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Absence of Efficacy of Everolimus in Neurofibromatosis 1-Related Plexiform Neurofibromas: Results from a Phase 2a Trial

2018; Elsevier BV; Volume: 139; Issue: 3 Linguagem: Inglês

10.1016/j.jid.2018.09.016

1523-1747

O. Zehou, S. Ferkal, Pierre Brugières, S. Barbarot, Sylvie Bastuji‐Garin, P. Combemale, L. Valeyrie‐Allanore, É. Sbidian, P. Wolkenstein,

Soft tissue tumor case studies

In neurofibromatosis-1 (NF1), internal plexiform neurofibromas can be life-threatening following transformation into malignant peripheral nerve sheath tumors, or cause significant morbidity through compression of organs, mainly the spine or nerve roots (Tucker et al., 2005Tucker T. Wolkenstein P. Revuz J. Zeller J. Friedman J.M. Association between benign and malignant peripheral nerve sheath tumors in NF1.Neurology. 2005; 65: 205-211Crossref PubMed Scopus (209) Google Scholar). Multiple or infiltrating tumors are surgically intractable. Thus, medical treatment to shrink such tumors to reduce organ compression or the long-term risk of malignant transformation would be highly valuable in the treatment of NF1. Deregulation of the mTOR pathway contributes to NF1 development (Bhola et al., 2010Bhola P. Banerjee S. Mukherjee J. Balasubramanium A. Arun V. Karim Z. et al.Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft.Int J Cancer. 2010; 126: 563-571Crossref PubMed Scopus (35) Google Scholar). The inhibition of mTOR by rapamycin potently suppressed the growth of aggressive NF1-associated malignancies in a genetically engineered murine model (Johannessen et al., 2008Johannessen C.M. Johnson B.W. Williams S.M.G. Chan A.W. Reczek E.E. Lynch R.C. et al.TORC1 is essential for NF1-associated malignancies.Curr Biol. 2008; 18: 56-62Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). These data suggest that rapamycin or its derivatives, such as everolimus, could be a potential therapy for NF1. This proof of concept has been performed in tuberous sclerosis, in which rapamycin and everolimus were able to efficiently treat angiomyolipomas and tubers (Sasongko et al., 2016Sasongko T.H. Ismail N.F.D. Zabidi-Hussin Z. Rapamycin and rapalogs for tuberous sclerosis complex.Cochrane Database Syst Rev. 2016; 7: CD011272PubMed Google Scholar). Therefore, we performed a trial to assess the efficacy of everolimus for surgically intractable and life-threatening internal neurofibromas in NF1 in adulthood. A detailed description of the methods is presented in the Supplementary Materials online. The NFitor trial, a multicenter, open-label, single-arm, non-randomized, single-stage phase 2a study, was conducted at three centers in France from April 2011 to October 2014, in accordance with the Declaration of Helsinki and local laws and regulations, and the protocol was approved by the CPP-Île-de-France IX Institutional Review Board (Paris, France, authorization no. 10-033). All participants gave written and informed consent. The ClinicalTrials.gov registration number is NCT01412892. Adult patients over 18 years old were included if they had NF1 with at least one internal plexiform neurofibroma that was life-threatening or causing significant morbidity and was surgically intractable. All patients received orally administrated everolimus (RAD001, two 5-mg tablets, i.e., 10-mg oral everolimus once daily) for 1 year and were followed for an additional year after the therapy was stopped. The primary end point was a 30% reduction in target lesion volume without an increase in the target volume of four other lesions after 1 year of treatment. Indeed, at baseline, up to five large internal neurofibromas were identified by magnetic resonance imaging per patient for volume measurement during the study. The largest lesion was designated as the target. The secondary efficacy end points were internal plexiform neurofibroma volume at 2 years, disease-related symptoms, such as pain and infirmity, and quality of life. Safety was assessed as the number of serious and/or nonserious adverse effects. With a sample size of 23 patients (single-arm trial with a Fleming single-stage procedure), an observation of at least four successes would lead to the conclusion that the drug warrants further investigation. A total of 23 patients (15 males) were included in the trial (Supplementary Figure S1 online), with a mean age of 31.6 years. Details of the population characteristics at baseline are available in Table 1. Details of the treatment (dosage, total duration, reasons leading to dosage modifications) are available in Supplementary Table S1 online. Overall, 16 of 23 patients received 5 to 10 mg/day everolimus for 1 year. Four patients stopped because of adverse events or serious adverse events, two because of disease progression, and two for personal convenience. No death occurred among the enrolled patients during the trial period. None of the 23 everolimus-treated patients in the intention-to-treat population reached the primary end point, that is, a 30% reduction in target lesion volume without an increase in the target volume of four other lesions after 1 year of treatment. We assessed the volume of the target lesion and the total volume of the internal neurofibromas at baseline (M0), month 12 (M12) (after 1 year of everolimus treatment), and month 24 (M24) (after 1 year of stopping the treatment) for the per-protocol population. There was no significant difference between M0 and M12, M0 and M24, or M12 and M24 for the total volume of the internal neurofibromas (Supplementary Tables S2 and S3 online). There was no difference over time for the visual analog scale–assessed global pain score, and for the global health status from the health-related quality of life scale (Supplementary Table S4 online). A high percentage of patients had at least one treatment-related adverse effect (Supplementary Table S5 online). Severe adverse effects occurred in 11 patients (Table 2).Table 1Study population characteristics (n = 23)CharacteristicsDataMissing DataMales, n (%)15 (65.2)—Age, years, mean ± SD31.6 ± 8.3—Total follow-up, months, mean ± SD (range)19.1 ± 8.7 (2.3–25.9)—Sporadic cases, n (%)16 (69.6)—Café-au-lait spots, n (%)23 (100)—At least six café-au-lait spots, n (%)18 (78.3)1Freckling, n (%)18 (78.3)—Absence of gliomas, n (%)19 (82.6)4Lisch nodules, n (%)8 (34.8)6Distinctive bony lesions , n (%)6 (26.1)—Abbreviation: SD, standard deviation. Open table in a new tab Table 2Serious adverse eventsIdPatAge at Baseline, YearsSexInclusion DateSAE DateType of SAEEnd of Follow-Up10339.25Male04/28/201112/20/2012Cat-scratch disease05/23/201310531.21Female05/12/201106/23/2011Aphtosis with weight loss07/21/201110921.68Male09/15/201101/20/2012Facial folliculitis09/05/201311633.85Male04/12/201210/12/2012Cytolytic hepatitis05/15/201411722.46Male04/19/201210/17/2013Traffic accident06/05/201412025.81Female01/10/201303/05/2013Viral E hepatitis09/09/201320127.62Female10/21/201104/01/2012Epistaxis04/16/201220442.77Male02/29/201201/20/2013Sub-cutaneous infectious09/19/201320530.34Male09/24/201201/14/2013Laryngitis09/04/201430146.43Female12/12/201107/30/2012Uncontrolled major Hypertension10/18/201230246.13Female02/06/201204/11/2012Menorrhagia02/24/2014Abbreviations: IdPat, patient identification number; SAE, serious adverse event. Open table in a new tab Abbreviation: SD, standard deviation. Abbreviations: IdPat, patient identification number; SAE, serious adverse event. In total, everolimus had essentially no effect in shrinking tumors in our trial. Another trial assessed the mTOR inhibitor sirolimus for the treatment of inoperable NF1-associated plexiform internal neurofibromas in a pediatric population (median age in the sirolimus group was 8.2 years old; range 3–17.7 years) (Weiss et al., 2015Weiss B. Widemann B.C. Wolters P. Dombi E. Vinks A. Cantor A. et al.Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.Neuro Oncol. 2015; 17: 596-603Crossref PubMed Scopus (93) Google Scholar). The time to progression (i.e., >20% increase in the sum of the volumes of all index plexiform neurofibromas) was significantly longer for the sirolimus group (15.4 months) than for the placebo group (11.9 months), but sirolimus treatment was not associated with a reduction in plexiform neurofibroma volume. The prevalence of internal plexiform neurofibromas increases during adolescence, whereas the sum of all internal plexiform neurofibromas appears to be stable in adulthood (Sbidian et al., 2012Sbidian E. Hadj-Rabia S. Riccardi V.M. Valeyrie-Allanore L.L. Barbarot S. Chosidow O. et al.Clinical characteristics predicting internal neurofibromas in 357 children with neurofibromatosis-1: results from a cross-selectional study.Orphanet J Rare Dis. 2012; 7: 62Crossref PubMed Scopus (16) Google Scholar). Thus, mTOR inhibitors may be effective during the early development of internal plexiform neurofibromas and not when once established. This study did not confirm the effect on chronic pain that we reported with sirolimus previously (Hua et al., 2014Hua C. Zehou O. Ducassou S. Minard-Colin V. Hamel-Teillac D. Wolkenstein P. et al.Sirolimus improves pain in NF1 patients with severe plexiform neurofibromas.Pediatrics. 2014; 133: e1792-e1797Crossref PubMed Scopus (23) Google Scholar). In conclusion, monotherapy with everolimus should not be considered as a treatment for NF1–related plexiform neurofibromas in adults. Further studies should investigate the potential effect of dual mTOR inhibitors, or the association of mTOR inhibitors with other innovative therapies. Other targeted therapies have been tested, such as imatinib for NF1-associated plexiform neurofibromas, with response rates of approximately 15% (Robertson et al., 2012Robertson K.A. Nalepa G. Yang F.-C. Bowers D.C. Ho C.Y. Hutchins G.D. et al.Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial.Lancet Oncol. 2012; 13: 1218-1224Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). The most promising approach currently seems to be the use of MEK inhibitors, as reported in a multicenter phase 1 trial of selumetinib in pediatric NF1 patients with inoperable internal plexiform neurofibromas (Dombi et al., 2016Dombi E. Baldwin A. Marcus L.J. Fisher M.J. Weiss B. Kim A. et al.Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas.N Engl J Med. 2016; 375: 2550-2560Crossref PubMed Scopus (369) Google Scholar). The authors observed tumor volume decreases from baseline of 20% in 17 of 24 (71%) children. These results open the field to new drug associations with targeted therapies or immunotherapies (Haworth et al., 2017Haworth K.B. Arnold M.A. Pierson C.R. Choi K. Yeager N.D. Ratner N. et al.Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy.Oncotarget. 2017; 8: 82037-82048Crossref PubMed Scopus (29) Google Scholar, Reilly et al., 2017Reilly K.M. Kim A. Blakely J. Ferner R.E. Gutmann D.H. Legius E. et al.Neurofibromatosis type 1-associated MPNST state of the science: outlining a research agenda for the future.J Natl Cancer Inst. 2017; 109Crossref PubMed Scopus (59) Google Scholar). SB received research grants from Pierre Fabre Laboratory and Fondation pour la dermatite atopique, personal fees from Bioderma, Laboratoire La Roche Posay, Sanofi-Genzyme, AbbVie; non-financial support from AbbVie, Novartis, Janssen. OZ received personal fees from Novartis and was investigator for Novartis. PW received fees from Pierre Fabre and was an investigator for Novartis. ES, SF, PB, SB-G, and LV-A state no conflict of interest. We would like to thank Amélie Anota for the statistical analysis of the Global Score Status (Methodology and Quality of Life: Oncology Unit & Quality of Life and Cancer Clinical Research Platform at Besancon, France). We thank the patient Association Neurofibromatose et Von Recklinghausen and Novartis who supported this work. Novartis provided the drug. The trial was designed, and the protocol written, independently by the authors (PW, SBG). Data were collected using case-report forms. The authors (PW, SF, OZ) vouch for the integrity and completeness of the data and the statistician (ES) verified the accuracy of the data analysis and computed all statistical analyses. The principal investigators had unrestricted access to the data after the database was locked; they prepared the manuscript and decided to publish. The trial was approved by the Institutional Review Board (CPP-Île-de-Francee–IX, Paris, France, authorization no. 10–033) and by the French Health Agency (Agence Franҫaise de Sécurité Sanitaire des Produits de Santé, AFSSAPS). This study is registered at ClinicalTrials.gov, NCT01412892. This paper was presented in part at the Journées Dermatologiques de Paris Congress, Paris, 2015. Download .pdf (.18 MB) Help with pdf files Supplementary Materials