An exploratory open-label, investigator-initiated study to evaluate the efficacy and safety of combination sonidegib and buparlisib for advanced basal cell carcinomas

Abstract

To the Editor: Although smoothened inhibitors (SIs) are Food and Drug Administration approved for advanced basal cell carcinomas (aBCCs), over 50% of patients do not respond. 1 Sekulic A. Migden M.R. Basset-Seguin N. et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017; 17: 332 Crossref PubMed Scopus (222) Google Scholar , 2 Lear J.T. Migden M.R. Lewis K.D. 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. August, 28 2017; ([Epub ahead of print])https://doi.org/10.1111/jdv.14542 Crossref Scopus (121) Google Scholar Preclinical work in models of hedgehog-dependent tumors has revealed the importance of phosphoinositide-3-kinase (PI3K) in promoting SI resistance, 3 Gonnissen A. Isebaert S. Haustermans K. Targeting the hedgehog signaling pathway in cancer: beyond smoothened. Oncotarget. 2015; 6: 13899-13913 Crossref PubMed Scopus (149) Google Scholar , 4 Buonamici S. Williams J. Morrissey M. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010; 2: 51ra70 Crossref PubMed Scopus (388) Google Scholar , 5 Rajurkar M. De Jesus-Monge W.E. Driscoll D.R. et al. The activity of GLI transcription factors is essential for KRAS-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2012; 109: E1038-E1047 Crossref PubMed Scopus (105) Google Scholar , 6 Zhou J. Zhu G. Huang J. et al. Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: a novel potential therapeutic target. Cancer Lett. 2016; 370: 313-323 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar with concurrent smoothened and PI3K inhibition delaying SI resistance in medulloblastoma 4 Buonamici S. Williams J. Morrissey M. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010; 2: 51ra70 Crossref PubMed Scopus (388) Google Scholar (Supplemental Fig 1; available at http://www.jaad.org). 1 Sekulic A. Migden M.R. Basset-Seguin N. et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017; 17: 332 Crossref PubMed Scopus (222) Google Scholar , 3 Gonnissen A. Isebaert S. Haustermans K. Targeting the hedgehog signaling pathway in cancer: beyond smoothened. Oncotarget. 2015; 6: 13899-13913 Crossref PubMed Scopus (149) Google Scholar , 4 Buonamici S. Williams J. Morrissey M. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010; 2: 51ra70 Crossref PubMed Scopus (388) Google Scholar , 5 Rajurkar M. De Jesus-Monge W.E. Driscoll D.R. et al. The activity of GLI transcription factors is essential for KRAS-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2012; 109: E1038-E1047 Crossref PubMed Scopus (105) Google Scholar , 6 Zhou J. Zhu G. Huang J. et al. Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: a novel potential therapeutic target. Cancer Lett. 2016; 370: 313-323 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar , 7 Chang A.L.S. Oro A.E. Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch Dermatol. 2012; 148: 1324-1325 Crossref PubMed Scopus (150) Google Scholar Due to the lack of good treatment options available to SI-resistant aBCC patients, this open-label, single-arm, proof-of-concept study of combined hedgehog and PI3K inhibition on aBCCs was explored using sonidegib, an SI, and buparlisib, a pan-PI3K inhibitor.