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

Abstract

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%) pembrolizumabaxitinib 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 aminotrans-* Corresponding author.

Case Study: A Japanese patient with metastatic renal cell carcinoma who achieved long‐term treatment‐free survival with pembrolizumab and axitinib in the KEYNOTE‐426 phase III trial of pembrolizumab and axitinib versus sunitinib

“…The course of the present case possibly indicated that cells in lesion#1 destroyed by axitinib triggered the immune system via antigen presentation and PD‐1/PD‐L1 suppression by pembrolizumab 8 . It is recently reported that median time to ALT elevation is 84.0 days (range: 7‐840 days) 9 . Delayed‐onset hepatitis (Day+629) appeared to support delayed immune activation.…”

“…8 It is recently reported that median time to ALT elevation is 84.0 days (range: 7-840 days). 9 Delayedonset hepatitis (Day+629) appeared to support delayed immune activation. We previously experienced a case with metastatic RCC, who died of severe hepatotoxicity presumably due to nivolumab followed by pazopanib regardless of nivolumab withdrawal.…”

Multiorgan failure caused by pembrolizumab and axitinib in a woman affected by metastatic clear cell renal cell carcinoma: A case report and literature review

“…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. [27] No other cases of MOF related to pembrolizumab-axitinib treatment are reported in literature; however, Nakazawa et al in 2022 reported a case of acute heart failure in a woman treated with lenvatinib plus pembrolizumab for a clear cell endometrial carcinoma. [28] The patient was treated with highdose steroids and made a full recovery, but the treatment with pembrolizumab and lenvatinib was discontinued.…”

Kinase Inhibitors’ Effects on Innate Immunity in Solid Cancers

“…Despite the promising results from the preclinical studies, the regimen of Sunitinib or Pazopanib combined with an anti-PD-1 antibody was largely offset by its excessive side effects (e.g., liver toxicity). Therefore, the combination with a more selective VEGFR-MKI, like Axitinib, has been investigated [91,92]. Although most of the clinical trials are still in the early phases, several international multi-centered randomized controlled trials (RCTs) have been conducted based on the tolerable dose and safety profile obtained from phase I/II trials.…”