Nicole Basset-Seguin1, Axel Hauschild2, Jean-Jacques Grob3, Rainer Kunstfeld4, Brigitte Dréno5, Laurent Mortier6, Paolo A Ascierto7, Lisa Licitra8, Caroline Dutriaux9, Luc Thomas10, Thomas Jouary11, Nicolas Meyer12, Bernard Guillot13, Reinhard Dummer14, Kate Fife15, D Scott Ernst16, Sarah Williams17, Alberto Fittipaldo17, Ioannis Xynos17, Johan Hansson18. 1. Hôpital Saint Louis, Paris, France. 2. University Hospital Schleswig-Holstein, Kiel, Germany. 3. Aix Marseille University and Timone Hospital, Marseille, France. 4. Medical University of Vienna, Vienna, Austria. 5. CHRU Hotel Dieu, Nantes, France. 6. University of Lille 2, Lille Regional University Hospital, Hopital Huriez, Lille, France. 7. Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. 8. Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy. 9. University Hospital of Bordeaux, Bordeaux, France. 10. LYON 1 University-Centre Hospitalier Lyon Sud and Lyons Cancer Research Center (Pr Puisieux), Lyon, France. 11. Saint Andre Hospital CHU de Bordeaux, Bordeaux, France. 12. Paul Sabatier University and Toulouse University Cancer Institute, Toulouse, France. 13. University Hospital of Montpellier, Montpellier, France. 14. University Hospital Zurich, Zurich, Switzerland. 15. Addenbrooke's Hospital, Cambridge, UK. 16. London Regional Cancer Program, London, ON, Canada. 17. Roche Products, Welwyn Garden City, UK. 18. Karolinska University Hospital, Solna, Stockholm, Sweden. Electronic address: Johan.Hansson@ki.se.
Abstract
BACKGROUND: The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. METHODS: In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing. FINDINGS: Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7-62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1-71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7-57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). INTERPRETATION: This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. FUNDING: F Hoffmann-La Roche.
BACKGROUND: The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. METHODS: In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing. FINDINGS: Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7-62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1-71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7-57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). INTERPRETATION: This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. FUNDING: F Hoffmann-La Roche.
Authors: Ximena Bonilla; Laurent Parmentier; Bryan King; Fedor Bezrukov; Gürkan Kaya; Vincent Zoete; Vladimir B Seplyarskiy; Hayley J Sharpe; Thomas McKee; Audrey Letourneau; Pascale G Ribaux; Konstantin Popadin; Nicole Basset-Seguin; Rouaa Ben Chaabene; Federico A Santoni; Maria A Andrianova; Michel Guipponi; Marco Garieri; Carole Verdan; Kerstin Grosdemange; Olga Sumara; Martin Eilers; Iannis Aifantis; Olivier Michielin; Frederic J de Sauvage; Stylianos E Antonarakis; Sergey I Nikolaev Journal: Nat Genet Date: 2016-03-07 Impact factor: 38.330