Neoadjuvant osimertinib followed by sequential definitive radiotherapy and/or surgery in stage III EGFR-mutant NSCLC: An open-label, single-arm, phase II study
Mené sur 24 patients n'ayant jamais reçu de traitement pour un cancer du poumon non à petites cellules de stade III non résécable avec mutation EGFR (âge médian : 73 ans), cet essai de phase II évalue la faisabilité et l'efficacité, du point de vue du taux de réponse objective, d'un traitement par osimertinib avant une radiothérapie définitive et/ou une chirurgie
Background: The treatment of unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT), followed by consolidation durvalumab. This study aims to evaluate the benefit of neoadjuvant osimertinib as an alternative therapy to this approach with the aim of reducing the radiation field. Methods: This investigation was a nonrandomized, open-label, single-arm, phase II prospective, proof-of-concept study. Eligible patients were treatment-naïve, nonoperable, stage III EGFR-mutant NSCLC patients. Patients received 80 mg oral osimertinib daily for 12 weeks prior to definitive radiotherapy (RT) and/or surgery. The response was assessed at week 6 and week 12. For responders, sequential definitive RT and/or surgery were planned. Nonresponders were started on standard CRT. After RT± surgery or CRT, patients were followed for two years without adjuvant therapy. The primary endpoint was the objective response rate (ORR), with September 20, 2022 set as the cut-off for data collection. Secondary endpoints were safety and the gross tumour volume (GTV), planned tumour volume (PTV) and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before vs. after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumour-free DNA (cfDNA) before osimertinib treatment, at weeks 6 and 12, at the end of RT, and 6 weeks post-RT. Results: Twenty-four patients were included (19 female; median age 73 years, range 51-82). Nineteen/24 had never smoked, 20/24 had adenocarcinoma, 16/24 had exon 19 deletions, and 8/24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (one dropped out, and two were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response (PR), 3 complete response (CR) & 1 progressive disease (PD)). After induction osimertinib, 13/20 patients were definitively radiated, 3/20 underwent surgery, and 5/20 were excluded. Four patients were restaged as stage IV (contralateral ground glass opacities responded to osimertinib), and one patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathological complete response (pCR). The median GTV, PTV & V20% before osimertinib treatment were 47.4 ± 76.9 cm3 (13.5–234.9), 227.0 ± 258.8 cm3 (77.8–929.2) and 27.1 ± 16.4% (6.2–60.3), respectively. The values after osimertinib treatment were 27.5 ± 42.3 cm3 (2.99–137.7; -48 ± 20%; p=0.02), 181.9 ±198.4 cm3 (54–718.1; -31 ±20%; p=0.01) and 21.8 ± 11.7% (9.1–44.15; -24 ± 40%; p=0.04), respectively. PTV/GTV/V20% reduction was associated with tumour size and central location. The median follow-up time was 28.71(range 0.4-45.1) months and median disease-free survival (DFS) was not reached (mean 30.59; standard error 3.94; (95% [22.86-38.31])). cfDNA was detected in 5 patients; 4/5 were positive for cfDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were cfDNA negative at baseline became weakly positive after radiotherapy and then were negative at follow-up. No significant adverse events were reported during the osimertinib or radiation phases. Conclusions: Neoadjuvant osimertinib therapy is feasible in stage III patients, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks prior to definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumour size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.
International Journal of Radiation Oncology, Biology, Physics