Biochemistry laboratory shift based on common terminology criteria in patients with advanced basal cell carcinoma receiving sonidegib 200 mg daily: Results from the 42-month BOLT study Alexander Guminski1,2, Peter Foley3,4,5, Jean-Jacques Grob6, Caroline Robert7, Ralf Gutzmer8, Nicholas Squittieri9, Felix Kiecker10 1Royal North Shore Hospital, Sydney, Australia; 2The University of Sydney, Sydney, Australia; 3Department of Dermatology, St Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia; 4The University of Melbourne, Parkville, Victoria, Australia; 5Skin Health Institute Inc., Carlton, Victoria, Australia; 6Department of Dermatology and Oncology, University of Aix-Marseille, Timone Hospital, Marseille, France; 7Department of Dermatology, Institut Gustave Roussy and Paris-Saclay University, Villejuif, France; 8University Clinic for Dermatology, Venereology, Allergology and Phlebology, Johannes Wesling Clinic Minden, Minden, Germany; 9Sun Pharmaceutical Industries, Inc., Princeton, NJ, USA; 10Department of Dermatology, Venereology, and Allergology, Charité Universitätsmedizin Berlin, Edmund-Lesser-Haus, Berlin, Germany BACKGROUND • Hedgehog inhibitors were developed to block aberrant Hedgehog signaling found in most sporadic basal cell carcinomas (BCCs); inhibition of the Hedgehog pathway is among the limited treatment options available for patients with advanced BCC1,2 • Sonidegib is a Hedgehog inhibitor that selectively targets Smoothened3 and is approved in the US, the EU, Switzerland, and Australia for the treatment of adult patients with locally advanced BCC (laBCC) not amenable to curative surgery or radiation therapy3–6 — Sonidegib is also approved to treat metastatic BCC (mBCC) in Switzerland and Australia5,6 • Through 42 months of the Phase 2 BOLT (Basal Cell Carcinoma Outcomes with LDE225 [sonidegib] Treatment trial (NCT01327053), sonidegib 200 mg daily demonstrated durable efficacy and consistent/ manageable toxicity7–10 • Evaluation of clinical biochemistry in patients with advanced BCC provides valuable information on the tolerability and safety of sonidegib OBJECTIVE • To characterize changes in biochemistry laboratory values in patients receiving sonidegib 200 mg daily through 42 months of treatment for advanced BCC METHODS Study design • BOLT was a randomized, double-blind, Phase 2 clinical trial conducted in 58 centers across 12 countries10 • Eligible patients had histologically confirmed laBCC or mBCC and were randomized 1:2 to receive sonidegib 200 or 800 mg orally daily, respectively (Figure 1) Figure 1. BOLT study design Patient population* • laBCC (aggressive and nonaggressive) • mBCC Sonidegib 200 mg daily Treatment Sonidegib 800 mg daily Stratification† Randomization (1:2) Treatment was continued until disease progression, unacceptable toxicity, death, study termination, or withdrawal of consent 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) *Patients previously treated with sonidegib or other HHI were excluded. †Stratification was based on stage, disease histology for patients with laBCC (nonaggressive vs aggressive), and geographic region. AE, adverse event; BCC, basal cell carcinoma; BOLT, Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment; HHI, Hedgehog inhibitor; laBCC, locally advanced BCC; mBCC, metastatic BCC; Q8W, every 8 weeks; Q12W, every 12 weeks. Assessments • The primary efficacy endpoint was objective response rate (ORR) per central review (Figure 2) • ORR was defined as the proportion of patients with a confirmed best overall response (determined based on consecutive assessments ≥4 weeks apart) of complete response or partial response Figure 2. BOLT study endpoints •OS •Safety •ORR and DOR per investigator review •PFS and TTR per central review Other secondary DOR and CR rates per central review according to mRECIST (laBCC) or RECIST v1.1 (mBCC) Key secondary ORR  best overall confirmed response of CR or PR per central review according to mRECIST (laBCC) or RECIST v1.1 (mBCC) Primary 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 RECIST; ORR, objective response rate; OS, overall survival; PFS, progression- free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to tumor response. • Tumor response was evaluated by central review using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for patients with laBCC and RECIST v1.1 for patients with mBCC Biochemistry assessments • Clinical biochemistry assessments were ideally performed in fasted patients at screening, biweekly for 14 weeks, then every 4 weeks until Week 77, and then as clinically indicated until end of treatment — Assessments included alanine aminotransferase (ALT), albumin, alkaline phosphatase, amylase, aspartate aminotransferase (AST), total bilirubin, total calcium, cholesterol, plasma and serum creatine kinase (CK), creatinine, glucose, lipase, magnesium, phosphorus, potassium, and sodium • Biochemistry evaluations were performed by a central laboratory until Week 182; after this, assessments were conducted locally • Abnormal laboratory values constituted adverse events (AEs) if they fulfilled ≥1 of the following criteria: — Induced clinical signs or symptoms — Considered clinically significant — Required concomitant therapy or procedures — Required changes in study treatment Safety assessments • Safety assessments included AE monitoring and recording until 30 days after the last dose through regular monitoring of hematology, clinical chemistry, electrocardiograms, 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 v4.0311 RESULTS Patient demographics and baseline disease characteristics • At baseline, 48 (60.8%) patients receiving sonidegib 200 mg daily (n = 79) were male; the median age of patients in this study was 67 years (Table 1) Table 1. Baseline demographics and disease characteristics in patients receiving sonidegib 200 mg daily Sonidegib 200 mg (n = 79) Age, years, mean (SD) 65.6 (15.7) Age, years, median (range) 67 (25–92) Sex, male 48 (60.8) ECOG performance status 0 50 (63.3) 1 19 (24.1) 2 8 (10.1) Unknown 2 (2.5) Stage laBCC 66 (83.5) mBCC 13 (16.5) Histologic/cytologic subtype Aggressive* 40 (50.6) Nonaggressive† 38 (48.1) Undetermined 1 (1.3) Number of lesions 0 0 1 30 (38.0) ≥2 49 (62.0) Metastasis 14 (17.7) Metastatic site Lung 10 (12.7) Lymph nodes‡ 1 (1.3) Bone 2 (2.5) Other§ 4 (5.1) Prior antineoplastic therapy Surgery 59 (74.7) Radiotherapy 19 (24.1) Data presented as n (%) unless otherwise indicated. *Includes micronodular, infiltrative, multifocal, basosquamous, and sclerosing histological subtypes. †Includes nodular and superficial histological subtypes. ‡Includes axillary, parotid, submandibular, supraclavicular, and other. §Includes trunk, brain, head, liver, neck, and upper extremities. BCC, basal cell carcinoma; ECOG, Eastern Cooperative Oncology Group; laBCC, locally advanced BCC; mBCC, metastatic BCC; SD, standard deviation. • At 42 months, ORRs (95% confidence interval) in patients with laBCC (n = 66) and mBCC (n = 13) receiving sonidegib 200 mg were 56.1% (43.3%–68.3%) and 7.7% (0.2%–36.0%), respectively; disease control rate (summed complete response, partial response, and stable disease rates) exceeded 90% in all patients Biochemistry assessments • Through 42 months of treatment with sonidegib 200 mg, most biochemistry laboratory values had shifts ≤Grade 2, with the majority being ≤Grade 1 (Figure 3) • Observed Grade 3 shifts included elevations in ALT, amylase, AST, bilirubin, plasma CK, serum CK, glucose, lipase, and potassium; 1 patient developed hyponatremia (Table 2) • Grade 4 shifts were minimal and included elevations in AST, serum CK, and lipase (Table 2) Figure 3A. Distribution of biochemistry shifts for enzyme, protein, and lipid parameters in patients receiving sonidegib 200 mg daily* ALT AST ALP Albumin Amylase Bilirubin Cholesterol Serum CK‡ Creatinine Lipase 0 20 40 60 80 100 P at ie nt s, % † WNL Grade 1 Grade 2 Grade 3 Grade 4 7.6 79.7 16.5 3.8 94.9 79.7 19.0 83.5 11.4 3.8 79.7 16.5 91.1 6.3 29.1 62.0 8.9 39.2 43.0 10.1 5.1 89.9 55.7 22.8 8.9 11.4 *n = 79. †Values <3.8% are not shown within corresponding bars. ‡Values for plasma CK were not included, as 86.1% of data values were missing for this parameter. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; WNL, within normal limits. Figure 3B. Distribution of biochemistry shifts for glucose and electrolyte parameters in patients receiving sonidegib 200 mg daily* WNL Grade 1 Grade 2 Grade 3 Grade 4 Hyper Hypo Hyper Hypo Hyper Hypo Hyper Hypo Hyper Hypo PhosphateCalciumGlucose Magnesium Potassium Sodium 77.2 22.8 82.3 16.5 49.4 39.2 7.6 78.5 20.3 98.7 69.6 30.4 81.0 6.3 12.7 82.3 13.9 3.8 94.9 5.1 83.5 12.7 3.8 91.1 7.6 3.8 Hypo 0 20 40 60 80 100 P at ie nt s, % † *n = 79. †Values <3.8% are not shown within corresponding bars. WNL, within normal limits. Table 2. Distribution of biochemistry shifts for parameters with Grade 3 or 4 shifts in patients receiving sonidegib 200 mg daily* Within normal limits Grade 1 Grade 2 Grade 3 Grade 4 ALT 63 (79.7) 13 (16.5) 0 3 (3.8) 0 Amylase 66 (83.5) 9 (11.4) 3 (3.8) 1 (1.3) 0 AST 63 (79.7) 13 (16.5) 0 2 (2.5) 1 (1.3) Bilirubin 72 (91.1) 5 (6.3) 1 (1.3) 1 (1.3) 0 Plasma CK 8 (10.1) 1 (1.3) 1 (1.3) 1 (1.3) 0 Serum CK 31 (39.2) 34 (43.0) 8 (10.1) 4 (5.1) 2 (2.5) Hyperglycemia 39 (49.4) 31 (39.2) 6 (7.6) 3 (3.8) 0 Lipase 44 (55.7) 18 (22.8) 7 (8.9) 9 (11.4) 1 (1.3) Hyperkalemia 65 (82.3) 0 11 (13.9) 3 (3.8) 0 Hyponatremia 72 (91.1) 6 (7.6) 0 1 (1.3) 0 All data presented as n (%). *n = 79. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase. Safety and tolerability at 42 months • The majority of AEs were Grade 1–2 in severity • The most common all-grade AEs in patients receiving sonidegib 200 mg daily were muscle spasms (54.4%), alopecia (49.4%), and dysgeusia (44.3%; Figure 4) Figure 4. Adverse events reported in ≥20% of patients receiving sonidegib 200 mg daily Percent of patients Diarrhea Fatigue Nausea Dysgeusia Alopecia Muscle spasm Decreased appetite CK increased Weight decreased 0 20 40 60 22.8 30.4 30.4 31.6 32.9 39.2 44.3 49.4 54.4 21.5 24.1 25.3 30.4 31.6 38.0 44.3 49.4 51.9 Grade 1–2 Grade 3–4 CK, creatine kinase. CONCLUSIONS • Through 42 months of treatment with sonidegib 200 mg daily, most patients experienced no biochemistry changes or Grade 1 biochemistry shifts • Overall safety findings at 42 months were consistent with observations at 30 months9 REFERENCES 1. Cortes JE, et al. Cancer Treat Rev. 2019;76:41–50. 2. Kim JYS, et al. J Am Acad Dermatol. 2018;78(3):540–59. 3. Odomzo (sonidegib capsules). Full Prescribing Information. Sun Pharmaceutical Industries, Inc., Cranbury, NJ, USA. 4. European Medicines Agency. Summary of Product Characteristics, WC500188762. http://www. ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002839/WC500192970. pdf. 5. Swissmedic, Authorization Number 65065, 2015. https://www.swissmedic.ch/swissmedic/de/home/ humanarzneimittel/authorisations/new-medicines/odomzo--200mg--kapseln--sonidegibum-.html. 6. Australian Government Department of Health, ARTG 292262. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/ pdf?OpenAgent&id=CP-2017-PI-02511-1&d=2018030216114622483. 7. Dummer R, et al. Br J Dermatol. 2020;182(6):1369–78. 8. Dummer R, et al. J Am Acad Dermatol. 2016;75(1):113–25.e115. 9. Lear JT, et al. J Eur Acad Dermatol Venereol. 2018;32(3):372–81. 10. Migden MR, et al. Lancet Oncol. 2015;16(6):716–28. 11. Health UDo, Services H. Common terminology criteria for adverse events (CTCAE) version 4.0. National Institutes of Health, National Cancer Institute. 2009;4(03). ACKNOWLEDGEMENTS Medical writing and editorial support were provided by Alex Milliken, PhD, of AlphaBioCom, LLC, and funded by Sun Pharma. DISCLOSURES AG participated in advisory boards for Bristol-Myers Squibb, Pfizer, and Sanofi; received honoraria from Novartis; and received travel support from Astellas, Bristol-Myers Squibb, and Sun Pharma. PF participated in clinical trials (investigator), served on an advisory board, served as a consultant, received speaker’s bureau fees/honoraria, and/or received research and/or travel grants from AbbVie, Akaal, Amgen, Arcutis, Aslan, AstraZeneca, Bristol- Myers Squibb, Boehringer Ingelheim, Botanix, Celgene, Celtaxsys, CSL, Cutanea, Dermira, Eli Lilly, Galderma, Geneseq, Genetech, GSK, Hexima, Janssen, LEO, Mayne Pharma, MedImmune, Merck; Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Reistone, Roche, Sanofi, Sun Pharma, UCB Pharma, and Valeant. J-JG has received personal fees from Amgen, Bristol-Myers Squibb, Merck/Pfizer, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche. CR has received consulting fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi. RG serves as consultant to Almirall, Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi Genzyme, Sun Pharma, and 4SC; has received travel grants and honoraria for lectures from Almirall, Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sun Pharma; and has received research funding from Amgen, Johnson & Johnson, Merck Serono, and Novartis. NS is an employee of Sun Pharmaceutical Industries, Inc. FK reports grants and personal fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi.