Efficacy of Sonidegib in Patients With Metastatic BCC (mbcc)

Transcription

1 AAD 216 eposter 3368 Efficcy of Sonidegib in Ptients With Metsttic BCC (mbcc) Colin Morton, 1 Michel Migden, 2 Tingting Yi, 3 Mnish Mone, 3 Dlil Sellmi, 3 Reinhrd Dummer 4 1 Stirling Community Hospitl, Stirling, UK; 2 The University of Texs MD Anderson Cncer Center, Houston, TX, USA; 3 Novrtis Phrmceuticls Corportion, Est Hnover, NJ, USA; 4 UniversitätsSpitl Zürich, Skin Cncer Center University Hospitl, Zürich, Switzerlnd. 1

2 Bckground Metsttic BCC (mbcc) is extremely rre (.28% to.55% of ll BCCs) nd is ssocited with poor survivl (medin survivl rnge from 8 months to 7.3 yers) 1-3 Most spordic BCCs hve muttions in the hedgehog (Hh) pthwy components ptched (> 85% of cses) or smoothened ( 1%), which leds to berrnt pthwy ctivtion 4 Sonidegib (LDE225), Hh pthwy inhibitor (HPI) tht trgets smoothened, demonstrted efficcy in ptients with dvnced BCC in phse 1 study 5 Of 6 ptients with mbcc enrolled, 3 ptients hd prtil responses (PRs), 2 hd stble disese (SD), nd 1 hd n unknown response The efficcy nd sfety of sonidegib ws further investigted in ptients with dvnced BCC in the phse 2 Bsl Cell Crcinom Outcomes With LDE225 Tretment (BOLT) study (NCT132753) 6 Bsed on the clinicl efficcy demonstrted in BOLT, sonidegib ws pproved for use in ptients with dvnced BCC 7 (or loclly dvnced BCC [lbcc]) 8,9 1. Dreno B, et l. Oncologist. 214;19: von Domrus H, Stevens PJ. J Am Acd Dermtol. 1984;1: Wlling HW, et l. Cncer Metstsis Rev. 24;23: Gupt S, et l. Ther Adv Med Oncol. 21;2: Rodon J, et l. Clin Cncer Res. 214;2: Migden M, et l. Lncet Oncol. 215;16: Swissmedic uthorized medicines Europen Medicines Agency. CHMP summry of opinion for Odomzo. _Initil_uthoristion/humn/2839/WC pdf. 9. Odomzo (sonidegib) [pckge insert]. Est Hnover, NJ: Novrtis Phrmceuticls Corportion; 215 2

3 BOLT Study Design Screening/Bseline Ptient popultion : 1) mbcc 2) lbcc (ggressive nd nonggressive) R A N D O M I Z E 1:2 Tretment Sonidegib 2 mg dily b Strtifiction (stge, disese histology [lbcc only], nd geogrphic region) Sonidegib 8 mg dily b Tretment until disese progression, uncceptble toxicity, deth, or discontinution from the study for ny other reson Follow-Up (fter tretment discontinution) Primry endpoint Secondry endpoints Objective response rte c (ORR; best overll confirmed tumor response of CR or PR) by centrl review ccording to RECIST v1.1 2 (mbcc) or mrecist (lbcc) CR rte by centrl review; durtion of response by centrl nd investigtor review ORR by investigtor review; time to tumor response nd progression-free survivl by centrl nd investigtor review CR, complete response; mrecist, modified Response Evlution Criteri In Solid Tumors; ORR, objective response rte Ptients with prior tretment with sonidegib or other HPIs were excluded. b Doses were chosen bsed on dt from the phse 1 study (sonidegib 2 mg once dily ws the lowest dosge tested with evidence of nti-tumor ctivity; sonidegib 8 mg once dily ws the highest well-tolerted, biologiclly ctive dosge). 1 c Point estimtes to meet or exceed 3% (mbcc nd lbcc combined) with lower bound of 95% CI > 2% in either tretment rm Sonidegib provided durble tumor responses nd mngeble sfety profile in ptients with dvnced BCC 3,4 Updted results in ptients with lbcc using dt from the 18-month nlysis (dt cutoff, July 11, 214; medin follow-up, 26.3 months) confirmed tht tumor responses (56%, 2 mg; 45%, 8 mg) were durble, with few responders experiencing disese progression or deth These dt will be presented in detil seprtely (Dummer R, et l. EADO 215 [PA2-OC59]) Efficcy nd sfety in ptients with mbcc re presented here bsed on dt from the 18-month nlysis 1. Rodon J, et l. Clin Cncer Res. 214;2: Eisenhuer EA, et l. Eur J Cncer. 29;45: Migden MR, et l. Lncet Oncol. 215; 16: Dummer R, et l. Ann Oncol. 214;25(4 suppl) [bstrct LBA33] 3

4 Bseline Demogrphics nd Disese Chrcteristics in Ptients With mbcc Bseline Chrcteristic Sonidegib 2 mg Once Dily (n = 13) Sonidegib 8 mg Once Dily (n = 23) Age, medin (rnge), yers 74 (49-86) 62 (34-88) Sex, mle, % Estern Coopertive Oncology Group performnce sttus, % Metsttic sites, % of totl with metstsis Lung Lymph nodes 8 26 Bone Other b 23 3 Prior ntineoplstic therpy, % Surgery 85 1 Rdiotherpy Includes xillry, protid, submndibulr, suprclviculr, nd other. b Includes trunk, brin, hed, liver, neck, nd upper extremities Tumor burden t bseline ws extensive: medin sum (rnge) of trget lesions per centrl review ws 4.6 cm ( cm) nd most ptients hd > 1 lesion 4

5 Exposure nd Disposition in Ptients With mbcc Prmeter Sonidegib 2 mg Once Dily (n = 13) Sonidegib 8 mg Once Dily (n = 23) Medin durtion of exposure (rnge), months 1.2 ( ) 11. ( ) Tretment ongoing, % 8 9 Tretment discontinued, % Primry resons for discontinution, % Adverse event Progressive disese b Ptient decision c Physicin decision c Deth Noncomplince Dt cutoff: July 11, 214; medin follow-up in ptients with mbcc in both rms: 26.6 months b More ptients in the 2-mg rm were ble to remin on tretment until disese progression due to improved tolerbility c Decisions to withdrw by ptient or physicin were mostly due to dverse events

6 Tumor Response in Ptients With mbcc Ptients With mbcc Sonidegib 2 mg Once Dily (n = 13) Centrl Review Investigtor Review Sonidegib 8 mg Once Dily (n = 23) Centrl Review Investigtor Review ORR (95% CI), % 8 (.2-36.) 23 ( ) 17 ( ) 35 ( ) CR 9 PR SD PD Unknown Disese control rte (CR + PR + SD), % CR, complete response; PD, progressive disese; PR, prtil response; SD, stble disese Dt cutoff: July 11, 214; medin follow-up in ptients with mbcc in both rms: 26.6 months Response rtes by investigtor review were higher thn tht reported by centrl review with both sonidegib doses 6

7 Best Chnge From Bseline in the Size of Trget Lesions, % Tumor Shrinkge in Ptients With mbcc Centrl Review Sonidegib 2 mg Once Dily (n = 12) Responder (CR/PR) SD PD Unknown Composite overll response ssessed by CT/MRI/photogrph (if vilble) Sonidegib 8 mg Once Dily (n = 19) Responder (CR/PR) SD PD Unknown Percentge chnge in sum of longest dimeters in trget lesions (mgnitude of brs) ssessed by CT/MRI/photogrph (if vilble) per RECIST v1.1 1 All modlities CT, computed tomogrphy; MRI, mgnetic resonnce imging Dt cutoff: July 11, 214; medin follow-up in ptients with mbcc in both rms: 26.6 months. Assessments were excluded from the nlysis if percentge chnge in the size of trget lesions ws not vilble or ws contrdicted by n overll lesion response of unknown Tumor shrinkge ws observed in most ptients treted with sonidegib 2 mg (92%) nd 8 mg (84.2%) In ddition, nerly complete Hh pthwy inhibition (> 98% decrese in levels of the pthwy biomrker gliom-ssocited oncogene homolog 1 [GLI1]) ws observed in ptients with mbcc following tretment with both sonidegib doses 1. Eisenhuer EA, et l. Eur J Cncer. 29;45:

8 Time To Tumor Response nd Durtion Of Response in Ptients With mbcc Sonidegib 2 mg Once Dily (n = 13) Centrl Review Investigtor Review Sonidegib 8 mg Once Dily (n = 23) Centrl Review Investigtor Review TTR, medin (95% CI), mo 1.8 (not estimble) 1. (.9-3.7) 1. (1.-2.1) 2.7 (1.-5.6) DOR, events b /responders, n/n Kpln-Meier medin (95% CI), mo /1 Not reched 1/ (not estimble) 1/4 Not reched 4/8 1.2 (not estimble) TTR, time to tumor response; DOR, durtion of response Dt cutoff: July 11, 214; medin follow-up in ptients with mbcc in both rms: 26.6 months b Progressive disese or deth due to ny cuse Ptients with mbcc hd rpid responses to tretment with sonidegib 2 nd 8 mg medin time to first observed tumor response (CR or PR) rnged from 1. to 2.7 months Tumor responses were durble, with 4/5 nd 6/11 responders by centrl nd investigtor review, respectively, mintining n objective response t the time of the dt cutoff Kpln-Meier medin DOR ws not reched by centrl review; t the time of the dt cutoff, the durtion of ongoing responses per centrl review were 618 dys for the responder treted in the 2-mg rm nd 181, 234, nd 39 dys for the responders treted in the 8-mg rm 8

9 Probbility of Event-Free Survivl, % Progression-Free Survivl in Ptients With mbcc 1 Centrl Review Number of ptients still t risk Kpln-Meier medin, months Sonidegib 2 mg: 13.1 Sonidegib 8 mg: 11.1 Censoring times Sonidegib 2 mg (n/n = 6/13) Sonidegib 8 mg (n/n = 11/23) Time, months Months Sonidegib 2 mg Sonidegib 8 mg Dt cutoff: July 11, 214; medin follow-up in ptients with mbcc in both rms: 26.6 months. Progression-free survivl ws defined s the time from rndomiztion to first documented disese progression or deth due to ny cuse > 5% of ptients treted with sonidegib 2 nd 8 mg were live without disese progression per centrl review t the time of the dt cutoff The Kpln-Meier medin for progression-free survivl per centrl review ws 13.1 nd 11.1 months in the 2- nd 8- mg rms, respectively Per investigtor review, the respective Kpln-Meier medins for progression-free survivl were 13.1 nd 14.3 months 9

10 Tumor Shrinkge in Ptient With mbcc Bseline (26 April 212) 8 months (27 December 212) Ptient with lung metstses treted with sonidegib 2 mg who hd n overll response of stble disese by centrl nd investigtor review per RECIST v1.1 showed visible improvement for > 8 months CT scns provided by M. Migden, Houston, Texs 1

11 Sfety in Ptients With mbcc Sonidegib 2 mg Once Dily (n = 13) Sonidegib 8 mg Once Dily (n = 23) AEs in 2% of Ptients, % Any Grde Grde 3/4 Any Grde Grde 3/4 All AEs Dirrhe Appetite decresed Muscle spsms Nuse Alopeci CK incresed Ftigue Dysgeusi Arthrlgi Mylgi Weight decresed Vomiting 8 39 AE, dverse event; CK, cretine kinse; CTCAE, Common Terminology Criteri for Adverse Events. Dt cutoff: July 11, 214; medin follow-up in ll ptients in both rms: 26.6 months. Sfety ws ssessed throughout tretment until 3 dys following the lst dose. AEs were ssessed ccording to CTCAE v4.3. Sonidegib 2 mg demonstrted better tolerbility thn the 8-mg dose with lower frequencies of grde 3/4 AEs (15% vs 61%) nd serious AEs (15% vs 48%) 11

12 Conclusions In the BOLT 18-month nlysis, sonidegib demonstrted meningful tumor responses nd disese control in ptients with mbcc Tumor responses were durble 4 of 5 responding ptients mintined n objective response by centrl review The mjority of ptients survived without disese progression medin progression-free survivl ws 13.1 months with sonidegib 2 mg by centrl nd investigtor review Sonidegib tretment provided ner-complete inhibition of the Hh pthwy Sonidegib hd cceptble sfety in ptients with mbcc, with the 2-mg dose demonstrting better tolerbility thn the 8-mg dose Additionlly, dt from the BOLT primry nlysis showed tht most ptients with mbcc reported mintennce of or improvement in qulity of life, supporting the tretment benefit of sonidegib in this difficult-to-tret ptient popultion 1 These dt support the potentil benefit of sonidegib in ptients with mbcc The uthors thnk the ptients nd their fmilies; globl study investigtors, their clinicl tems, nd study site stff; the study steering committee, independent dt monitoring committee, efficcy independent review committee, muscle sfety review nd djudiction committee, nd Novrtis clinicl study personnel. Dr. Colin Morton hs received speker honorri nd/or prticipted in dvisory bords for Novrtis, Almirll, Glderm, Leo Phrm, Spirit Helthcre nd Biofronter 1. Dummer R, et l. Ann Oncol. 214;25(suppl 4) [bstrct 1125P] 12