Advanced basal cell carcinoma, the hedgehog pathway, and treatment options – role of smoothened inhibitors

Figures & data

Table 1 Summary of clinical trials with hedgehog pathway inhibitors in basal cell carcinoma

Trial phase	Drug	Drug dose	Primary endpoint/clinical intent	n	BCC status/stage	BCC tumor shrinkage/response	Median duration of response	Median PFS/Median OS	Discontinued for AEs
I^Citation72,Citation73	Vismodegib (GDC-0449)	Dose escalation/expansion: 150–540 mg/D	Safety and PK-PD/palliation	68 BCC cohort: 33	Unresectable laBCC (n=15), mBCC (n=18)	Total BCC RR: 58% (19/33)	12.8 mo and ongoing	Not reported	1 withdrawal
						SD: 33%
						–laBCC RR: 60% (2 CRs)
						SD: 27%
						–mBCC RR: 50%
						SD: 39%
II-ERIVANCE^Citation76	Vismodegib (GDC-0449)	150 mg/D	Independently assessed RR (IARR)/palliation	104 (96 eligible for analysis)	Unresectable laBCC (n=63), mBCC (n=33)	IARR:	Independent	laBCC: 9.5 mo/NM	13 (12%)
						–laBCC RR: 43% (13 CRs)	assess:	mBCC: 9.5 mo/NM
						SD: 38%	laBCC: 7.6 mo
						–mBCC RR: 30%	mBCC: 7.6 mo
						SD: 64%	INV assess:
						INV RR: –laBCC RR: 60% (13 CRs)	laBCC: 7.6 mo
						SD: 24%	mBCC: 12.9 mo
						–mBCC RR: 45%
						SD: 45%
Final update at 30 mo^Citation77						INV RR: –laBCC RR: 60.3%	INV assess:	laBCC: 12.9 mo/NR	23 (22.1%)
						–mBCC 48.5%	laBCC: 26.2 mo	mBCC: 9.3 mo/33.4 mo
							mBCC: 14.8 mo
EAP^Citation79	Vismodegib (GDC-0449)	150 mg/D	Efficacy, safety, and access/palliation	120	Unresectable laBCC (n=62), mBCC (n=58)	laBCC RR: 46.4% (6 CRs)	Not reported	Not reported	7
						SD: 48.2%
						mBCC RR: 30.8% (2 CRs)
						SD: 51.3%
Global safety study-STEVIE^Citation80	Vismodegib (GDC-0449)	150 mg/D	Safety/palliation	300	Unresectable laBCC (n=278), mBCC (n=22)	Third interim analysis (ongoing)-	Not reported	Not reported	35 (11.7%)
						RR: 57.3% (44 CRs)
						SD: 39%
I^Citation87	Sonedegib (LDE225)	Dose escalation/expansion: 100–3,000 mg/D and 250–750 mg bid	Safety and PK-PD/palliation	103 BCC cohort: 16	Unresectable laBCC, mBCC	BCC RR 37.5% (with 1 CR)	Not reported	Not reported	20 (19%)
Randomized phase II BOLT^Citation88	Sonedegib (LDE225)	200 mg daily vs 800 mg daily	RR per central review/palliation	230	Unresectable laBCC (n=194), mBCC (n=36)	200 mg cohort:	200 mg cohort:	200 mg cohort:	200 mg
						laBCC RR: 47% (2 CRs)	laBCC: NE	laBCC: NE	cohort: 20%
						SD: 44%	mBCC: NE	mBCC: 13.1 mo	800 mg
						mBCC RR: 15%	800 mg cohort:	800 mg cohort:	cohort: 32%
						SD: 77%	laBCC: NE	laBCC: NE
						800 mg cohort: laBCC RR: 35%	mBCC: 8.3 mo	mBCC: 7.6 mo
						SD: 43%		mOS not reported
						mBCC RR: 17%
						SD: 66%
I^Citation89	Saridegib (IPI-926)	Dose escalation/expansion: 20–210 mg/D	Safety and PK-PD/palliation	94 BCC cohort: 39	BCC stage:	28 evaluable and vismodegib-naïve	9 remained on drug, including 2 >700 days	Not reported	6 (6%)
					II: 26%	–RR: 29% (all laBCC) (2 CRs)
					III: 26%	–SD: 68% (19/28)
					IV: 48%
IIT^Citation94	Vismodegib (GDC-0449)	150 mg/D	Change in target tumor surgical defect area/neoadjuvant	15	At least one operable primary BCC ≥5 mm	Eleven pts completed tx-27% reduction in surgical defect area from baseline	n/a	Not reported	4/14 unable to complete >3 mo of tx
Randomized	Vismodegib vs	150 mg/D	Reduction in	41	NBCCS pts with	Per-patient rate of new surgically	n/a	Not reported	54% (14/26)
II^Citation95	placebo (2:1)		incidence of new BCC eligible for surgery/neoadjuvant		multiple primary BCCs	resectable BCCs in vismodegib cohort: 2 vs 29 cases per group/yr, and significant reduction in size of existing BCCs (−65% vs −11%)			on vismodegib
Exploratory II^Citation110	Itraconazole	200 mg vs 100 mg bid and control	Change in Ki67 and GLI1 mRNA/neoadjuvant	29 enrolled, 19 treated	≥1 operable	45% reduction in Ki67 and 65% reduction in HH activity; 24% reduction in size of tumor	n/a	Not reported	11% (2/19)
					BCC >4 mm

Abbreviations: BCC, basal cell carcinoma; PFS, progression free survival; OS, overall survival; AE, adverse event; D, day; mo, month; yr, year; RR, response rate; NR, not reached; bid, twice daily; PK, pharmacokinetics; PD, pharmacodynamics; laBCC, locally advanced BCC; mBCC, metastatic BCC; SD, stable disease; INV, investigator assessed; CR, complete response; EAP, expanded access program; NM, not mature; NE, not estimable; IIT, investigator initiated trial; n/a, not applicable; IARR, independently assessed response rate; mOS, median overall survival; tx, treatment; pts, patients, NBCCS; nevoid basal cell carcinoma syndrome; HH, hedgehog.

Von HoffDDLoRussoPMRudinCMInhibition of the hedgehog pathway in advanced basal-cell carcinomaN Engl J Med20093611164117219726763

 PubMed Web of Science ®Google Scholar

LoRussoPMRudinCMReddyJCPhase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumorsClin Cancer Res2011172502251121300762

 PubMed Web of Science ®Google Scholar

SekulicAMigdenMROroAEEfficacy and safety of vismodegib in advanced basal-cell carcinomaN Engl J Med20123662171217922670903

 PubMed Web of Science ®Google Scholar

SekulicAMigdenMRBasset-SeguinNLong-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update (30-month) of the pivotal ERIVANCE BCC study [abstract]J Clin Oncol2014325s Suppl; abstr 9013

 Web of Science ®Google Scholar

ChangALSolomonJAHainsworthJDExpanded access study of patients with advanced basal cell carcinoma treated with the hedgehog pathway inhibitor, vismodegibJ Am Acad Dermatol201470606924189279

 PubMed Web of Science ®Google Scholar

GrobJJKunstfeldRDrenoBVismodegib, a Hedgehod pathway inhibitor (HPI), in advanced basal cell carcinoma (aBCC): STEVIE study interim analysis in 300 patients [abstract]J Clin Oncol201331Suppl abstr 9036

 Google Scholar

RodonJTawbiHAThomasALA phase I, multicenter, open-label, first-in-human, dose escalation study of the oral smoothened inhibitor sonidegib (LDE225) in patients with advanced solid tumorsClin Ca Res201420719001909

 PubMed Web of Science ®Google Scholar

MigdenMRGuminskiADGutzmerRandomized, double-blind study of sonidegib (LDE225) in patients with locally advanced or metastatic basal-cell carcinoma [abstract]J Clin Oncol2014325s Suppl; abstr 9009a

 Google Scholar

JimenoAWeissGJMillerWHPhase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumorsClin Cancer Res201319102766277423575478

 PubMed Web of Science ®Google Scholar

AllyMSAasiSWysongAAn investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinomaJ Am Acad Dermatol2014715904911.e1 Epub June 11, 201424929884

 PubMed Web of Science ®Google Scholar

TangJYMackay-WigganJMAszterbaumMInhibiting the hedgehog pathway in patients with the basal-cell nevus syndromeN Engl J Med20123662180218822670904

 PubMed Web of Science ®Google Scholar

KimDJKimJSpaunhurstKOpen–label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinomaJ Clin Oncol201410;328745751 Epub February 3, 2014

 Web of Science ®Google Scholar