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Efficacy of sonidegib in patients with locally advanced basal cell carcinoma (laBCC) by tumor burden
3359 Efficacy following discontinuation of sonidegib treatment in patients with locally advanced basal cell carcinoma (laBCC) Ruth Plummer, Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom; John Lear, Manchester Royal Infirmary, Manchester, United Kingdom; Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover, Germany; Alexander Guminski, Royal North Shore Hospital, New South Wales, Australia; Tingting Yi, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Celine Pallaud, Novartis Pharma AG, Basel, Switzerland; Jocelyn Zhou, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Dalila Sellami, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Reinhard Dummer, Universit€atsSpital Z€ urich, Z€ urich, Switzerland; Michael Migden, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Background: Despite the risk of significant morbidity and disfigurement, patients (pts) with laBCC may not perceive their disease as life-threatening. In BOLT, a phase 2 study of the hedgehog (Hh) pathway inhibitor sonidegib (NCT01327053), some pts discontinued (DC) treatment before disease progression (PD), potentially due to adverse events (AEs). This analysis assesses efficacy in pts with laBCC who DC sonidegib before PD using data from the 18-mo analysis (median follow-up, 26.3 mo; cutoff, July 11, 2014). Methods: Pts with laBCC were randomized 1:2 to sonidegib 200 (n ¼ 66) or 800 (n ¼ 128) mg daily. Objective response rate (ORR; complete response [CR] + partial response [PR]) and duration of response (DOR) were assessed by central and investigator (INV) review per mRECIST. Safety was assessed per CTCAE v4.03 in treated pts until 30 d postlast dose. Results: By the data cutoff, 86% of pts with laBCC DC treatment, primarily due to PD (29%/8%; 200/800 mg), AEs (27%/41%), physician decision (14%/9%), or pt decision (11%/21%). Response was durable in pts who DC treatment before reaching PD and was sustained postDC; median DOR by central review was 24.8 mo (800 mg) and not reached (200 mg), regardless of whether tumor assessment data was analyzed through 30 d postlast dose or through PD. Eleven pts who DC long before ($180 d) PD were further profiled (200 mg, n ¼ 4; 800 mg, n ¼ 7); DC was due to AEs (n ¼ 8, mostly Grade 1/2), physician decision (n ¼ 1), or pt decision (n ¼ 2). Seven pts had baseline tumor burden [ 300 mm2 (range, 150-2675 mm2), and 7 pts had histologic clearance at last dose. At last dose, 7 pts had PRs, 3 had stable disease (SD) (1 of them had PR postDC), and 1 had an unknown response, as assessed by central review; by INV review, 3 pts had CR and 8 had PR. DOR ranged from 7.2-15.6 mo for 8 responders per central review, and ranged from 5.8-23.0 mo for 11 responders per INV review. By the data cutoff, 6/11 pts had PD (range, 4.7-14.8 mo postlast dose), as assessed by central review; by INV review, 10/11 pts had PD (range, 3.3-17.5 mo postlast dose). Based on previous established PK-Gli-1 relationship, GLI1 (biomarker for Hh pathway activity) is predicted and appears to remain inhibited after treatment DC, likely due to sonidegib’s long half-life (28 d). Conclusions: Sonidegib demonstrated clinical benefit persisting beyond treatment DC in pts with laBCC. Most pts who DC long before PD had objective responses and DC due to grade 1/2 AEs. Supported by Novartis Pharma AG, Basel, Switzerland.
3356 Efficacy of sonidegib in patients with aggressive and nonaggressive subtypes of locally advanced basal cell carcinoma John Lear, Manchester Royal Infirmary, Manchester, United Kingdom; Michael Migden, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Alexander Guminski, Royal North Shore Hospital, Sydney, Australia; Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover, Germany; Karl Lewis, University of Colorado Cancer Center, Aurora, CO, United States; Patrick Combemale, Centre Leon Berard, Lyon, France; Dalila Sellami, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Patrick Burnett, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Tingting Yi, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Reinhard Dummer, Universit€atsSpital Z€ urich, Zurich, Switzerland Introduction and objectives: BCCs with aggressive (eg, micronodular or infiltrative) histology are associated with higher rates of recurrence and, for certain subtypes, an increased likelihood of subclinical spread. The hedgehog pathway inhibitor sonidegib has demonstrated clinical benefit in [ 90% of patients (pts) with locally advanced (la)BCC in the BOLT phase 2 study, with durable tumor responses observed through a median follow-up of 20 months (mo). Here we evaluate the efficacy and safety of sonidegib in pts with aggressive vs nonaggressive histologic subtypes of laBCC based on a median follow-up of 26.3 mo (BOLT 18-mo analysis; cutoff July 11, 2014). Methods: Pts with laBCC not amenable to curative surgery or radiotherapy received sonidegib 200 or 800mg daily (1:2 randomization). Objective response rate (ORR; confirmed complete response [CR] + partial response [PR]), duration of response (DOR), and progression-free survival (PFS) were assessed according to modified RECIST criteria. Safety was assessed in treated pts according to CTCAE v4.03 until 30 days post last treatment. Results: ORRs in all pts with laBCC (n ¼ 194) by central review were 56.1% and 45.3% in the 200 and 800 mg arms, respectively. Aggressive tumor histology was found in 57.7% of pts with laBCC. ORR was similar in pts with aggressive subtype (59.5% in 200 mg, 44.0% in 800 mg) and nonaggressive subtypes (51.7% in 200 mg, 47.2% in 800 mg). PFS events (progressive disease or death) occurred in 6/22 responders in the 200 mg group and 10/33 in the 800 mg group for pts with aggressive subtype, compared with 4/15 and 7/25 respectively in the nonaggressive groups. Median DOR was not reached in both aggressive and nonaggressive 200 mg groups. Median PFS was 22.1 mo and 19.4 mo in the aggressive 200 and 800 mg groups, and 30.5 mo in the nonaggressive 800 mg group. Median PFS was not reached in the nonaggressive 200 mg group. In pts with laBCC (n ¼ 193), the most
MAY 2016
common adverse events (AEs; any grade; 200 mg/800 mg) were muscle spasms (56%/69%), alopecia (52%/61%), and dysgeusia (47%/59%). AEs leading to discontinuation in [5% of pts with laBCC were muscle spasms (200 mg/800 mg: 3%/9%), decreased weight (3%/6%), and alopecia (2%/7%). Conclusions: Sonidegib demonstrated sustained, clinically meaningful responses in pts with laBCC, with similar efficacy observed in pts with aggressive and nonaggressive tumor histologies. The 200 mg dose showed an improved benefitrisk profile in pts with laBCC. Supported by Novartis Pharma AG, Basel, Switzerland.
3349 Efficacy of sonidegib in patients with locally advanced basal cell carcinoma (laBCC) by tumor burden Patrick Combemale, Centre Leon Berard, Lyon, France; Reinhard Dummer, Skin Cancer Center University Hospital, Zurich, Switzerland; Michael Migden, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Alexander Guminski, Royal North Shore Hospital, St Leonards, Australia; Karl Lewis, University of Colorado Cancer Center, Denver, CO, United States; Tingting Yi, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Patrick Burnett, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Dalila Sellami, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; John Lear, Manchester Royal Infirmary, Manchester, United Kingdom; Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover, Germany Background: Large BCCs can be difficult to manage with surgery and/or radiotherapy and are more likely to recur and lead to further advanced disease. Treatment with the hedgehog pathway inhibitor sonidegib resulted in tumor shrinkage in [90% of patients (pts) with laBCC in the phase 2 BOLT study (NCT01327053; Migden et al. Lancet Oncol. 2015). Here, efficacy by tumor burden in pts with laBCC treated with sonidegib using updated data (18-mo analysis; cutoff, July 11, 2014; median follow-up, 26.3 mo) is reported. Methods: Pts with laBCC, not amenable to curative surgery or radiotherapy, were randomized to sonidegib 200 mg (n ¼ 66) or 800 mg (n ¼ 128) daily. Objective response rate (ORR; confirmed complete response [CR] + partial response [PR]), duration of response (DOR), and progression-free survival (PFS) were evaluated according to BCC-modified RECIST by central review. Tumor burden was evaluated based on target lesion size, with the median determined using combined data from both doses. Pts without photos or target lesions were excluded from the analysis. Results: By the data cutoff, median duration of exposure was 11.1 and 6.3 mo for the 200 mg and 800 mg arms, respectively. Median tumor burden at baseline was 12.10 cm2 (0.70-570.35 cm2). The ORRs for all patients were 56.1% with sonidegib 200 mg and 45.3% for 800 mg. ORRs were numerically higher in pts with a tumor burden \ the median [200 mg: 69.6%, n ¼ 23; 800 mg 58.9%, n ¼ 56] than in pts with a tumor burden $ the median [200 mg: 56.7%, n ¼ 30; 800 mg: 42.9%, n ¼ 49]. With both doses, [ 50% of responders had DOR [ 6 mo regardless of tumor burden (200 mg: 11/16 for pts with tumor burden \ median, 10/17 $ median; 800 mg: 21/33 \ median, 13/21 $ median). Median PFS was 22.1 mo with sonidegib 200 mg and 22.0 mo with 800 mg. With sonidegib 200 mg, 3 and 10 PFS events (progressive disease or death) occurred in pts with a tumor burden \ the median and pts with tumor burden $ the median, respectively. At the 800 mg dose, 12 PFS events occurred in both subgroups. Conclusions: Sonidegib continued to demonstrate meaningful clinical benefit and sustained tumor responses in pts with laBCC, with more objective responses occurring in pts with a tumor burden \ the median. These results are not unexpected, as patients with a greater tumor burden may be more difficult to treat due to the extent of their disease. Supported by Novartis Pharma AG, Basel, Switzerland.
J AM ACAD DERMATOL
AB197
3356 Efficacy of sonidegib in patients with aggressive and nonaggressive subtypes of locally advanced basal cell carcinoma John Lear, Manchester Royal Infirmary, Manchester, United Kingdom; Michael Migden, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Alexander Guminski, Royal North Shore Hospital, Sydney, Australia; Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover, Germany; Karl Lewis, University of Colorado Cancer Center, Aurora, CO, United States; Patrick Combemale, Centre Leon Berard, Lyon, France; Dalila Sellami, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Patrick Burnett, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Tingting Yi, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Reinhard Dummer, Universit€atsSpital Z€ urich, Zurich, Switzerland Introduction and objectives: BCCs with aggressive (eg, micronodular or infiltrative) histology are associated with higher rates of recurrence and, for certain subtypes, an increased likelihood of subclinical spread. The hedgehog pathway inhibitor sonidegib has demonstrated clinical benefit in [ 90% of patients (pts) with locally advanced (la)BCC in the BOLT phase 2 study, with durable tumor responses observed through a median follow-up of 20 months (mo). Here we evaluate the efficacy and safety of sonidegib in pts with aggressive vs nonaggressive histologic subtypes of laBCC based on a median follow-up of 26.3 mo (BOLT 18-mo analysis; cutoff July 11, 2014). Methods: Pts with laBCC not amenable to curative surgery or radiotherapy received sonidegib 200 or 800mg daily (1:2 randomization). Objective response rate (ORR; confirmed complete response [CR] + partial response [PR]), duration of response (DOR), and progression-free survival (PFS) were assessed according to modified RECIST criteria. Safety was assessed in treated pts according to CTCAE v4.03 until 30 days post last treatment. Results: ORRs in all pts with laBCC (n ¼ 194) by central review were 56.1% and 45.3% in the 200 and 800 mg arms, respectively. Aggressive tumor histology was found in 57.7% of pts with laBCC. ORR was similar in pts with aggressive subtype (59.5% in 200 mg, 44.0% in 800 mg) and nonaggressive subtypes (51.7% in 200 mg, 47.2% in 800 mg). PFS events (progressive disease or death) occurred in 6/22 responders in the 200 mg group and 10/33 in the 800 mg group for pts with aggressive subtype, compared with 4/15 and 7/25 respectively in the nonaggressive groups. Median DOR was not reached in both aggressive and nonaggressive 200 mg groups. Median PFS was 22.1 mo and 19.4 mo in the aggressive 200 and 800 mg groups, and 30.5 mo in the nonaggressive 800 mg group. Median PFS was not reached in the nonaggressive 200 mg group. In pts with laBCC (n ¼ 193), the most
MAY 2016
common adverse events (AEs; any grade; 200 mg/800 mg) were muscle spasms (56%/69%), alopecia (52%/61%), and dysgeusia (47%/59%). AEs leading to discontinuation in [5% of pts with laBCC were muscle spasms (200 mg/800 mg: 3%/9%), decreased weight (3%/6%), and alopecia (2%/7%). Conclusions: Sonidegib demonstrated sustained, clinically meaningful responses in pts with laBCC, with similar efficacy observed in pts with aggressive and nonaggressive tumor histologies. The 200 mg dose showed an improved benefitrisk profile in pts with laBCC. Supported by Novartis Pharma AG, Basel, Switzerland.
3349 Efficacy of sonidegib in patients with locally advanced basal cell carcinoma (laBCC) by tumor burden Patrick Combemale, Centre Leon Berard, Lyon, France; Reinhard Dummer, Skin Cancer Center University Hospital, Zurich, Switzerland; Michael Migden, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Alexander Guminski, Royal North Shore Hospital, St Leonards, Australia; Karl Lewis, University of Colorado Cancer Center, Denver, CO, United States; Tingting Yi, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Patrick Burnett, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; Dalila Sellami, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; John Lear, Manchester Royal Infirmary, Manchester, United Kingdom; Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover, Germany Background: Large BCCs can be difficult to manage with surgery and/or radiotherapy and are more likely to recur and lead to further advanced disease. Treatment with the hedgehog pathway inhibitor sonidegib resulted in tumor shrinkage in [90% of patients (pts) with laBCC in the phase 2 BOLT study (NCT01327053; Migden et al. Lancet Oncol. 2015). Here, efficacy by tumor burden in pts with laBCC treated with sonidegib using updated data (18-mo analysis; cutoff, July 11, 2014; median follow-up, 26.3 mo) is reported. Methods: Pts with laBCC, not amenable to curative surgery or radiotherapy, were randomized to sonidegib 200 mg (n ¼ 66) or 800 mg (n ¼ 128) daily. Objective response rate (ORR; confirmed complete response [CR] + partial response [PR]), duration of response (DOR), and progression-free survival (PFS) were evaluated according to BCC-modified RECIST by central review. Tumor burden was evaluated based on target lesion size, with the median determined using combined data from both doses. Pts without photos or target lesions were excluded from the analysis. Results: By the data cutoff, median duration of exposure was 11.1 and 6.3 mo for the 200 mg and 800 mg arms, respectively. Median tumor burden at baseline was 12.10 cm2 (0.70-570.35 cm2). The ORRs for all patients were 56.1% with sonidegib 200 mg and 45.3% for 800 mg. ORRs were numerically higher in pts with a tumor burden \ the median [200 mg: 69.6%, n ¼ 23; 800 mg 58.9%, n ¼ 56] than in pts with a tumor burden $ the median [200 mg: 56.7%, n ¼ 30; 800 mg: 42.9%, n ¼ 49]. With both doses, [ 50% of responders had DOR [ 6 mo regardless of tumor burden (200 mg: 11/16 for pts with tumor burden \ median, 10/17 $ median; 800 mg: 21/33 \ median, 13/21 $ median). Median PFS was 22.1 mo with sonidegib 200 mg and 22.0 mo with 800 mg. With sonidegib 200 mg, 3 and 10 PFS events (progressive disease or death) occurred in pts with a tumor burden \ the median and pts with tumor burden $ the median, respectively. At the 800 mg dose, 12 PFS events occurred in both subgroups. Conclusions: Sonidegib continued to demonstrate meaningful clinical benefit and sustained tumor responses in pts with laBCC, with more objective responses occurring in pts with a tumor burden \ the median. These results are not unexpected, as patients with a greater tumor burden may be more difficult to treat due to the extent of their disease. Supported by Novartis Pharma AG, Basel, Switzerland.
J AM ACAD DERMATOL
AB197