TABLE 1.
Oncology Therapies Approved by the FDA Since 2018 With Hepatotoxicity Warnings in the Product Label
| Drug (Ref) | Drug Class/Therapeutic Use | Warning | Liver Chemistry Elevations | Dose Modifications |
|---|---|---|---|---|
| Tumorocentric drugs | ||||
| Selpercatinib24 | Kinase inhibitor/various solid tumors | Hepatotoxicity: monitor ALT and AST before starting the therapy and Q2W for first 3 mo, then monthly | Serious hepatic AE in 2.6% ALT increased: G3–4, 9% AST increased: G3–4, 8% Bilirubin increased: G3–4, 2% | G3–G4 AST or ALT: withhold doses until G1 or baseline Reduce dose by 2 dose levels and monitor ALT/AST weekly Increase by 1 dose level after a minimum of 2 wk |
| Capmatinib25 | Kinase inhibitor/metastatic NSCLC | Hepatotoxicity: monitor liver chemistry before starting therapy and Q2W for 3 mo, then monthly | ALT increased: G3–4, 8% AST increased: G3–4, 4.9% | G3 AST or ALT without increase in bilirubin: withhold doses until recovery to baseline ALT/AST G4: permanently discontinue Hy law criteria: permanently discontinue |
| Tucatinib26 | Kinase inhibitor/HER2+ breast cancer | Severe hepatotoxicity (G3–4, 9.2%); monitor ALT, AST, bilirubin before starting therapy and Q3W | ALT increased: ≥G3, 8% AST increased: ≥G3, 6% Bilirubin increased: ≥G3, 1.5% | G3 AST/ALT or G3 bilirubin: withhold until recovery to G1 or baseline levels; resume at next lower dose level G4 AST/ALT or G4 bilirubin: permanently discontinue Hy law criteria: permanently discontinue |
| Entrectinib27 | Kinase inhibitor/NSCLC, solid tumors | Hepatotoxicity: monitor ALT, AST Q2W during first month and then monthly | ALT increased: G3–4, 2.9% AST increased: G3–4, 2.7% | G3–4 AST/ALT: withhold until recovery to G1 or baseline, resume at same dose if G3 event resolved within 4 wk, or a reduced dose for recurrent G3 events or G4 event Recurrent G4 AST/ALT: permanently discontinue Hy law criteria: permanently discontinue |
| Pexidartinib28 | Kinase inhibitor/TGCT | Boxed warning: can cause serious and potentially fatal liver injury, available only through a restricted program | ALT increased: ≥G3, 20% AST increased: ≥G3, 12% ALP increased: ≥G3, 4.9% Bilirubin increased: ≥G3, 3.3% | ALT/AST ≥3–5×ULN: withhold and monitor weekly, if ≤3×ULN within 4 wk, resume at reduced dose; otherwise, permanently discontinue ALT/AST >5–10×ULN: withhold and monitor twice weekly, if ≤3×ULN within 4 wk, resume at reduced dose; otherwise, permanently discontinue ALT/AST >10×ULN, permanently discontinue (continue to monitor) |
| Polatuzumab vedotin-piiq29 | CD79b-directed antibody-drug conjugate/relapsed or refractory diffuse large B-cell lymphoma | Hepatotoxicity; monitor liver enzymes and bilirubin | G3 and G4 transaminase elevations developed in 1.9% and 1.9%, respectively; laboratory values suggestive of DILI occurred in 2.3% of patients | Bilirubin >ULN to ≤1.5×ULN or AST >ULN; no starting dose adjustments required when administering polatuzumab vedotin to patients with mild hepatic impairment (bilirubin >ULN to ≤1.5×ULN or AST >ULN). |
| Tagraxofusp-erzs30 | CD123-directed cytotoxin/BPDCN | Hepatotoxicity: monitor liver enzymes and bilirubin | ALT increased: ≥G3, 30% AST increased: ≥G3, 37% ALP increased: ≥G3, 1% Bilirubin increased: ≥G3, 0% | ALT or AST increase >5×ULN; withhold treatment until transaminase elevations are ≤2.5×ULN |
| Calaspargase pegol –mknl31 | Asparagine-specific enzyme | Hepatotoxicity: monitor for toxicity through recovery from cycle | Transaminases increased, ≥G3, 52% Bilirubin increased, ≥3G, 20% | Total bilirubin >3×ULN to no more than 10×ULN; withhold treatment until total bilirubin levels go down to ≤1.5×ULN Total bilirubin >10×ULN; discontinue and do not make up for missed doses |
| Larotrectinib32 | Kinase inhibitor/solid tumors with an NTRK gene fusion without a resistance mutation, that are metastatic without the option of surgical resection, with no satisfactory alternative treatments | Hepatotoxicity: monitor liver test results, including ALT and AST Q2W during the first month of treatment, then monthly and as clinically indicated | ALT increased: G3–4, 3% AST increased: G3–4, 3% ALP increased: G3–4, 3% | Withhold and modify dosage, or permanently discontinue based on severity Reduce the starting dose by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment |
| Duvelisib33 | Kinase inhibitor/relapsed or refractory CLL or SLL, relapsed or refractory follicular lymphoma | Hepatotoxicity: monitor hepatic function | ALT or AST increase >3×ULN and total bilirubin >2×ULN, 2% Patients with B-cell malignancies ALT increased: ≥G3, 8% AST increased: ≥G3, 6% ALP increased: ≥G3, 2% Patients with CLL/SLL ALT increased: ≥G3, 7% AST increased: ≥G3, 3% ALP increased: ≥G3, 0% | G2 ALT/AST elevation (3–5×ULN): maintain dose and monitor at least weekly until return to <3×ULN G3 ALT/AST elevation (>20×ULN): withhold and monitor at least weekly until return to <3×ULN; resume treatment at same dose (first occurrence) or at reduced dose for subsequent occurrence G4 ALT/AST elevation (>20×ULN): discontinue treatment |
| Binimetinib34 | Kinase inhibitor in combination with encorafenib/unresectable or metastatic melanoma with BRAF V600E or V600K mutations | Hepatotoxicity: monitor liver chemistry before and during treatment and as clinically indicated | In combination with encorafenib ALT increased: G3–4, 6% AST increased: G3–4, 2.6% ALP increased: G3–4, 0.5% | G2 AST or ALT increased: maintain dose; if no improvement within 2 wk, withhold treatment until improved to G0–1 or to pretreatment/baseline levels and then resume at the same dose G3 AST or ALT increased: for first occurrence of G3 (or recurrent G2), withhold treatment for ≤4 wk; if levels improve to G0–1 or pretreatment/baseline levels, resume at the same dose; if no improvement, discontinue. For recurrent events, consider permanent discontinuation G4 AST or ALT increased: for first occurrence, permanently discontinue or withhold treatment for ≤4 wk; if levels improve to G0–1 or pretreatment/baseline levels, resume at the same dose; if no improvement, discontinue; for recurrent events, permanent discontinuation For patients with moderate or severe hepatic impairment, the recommended dosage is 30 mg orally taken BID |
| Lutetium Lu 177 dotatate35 | Radiolabeled somatostatin analog/GEP-NET | Hepatotoxicity: monitor transaminases, bilirubin and albumin | ALT increased: G3–4, 4% AST increased: G3–4, 5% ALP increased: G3–4, 5% Bilirubin increased: G3–4, 2% | Bilirubinemia >3×ULN, or hypoalbuminemia <30 g/L, with a prothrombin ratio <70%: withhold until complete resolution, resume at reduced dose; for hepatotoxicity requiring treatment delay of ≥16 wk, permanent discontinuation |
| Immuno-Oncology Drugs | ||||
| Cemiplimab-rwlc36 | PD-1–blocking antibody/metastatic CSCC or locally advanced CSCC not qualified surgery or curative radiation | Evaluate clinical chemistries, including hepatic and thyroid function, at baseline and periodically during treatment | Immune-mediated hepatitis: any grade, 2.1%; G4, 0.2%; G5, 0.2% AST increased: G3–4, 3% | Hepatitis: withhold if AST/ALT increases to >3×ULN/baseline to ≤10×ULN/baseline or if total bilirubin increases ≤3×ULN Discontinue if AST/ALT increases to >10×ULN/baseline or total bilirubin increases to >3×ULN |
ALP indicates alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; BPDCN, blastic plasmacytoid dendric cell neoplasm; CLL, chronic lymphocytic leukemia; CSCC, cutaneous squamous cell carcinoma; DILI, drug-induced liver injury; FDA, US Food and Drug Administration; G, Grade; GEP-NET, gastroenteropancreatic neuroendocrine tumor; NSCLC, non–small cell lung cancer; NTRK, neurotrophic receptor tyrosine kinase; PD-1, programmed death receptor-1; Q2W, every 2 weeks; SCLC, small-cell lung cancer; SLL, small lymphocytic lymphoma; TGCT, tenosynovial giant cell tumor; ULN, upper limit of normal.