Second Line Therapy with Suni3nib as Single Agent In Pa3ents With Advanced Intrahepa3c Cholangiocarcinoma Update on SUN-­‐CK phase II trial Cindy Neuzillet1, Jean-­‐François Seitz2, Lae::a Fartoux3, David Malka4, Gérard Lledo5, Annemilaï Tijeras-­‐Raballand6, 7, Armand de Gramont6, 8, Maxime Ronot9, Mohamed BouaRour1, Chantal Dreyer1, Alexandre Amin10, Philippe Bourget10, Alexandra Hadengue11, Nelly Roldan11, Benoist Chibaudel11, Eric Raymond1, 8, Sandrine Faivre1, 12 1Medical Oncology, Beaujon University Hospital, Clichy, 2Diges:ve Oncology, La Timone Hospital, Marseille, 3Saint-­‐Antoine University Hospital, Paris, 4Gastroentrology Unit, Gustave Roussy Ins:tute, Villejuif, 5Gastroenterology Unit, Jean Mermoz University Hospital, Lyon, 6Transla:onnal Department, AAREC Filia Research, Boulogne-­‐Billancourt, 7Inserm U773, Clichy, 8Inserm U728, Paris, 9Radiological Unit, Beaujon University Hospital, Clichy, 10Clinical Pharmacy Department, Necker-­‐EM University Hospital, 11GERCOR, 12Inserm U773, Paris, France BACKGROUND
ü B eyond standard first-­‐line gemcitabine plus pla:num combina:on for advanced cholangiocarcinoma (CK) (Valle et al., N Engl J Med 2010), second-­‐line 5FU-­‐based chemotherapy yields median progression-­‐free survival (PFS) of about 3 months and median overall survival (OS) of 6-­‐7 months (Brieau et al., ASCO 2014), warran:ng exploring further treatment op:ons. ü Intrahepa:c CK subtype overexpresses VEGF (Guedj et al., J Hepatol 2009) and displays highly vascularized paRern on imaging, providing a ra:onale for inves:ga:ng the an:angiogenic tyrosine kinase inhibitor suni:nib as second-­‐line treatment in pa:ents (pts) with advanced intrahepa:c CK. METHODS
Study design: mul:center single-­‐arm phase 2 study. Two-­‐stage
Simon design. Suni:nib was given at the con:nuous daily dose of 37.5 mg in pa:ents with advanced intrahepa:c CK treated with suni:nib as second-­‐line therapy. RESULTS
Pa:ent characteris:cs: Efficacy: tumor response was evaluated by CT scan every 8 weeks (N = 34/53 evaluable pts). Number of pa3ents enrolled Not yet evaluable Evaluable for toxicity Evaluable for response 53 19 34 34 Median age (years) 62 (36-­‐80) Response (RECIST v1.1)
Complete Response (CR)
Par:al Response (PR)
N
0
5
24
29
%
0
70.6
85.3
23/11 Stable Disease (SD)
Gender: Male/Female 15/19 Disease Control Rate* (DCR)
Previous surgery on primary tumor: Yes/No 16/18 *10 pa7ents with disease control > 6 months (range 6-­‐14 months) Adjuvant systemic therapy: Yes/No 8/26 Median size of target lesions at inclusion (cm) 7.3 (1.3-­‐18) Timing of suni3nib treatment First line ager adjuvant therapy 5 Second line for advanced stage 29 Illustra3ve example of tumor regression and major hypodensity with suni3nib Plasma concentra3ons of suni3nib and main metabolite desethylsuni3nib (N = 9 pts, 82 blood samples) 14.7
Performance status: 0/1 Transla:onal analysis: preliminary results of PK and plasma biomarker analysis. Changes in tumor size and density (N = 15 pts) Plasma concentra3ons of suni3nib and desethylsuni3nib vs. grade 3 thrombopenia at cycle 1 (N = 9 pts) Thrombopenia may be related to drug exposure, with higher plasma concentra3ons of both suni3nib and desethylsuni3nib in pts experiencing grade 3 thrombopenia at cycle 1 (above the cut-­‐off value of 100 ng/mL as previously reported). Concentration
Safety: most toxici:es were mild and manageable upon symptoma:c treatment or dose reduc:on to 25 mg/day (grade 3-­‐4). Clinical AEs All grades (%) Grade 1-­‐2 (%) Grade 3-­‐4 (%) Plasma biomarkers (N = 15 pts) Asthenia
93.3
80.0 13.3 Diarrhea
60.0 60.0 -­‐ Aims of the study: main objec:ve: OS (median OS > 6.3 months). Secondary objec:ves: PFS and objec:ve response rate (RECIST v1.1 and Choi criteria), safety (CTCAE v4.0), several pharmacokine:c (PK) parameters and biomarker analysis (VEGFA, VEGFC, sKIT, HGF, SDF1, and osteopon:n). Mucosi3s
50.0
46.6
3.4 Survival analysis (N = 34 pts, median follow-­‐up: 15.4 months) HFS 46.7
43.3
3.4 Median PFS: 5.2 months Vomi3ng 43.4
36.7
6.7 Hypertension 43.3 20.0
23.3 Main inclusion/non inclusion criteria Inclusion criteria Nausea
40.0 40.0 Responders (R) and non responders (NR) may have different biological profiles with higher baseline VEGF-­‐C concentra3ons in R and higher increase in VEGF-­‐A concentra3ons at progression in NR. Analysis of other poten:al predic:ve biomarkers (sKIT, HGF, SDF1, and osteopon:n) is ongoing. Dysgueusia 33.3 33.3
-­‐ Histologically or cytologically proven intrahepa:c CK -­‐ Progression ager gemcitabine +/-­‐ pla:num -­‐ ECOG PS 0-­‐1 -­‐ Advanced disease not amenable to cura:ve therapy -­‐ Presence of measurable lesions using spiral CT scan -­‐ Adequate hematological, liver (AP < 5 UNL, bilirubin < 1.5 UNL), and kidney func:on Cons3pa3on 30.0 30.0 -­‐ Biological AEs All grades (%) Grade 1-­‐2 (%) Grade 3-­‐4 (%) Thrombopenia* 93.0 68.9 24.1 Neutropenia* 75.8
48.3
27.5 Anemia 72.3
68.9
3.4 -­‐ Hilar CK, gallbladder cancer, liver capsule effrac:on -­‐ Uncontrolled concomitant diseases and/or infec:on Lymphopenia 58.5
34.4
24.1 Non-­‐inclusion criteria -­‐ 95%CI: 3.1-­‐6.8 months Median OS: 9.6 months 95%CI: 5.9-­‐13.1 months -­‐ *No febrile neutropenia or bleeding was observed CONCLUSIONS
ü Suni3nib given at 37.5 mg/day con3nuously shows a safe clinical profile in chemotherapy-­‐pretreated pa3ents with advanced intrahepa3c CK ü Suni3nib achieves 15% objec3ve response rate and disease control in 85% of cases ü Blood biomarkers preliminary analysis suggests a different profile for responders vs. non-­‐responders ü Suni3nib as second line yields a median OS of 9.6 months and a median PFS of 5.2 months in pa3ents with advanced intrahepa3c CK