METHODS: Patients from FLAURA who received first-line osimertinib and from the AURA program (AURA, AURA2, AURA3) who received ≥ second-line osimertinib were included. Patients received osimertinib 80 mg once daily. Safety data were analyzed in patients who remained on treatment for ≥ 36 months. The post-study global safety database captured investigator-reported serious adverse events (SAEs) in patients who continued osimertinib beyond final data cut-off (DCO) of the studies. Best response data were analyzed in patients on treatment for ≥ 54 months (FLAURA) or ≥ 36 months (AURA program).

RESULTS: In FLAURA, 76 (28 %) and 36 (13 %) of 267 patients received first-line osimertinib for ≥ 36 and ≥ 54 months, respectively; median exposure: 52.5 and 64.5 months, respectively. Across the AURA program,124 (16 %) of 799 patients received ≥ second-line osimertinib for ≥ 36 months; median exposure: 44.7 months. Investigators reported on-study SAEs in 17 % (FLAURA) and 35 % (AURA program) of patients who continued treatment for ≥ 36 months. Post-study incidences of SAEs were 11 % (FLAURA) and 21 % (AURA program). On-study, adverse events (AEs) of cardiac effects (indicative of cardiac failure; grouped term) occurred in 7 % (FLAURA) and 5 % (AURA program) of patients; AEs of interstitial lung disease (ILD; grouped term) occurred in 0 (FLAURA) and 1 (AURA program) patient. No post-study SAEs were reported for the grouped terms cardiac effects and ILD. Most patients treated for ≥ 54 months (FLAURA) and ≥ 36 months (AURA program) had a best on-study response of partial response.

METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete).

FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea.

INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated.