Activity of Cabozantinib (XL184) in Hepatocellular Carcinoma: Results From a Phase 2 Randomized Discontinuation Trial (RDT) Chris Verslype 1 , Allen Lee Cohn 2 , Robin Katie Kelley 3 , Tsai-Shen Yang 4 , Wu-Chou Su 5 , David A. Ramies 6 , Yihua Lee 6 , Xiaodong Shen 6 , Eric Van Cutsem 1 University Hospitals Gasthuisberg, Leuven, Belgium 1 ; Rocky Mountain Cancer Center, LLP, Denver, CO 2 ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 3 ; Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan 4 ; National Cheng Kung University Hospital, Tainan, Taiwan 5 ; Exelixis, South San Francisco, CA 6
Introduction • MET overexpression is associated with metastasis and reduced survival in advanced HCC • MET up-regulation is implicated in evasive resistance to VEGF targeted therapies • Cabozantinib is a potent targeted therapy that inhibits MET and VEGFR2 • Cabozantinib blocks metastasis and improves survival in mouse models HCC tumor cell
Improved Survival in HCC Model 100 Cabozantinib (n = 8) 80 Survival (%) 60 40 Vehicle 20 (n = 8) 0 380 420 460 500 Days after Birth Human MET transgenic model (hepatocellular carcinoma) Data courtesy of D. Yang and J.M. Bishop, UCSF
Study Design • This cohort was investigated as part of a Phase 2 randomized discontinuation trial (RDT) LEAD-IN STAGE Cabozantinib PR or CR Open Label Extension Open Label Discontinue (100mg) Cabozantinib Blinded Randomized Stage Week 12 SD Advanced Unblind at Disease Tumor Cabozantinib vs. Placebo Progression HCC Staging (1:1) Placebo patients PD Discontinue may cross over to Study Treatment Cabozantinib Study Endpoints • Efficacy -Lead-In Stage: objective response per original RECIST 1.0 -Randomized Stage: progression-free survival • Safety
Methods Key Eligibility Criteria • Confirmed diagnosis of advanced HCC – By core biopsy, or accepted radiographic imaging per AASLD guideline • Up to one line of prior systemic treatment • Platelets ≥ 60,000/mm 3 ; hemoglobin ≥ 8g/dL • Documented progressive disease and measurable target lesion(s) per original RECIST 1.0* • Child-Pugh Score A only Assessments • Tumor assessments per original RECIST* using CT/MRI at baseline and every 6 weeks thereafter • Pharmacokinetics – Pre- and post-dose on Day 1 and end of Week 6; pre-dose and every 6 weeks thereafter * Tumor assessment was not done using radiographic enhancement of arterial phase
Baseline Characteristics (N = 41) Median age, years (range) 61 (33-83) Sex, n (%) Male 31 (76) Female 10 (24) Race, n (%) Asian 15 (37) Non-Asian 26 (63) ECOG PS, n (%) 0 19 (46) 1 22 (54) Etiology of disease, n (%) Hepatitis B 10 (24) Hepatitis C a 9 (22) Alcohol-related 6 (15) Other/unknown 16 (39) a 2 HCV patients also had alcohol-related etiology
Baseline Characteristics (N = 41), cont. Measurable disease, n (%) 41 (100) Extrahepatic spread, n (%) 30 (73) Hypersplenic/cytopenic, n (%) Hemoglobin < 11 g/dL 16 (39) Thrombocytopenia 14 (34) Median AFP, ng/mL (range) 368 (3-259298) Prior lines of systemic therapy, n (%) 0 8 (20) 1-2 33 (80) Prior anticancer therapy, n(%) Prior TKI 23 (56) Sorafenib 21 (51) Surgical resection 17 (42) Locoregional therapy a 16 (39) a Locoregional therapy includes transarterial embolization, percutaneous ethanol injection radiofrequency ablation, radiotherapy applied to extrahepatic metastatic lesions
Patient Disposition Patients Enrolled N =41 Week 12 Off-Treatment ≤ Week 12 n = 12 (29%) Randomized Open Label Extension Disease Progression at Week 12 > Week 12 9 (22%) n = 22 (54%) n = 7 (17%) Adverse Event 0 (0%) Active Active 0 1 Death Discontinued Discontinued 0 (0%) 10 6 Other a Cross-over to cabozantinib 3 (7%) 12 a Patient request other than AE (n=2; investigator decision (n=1)
Most Frequently Reported Adverse Events During Lead-In Stage Regardless of Causality (N = 41) Grade ≥ 3 a , n (%) Adverse Event All Grades, n (%) Fatigue 28 (68) 4 (10) Diarrhea 26 (63) 8 (20) Hand-foot syndrome 23 (56) 6 (15) Nausea 16 (39) 1 (2) Vomiting 15 (37) 1 (2) Thrombocytopenia 15 (37) 6 (15) Decreased appetite 12 (29) -- Aspartate aminotransferase increased 11 (27) 4 (10) Rash 10 (24) -- Asthenia 9 (22) 3 (7) Hypertension 9 (22) 3 (7) Weight decreased 9 (22) 1 (2) Constipation 9 (22) -- Hair color changes 9 (22) -- a No related Grade 5 events reported • No clinically significant bleeding reported • 24/41 of patients (59%) had ≥ 1 dose reduction during the Lead-In Stage
Cabozantinib Effects on Platelet Count, n=40* 600 Proportion Progression-Free *includes patients with >1 500 Platelets (10 9 / L) post-baseline lab 400 ≈ 300 200 100 20 x 10 9 / L 0 g 4 8 2 5 1 7 3 9 1 1 2 2 3 3 n k k ) ) 9 0 i e e k k k k k k n 4 = e e e e e e e e e = W W e e e e e e e n W W W W W W ( r n c ( S
Summary of Response by Original RECIST 1.0 Original RECIST response evaluable, N 41 a Objective response rate, n (%) Confirmed partial response 2 (5) Stable disease 32 (78) Progressive disease 3 (7) Week 12 DCR b , n (%) 27 (66) AFP response evaluable c 26 c 50% decrease from baseline 9 (35) a No post-baseline tumor assessments available for 4 patients b Disease control rate (DCR) defined as PR + SD at Week 12 c Baseline AFP ≥ 20 ng/mL
Duration of PFS Not Affected By Sorafenib Pretreatment Status* (N = 41) Median PFS 1.00 Sorafenib-Pretreated (n=21) 5.2 months 4.2 months Sorafenib-Naive (n=20) Progression-Free 0.75 Proportion Overall median PFS: 4.4 months 0.50 0.25 0.00 0 2 4 6 8 10 12 14 PFS per RECIST (months) * Method described by Ratain et al, J. Clin. Oncol. v24 p2505 (2006)
Overall Survival (N = 41) Proportion Progression-Free 1.00 Median OS (95% CI) # Events 15.1 months (8.9, 18.3) 26 Overall Survival 0.75 Proportion 0.50 0.25 0.00 0 5 10 15 20 25 30 OS (months)
Best Target Lesion Regression of Patients with ≥ 1 Post-Baseline Tumor Assessment (N=36)* Prior sorafenib Confirmed PRs ‡ No prior sorafenib ‡ ‡ *per Original RECIST 1.0
Best AFP Time Point Response of Patients with ≥ 1 Post-Baseline Measurement (N=26)* + + + Prior sorafenib No prior sorafenib + Increase >100% from Baseline * Only Patients with AFP ≥ 20ng/mL at baseline are shown.
AFP Response in Patient Randomized to Placebo 1400 Start Unblinded, 1200 cabozantinib re ‐ started cabozantinib 1000 AFP μ g/L 800 Randomized to AFP 600 placebo 400 200 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 / / / / / / / / / / / 9 9 9 9 9 9 9 9 9 9 9 / / / / / / / / / / / 2 3 4 5 6 7 8 9 0 1 2 1 1 1
Increases in Hemoglobin Over Time in Patients With Hb <11 g/dL at Baseline (N = 13) Change in Hb from Baseline (g/dL) 8 7 6 5 4 3 2 1 0 -1 2 4 6 8 10 12 Study Week The median maximum rise in Hb was 3.1 g/dL (range 1.3 to 7.8)
Summary • Cabozantinib shows encouraging clinical activity in HCC – 78% measurable disease regression per original RECIST – 35% AFP response (reduction of ≥ 50%) – Median PFS of 4.4 months regardless of prior sorafenib treatment – Median overall survival of 15.1 months • Safety profile similar to other TKIs with manageable AEs • Randomized Phase 2 study at 60 mg in 2 nd line HCC planned
Acknowledgments • We thank the patients and their families • XL184-203 investigators and staff
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