Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study.

PURPOSE: The treatment for unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT) followed by consolidation durvalumab. This study aimed to evaluate the benefit of neoadjuvant osimertinib as an alternative therapy to this approach with the aim of reducing the radiation field. METHODS AND MATERIALS: This investigation was a nonrandomized, open-label, single-arm, phase 2, prospective, proof-of-concept study. Eligible patients were classified as having treatment-naïve, nonoperable, stage III epidermal growth factor receptor-mutant NSCLC. Patients received 80 mg of oral osimertinib daily for 12 weeks before definitive radiation therapy (RT) and/or surgery. The response was assessed at weeks 6 and 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 2 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 tumor volume (GTV), planned tumor volume (PTV), and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before versus after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumor-free DNA (ctDNA) 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 women; median age, 73 years; range, 51-82 years). Nineteen of 24 had never smoked, 20 of 24 had adenocarcinoma, 16 of 24 had exon 19 deletions, and 8 of 24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (1 dropped out and 2 were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response, 3 complete response, and 1 progressive disease). After induction osimertinib, 13 of 20 patients were definitively radiated, 3 of 20 underwent surgery, and 5 of 20 were excluded. Four patients were restaged as stage IV (contralateral ground-glass opacities responded to osimertinib), and 1 patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathologic complete response. The median GTV, PTV, and 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 = .02), 181.9 ±198.4 cm3 (54-718.1; -31 ± 20%; P = .01), and 21.8 ± 11.7% (9.1-44.15; -24 ± 40%; P = .04), respectively. PTV/GTV/V20% reduction was associated with tumor size and central location. The median follow-up time was 28.71 months (range, 0.4-45.1 months), and median disease-free survival was not reached (mean, 30.59; standard error, 3.94; 95% confidence interval, 22.86-38.31). ctDNA was detected in 5 patients; 4 of 5 were positive for ctDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were ctDNA negative at baseline became weakly positive after RT 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 patients with stage III lung cancer NSCLC, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks before definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumor size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.

Antibiotic resistance in soil and tomato crop irrigated with freshwater and two types of treated wastewater.

Agricultural use of treated wastewater (TWW) is an effective means to reduce freshwater (FW) consumption. However, there is a growing concern regarding the potential dissemination of antibiotic resistance elements by TWW irrigation. We hypothesized that higher levels of antibiotic resistance genes (ARGs) would be detected in soil and crops irrigated with TWW compared to FW irrigation. To test our prediction, samples of water (FW, secondary TWW, and tertiary TWW), irrigated soils, and crops (tomato) surface wash were collected during two consecutive growing seasons. The ARGs conferring resistance to sulfonamide, fluoroquinolone, penicillin, erythromycin and tetracycline were quantified in the samples, alongside Class 1 integron-integrase and the bacterial 16 S rRNA encoding genes. Contrary to our hypothesis, ARGs in the irrigation water were not propagated to either the irrigated soil, or the tomato. The tomato surface wash featured a variety of ARGs that were undetected in neither the waters nor the irrigated soils. Therefore, we cautiously question the link between irrigation water quality and the soil and produce resistomes.

Next-Generation Sequencing Liquid Biopsy-Guided Osimertinib Rechallenge in EGFR-Mutated Advanced Non-Small-Cell Lung Cancer Patients.

BACKGROUND AND OBJECTIVES: Osimertinib is considered the treatment of choice for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine kinase inhibitors (TKIs). It has recently been shown to have superior efficacy over first-/second-generation TKIs as first-line treatment for advanced NSCLC. However, eventual development of resistance to osimertinib is inevitable, amplifying the need for new treatment options in these cases. Rechallenge with early-generation TKIs has been described as an optional treatment method after development of resistance. Nonetheless, osimertinib rechallenge has not yet been widely investigated. Herein, we describe a case series of six patients who, after acquiring resistance to their initial osimertinib treatment, were rechallenged with osimertinib following intervening carboplatin-based chemotherapy. METHODS: All patients had advanced NSCLC with a sensitizing EGFR mutation (EGFRm NSCLC). After acquiring resistance to first- or second-line osimertinib treatment, patients were rechallenged with osimertinib 80 mg following a period of carboplatin-based chemotherapy. To track tumor evolution and guide treatment decisions, all patients underwent serial NGS-based liquid biopsy testing throughout their disease course. RESULTS: Six EGFRm NSCLC patients were rechallenged with osimertinib following chemotherapy treatment. Osimertinib was given either as a single agent or as part of combination therapy. Median duration of treatment (DOT) was 5.0 [95% confidence interval (CI) = 2.0-7.0] months and the median OS was 45.0 (95% CI = 34.9-55.1) months. Treatment was generally feasible without serious adverse events. CONCLUSIONS: Osimertinib rechallenge as either a single agent or as part of a combination therapy may be an effective and well-tolerated approach with the potential to improve survival by a few months.