Sonidegib Efficacy and Safety in Patients with Locally Advanced Basal Cell Carcinoma Based on Tumor Aggressiveness Michael R. Migden, MD1, and Reinhard Dummer, MD2 1Departments of Dermatology and Head and Neck Surgery MD Anderson Cancer Center, Houston, TX, USA 2Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland BACKGROUND Basal cell carcinomas (BCCs) can be categorized as aggressive or nonaggressive based on their histology1,2 – Most BCCs have nonaggressive histology, including superficial and nodular subtypes2 – Aggressive subtypes (eg, micronodular, infiltrative, or sclerosing) are rarer but tend to have a higher rate of recurrence1,2 Sonidegib (LDE225) is a hedgehog (Hh) pathway inhibitor approved for the treatment of patients with locally advanced BCC (laBCC) not amenable to surgery or radiotherapy3-5 – Sonidegib was approved based on results from the phase 2 Basal Cell Carcinoma Outcomes With LDE225 Treatment (BOLT) study (NCT01327053), which included patients with aggressive or nonaggressive laBCC subtypes6 OBJECTIVE In patients with laBCC regardless of tumor aggressiveness, durable tumor responses were observed – These results are significant, given the higher rate of recurrence and higher chance of subclinical spread associated with aggressive laBCC subtypes Here we present the efficacy and safety of sonidegib 200 mg in patients with laBCC, based on tumor aggressiveness, from the BOLT 30-month analysis METHODS BOLT was a multicenter, randomized, double-blind, phase 2 study that enrolled patients with laBCC (aggressive or nonaggressive) or metastatic BCC (mBCC; Figure 1) Patients with laBCC not amenable to curative surgery or radiotherapy were randomized in a 1:2 ratio to 200 mg or 800 mg once daily (QD); only results from the 200-mg QD dose will be discussed here Objective response rate (ORR: confirmed complete response [CR] + partial response [PR]). Duration of response, and progression-free survival (PFS) were assessed according to stringent criteria, defined as modified Response Evaluation Criteria In Solid Tumors (mRECIST; Figure 2), by central review – Overall survival (OS) was also assessed Safety was assessed until 30 days after the final treatment; Common Terminology Criteria for Adverse Events (CTCAE) v4.03 guidelines were used to evaluate adverse events (AEs)6 Figure 1: BOLT Study Design Screening/ baseline Treatment Follow-Up (after treatment discontinuation) Patientsa: (1) laBCC (2) mBCCc Sonidegib 200 mg daily • laBCC n = 66 • mBCC n = 13 Sonidegib 800 mg daily • laBCC n = 128 • mBCC n = 23 Stratificationb Randomization (1:2) Treatment until: • Disease progression • Unacceptable toxicity • Death • Discontinuation from the study for any other reason (1) Tumors assessed Q8W during year 1 and Q12W thereafter until disease progression (2) Information collected on any further anticancer therapy received (3) AEs collected until 30 days after last dose of study treatment (4) Survival follow-up Q12W until patient died, was lost to follow-up, or withdrew consent (and at the time of the final analysis) aPatients treated with previous sonidegib or other hedgehog pathway inhibitors were excluded. bStratification was based on stage, history, disease histology for patients with laBCC (aggressive vs nonaggressive), and geographic region. AEs, adverse events; laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma; Q8W, every 8 weeks; Q12W, every 12 weeks. Evaluated By: a d aAssessed by central review per RECIST v1.1.9. bStandard and annotated color photography assessed per WHO criteria.9 Partial response ≥50% reduction in the sum of products of perpendicular diameters from baseline; progressive disease ≥25% increase in the sum of products of perpendicular diameters from the lowest point. cHistology was assessed in multiple biopsies surveying the lesion area. dComposite overall response was determined by an independent review committee that reread all available data, including histology reports for laBCC. CR, complete response; laBCC, locally advanced basal cell carcinoma; mRECIST, modified Response Evaluation Criteria In Solid Tumors; MRI, magnetic resonance imaging; WHO, World Health Organization. Figure 2: Stringent Tumor Response Evaluation Criteria RESULTS 66 patients with laBCC received 200 mg QD sonidegib – Of these, 37 (56%) patients had aggressive laBCC subtypes and 29 (44%) had nonaggressive subtypes 92% of patients were no longer receiving sonidegib as of the cut-off date for the 30-month analysis Median duration of exposure was 11.1 months Most common reasons for discontinuation were AEs (29%) and progressive disease (37%) Efficacy ORRs per central review were similar for patients with aggressive or nonaggressive laBCC subtypes (Table 1; Figure 3) – In patients with aggressive subtypes, ORR per central review was 59% in the 200-mg treatment arm – In patients with nonaggressive subtypes, ORR per central review was 52% in the 200-mg treatment arm Table 1: Sonidegib Efficacy in laBCC at 30 Months Sonidegib 200 mg QD Central Review Aggressive a (n = 37) Nonaggressive b (n = 29) Best overall response, n (%) • CRc • PRc • SD • PD • Unknown 2 (5) 20 (54) 12 (32) 1 (3) 2 (5) 1 (3) 14 (48) 11 (38) 0 3 (10) ORR (95% CI); % CR, % PR 59 (42-75); 5,54 52 (32.5-71); 3, 48 DCR, %d 92 90 DOR, no. of eventse/ responders; Median (95% CI), mo 7/22; 26.1 (not estimable) 4/15; Not reached Kaplan-Meier-estimated median (95% CI), moe 26.1 (NE) NE PFS, no. of events; Median (95% CI), mo 11; 22.1 (not estimable) 5; Not reached OS, median (95% CI), mo; 2-yr OS (95% CI), % Not reached; 92 (71-98) Not reached; 95 (68-99) aIncludes micronodular, infiltrative, multifocal, basosquamous, and sclerosing laBCC; bIncludes nodular and superficial laBCC; cRequired confirmation on repeat assessments >4 weeks apart; dCR+PR+SD; eKM-estimated time from first CR or PR until disease progression or death due to any cause (among responders). CR, complete response; DCR, disease control rate; DOR, duration of response; ORR, overall response rate; OS, overall survival; PR, partial response; PFS, progression-free survival, QD, once daily; SD, stable disease. Table 2: PFS and OS in Patients by laBCC Subtype Sonidegib 200 mg QD Aggressive (n = 37) Nonaggressive (n = 29) PFS events, n (%) 11 (30) 5 (17) KM-estimated media PFS duration (95% CI), months 21.1 (NE) NE Deaths, n (%) 4 (11) 1 (3) KM-estimated 2-uear OS (95% Ci), % 92 (71-98) 9 (68-99) CI, confidence interval; KM, Kaplan-Meier; laBCC, locally advanced BCC; OS, overall survival; PFS, progression-free survival Progression and Survival PFS and OS were similar for patients with aggressive or nonaggressive laBCC subtypes (Table 2) Overall, 5 deaths in patients with laBCC in the 200-mg arm were reported by the data cutoff date Median OS was not reached for either histological subgroup in either arm Safety The observed safety profile of sonidegib remained similar to that of previous analyses, with the 200-mg dose continuing to show a favorable profile7,8,10 >50% of patients with laBCC experienced grade 1/2 AEs The most common AEs of any grade among patients with laBCC were muscle spasms, alopecia, dysgeusia, and nausea (Figure 4) There were no treatment-related deaths There were no significant differences noted between the subtypes CONCLUSIONS With 30 months of follow-up, patients with aggressive or nonaggressive laBCC subtypes experienced durable responses when given sonidegib 200 mg daily The efficacy of sonidegib was similar for patients with aggressive or nonaggressive laBCC subtypes in this analysis No new safety concerns were detected, and sonidegib 200 mg demonstrated a good benefit– risk profile Together, these data support the use of sonidegib 200 mg daily in patients with laBCC regardless of tumor aggressiveness, in accordance with local guidelines REFERENCES 1. LeBoit PE, et al, eds. WHO Classification of Tumours: Pathology and Genetics of Skin Tumours. Lyon, France: IARC Press; 2006. 2. Kuijpers DI, et al. Am J Clin Dermatol. 2002;3:247-259. 3. Swissmedic. Human and veterinary medicines. www. swissmedic.ch/arzneimittel/00156/00221/00222/00230/ index.html?lang=en. Accessed August 10, 2016. 4. European Medicines Agency. CHMP summary of opinion for Odomzo. www.ema.europa.eu/docs/ en_GB/document_library/ Summary_of_opinion_-_Initial_authorisation/human/ 002839/ WC500188762.pdf. Accessed August 10, 2016. 5. Odomzo (sonidegib) package insert. Cranbury, NJ: Sun Pharmaceutical Industries Ltd; 2017. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. http://evs. nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7. pdf. Accessed August 10, 2016. 7. Migden M, et al. Lancet Oncol. 2015;16:716-728. 8. Rodon J, et al. Clin Cancer Res. 2014;20:1900-1909. 9. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. http://whqlibdoc.who.int/offset/ WHO_OFFSET_48.pdf. Accessed March 30, 2016. 10. Dummer R, et al. J Am Acad Dermatol. 2016;75:113-125.e5. ACKNOWLEDGEMENTS Medical writing and editorial support were provided by Beverly E. Barton, PhD, of ScioScientific, LLC. DISCLOSURES Funding source: This study was funded by Novartis Pharmaceuticals Corporation. Novartis Pharmaceuticals Corporation was involved in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, and approval of the data. The decision to submit the data for presentation was made by Sun Pharmaceutical Industries Ltd. Dr Migden has participated on advisory boards and received honoraria from Genentech Incorporated, Novartis Pharmaceuticals Corporation, Sun Pharmaceutical Industries Ltd, and Eli Lilly & Company. Dr Dummer has received research funding from Novartis Pharmaceuticals Corporation, Merck Sharp & Dohme, Bristol- Myers Squibb, Roche, and GlaxoSmithKline. He has served as a consultant or participated on advisory boards for Novartis Pharmaceuticals Corporation, Merck Sharp & Dohme, Bristol- Myers Squibb, Roche, GlaxoSmithKline, Amgen, and Takeda. Figure 3: Best Overall Response by laBCC Subtype at 30 Months Figure 4: Adverse Events Regardless of Cause in ≥20% of Patients with laBCC DCR, disease control rate; laBCC, locally advanced BCC; ORR, objective response rate. AE, adverse event; CK, creatinine kinase; laBCC, locally advanced BCC. 0% 20% 40% 60% 80% 100% P at ie nt s, % Aggressive n = 37 Nonaggressive n = 29 5% 3% 32% 54% 5% 10% 38% 48% 3% DCR: 90% ORR: 52% DCR: 92% ORR: 59% Complete Response Partial Response Stable Disease Progressive Disease Unknown Sonidegib 200 mg 45 8 3 38 14 36 12 24 12 2 18 8 6 15 9 3 2 17 11 2 23 3 2 8 9 2 15 3 11 2 Muscle spasms Alopecia Dysgeusia Nausea Weight decrease CK increase Fatigue Diarrhea Appetite decrease Myalgia Vomiting 0 10 20 30 40 50 60 70 80 Patients, % A E s in ≥ 2 0% o f p at ie nt s w ith la B C C tr ea te d w ith s on id eg ib 2 00 m g Figure 4: Adverse Events Regardless of Cause in ≥20% of Patients with laBCC 56% 52% 47% 38% 32% 29% 29% 27% 18% 18% 12% All grades AE, adverse event; CK, creatinine kinase; laBCC, locally advanced BCC Grade 1 Grade 2 Grade 3 Grade 4 Presented at 2017 Fall Clinical Dermatology Conference®, Las Vegas, NV, USA FC17PosterSunMigdenSonidegibEfficacy.pdf