Long-term Safety of Sonidegib in Basal Cell Carcinoma: 30-Month Results from the BOLT Trial Ragini Kudchadkar, MD1; Anne Lynn S. Chang, MD2 1Associate Professor, Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 2Associate Professor, Dermatology, Stanford University School of Medicine, Redwood City, CA, USA. Presented at 2018 Winter Clinical Dermatology Conference – Hawaii, Lahaina, Hawaii, USA BACKGROUND Basal cell carcinoma (BCC) is the most common form of skin cancer1 – More than 4 million cases are diagnosed in the United States (US) each year2 The incidence and prevalence of BCC is expected to increase as the population ages3 ~95% of patients with BCC have mutations in the hedgehog (HH) signaling pathway components Patched-1 (PTCH1; >85%) or Smoothened (SMO; ~10%)4 Sonidegib blocks the HH signaling pathway by selective inhibition of the SMO protein5 (Figure 1) Sonidegib was approved based on results of the pivotal phase BOLT (Basal Cell Carcinoma Outcomes with LDE225 [sonidegib] Treatment) trial (NCT01327053)6 (Figure 2) Sonidegib is approved in the US, the European Union, Switzerland, and Australia for the treatment of patients with locally advanced basal cell carcinoma (laBCC)6 In Switzerland and Australia, sonidegib is also approved for the treatment of metastatic BCC (mBCC)6 RESULTS Patient Demographics and Disposition Two-hundred-thirty patients with laBCC (n=194) or mBCC (n=36) were enrolled between July 20, 2011, and January 10, 20139 (Table 1) Patients were randomized to sonidegib 200 mg (laBCC, n=66; mBCC, n=13) or 800 mg (laBCC, n=128; mBCC, n=23)9 Baseline demographics were well balanced between arms Separated Adverse Events Profile for laBCC and mBCC The most common AE for sonidegib at either dosage in laBCC was muscle spasms9 (Figure 4) The most common AE for 200 mg QD in mBCC was diarrhea; for 800 mg QD, it was muscle spasm9 (Figure 5) A total of 8 deaths were reported in BOLT, none of which were deemed related to treatment9 – 4 deaths occurred in patients with laBCC; 1 death occurred in the 200-mg arm, and 3 deaths occurred in the 800-mg arm9 – 4 deaths occurred in patients with mBCC; all occurred in the 800-mg arm9 Adverse Events Profile for laBCC and mBCC Combined At 30 months, the most common (>20% of patients) AEs associated with a once-daily 200-mg dose of sonidegib were muscle spasms (54%; 51% grades 1-2), alopecia (50%; all grades 1-2), dysgeusia (44%; all grades 1-2), and nausea (39%; 38% grades 1-2) Few grade 3-4 AEs were reported9 Increased creatine kinase (CK) and rhabdomyolysis were the most commonly reported serious AEs among all patients – Because there was no renal impairment, none of the cases of rhabdomyolysis were confirmed by an independent review and adjudication committee of experts on muscle toxicity – Rhabdomyolysis was defined as CK concentrations >10-fold higher than baseline + 1.5-fold increase in creatinine concentration in serum from baseline9 At the time of the 30-month analysis, >90% of patients in each arm had discontinued treatment9 (Table 2) AEs leading to treatment discontinuation in the 200-mg arm occurred in 29% of patients compared to 38% in the 800-mg arm9 More patients receiving sonidegib 200 mg QD were able to stay on treatment until disease progression compared fo in the 800-mg QD group9 CONCLUSIONS At the BOLT 30-month analysis, sonidegib treatment demonstrated long-term safety and tolerability, with no new safety concerns emerging in patients with either laBCC or those with mBCC Sonidegib 200 mg demonstrated a better benefit– risk profile compared with sonidegib 800 mg QD These data support the use of sonidegib 200 mg for the treatment of patients with laBCC or mBCC according to local treatment guidelines REFERENCES 1. Mohan SV, Chang ALS. Advanced basal cell carcinoma: epidemiology and therapeutic innovations. Curr Dermatol Rep. 2014;3(1):40-45. 2. Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol 2015;151(10):1081-1086. 3. Kish T, Corry L. Sonidegib (Odomzo) for the systemic treatment of adults with recurrent, locally advanced basal cell skin cancer. P T. 2016;41(5):322-325. 4. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-754. 5. Chen L, Aria AB, Silapunt S, Lee HH, Migden MR. Treatment of advanced basal cell carcinoma with sonidegib: perspective from the 30-month update of the BOLT trial. Future Oncol. 2017 Nov 9. doi: 10.2217/fon-2017-0457. [Epub ahead of print] 6. Burness CB. Sonidegib: first global approval. Drugs. 2015;75(13):1559-1566. 7. Migden MR, Guminski A, Gutzmer R. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716-728. 8. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Washington, DC: National Institutes of Health; May 28, 2009 (v4.03: June 14, 2010). NIH Publication No. 09-5410. Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_8.5x11.pdf. 9. Lear JT, Migden MR, Lewis KD, et al. Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. 2017 Aug 28. doi: 10.1111/ jdv.14542. [Epub ahead of print] ACKNOWLEDGMENTS The funding for this presentation was contributed by Sun Pharmaceutical Industries Ltd. Writing assistance was provided by Beverly E. Barton, PhD, and Nicola Donelan, PhD, of ScioScientific, LLC. DISCLOSURES Dr. Kudchadkar has participated on advisory boards, received research funding from Merck, consulting fees from Bristol-Myers Squibb, and received honoraria from Genentech, Inc., Novartis Pharmaceuticals Corporation, Sun Pharmaceutical Industries Ltd., and Eli Lilly & Company. Dr. Chang has received honoraria for participation on an advisory board for Genentech, Inc., and has served as an investigator and received grants from Genentech, Inc. and Novartis Pharmaceuticals Corporation. GLI1, human glioma-associated oncogene homolog 1; HH, Hedgehog; PTCH1, Patched-1; SMO, Smoothened. (Adapted from 5) Figure 1. Sonidegib Mechanism of Action • Binding of HH signaling ligand to PTCH1 leads to release of SMO inhibition • SMO activation causes GLI1 to cross the nuclear membrane, where it activates genes involved in tumorigenesis • Sonidegib inhibits HH pathway signaling via SMO antagonism OBJECTIVES Hedgehog pathway inhibitors are a relatively recent class of drugs Their long-term safety profile is not yet well characterized Safety was one of the key secondary endpoints from the BOLT clinical trial Adverse events (AEs) monitored at 30 months in laBCC and mBCC are reported here METHODS BOLT Study Design BOLT was a randomized, double-blind phase 2 clinical trial conducted in 58 centers across 12 countries7 (Figure 2) Adults enrolled had either histologically confirmed laBCC (not amenable to curative surgery or radiation) or had mBCC (where all other treatment options had been exhausted) Patients received either 200 mg or 800 mg of sonidegib once daily (Figure 2) Patient populationa: • laBCC (aggressive and nonaggressive subtypes) • mBCC 21 days Treatment until one of the following: • Disease progression • Unacceptable toxicity • Death • Discontinuation for any other reason Patient populationa: • laBCC (aggressive and nonaggressive subtypes) • mBCC Screening/ baseline Treatment Follow-Up Sur vival Patient population: • laBCC (aggressive and nonaggressive subtypes) • mBCC • Tumor assessments until disease progression • Information collected on other antineoplastic therapy received • Safety follow-up 30 days after last dose of study treatment Survival follow- up every 12 weeks until one of the following: • Death • Loss to follow-up • Withdrawal of consent • Final analysis Stratification and randomization (1:2) Sonidegib 800 mg QD ≤ Sonidegib 200 mg QD Figure 2. BOLT Study Design laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma; QD, once daily. Safety/Monitoring AEs Monitoring of AEs was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.038 AEs were assessed by central and investigator review from the first dose until 30 days after the last dose in patients who received at least one dose of sonidegib Muscle-related events were also assessed by an independent safety review and adjudication committee composed of three external experts Table 1. Patient Demographics and Disease History Sonidegib Dose (QD) 200 mg (n=79) 800 mg (n=151) Median age (range), years 67 (25-92) 65 (24-93) Male, % 61 64 Eastern Cooperative Oncology Group performance status, % 0 63 63 1 24 29 2 10 7 Unknown 3 1 Aggressive histological/cytological subtype for patients with laBCC based on randomization/stratification, % n=66 n=128 Aggressive subtypea 56 59 Nonaggressive subtypeb 44 41 Metastasis, % 18 15 Metastatic sites, % of total patients with metastasis Lung 71 52 Lymph nodesc 7 30 Bone 14 22 Otherd 21 30 Prior antineoplastic therapy, % Surgery 75 83 Radiotherapy 24 32 aIncludes micronodular, infiltrative, multifocal, basosquamous, and sclerosing histological subtypes. bIncludes nodular and superficial histological subtypes. cIncludes axillary, parotid, submandibular, supraclavicular, and other. dIncludes trunk, brain, head, liver, neck, and upper extremities. laBCC indicates locally advanced basal cell carcinoma; QD, once daily. Table 2. Patient Disposition Sonidegib Dose (QD) 200 mg (n=79) 800 mg (n=150) Analysis Primarya 30-Monthb Primarya 30-Monthb Median duration of exposure (range), months 8.9 (1.3-21.4) 11.0 (1.3-41.3) 6.5 (0.3-19.1) 6.6 (0.3-43.5) Treatment ongoing, % 49 8 31 6 Treatment discontinued, % 51 92 69 94 Primary reasons for discontinuation, % Adverse event Progressive diseasec Patient decisiond Physician decisiond Loss to follow-up Death Nonadherence Protocol deviation 20 19 6 4 1 0 0 0 29 37 10 13 3 1 0 0 32 4 19 7 3 3 2 1 38 15 22 9 3 3 3 1 aData cutoff: June 28, 2013; median follow-up was 13.9 months in both treatment arms combined. bData cutoff: July 10, 2015; median follow-up was 38.2 months in both treatment arms combined. cImproved tolerability of the 200-mg dose allowed more patients to stay on treatment until disease progression than with the 800-mg dose. dDiscontinuations due to patient or physician decision were primarily attributed to adverse events. QD, once daily. Figure 4. Adverse Events (AEs) Reported in ≥20% of laBCC Patients Treated with Sonidegib Figure 3. Adverse Events (AEs) Reported in ≥20% of All (laBCC and mBCC) Patients Treated with Sonidegib Figure 5. Adverse Events (AEs) Reported in ≥20% of mBCC Patients Treated with Sonidegib 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 Muscle spasms Alopecia Dysgeusia Nausea Weight decrease Fatigue Diarrhea Appetite decrease 11Vomiting MyalgiaAd ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith la BC C in 8 00 -m g ar m Patients, % 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 45 8 3Muscle spasms 56% 38 14Alopecia 52% 35 12Dysgeusia 47% 24 12 2Nausea 38% 18 8 6Weight decrease 32% 15 9 3 2Creatine kinase increase Creatine kinase increase 29% 17 11 2Fatigue 29% 23 3 2Diarrhea 27% All grades , % Ad ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith la BC C in 2 00 -m g ar m Patients, % 800 mg 200 mg 36 28 5 69% 35 26 61% 42 17 59% 31 12 2 46% 13 21 6 40% 13 11 10 5 39% 24 7 2 32% 17 7 24% 24 9 3 36% 20 5 2 27% 21 4 2 27% All grades , % 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 Muscle spasms Alopecia Dysgeusia Nausea Weight decrease Fatigue Diarrhea Appetite decrease 11Vomiting Myalgia Patients, % 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 44 8 3Muscle spasms 54% 37 13Alopecia 49% 32 13Dysgeusia 44% 27 11 1Nausea 39% 16 9 5Weight decrease 30% 15 9 4 3Creatine kinase increase Creatine kinase increase 30% 18 11 1Fatigue 30% 27 4 1Diarrhea 32% 10 11 1Appetite decrease 23% All grades , % All grades , % Ad ve rs e ev en ts in ≥ 20 % o f a ll pa tie nt s (la BC C + m BC C) Ad ve rs e ev en ts in ≥ 20 % o f a ll pa tie nt s (la BC C + m BC C) Patients, % 800 mg 200 mg 37 27 5 69% 35 23 58% 41 19 60% 31 13 3 47% 12 25 6 43% 12 12 9 4 37% 26 9 2 37% 15 9 24% 21 11 4 35% 20 6 2 28% 24 3 1 29% 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 Muscle spasms Alopecia Dysgeusia Nausea Weight decrease Fatigue Diarrhea Appetite decrease 11Vomiting MyalgiaAd ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith la BC C in 8 00 -m g ar m Patients, % 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 45 8 3Muscle spasms 56% 38 14Alopecia 52% 35 12Dysgeusia 47% 24 12 2Nausea 38% 18 8 6Weight decrease 32% 15 9 3 2Creatine kinase increase Creatine kinase increase 29% 17 11 2Fatigue 29% 23 3 2Diarrhea 27% All grades , % Ad ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith la BC C in 2 00 -m g ar m Patients, % 800 mg 200 mg 36 28 5 69% 35 26 61% 42 17 59% 31 12 2 46% 13 21 6 40% 13 11 10 5 39% 24 7 2 32% 17 7 24% 24 9 3 36% 20 5 2 27% 21 4 2 27% All grades , % 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 Muscle spasms Alopecia Dysgeusia Nausea Weight decrease Fatigue Diarrhea Appetite decrease 11Vomiting Myalgia Patients, % 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 44 8 3Muscle spasms 54% 37 13Alopecia 49% 32 13Dysgeusia 44% 27 11 1Nausea 39% 16 9 5Weight decrease 30% 15 9 4 3Creatine kinase increase Creatine kinase increase 30% 18 11 1Fatigue 30% 27 4 1Diarrhea 32% 10 11 1Appetite decrease 23% All grades , % All grades , % Ad ve rs e ev en ts in ≥ 20 % o f a ll pa tie nt s (la BC C + m BC C) Ad ve rs e ev en ts in ≥ 20 % o f a ll pa tie nt s (la BC C + m BC C) Patients, % 800 mg 200 mg 37 27 5 69% 35 23 58% 41 19 60% 31 13 3 47% 12 25 6 43% 12 12 9 4 37% 26 9 2 37% 15 9 24% 21 11 4 35% 20 6 2 28% 24 3 1 29% Ad ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith m BC C in 8 00 -m g ar m 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 43 8 8 8 46 48 8 8 8 Muscle spasms 46%38 39 39 8 46%38 54% Alopecia Dysgeusia 46% Nausea 38% Weight decrease 38% Creatine kinase increase 38%15 15 15 15 Fatigue 31% 23 23 23 15 Diarrhea 23%8 158 15 8 Appetite decrease 23%Myalgia Arthralgia 23% Ad ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith m BC C in 2 00 -m g ar m Patients, % 200 mg 35 35 30 31 17 17 17 9 9 9 0 10 20 30 40 50 60 700 80 Grade 1 Grade 2 Grade 3 Grade 4 4 4 179 4 17 4 4 4 Muscle spasms 74% 57% 26% Alopecia Dysgeusia 30% Nausea 61% Weight decrease 43% Creatine kinase increase 30% Fatigue 65% 22 22 22 Diarrhea 61% 13 Appetite decrease 35% Vomiting 39% Myalgia Arthralgia 22% Patients, % 800 mg 30 9 9 All grades , % All grades , % Ad ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith m BC C in 8 00 -m g ar m 0 10 20 30 40 50 60 70 Grade 1 Grade 2 Grade 3 Grade 4 43 8 8 8 46 48 8 8 8 Muscle spasms 46%38 39 39 8 46%38 54% Alopecia Dysgeusia 46% Nausea 38% Weight decrease 38% Creatine kinase increase 38%15 15 15 15 Fatigue 31% 23 23 23 15 Diarrhea 23%8 158 15 8 Appetite decrease 23%Myalgia Arthralgia 23% Ad ve rs e ev en ts in ≥ 20 % o f p at ie nt s w ith m BC C in 2 00 -m g ar m Patients, % 200 mg 35 35 30 31 17 17 17 9 9 9 0 10 20 30 40 50 60 700 80 Grade 1 Grade 2 Grade 3 Grade 4 4 4 179 4 17 4 4 4 Muscle spasms 74% 57% 26% Alopecia Dysgeusia 30% Nausea 61% Weight decrease 43% Creatine kinase increase 30% Fatigue 65% 22 22 22 Diarrhea 61% 13 Appetite decrease 35% Vomiting 39% Myalgia Arthralgia 22% Patients, % 800 mg 30 9 9 All grades , % All grades , % laBCC, locally advanced basal cell carcinoma, mBCC metastatic BCC. laBCC, locally advanced basal cell carcinoma. mBCC, metastatic basal cell carcinoma.