapies: detailing the present and exploring the future. Crit Rev Oncol Hematol 133:99–111Google Scholar
- 22.Torino F et al (2012) Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist 17(4):525–535Google Scholar
- 23.Brahmer JR et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol 36(17):1714–1768Google Scholar
- 24.Chang LS et al (2019) Endocrine toxicity of cancer immunotherapy targeting immune checkpoints. Endocr Rev 40(1):17–65Google Scholar