Phase I trial of everolimus in combination with thoracic radiotherapy in non-small cell lung cancer
Mené en France sur 26 patients atteints d'un cancer du poumon non à petites cellules de stade localement avancé ou oligométastatique (durée médiane de suivi : 29 mois), cet essai de phase I évalue l'efficacité, du point de vue des taux actuariels de survie sans progression et de survie globale à 2 ans, et la toxicité de différentes doses d'evérolimus, un inhibiteur de mTOR administré par voie orale, en combinaison avec une radiothérapie thoracique et une chimiothérapie de consolidation
Background : This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small cell lung cancer (NSCLC). Materials and Methods : Everolimus dose was escalated in incremental steps (sequential cohorts of 3 patients until the occurrence of dose-limiting toxicity [DLT]) and administered orally weekly (weekly group:dose of 10,20 or 50 mg) or daily (daily group:2.5,5 or 10 mg), one week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin-navelbine) were administrated 4.5 weeks after the end of radiotherapy. Results : Twenty six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 evaluable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg;however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 evaluable patients):one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg;2 other DLTs (one grade 3 oesophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were 5 patients with G3-4 interstitial pneumonitis related to treatment. In 22 evaluable patients for response, there were 9 (41%) partial response, and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively. Conclusion : In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy.