Induction osimertinib followed by definitive sequential radiation therapy and/or surgery in unresectable EGFR-mutant stage III NSCLC: An open-label, single-arm, phase II study

The treatment of unresectable, locally advanced stage III NSCLC is concurrent chemoradiation therapy (CRT), followed by consolidation durvalumab. EGFR-mut poorly responds to this treatment. Non-randomized, open-label, single-arm, phase 2, prospective, proof-of-concept. Eligible patients were treatment-naïve, non-operable, stage III EGFR-mut NSCLC. Received 80 mg oral osimertinib daily for 12 weeks before definitive RT and/or surgery. Response assessed at baseline, weeks 6 & 12. Responders planned for definitive sequential RT or surgery (if downgraded to IIIA). Non-responders began definitive CRT. After RT+/- surgery or CRT, patients were followed without adjuvant therapy. Primary endpoint was objective response rate (ORR), with data cutoff on Jan 22, 2022. Secondary endpoints were gross tumor volume (GTV) & planned tumor volume (PTV), compared before and after osimertinib, V20 and safety. Patients followed for 2 years. This preliminary analysis includes 20 patients (16 female; median age 72 years, range 51-82)). 15/20 were never-smokers, all had adenocarcinoma, 14/20 had exon 19 deletions, and 6/20 had exon 21 mutations. Participants had IIIA (9), IIIB (6), IIIC (3), or IVA oligometastatic (2) disease. The ORR was 93.75%, (16 PR & 1 PD). Of 11 patients who began RT following induction, 9 completed RT, and 2 were still undergoing RT. 2 patients underwent surgery with pT1aN0 (1 post-RT & 1 without RT). 4 patients did not receive RT (2 unfit, 2 refused). Pre-osimertinib median GTV, PTV & V20% were 48.91 cm3 (13.5 – 234.9), 322.96 cm3 (81.4 – 929.2) and 34.35% (12.8– 60.3) respectively. Post-Osimertinib, all variables reduced to 33.5 cm3 (2.99 – 137.7; 31.5% reduction), 202.28 cm3 (55.1 – 718.1; 37.36% reduction) and 28.59% (18.05 – 44.15; 17% reduction), respectively. No particular SAEs were reported during the osimertinib or the radiation phases. This chemotherapy-free approach is a potentially good option for downstaging locally advanced, inoperable, EGFR-mut NSCLC, allowing reduction of the radiation field, preservation of lung tissue, and reduced radiation-induced toxicity.