Multinational phase 2 umbrella trial of biomarker-directed targeted therapy plus durvalumab for advanced non-small lung cancer

For patients with non-small lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, resistance to immune checkpoint blockade is common. There is an unmet need for therapies to overcome this resistance. The multinational phase 2 umbrella HUDSON trial included 268 advanced NSCLC patients after failure of anti-PD-(L)1 containing immunotherapy and platinum-doublet therapy. The patients received durvalumab in combination with one of four targeted therapies: ceralasertib (ATR kinase inhibitor), olaparib (PARP inhibitor), danvatisen (STAT3 antisense oligonucleotide), or oleclumab (anti-CD73). The primary outcomes was objective response rate. The greatest clincal benefit was seen with durvalumab-ceralasertib (ORR 13.9% versus 2.6% with the pooled three other regimens). Progression-free and overall survival were 5.8 versus 2.7 months and 17.4 versus 9.4 months, respectively. The safety/tolerabilty profile of durvalumab-ceralasertib was manageable. This combination is under further investigation in immunotherapy-refractory NSCLC.