Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial

Eur Urol Oncol. 2022 Apr;5(2):225-234. doi: 10.1016/j.euo.2021.05.007. Epub 2021 Jul 6.


Background: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed.

Objective: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib.

Design, setting, and participants: Patients enrolled in KEYNOTE-426 were included in this study.

Outcome measurements and statistical analysis: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s).

Results and limitations: The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred.

Conclusions: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment.

Patient summary: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.

Keywords: Advanced renal cell carcinoma; Aminotransferase elevations; Axitinib; PD-1 checkpoint inhibitor; Pembrolizumab; Vascular endothelial growth factor receptor inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Axitinib / therapeutic use
  • Carcinoma, Renal Cell* / drug therapy
  • Carcinoma, Renal Cell* / pathology
  • Female
  • Humans
  • Kidney Neoplasms* / drug therapy
  • Kidney Neoplasms* / pathology
  • Male
  • Sunitinib / adverse effects


  • Antibodies, Monoclonal, Humanized
  • Axitinib
  • pembrolizumab
  • Alanine Transaminase
  • Sunitinib

Associated data