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 2 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 FH, IDH1/2, SDHx, or MDH2, and measurable disease per RECIST v1.1 or RANO 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. Primary endpoint was objective response rate(ORR); secondary endpoints were progression-free survival(PFS), overall survival(OS), and safety.
Results: From February to November 2023, 35 were enrolled: 19 with biliary tract cancer(BTC, 54.3%), 7 with brain tumors(20.0%), and 5 with FH-deficient renal cell carcinomas(FH-deficient RCC, 17.1%). ORR was 37.1%(1 complete, 12 partial responses). Disease control rate was 85.7%. Subgroup ORRs were 80.0% in FH-deficient RCC, 36.8% in BTC, and 28.6% in brain tumors. At a median follow-up of 11.7 months, median PFS was 8.3 months; median OS 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 with poor PFS.
Conclusions: Bevacizumab plus erlotinib demonstrated promising efficacy in tumors with Krebs cycle gene mutations, warranting further investigation beyond FH-deficient RCC.