Multicenter phase 2 trial of bevacizumab plus erlotinib in advanced solid cancer with Krebs cycle gene mutations

Solid tumors with alterations in genes encoding Krebs cycle enzymes rely on aerobic glycolysis and promote VEGF-dependent angiogenesis; furthermore, EGFR signaling enhances aerobic glycolysis. A multicenter phase 2 trial in South Korea evaluated bevacizumab plus erlotinib in patients with advanced solid tumors harboring Krebs cycle gene mutations (fumarate hydratase, isocitrate dehydrogenase 1/2, succinate dehyrogenase, or maleate dehyrogenase 2). The trial included 35 participants (19 with biliary tract cancer, 7 with brain tumors, and 5 with fumarate hydratase-deficient renal cell carcinomas). The primary endpoint was objective response rate. ORR was 37.1% (one complete and 12 partial responses); disease control rate was 85.7%. ORR was 80.0% in fumarate hydratase-deficient RCC, 36.8% in BTC, and 28.6% in brain tumors. At a median follow-up of 11.7 months, the median progression-free survival was 8.3 months and median overall survival was not reached. The authors conclude that bevacizumab plus erlotinib demonstrated promising efficacy in tumors with Krebs cycle gene mutations.