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 T Lear, M R Migden, K D Lewis, A L S Chang, A Guminski, R Gutzmer, L Dirix, P Combemale, A Stratigos, R Plummer, H Castro, T Yi, M Mone, J Zhou, U Trefzer, M Kaatz, C Loquai, R Kudchadkar, D Sellami, R Dummer, J T Lear, M R Migden, K D Lewis, A L S Chang, A Guminski, R Gutzmer, L Dirix, P Combemale, A Stratigos, R Plummer, H Castro, T Yi, M Mone, J Zhou, U Trefzer, M Kaatz, C Loquai, R Kudchadkar, D Sellami, R Dummer

Abstract

Background: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.

Objective: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses.

Methods: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.

Results: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).

Conclusion: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

© 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

Figures

Figure 1
Figure 1
Duration of response (DOR) in patients with locally advanced basal cell carcinoma (laBCC) and progression‐free survival (PFS) by central and investigator review in patients with laBCC or metastatic BCC (mBCC) treated with sonidegib 200 mg. (a) Kaplan–Meier plots of DOR in patients with laBCC who responded to treatment with sonidegib 200 mg per central (n = 37) and investigator (n = 47) review. (b) Kaplan–Meier plots of PFS in patients with laBCC (n = 66) and mBCC (n = 13) treated with sonidegib 200 mg per central and investigator review.
Figure 2
Figure 2
Overall survival (OS) in patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC) treated with sonidegib 200 mg. Kaplan–Meier plot of OS in patients with laBCC (n = 66) or mBCC (n = 13) treated with sonidegib 200 mg. NE, not estimable.
Figure 3
Figure 3
Adverse events (AEs), regardless of causality, reported in ≥20% of all patients treated with sonidegib, by treatment arm. The most common AEs reported in patients treated with sonidegib 200 mg (n = 79) or 800 mg (n = 150) assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.03.20 Reported AEs include those that occurred during treatment and within 30 days of treatment discontinuation. For a patient who had multiple occurrences of the same AE, the AE is reported only once at the highest severity rating. CK, creatine kinase; laBCC, locally advanced basal cell carcinoma; mBCC, metastatic BCC.

References

    1. Lear JT, Corner C, Dziewulski P, et al Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective. Br J Cancer 2014; 111: 1476–1481.
    1. Wong CS, Strange RC, Lear JT. Basal cell carcinoma. BMJ 2003; 327: 794–798.
    1. Madan V, Lear JT, Szeimies RM. Non‐melanoma skin cancer. Lancet 2010; 375: 673–685.
    1. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol 2010; 2: 237–250.
    1. Reifenberger J, Wolter M, Knobbe CB, et al Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005; 152: 43–51.
    1. Pan S, Wu X, Jiang J, et al Discovery of NVP‐LDE225, a potent and selective smoothened antagonist. ACS Med Chem Lett 2010; 1: 130–134.
    1. Rodon J, Tawbi HA, Thomas AL, et al A phase I, multicenter, open‐label, first‐in‐human, dose‐escalation study of the oral smoothened inhibitor sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res 2014; 20: 1900–1909.
    1. Migden MR, 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: 716–728.
    1. Dummer R, Guminski A, Gutzmer R, et al The 12‐month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): a phase II, randomized, double‐blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol 2016; 75: 113–125.
    1. Lorusso PM, Rudin CM, Reddy JC, et al Phase I trial of hedgehog pathway inhibitor GDC‐0449 in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 2011; 17: 2502–2511.
    1. Sekulic A, Migden MR, Oro AE, et al Efficacy and safety of vismodegib in advanced basal‐cell carcinoma. N Engl J Med 2012; 366: 2171–2179.
    1. Sekulic A, Migden MR, Lewis K, et al Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12‐month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol 2015; 72: 1021–1026. e8
    1. Sekulic A, Migden M, Basset‐Seguin N, et al Long‐term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update (30‐month) of the pivotal ERIVANCE BCC study. J Clin Oncol 2014; 32: 9013.
    1. Novartis Pharmaceuticals Corporation . Odomzo (sonidegib) Prescribing Information. 2016. URL (last accessed: 28 September 2016).
    1. European Medicines Agency: Committee for Medicinal Products for Human Use . CHMP summary of opinion for Odomzo. 2015. URL (last accessed: 28 September 2016).
    1. Swissmedic authorized medicines . Swissmedic authorization of Odomzo. 2015. URL (last accessed: 28 September 2016).
    1. Australian Government . Department of Health and Ageing: Therapeutic Goods Administration. Australian public assessment report for Odomzo, 2015.
    1. World Health Organization . WHO Handbook for Reporting Results for Cancer Treatment. World Health Organization, Geneva, 1979.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247.
    1. US Department of Health and Human Services . National Cancer Institute. Common terminology criteria for adverse events (CTCAE) version 4.03, 2010. URL (last accessed: 28 September 2016)
    1. American Cancer Society . Basal and squamous cell skin cancers, 2016. URL (last accessed: 28 September 2016).
    1. National Cancer Institute . Skin cancer treatment (PDQ®)–health professional version, 2016. URL (last accessed: 28 September 2016).
    1. von Domarus H, Stevens PJ. Metastatic basal cell carcinoma. Report of five cases and review of 170 cases in the literature. J Am Acad Dermatol 1984; 10: 1043–1060.
    1. Raszewski RL, Guyuron B. Long‐term survival following nodal metastases from basal cell carcinoma. Ann Plast Surg 1990; 24: 170–175.
    1. Danial C, Lingala B, Balise R, et al Markedly improved overall survival in 10 consecutive patients with metastatic basal cell carcinoma. Br J Dermatol 2013; 169: 673–676.
    1. Lorusso PM, Jimeno A, Dy G, et al Pharmacokinetic dose‐scheduling study of hedgehog pathway inhibitor vismodegib (GDC‐0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res 2011; 17: 5774–5782.
    1. Genentech, Inc . Erivedge (vismodegib) prescribing information, 2012. URL (last accessed: 28 September 2016).
    1. Zhou J, Quinlan M, Hurh E, Sellami D. Exposure‐response analysis of sonidegib (LDE225), an oral inhibitor of the hedgehog signaling pathway, for effectiveness and safety in patients with advanced solid tumors. J Clin Pharmacol 2016; 56: 1406–1415.
    1. Goel V, Hurh E, Stein A, et al Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors. Cancer Chemother Phramacol 2016; 77: 745–755.
    1. Basset‐Seguin N, Hauschild A, Grob JJ, et al Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre‐planned interim analysis of an international, open‐label trial. Lancet Oncol 2015; 16: 729–736.
    1. Chang AL, Solomon JA, Hainsworth JD, et al Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol 2013; 70: 60–69.
    1. Gajjar AJ, Gururangan S, Qaddoumi IA, et al A prospective phase II study to determine the efficacy of GDC 0449 (vismodegib) in adults with recurrent medulloblastoma (MB): a Pediatric Brain Tumor Consortium study (PBTC 25B) [abstract]. J Clin Oncol 2013; 31: 2035.
    1. Goldman J, Eckhardt SG, Borad MJ, et al Phase 1 Dose‐escalation trial of the oral investigational hedgehog signaling pathway inhibitor TAK‐441 in patients with advanced solid tumors. Clin Cancer Res 2014; 21: 1002–1009.
    1. Italiano A, Le Cesne A, Bellera C, et al GDC‐0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single‐Arm Phase II Collaborative Study. Ann Oncol 2013; 24: 2922–2926.
    1. Jimeno A, Weiss GJ, Miller WH Jr, et al Phase I study of the hedgehog pathway inhibitor IPI‐926 in adult patients with solid tumors. Clin Cancer Res 2013; 19: 2766–2774.
    1. Siu LL, Papadopoulos K, Alberts SR, et al A first‐in‐human, phase I study of an oral hedgehog (HH) pathway antagonist, BMS‐833923 (XL139), in subjects with advanced or metastatic solid tumors [abstract]. J Clin Oncol 2010; 28: 2501.
    1. Tang JY, Mackay‐Wiggan JM, Aszterbaum M, et al Inhibiting the hedgehog pathway in patients with the basal‐cell nevus syndrome. N Engl J Med 2012; 366: 2180–2188.
    1. Wagner AJ, Messersmith WA, Shaik MN, et al A phase I study of PF‐04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 1044–1051.
    1. Ally MS, Aasi S, Wysong A, et al An investigator‐initiated open‐label clinical trial of vismodegib as a neoadjuvant to surgery for high‐risk basal cell carcinoma. J Am Acad Dermatol 2014; 71: 904–911.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever