Efficacy of sonidegib in histologic subtypes of advanced basal cell carcinoma: Results from the final analysis of the randomized phase 2 Basal Cell Carcinoma Outcomes With LDE225 Treatment (BOLT) trial at 42 months
Authors: Reinhard Dummer, John T. Lear, Alex Guminski, Liang Joo Leow, Nicholas Squittieri, Michael Migden
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Basal cell carcinoma (BCC) is the most common cancer worldwide.1Marzuka A.G. Book S.E. Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management.Yale J Biol Med. 2015; 88: 167-179PubMed Google Scholar Major histologic subtypes of BCC include nonaggressive (nodular and superficial) and aggressive forms (morpheaform, infiltrative, micronodular, and basosquamous).1Marzuka A.G. Book S.E. Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management.Yale J Biol Med. 2015; 88: 167-179PubMed Google Scholar Locally advanced BCC and metastatic BCC can cause extensive tissue destruction, limiting effective treatment options.1Marzuka A.G. Book S.E. Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management.Yale J Biol Med. 2015; 88: 167-179PubMed Google Scholar Sonidegib, a Hedgehog pathway inhibitor selectively targeting Smoothened, is approved in the United States for the treatment of adult patients with recurrent locally advanced BCC after surgery or radiation therapy or those who are not candidates for surgery or radiation therapy.2Odomzo (sonidegib capsules). Full prescribing information. Sun Pharmaceutical Industries, Inc., Cranbury, NJ.Google Scholar Here we examine the long-term efficacy of sonidegib 200 and 800 mg once daily across histologic subtypes of BCC at 42 months. Basal Cell Carcinoma Outcomes With LDE225 Treatment (BOLT; NCT01327053) is an international, randomized, double-blind, phase 2 study with patients randomized 1:2 to sonidegib 200 or 800 mg once daily. The primary endpoint was objective response rate (ORR) by central review. Key secondary endpoints included duration of response, time to tumor response, progression-free survival, and overall survival. Tumor evaluations and ORR were assessed per BCC-modified Response Criteria In Solid Tumors (mRECIST) for locally advanced BCC and RECIST version 1.1 for metastatic BCC.3Migden M.R. Guminski A. Gutzmer R. et al.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: 716-728Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Tumor evaluations were conducted at baseline, weeks 5 and 9, every 8 weeks during the first year, and every 12 weeks thereafter. Overall, 230 patients enrolled; 36 (15.7%) with metastatic BCC and 194 (84.3%) with locally advanced BCC (aggressive, 112 of 194 [57.7%]; nonaggressive, 82 of 194 [42.3%]). The ORRs at 42 months for patients with aggressive and nonaggressive locally advanced BCC were 59.5% (22 of 37) and 51.7% (15 of 29) for 200 mg and 45.3% (34 of 75) and 47.2% (25 of 53) for 800 mg, respectively. Among patients with metastatic BCC, ORRs were 7.7% (200 mg) and 17.4% (800 mg). Highest ORRs were in infiltrative (200 mg, 51.6% [16 of 31]; 800 mg, 36.8% [21 of 57]) and morpheaform (200 mg, 50.0% [3 of 6]; 800 mg, 75.0% [6 of 8]) for aggressive subtypes. Approximately 50% of patients with nonaggressive subtypes in each group achieved objective response (Table I). Median duration of response for patients with nodular subtype was not estimable and was 15.7 months (95% confidence interval, 7.4-26.4 months) for 200 mg and 800 mg, respectively (Table II).Table IBest overall response in patients with aggressive and nonaggressive subtypes of advanced basal cell carcinoma treated with sonidegibBest overall response∗Data are shown as number (%).Sonidegib 200 mgSonidegib 800 mgAggressiveNonaggressiveAggressiveNonaggressiveInfiltrative (n = 31)Morpheaform (n = 6)Nodular (n = 28)Superficial (n = 10)Infiltrative (n = 57)Morpheaform (n = 8)Nodular (n = 42)Superficial (n = 25)Complete response1 (3.2)02 (7.1)001 (12.5)01 (4.0)Partial response15 (48.4)3 (50.0)11 (39.3)5 (50.0)21 (36.8)5 (62.5)20 (47.6)12 (48.0)Stable disease12 (38.7)2 (33.3)12 (42.9)5 (50.0)24 (42.1)2 (25.0)17 (40.5)8 (32.0)Progressive disease1 (3.2)0001 (1.8)000Unknown2 (6.5)1 (16.7)3 (10.7)011 (19.3)05 (11.9)4 (16.0)Overall response rate†Calculated as complete response + partial response.16 (51.6)3 (50.0)13 (46.4)5 (50.0)21 (36.8)6 (75.0)20 (47.6)13 (52.0)∗ Data are shown as number (%).† Calculated as complete response + partial response. Open table in a new tab Table IIResponse characteristics in patients with histologic subtypes of advanced basal cell carcinomaCharacteristic∗Data are presented as the median (95% confidence interval).Sonidegib 200 mgSonidegib 800 mgTTR, mo Infiltrative4.7 (1.9-6.6)3.7 (1.9-5.5) Morpheaform3.7 (1.2-5.7)3.7 (1.3-5.6) Nodular3.9 (2.1-4.2)3.8 (1.9-7.4) Superficial5.6 (1.9-9.3)3.9 (1.8-5.6)DOR, mo Infiltrative12.9 (NE)23.7 (NE) MorpheaformNENE NodularNE15.7 (7.4-26.4) SuperficialNE29.6 (NE)PFS, mo Infiltrative16.9 (11.0-39.6)29.3 (NE) MorpheaformNE18.3 (NE) Nodular24.7 (NE)19.2 (13.2-30.5) SuperficialNE24.9 (NE)DOR, Duration of response; NE, not estimable; PFS, progression-free survival; TTR, time to tumor response.∗ Data are presented as the median (95% confidence interval). Open table in a new tab DOR, Duration of response; NE, not estimable; PFS, progression-free survival; TTR, time to tumor response. Patients with infiltrative locally advanced BCC receiving 800 mg had a longer median progression-free survival but lower ORR vs patients receiving 200 mg, highlighting that this analysis was underpowered to determine differences between treatment groups within a histologic subtype. Subtypes with more enrolled patients generally demonstrated ORRs similar to those observed in the entire population, suggesting a consistent response to sonidegib across histologic subtypes. Comparably, BCC histopathologic subtype did not appear to influence overall tumor response to vismodegib over 12 to 24 weeks.4Fosko S.W. Chu M.B. Armbrecht E. et al.Efficacy, rate of tumor response, and safety of a short course (12-24 weeks) of oral vismodegib in various histologic subtypes (infiltrative, nodular, and superficial) of high-risk or locally advanced basal cell carcinoma, in an open-label, prospective case series clinical trial.J Am Acad Dermatol. 2020; 82: 946-954Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Limitations of this study include the small patient sample size and the exclusion of patients with recurrent disease previously treated with a Hedgehog inhibitor. The 42-month results from the BOLT study demonstrate long-term positive responses for patients with aggressive and nonaggressive histologic subtypes of advanced BCC. These results are similar to those at 6 and 30 months.3Migden M.R. Guminski A. Gutzmer R. et al.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: 716-728Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar,5Lear J. Migden M.R. Lewis K. 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. 2018; 32: 372-381Crossref PubMed Scopus (92) Google Scholar Future investigations may clarify whether differences within subtypes remain consistent in larger populations. The authors thank the patients and their families; the study investigators, their clinical teams, and the study site staff; and the members of the study committees. The authors also thank the Novartis BOLT clinical study team, Yi Wu of Novartis for statistical support, the independent data monitoring committee (Mark R. Pittelkow, Jürgen C. Becker, and Stephen L. George), the efficacy independent review (Vernon K. Sondak, James Grichnik, and Lawrence Schwartz), and the muscle safety review and adjudication committee (Robert S. Rosenson, Vinay Chaudhry, and Paul D. Thompson). Medical writing and editorial assistance were provided by Leila Strickland, PhD; and Sherri Damlo, BA, of MedThink SciCom; and Zehra Gundogan, VMD, of AlphaBioCom, LLC, under the direction of the authors and funded by Sun Pharmaceutical Industries, Inc. They have nothing to disclose. Response to "Efficacy of sonidegib in histologic subtypes of advanced basal cell carcinoma: Results from the final analysis of the randomized phase 2 Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT) trial at 42 months"Journal of the American Academy of DermatologyVol. 84Issue 6PreviewTo the Editor: Basal cell carcinoma (BCC) constitutes approximately 80% of nonmelanoma skin cancers. Tumor size, location, histologic characteristics, margins, and recurrence rates are the most commonly used prognostic factors to classify BCCs. The most common histologic subtypes of BCC are the nonaggressive ones (nodular and superficial), followed by morpheaform, infiltrative, micronodular, and basosquamous, which are considered to be the most aggressive forms.1,2 Although surgical excision is the treatment of choice for the majority of BCCs, alternative treatments using targeted therapy to inhibit the Hedgehog signaling pathway have been recently developed to treat invasive forms. Full-Text PDF