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Background: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas., Methods: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment., Findings: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock., Interpretation: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas., Funding: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant., Competing Interests: Declaration of interests EB has received grants from Novartis and HRA; consulting fees from Novartis; support from HRA, Novartis, and Enterome; has been on the Board or Advisory Board for Ipsen, Novartis AAA, Pfizer, and Hutchinson Ph; has a leadership role for the French ENDOCAN network; and is a recipient of the interventions used in this study (sunitinib and placebo) from Pfizer. AB has received payment or honoraria from Novartis AAA and HRA; and has been on the Board or Advisory Board for Novartis AAA, Amgen, Bayer, and Ferring. JH has received consulting fees from Roche, Lilly, Pharma Mar, and EISAI; payment or honoraria from Novartis AAA; support from Ipsen and Novartis AAA; and has been on the Board or Advisory Board for Lilly. TD has received support from Recordati; has been on the Board or Advisory Board for Recordati; and has a leadership role for the German Pituitary Group. LL has received payment or honoraria from EISAI, Lilly, and ROCHE; and has been on the Board or Advisory Board for Bayer, EISAI, and IPSEN. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)