Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study
Mené en Chine sur 70 patients atteints d'un carcinome sarcomatoïde pulmonaire ou d'un autre type de cancer du poumon non à petites cellules présentant des mutations au niveau de l'exon 14 du gène MET, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du savolitinib (durée médiane de suivi : 17,6 mois)
Résumé en anglais
Background : Savolitinib is a selective MET tyrosine-kinase inhibitor. We investigated the activityand safety of savolitinib in patients with pulmonary sarcomatoid carcinoma and other non-small-cell lung cancer (NSCLC) subtypes positive for MET exon 14 skipping alterations (METex14-positive).
Methods : We did a multicentre, single-arm, open-label, phase 2 study across 32 hospitals in China. Eligible patients were 18 years or older with locally advanced or metastatic METex14-positive pulmonary sarcomatoid carcinoma or other NSCLC subtypes, had eitherpresented with disease progression or toxicity intolerance towards one or more standardtreatments or were deemed clinically unsuitable for standard treatment, were MET inhibitor-naive,and had measurable disease. Patients received either 600 mg (bodyweight ≥50 kg) or400 mg (bodyweight <50 kg) of oral savolitinib once daily until disease progression,death, intolerable toxicity, initiation of other anti-tumour therapy, non-compliance,patient withdrawal, or patient discontinuation. Radiographic tumour evaluation wasdone at baseline, every 6 weeks within 1 year of the first dose, and every 12 weeksthereafter. The primary endpoint was objective response rate, defined as the proportionof patients with confirmed complete or partial responses by independent review committee(IRC) assessment. The primary endpoint was assessed in the tumour response evaluableset, which comprised all treated patients with a measurable lesion at baseline andat least one adequate scheduled post-baseline tumour assessment or the presence ofradiological disease progression, with a sensitivity analysis done in the full analysisset, which comprised all patients who received at least one dose of savolitinib. Safetywas also evaluated in the full analysis set. This study is registered with ClinicalTrials.gov, NCT02897479, and recruitment is complete, with treatment and follow-up ongoing.
Findings : From Nov 8, 2016, to Aug 3, 2020, 84 patients with METex14 skipping alterations were screened for eligibility, of whom 70 were enrolled,received savolitinib, and comprised the full analysis set. The IRC-assessed tumourresponse evaluable set comprised 61 patients. At a median follow-up of 17·6 months(IQR 14·2–24·4), the IRC-assessed objective response rate was 49·2% (36·1–62·3; 30of 61 patients) in the tumour response evaluable set and 42·9% (95% CI 31·1–55·3;30 of 70 patients) in the full analysis set. All 70 patients reported at least onetreatment-related adverse event. Treatment-related adverse events of grade 3 or moreoccurred in 32 (46%) patients, the most frequent of which were increased aspartateaminotransferase (n=9), increased alanine aminotransferase (n=7), and peripheral oedema(n=6). Treatment-related serious adverse events occurred in 17 (24%) patients, themost common being abnormal hepatic function (n=3) and hypersensitivity (n=2). Onedeath due to tumour lysis syndrome in a patient with pulmonary sarcomatoid carcinomawas assessed to be probably related to savolitinib by the investigator.
Interpretation : Savolitinib yielded promising activity and had an acceptable safety profile in patientswith pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 skipping alterations. Savolitinib could therefore be a novel treatment optionin this population.
