Bevacizumab plus Erlotinib in Advanced Solid Cancers with Krebs Cycle Gene Mutations: A Multicenter Phase II Study (BRISK; KCSG AL22-16)

Abstract

Purpose: Targeting aberrant metabolism in tumors with alterations in genes encoding Krebs cycle enzymes, a central component of glucose metabolism, is a promising therapeutic strategy. These tumors rely on aerobic glycolysis and promote VEGF-dependent angiogenesis; furthermore, EGFR signaling enhances aerobic glycolysis. This phase II trial evaluated bevacizumab and erlotinib in patients with solid tumors harboring Krebs cycle gene mutations.Patients and Methods: Eligible patients had solid tumors bearing pathogenic mutations in fumarate hydratase (FH), isocitrate dehydrogenase 1/2, succinate dehydrogenase, or maleate dehydrogenase 2 and measurable disease per RECIST version 1.1 or Response Assessment in Neuro-Oncology 2.0 criteria. Participants received bevacizumab (10 mg/kg IV on day 1) and erlotinib (150 mg orally once daily) every 14 days until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival, and safety.Results: From February to November 2023, 35 participants were enrolled: 19 with biliary tract cancer (54.3%), seven with brain tumors (20.0%), and five with FH-deficient renal cell carcinomas (FH-deficient RCC, 17.1%). ORR was 37.1% (one complete and 12 partial responses). The disease control rate was 85.7%. Subgroup ORR were 80.0% in FH-deficient RCC, 36.8% in biliary tract cancer, and 28.6% in brain tumors. At a median follow-up of 11.7 months, the median PFS was 8.3 months; median overall survival was not reached. No new safety signals were observed. Exploratory transcriptomic analyses revealed VEGF and immune pathway enrichment in patients with favorable PFS, whereas amino acid, fatty acid metabolism, and oxidative phosphorylation-related pathways were enriched in those with poor PFS.Conclusions: Bevacizumab plus erlotinib demonstrated promising efficacy in tumors with Krebs cycle gene mutations, warranting further investigation beyond FH-deficient RCC.