Category: Pituitary Disorders/Neuroendocrinology

CAUTION ADVISED USING COMBINATION KETOCONAZOLE AND PD-L1 INHIBITORS

Monday, Apr 8
1:00 AM – 2:00 AM

Objective :

Immunomodulatory therapies have improved outcomes in many solid tumors including pituitary and adrenal tumors. Inhibition of glucocorticoid synthesis with Ketoconazole (KTZ) is used in Cushing syndrome. We report severe liver failure in two consecutive patients co-treated with PD-L1 inhibitors and KTZ.


Methods : Report of two cases


Results :

A 68 yr-old female underwent 3 surgeries and stereotactic radiation therapy for recurrent Cushing disease due to an atypical invasive corticotroph tumor. Despite Temozolomide chemotherapy, PET-CT showed progressive metastatic pituitary carcinoma. KTZ (800mg/day) attained eucortisolism and she commenced Nivomumab (3mg/kg, q 2 weeks) 2 months later. Shortly thereafter, she developed 50-fold increased hepatic transaminases with increased bilirubin and prothrombin time.


A second 48-yr-old female presented with weight gain, facial swelling and hirsutism. Serum cortisol was elevated (20 ug/dl) and ACTH suppressed (2 pg/ml) and CT showed a 6cm right (R) adrenal mass with inferior vena cava invasion and 3 metastatic liver lesions. Following R adrenalectomy, pathology confirmed stage IV adrenal cortical carcinoma. She commenced Mitotane (3 gm/day) and KTZ (1600mg/day) in addition to etoposide-cisplatin chemotherapy (40mg/m2 weekly for ten weeks). PET-CT showed progression at 10 weeks and prembrolizumab (200mg IV, q3weeks) was started. A month later, she noted dark urine and abdominal pain with marked hepatic derangement and hyperbilirubinemia.


In both cases, viral serology was negative and liver biopsy confirmed drug-induced liver injury. Liver function normalized on discontinuation of KTZ and PD-L1 inhibitor in combination with high dose steroid administration.


Discussion :

Liver hepatotoxicity is a recognized complication of both KTZ (4% to 4.2%) and anti-PD-L1 (7%) monotherapy. We describe 2 cases of severe liver failure with combination KTZ treatment and 2 different PD-L1 inhibitors. The mechanism(s) are unclear, studies have shown that KTZ inhibits CYP1A1 and 3A4 enzymes and immunotherapy which can facilitate T-cell activation can impair drug metabolism. Fortunately, liver function fully recovered in both our patients on KTZ and PD-L1 inhibitor cessation and high dose steroid therapy.


Conclusion :

The occurrence of liver failure in 100% of consecutively treated patients with combination KTZ+ PD-L1 inhibitors serves to warrant extreme caution using these agents together. Furthermore, given the increasing use of PD-L1 inhibitors and other immunomodulatory agents in oncology and possible co-treatment with antifungal agents such as ketoconazole, our experience would proffer caution using these 2 classes of drugs together.


 

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Yingying Yang

Visiting graduate researcher
UCLA

Dr. Yingying Yang is a visiting graduate research in Dr. Heaney laboratory at UCLA and she participated in the statistical analysis

Joel Hecht

Dr.
UCLA

Dr. Hecht is a Professor of Clinical Medicine in the David Geffen School of Medicine at UCLA School of Medicine. He holds the Carol and Saul Rosenzweig Chair for Cancer Therapies Development and is the Director of the UCLA Gastrointestinal Oncology Program. Dr. Hecht attended medical school at Eastern Virginia Medical School. He took his internal medicine residency at Northwestern and completed fellowships in gastroenterology research at the University of Chicago, and in gastroenterology and medical oncology at UCLA. Dr. Hecht is an internationally known clinical and translational researcher in the field of gastrointestinal cancers. He has published widely on the molecular biology, early detection, and treatment of gastrointestinal malignancies. He has lead and is currently directing small trials with new molecules as well as large international randomized trials. Current ongoing research includes preclinical models of therapy with biological agents, early studies with gene therapy vectors and tyrosine kinase inhibitors, and leading phase II and phase III trials with novel agents.

Sandy Liu

Dr.
UCLA

Dr. Liu practices general oncology and specializes in genitourinary (GU) cancers which include cancers of the kidney, prostate, bladder, testis, and urethra. She is the sponsoring physician for UCLA VHL Comprehensive Clinical Care Center, which includes a team of VHL specialists working together to provide coordinated care to ensure VHL patients receive access to services and adhere to surveillance guidelines.

Melissa Cohen

Dr.
UCLA

Dr. Melissa J. Cohen is assistant clinical professor of medicine at the David Geffen School of Medicine at UCLA and a board certified medical oncologist practicing at UCLA Hematology/Oncology in Westlake Village and Porter Ranch. She began her medical training at George Washington University in Washington D.C., and then moved to Denver where she completed her internal medicine residency training at the University of Colorado. In 2008, she relocated to Southern California to complete her fellowship training in both geriatrics and medical oncology at UCLA.

Steven Hart

Dr.
UCLA

Dr. Steven Hart is Chief of Pathology and Medical Director of the Clinical Laboratories at UCLA Medical Center, Santa Monica. Dr. Hart received his medical degree from the University of California, Los Angeles, David Geffen School of Medicine at UCLA. He then completed his anatomic and clinical pathology residency training at UCLA, and subspecialty fellowship training in gastroenterologic pathology and cytopathology. Dr. Hart joined the Department of Pathology and Laboratory Medicine as a faculty member in 2008, with his primary location at UCLA Medical Center, Santa Monica. Academically, Dr. Hart is also devoted to medical and resident education, and his innovation and impact has been recognized by the Roberta Nieberg Anatomic Pathology award for outstanding teaching. Clinically, he has served as CLIA Laboratory Medical Director and head of Santa Monica-UCLA gastrointestinal pathology. His clinical and leadership activities are distinguished by his exceptional communication skills and his expertise and innovation in clinical and pathologic data integration to create reports recognized and highly valued for their great clinical relevance and utility.

Hanlin Wang

Dr.
UCLA

Dr. Hanlin L. Wang is a Professor at the David Geffen School of Medicine and a Gastrointestinal/Liver Pathology faculty. He received his medical degree from the Wuhan University School of Medicine in China and his Ph.D. in Biomedical Sciences from the Mayo Clinic in Minnesota. He completed his pathology residency and Gastrointestinal/Liver Pathology fellowship at the University of Chicago Hospitals. Dr. Wang is board-certified in Anatomic and Clinical Pathology. He has authored more than 130 journal articles, numerous book chapters and invited reviews, and 1 pathology textbook (co-editor). He has been an invited speaker at numerous national and international meetings and serves on the editorial boards for several pathology/medical journals. Dr. Wang was Director of Gastrointestinal Pathology at Cedars-Sinai Medical Center and an Associate Professor at Washington University Barnes-Jewish Hospital in St. Louis before joining UCLA. His clinical and research interests include medical and neoplastic gastrointestinal and liver diseases.

Anthony P. Heaney

Professor
UCLA

Anthony P. Heaney, MD, PhD is an Associate Professor at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). His primary areas of clinical and research interest involve the pathogenesis of pituitary tumors and exploiting novel molecular targets to develop innovative treatments for pituitary tumors, and other neuroendocrine tumors.