Overall efficacy at 42 months • Clinically relevant objective response rates (ORRs) continued to be reported for patients receiving 200 mg/day of sonidegib at 42 months (Table 2) • At 42 months, the ORR (95% confidence interval) was 48.1% (36.7%–59.6%) for all 79 patients receiving 200 mg/d of sonidegib • Disease control rate exceeded 90% and further supports treatment benefit (Table 2) • Sustained duration was confirmed, with a median duration of response of 26.1 months (Table 2) Table 2. Efficacy outcomes per central review in patients with advanced BCC receiving sonidegib 200 mg daily IaBCC (n = 66) mBCC (n = 13) ORR, % (95% CI) 56.1 (43.3, 68.3) 7.7 (0.2, 36.0) CR, % (95% CI) 4.5 (0.9, 12.7) 0 (0.0, 24.7) DCR, % 90.9 92.3 DOR, median, months (95% CI) 26.1 (NE) 24.0 (NE) PFS, median, months (95% CI) 22.1 (NE) 13.1 (5.6, 33.1) TTR, median, months (95% CI) 4.0 (3.8, 5.6) 9.2 (NE) BCC, basal cell carcinoma; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; laBCC, locally advanced BCC; mBCC, metastatic BCC; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; TTR, time to tumor response. Overall safety/tolerability at 42 months • Median duration of sonidegib exposure was 11.0 months in the 200 mg/day group • Overall, 54 (68.4%), 34 (43.0%), and 19 (24.1%) patients were exposed to sonidegib 200 mg/day for ≥8, ≥12, and ≥20 months, respectively • The majority of AEs were grade 1−2 in severity • The most common all-grade AEs in patients receiving sonidegib 200 mg/day were muscle spasms (54.4%, n = 43), alopecia (49.4%, n = 39), dysgeusia (44.3%, n = 35), nausea (39.3%, n = 31), fatigue (33.0%, n = 26), diarrhea (31.7%, n = 25), weight decrease (30.5%, n = 24), and creatine kinase (CK) increase (30.4%, n = 24) (Figure 4) Figure 4. Adverse events reported in ≥30% of patients receiving 200 mg daily N = 79. AE, adverse event; CK, creatine kinase. BACKGROUND • Sonidegib—a hedgehog inhibitor (HHI) that selectively targets Smoothened1—is approved in the US, the EU, and Australia for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiation therapy1-4 — Sonidegib is also approved for the treatment of metastatic BCC (mBCC) in Switzerland and Australia3,4 • Through 42 months of the phase 2 BOLT (Basal Cell Carcinoma Outcomes with LDE225 [sonidegib] Treatment) trial (NCT01327053), sonidegib 200 mg/day demonstrated durable efficacy and consistent/manageable toxicity5-9 OBJECTIVES • Here, we report the incidence and impact of HHI class-effect adverse events (AEs) from the BOLT 42-month results METHODS • BOLT was a randomized, double-blind, phase 2 clinical trial conducted in 58 centers across 12 countries5 (Figure 1) Adverse events of special interest in patients with advanced basal cell carcinoma receiving sonidegib: Long-term 42-month results from the BOLT study Alexander Guminski,1,2 Nicholas Squittieri,3 John T Lear4 1Royal North Shore Hospital, St Leonards, NSW, Australia; 2University of Sydney, Sydney, Australia; 3Sun Pharmaceutical Industries, Inc., Princeton, NJ, USA; 4Manchester Academic Health Science Centre, University of Manchester, Manchester, UK Figure 1. BOLT study design aPatients previously treated with sonidegib or other HHI were excluded. bStratification was based on stage, disease histology for patients with laBCC (nonaggressive vs aggressive), and geographic region. cTreatment was continued until disease progression, unacceptable toxicity, death, study termination, or withdrawal of consent. AE, adverse event; BCC, basal cell carcinoma; BOLT, Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment; CR, complete response; DOR, duration of response; HHI, hedgehog inhibitor; laBCC, locally advanced BCC; mBCC, metastatic BCC; mRECIST, modified Response Evaluation Criteria in Solid Tumors; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q8W, every 8 weeks; Q12W, every 12 weeks; TTR, time to tumor response. • Safety/tolerability were assessed through monitoring and recording AEs; regular monitoring of hematology, clinical chemistry, and electrocardiograms; and routine monitoring of vital signs and physical condition — AEs were coded using the Medical Dictionary for Regulatory Activities terminology v19.0 and toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0312 — Muscle-related events were evaluated by an independent Safety Review and Adjudication Committee — AEs of special interest for HHI-class drugs included muscle-related events, alopecia, nausea and/or vomiting, dysgeusia, decreased appetite and/or weight loss, fatigue/lethargy, diarrhea, hypersensitivity, second primary malignancies, QT prolongation, lipase and amylase elevations, fractures, and cardiac disorders • Dose modifications were based on the worst grade of toxicity observed • Dose delays of ≤21 days and dose reductions were permitted for AEs suspected to be related to sonidegib • Data presented here are based on the US Food and Drug Administration-approved 200-mg dose at 42 months RESULTS • At baseline, 60.8% of the 79 patients receiving sonidegib 200 mg/day were male and had a median age of 67.0 years; the majority (83.5%) of patients had laBCC and 62.0% had ≥2 lesions (Table 1) Table 1. Baseline demographics and disease characteristics in patients receiving sonidegib 200 mg daily Sonidegib 200 mg (n = 79) Median age (range), years 67 (25–92) Male 48 (61) ECOG performance status 0 1 2 Unknown 50 (63) 19 (24) 8 (10) 2 (3) Stage laBCC mBCC 66 (84) 13 (16) Histologic/cytologic subtype Aggressivea Nonaggressiveb Undetermined 40 (51) 38 (48) 1 (1) Number of lesions 1 ≥2 30 (38) 49 (62) Metastasis Sites Lung Bone Axillary lymph node Trunk Otherc 14 (18) 10/14 (71) 2/14 (14) 1/14 (7) 1/14 (7) 3/14 (21) Prior antineoplastic therapy Surgery Radiotherapy 59 (75) 19 (24) Data presented as n (%) unless otherwise indicated. aIncludes micronodular, infiltrative, multifocal, basosquamous, and sclerosing histological subtypes. bIncludes nodular and superficial histological subtypes.cIncludes retro- orbital and left mandible, pelvic side wall and lung, and bilateral scalp. BCC, basal cell carcinoma; ECOG, Eastern Cooperative Oncology Group; laBCC, locally advanced BCC; mBCC, metastatic BCC. • Muscle-related events leading to discontinuation were grade 2 muscle spasms (n = 1), grade 3 muscle spasms (n = 3), and grade 3 blood CK increase (n = 1). The event requiring dose adjustment was muscle weakness • Fatigue and asthenia events leading to discontinuation were grade 3 asthenia (n = 1), grade 2 asthenia (n = 2), and grade 1/2 fatigue (n = 2); there were no lethargy events leading to discontinuation • Decreased appetite and weight loss events leading to discontinuation were grade 1/2 decreased appetite (n = 2) and grade 2 weight loss (n = 2) • No new second primary malignancies were reported at 42 months in patients receiving sonidegib 200 mg/day. The 2 events leading to discontinuation were grade 3 invasive papillary breast carcinoma and grade 2 prostate cancer; both were determined not related to the study drug CONCLUSIONS • Patients receiving sonidegib 200 mg/day experienced consistent and robust efficacy and manageable tolerability, with rare grade 3/4 AEs and discontinuations • Safety and tolerability of sonidegib 200 mg/day at 42 months was consistent with earlier data • AEs of special interest associated with HHI-class drugs were manageable and few led to discontinuations or dose reductions in patients receiving sonidegib 200 mg/day REFERENCES 1. Migden MR, et al. Lancet Oncol. 2015;16(6):716–28. 2. Odomzo (sonidegib) [package insert]. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.; 2017. 3. Australian Government Department of Health, ARTG 292262. 4. European Medicines Agency. Summary of Product Characteristics, WC500188762. 5. Swissmedic, Authorization Number 65065, 2015. 6. Migden MR, et al. J Clin Oncol. 2018; 36: Suppl abstr 9551. 7. Lear JT, et al. J Eur Acad Dermatol Venereol. 2018; 32 (3): 372–81. 8. Dummer R, et al. J Am Acad Dermatol. 2016; 75 (1): 113–25 e5. 9. Dummer R, et al. Br J Dermatol. 2019; 10.1111/bjd.18552. 10. Eisenhauer EA, et al. Eur J Cancer. 2009; 45 (2): 228–47. 11. World Health Organization. http://whqlibdoc.who.int/offset/WHO_OFFSET_48.pdf. 12. National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03. ACKNOWLEDGMENTS Medical writing and editorial support provided by Jennifer Meyering, RN, MS, CCMP, of AlphaBioCom, LLC, and funded by Sun Pharmaceutical Industries, Inc. DISCLOSURES AG has participated on advisory boards for Bristol-Myers Squibb, Pfizer, and Sanofi; received honoraria from Novartis Pharmaceuticals Corporation; and received travel support from Astellas and Bristol-Myers Squibb. NS is an employee of Sun Pharmaceutical Industries, Inc. JTL has served as a consultant for Novartis and received personal fees from Sun Pharmaceutical Industries, Inc. Figure 2. BOLT study endpoints BCC, basal cell carcinoma; BOLT, Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment; CR, complete response; DOR, duration of response; laBCC, locally advanced BCC; mBCC, metastatic BCC; mRECIST, modified Response Evaluation Criteria in Solid Tumors; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; TTR, time to tumor response. • Of all 79 patients receiving sonidegib 200 mg/day, 16.5% of patients (n = 13) had a dose reduction and 68.4% (n = 54) had ≥1 dose interruption; 44.3% (n = 35) had ≥2 dose interruptions • Most AEs of special interest were of grade <3. The most common grade 3/4 AEs of special interest (occurred in ≥5%) were increased CK (6.3%, n = 5); weight loss (5.1%, n = 4); lipase and amylase elevations (6.3%, n = 5); nausea and/or vomiting and their complications (5.1%, n = 4); and fatigue and asthenia (5.1%, n = 4) — The majority of high-grade AEs were reversible with interruptions in treatment — The time-to-first onset of grade 3/4 muscle-related events ranged from 1.9 to 11.0 months in patients receiving sonidegib 200 mg/day • Few AEs of special interest required discontinuation of sonidegib or reductions in dose (Table 3) Table 3. Adverse events of special interest leading to discontinuation or dose adjustments in patients receiving sonidegib 200 mg daily Adverse event Leading to discontinuation Requiring dose adjustment Muscle-related events 5 (6.3) 1 (1.3) Fatigue and asthenia 5 (6.3) 1 (1.3) Decreased appetite and/or weight loss 4 (5.1) 0 Dysgeusia 3 (3.8) 1 (1.3) Nausea and/or vomiting 3 (3.8) 0 Second primary malignancies 2 (2.5) 0 Increased lipase 2 (2.5) 3 (3.8) Alopecia 1 (1.3) 1 (1.3) Hypersensitivity 1 (1.3) 0 Fractures 1 (1.3) 0 Cardiac disorders 0 0 N = 79. Data are presented as n (%). • Eligible patients had either histologically confirmed laBCC (not amenable to curative surgery or radiation) or mBCC (for which all other treatment options had been exhausted) • Primary and secondary endpoints are summarized in Figure 2 ORR→ best overall confirmed response of CR or PR per central review according to mRECIST (laBCC) or RECIST v1.1 (mBCC)Primary DOR and CR rates per central review according to mRECIST (laBCC) or RECIST v1.1 (mBCC) Key Secondary • OS • Safety Other Secondary • ORR and DOR per investigator review • PFS and TTR per central and investigator review Figure 3. Tumor evaluation per mRECIST (laBCC) mRECIST is a composite multimodal evaluation used to integrate MRI according to RECIST v1.1,10 standard and annotated color photography using bidimensional WHO criteria,11 and histology in multiple biopsies based on lesion surface area in the complex setting of posttreatment scarring, fibrosis, and ill- defined lesion borders. Complete response is defined as a negative MRI, negative photo, and negative histology. Partial response is defined as ≥50% reduction in bidimensional format. BCC, basal cell carcinoma; laBCC, locally advanced BCC; mRECIST, modified Response Evaluation Criteria in Solid Tumors; MRI, magnetic resonance imaging; WHO, World Health Organization. + + Composite overall response per mRECIST MRI per RECIST v1.1 HistologyPhoto per WHO criteria • Tumor response was evaluated by investigator review and by central review using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for patients with laBCC and RECIST v1.1 for patients with mBCC (Figure 2 and Figure 3) Follow-up (after treatment discontinuation) • Tumor response Q8W during year 1 and then Q12W until progression • Subsequent anticancer therapy • AEs until 30 days after last dose of sonidegib • Survival follow-up Q12W until death, lost to follow-up, or withdrawn consent (and at time of final analysis) Endpoints Primary: ORR (central review) by mRECIST (laBCC) or RECIST v1.1 (mBCC) Key Secondary: DOR, CR (central review) Other Secondary: ORR, DOR (investigator review); PFS, TTR (central and investigator review); OS, safety Stratificationb Randomization (1:2) Sonidegib 200 mg dailyc Sonidegib 800 mg dailyc Patient populationa • laBCC (aggressive and nonaggressive) • mBCC Adverse events of special interest at 42 months • Incidence and severity of HHI class-effect AEs at 42 months were consistent with reports at 30 months • The most common all-grade AEs of special interest in patients receiving sonidegib 200 mg/day (N = 79) were all muscle-related events (68.4%); muscle spasms (54.4%); alopecia (49.4%); dysgeusia (44.3%); and nausea (39.2%) (Figure 5) Figure 5. Adverse events of special interest reported in ≥30% of patients receiving sonidegib 200 mg daily N = 79. AE, adverse event; CK, creatine kinase. 25.4 24.1 30.4 31.7 38.0 44.3 49.4 51.9 5.1 6.3 1.3 1.3 1.3 0 0 2.5 0 10 20 30 40 50 60 Weight decrease CK increase Diarrhea Fatigue Nausea Dysgeusia Alopecia Muscle spasms Grade <3 Grade 3-4 Patients reporting AEs (%) CK increased Weight decreased Diarrhea Fatigue Nausea Dysgeusia Alopecia Muscle spasm Patients reporting AEs (%) Grade 3–4 Grade 1–2 51.9 49.4 44.3 38.0 31.6 30.4 25.3 24.1 2.5 0 0 1.3 1.3 1.3 5.1 6.3 10 20 30 40 50 600 Presented at Fall Clinical Dermatology Conference for PAs & NPs 2020, April 3–5, Orlando, FL, USA