E Deutsch1, C Le Péchoux2, L Faivre3, S Rivera4, Y Tao4, J-P Pignon3, M Angokai3, R Bahleda5, D Deandreis6, E Angevin5, C Hennequin7, B Besse8, A Levy9, J-C Soria10. 1. Department of Radiation Oncology; Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif; Paris-Sud University, Kremlin-Bicêtre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT; INSERM 1030 Molecular Radiotherapy, Cancer research institute, Villejuif. Electronic address: eric.deutsch@gustaveroussy.fr. 2. Department of Radiation Oncology; Institut d'Oncologie Thoracique (IOT). 3. Departments of Biostatistics. 4. Department of Radiation Oncology; Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif. 5. Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif. 6. Nuclear Medicine, Gustave Roussy, Villejuif. 7. Department of Radiation Oncology, Saint Louis Hospital, Paris. 8. Institut d'Oncologie Thoracique (IOT); Department of Medicine, Gustave Roussy, Villejuif, France. 9. Department of Radiation Oncology; Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif; INSERM 1030 Molecular Radiotherapy, Cancer research institute, Villejuif; Institut d'Oncologie Thoracique (IOT). 10. Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif; Paris-Sud University, Kremlin-Bicêtre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT; Institut d'Oncologie Thoracique (IOT).
Abstract
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). PATIENTS AND METHODS: Everolimus dose was escalated in incremental steps [sequential cohorts of three 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), 1 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 assessable 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 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable 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. EUDRACT N: 2007-001698-27.
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). PATIENTS AND METHODS: Everolimus dose was escalated in incremental steps [sequential cohorts of three 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), 1 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 assessable 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 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable 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 NSCLCpatients, 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. EUDRACT N: 2007-001698-27.
Authors: Ramon Andrade De Mello; Pedro Nazareth Aguiar; Hakaru Tadokoro; Tállita Meciany Farias-Vieira; Pedro Castelo-Branco; Gilberto de Lima Lopes; Daniel Humberto Pozza Journal: J Thorac Dis Date: 2018-06 Impact factor: 2.895
Authors: Nabil F Saba; Seth Force; Charley Staley; Felix Fernandez; Field Willingham; Allan Pickens; Kenneth Cardona; Zhengjia Chen; Laura Goff; Dana Cardin; Eric Lambright; Jon Nesbitt; Alyssa Krasinskas; Kristin Higgins; R Donald Harvey; Taofeek Owonikoko; Suresh S Ramalingam; Dong M Shin; Jonathan J Beitler; Bassel F El-Rayes; Safia Salaria; Wael El-Rifai; Jerome Landry; A B Chakravarthy Journal: Am J Clin Oncol Date: 2019-04 Impact factor: 2.339
Authors: Moataz Reda; Worapol Ngamcherdtrakul; Shenda Gu; Daniel S Bejan; Natnaree Siriwon; Joe W Gray; Wassana Yantasee Journal: Cancer Lett Date: 2019-09-26 Impact factor: 8.679
Authors: Angela Boros; Ludovic Lacroix; Benjamin Lacas; Julien Adam; Jean-Pierre Pignon; Caroline Caramella; David Planchard; Vincent de Montpreville; Eric Deutsch; Antonin Levy; Benjamin Besse; Cécile Le Pechoux Journal: Oncotarget Date: 2017-04-11
Authors: K Haslett; P Koh; A Hudson; W D Ryder; S Falk; D Mullan; B Taylor; R Califano; F Blackhall; C Faivre-Finn Journal: Clin Transl Radiat Oncol Date: 2021-02-25