An oncology reviewer s perspective on hepatotoxicity

Transcription

1 An oncology reviewer s perspective on hepatotoxicity Gideon Blumenthal, MD March FDA/Critical Path DILI conference Disclaimer: Views expressed herein are my own and may not necessarily reflect those of OHOP/ CDER/ FDA 1

2 Some of the issues In oncology drug development, efficacy trumps all Dr Richard Pazdur Benefit-risk thresholds and tolerance of drug toxicities are different than other therapeutic areas Oncology Drugs are typically developed in sick patients Heavily pre-treated, refractory to multiple regimens, liver metastasis or primary liver cancer, multiple comorbidities, multiple concomitant medications Attribution of adverse events to study drugs is challenging 2

3 Challenges with interpreting Hy s law in oncology Alkaline Phosphatase is commonly elevated Multiple potential confounders may exist Liver metastases Concomitant medications Injury to other organ systems, etc. Sub-optimal DILI work-ups are common Lack of liver biopsy, hepatitis serologies, autopsies, etc. 3

4 Case study 1 54 y.o. female from India with heavily pre-treated metastatic breast cancer PMH: HTN, hypothyroid liver metastases: 1.4, 3.3, 6.0 cm Day -8: screening ALT 39, AST 42, TBIL 1.2 Cycle 1 Day 1: baseline ALT 68, AST 70, TBL 1.4 received one dose of I.V. study drug on phase 3 trial* Cycle 1 Day 5: Jaundice (Gr4 bilirubin), AMS Cycle 1 Day 6 : ALT 159, AST 820, TBL 12.8, cre 2.3, NH3 78 Cycle 1 Day 7: Died. No autopsy. No testing for acute hepatitis. Fatal fulminant liver failure related to study drug per investigator * Unclear if investigator knew of rising liver tests prior to dosing, but still acceptable numbers as per protocol 4

5 Case study 1 (continued) ALT (xuln) AST (XULN) TBILI (XULN) Day Day Day Would an unacceptable rate of ALT rise (68-39)/8 = 3.6 IU per day have been useful to screen out bad actors? 5

6 Case Study 2 37 y.o. female with sarcoma on investigational TKI trial. Normal hepatic tests at entry and no liver metastasis. On day 33, TKI discontinued due to fatigue, anorexia, diarrhea, and transaminase elevations Applicant Conclusion: drug-induced liver injury cannot be ruled out; the injury may be due to ischemia Challenge: Limited evidence provided to attribute death to possible non-hepatic etiologies. Acetaminophen levels and autopsy data very helpful in this case. Slide Courtesy of Dr Max Ning, MD PhD, ODAC presentation and clinical review (drugs@fda.gov) 6

7 Types of anti-neoplastic Agents Cytotoxics Monoclonal antibodies Antibody drug conjugates Tyrosine kinase inhibitors (TKI) Others (proteasome inhibitors, mtor inhibitors, immunomodulatory, hedgehog, HDAC inhibitors, etc.) 7

8 TKI labeling for hepatotoxicity circa 2011 Drug Boxed Warning Warnings and Precautions Imatinib Fatal hepatotoxicity, severe liver injury, transplant Adverse Reactions Elevated liver tests Add l Data (clinical trials or postmarketing) Hepatitis, Hepatic Failure, Hepatic Necrosis Dasatinib Elevated liver tests Nilotinib Elevated liver tests Elevated liver tests Erlotinib Lapatinib Sunitinib Sorafenib Pazopanib Fatal hepatotoxicity Fatal hepatotoxicity Fatal hepatotoxicity Hepatic failure and hepatorenal Fatal hepatotoxicity Fatal hepatotoxicity Elevated liver tests Hepatotoxicity Hepatotoxicity Liver dysfunction Hepatitis Hepatitis, Hepatotoxicity Drug-induced hepatitis Fatal hepatotoxicity Elevated liver tests 8 Chang, Rand, Blumenthal et al ASCO 2011

9 Drug Axitinib TKIs approved since ASCO 2011 Boxed Warning Warnings and Precautions Liver enzyme elevation Adverse Reactions Liver enzyme elevation Add l Data Crizotinib Hepatotoxicity Liver enzyme elevation Vemurafenib Ponatinib Hepatotoxicity, liver failure death Liver laboratory abnormalities Hepatotoxicity Liver enzyme elevation Liver test elevation Bosutinib Hepatotoxicity Liver test elevation Cabozantinib Liver test elevation Regorafinib Hepatotoxicity, severe and fatal Hepatotoxicity Liver test elevation Vandetanib Liver enzyme elevation 9

10 Concluding remarks In oncology we have a much higher tolerance for hepatotoxicity than other therapeutic areas New criteria for liver dysfunction beyond Hy s law should be discussed for oncology Better predictive biomarkers and understanding of pathophysiology of liver injury should be explored (e.g. lapatinib and HLA- DQA1*02:01) a We should strive for greater uniformity in: recommendations for eligibility, dose modification, dose discontinuation diagnostic DILI workup (excluding other causes, liver biopsy, autopsy) drug labeling a Spraggs et al J Clin Oncol