Activity of Cabozantinib (XL184) in Hepatocellular Carcinoma: - - PowerPoint PPT Presentation

Activity of Cabozantinib (XL184) in Hepatocellular Carcinoma: Results From a Phase 2 Randomized Discontinuation Trial (RDT)

Chris Verslype1, Allen Lee Cohn2, Robin Katie Kelley3, Tsai-Shen Yang4, Wu-Chou Su5, David A. Ramies6, Yihua Lee6, Xiaodong Shen6, Eric Van Cutsem1

University Hospitals Gasthuisberg, Leuven, Belgium1; Rocky Mountain Cancer Center, LLP, Denver, CO2; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA3; Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan4; National Cheng Kung University Hospital, Tainan, Taiwan5; Exelixis, South San Francisco, CA6

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

20 40 60 80 100 380 420 460 500

Days after Birth Survival (%) Cabozantinib (n = 8) Vehicle (n = 8) Human MET transgenic model (hepatocellular carcinoma)

Data courtesy of D. Yang and J.M. Bishop, UCSF

Study Design

Advanced HCC Open Label Extension Cabozantinib Discontinue Study Treatment Blinded Randomized Stage Cabozantinib vs. Placebo (1:1) Unblind at Disease Progression Discontinue Placebo patients may cross over to Cabozantinib PR or CR PD Week 12 Tumor Staging LEAD-IN STAGE SD Cabozantinib Open Label (100mg)

Study Endpoints

• Efficacy
• Lead-In Stage: objective response per original RECIST 1.0
• Randomized Stage: progression-free survival
• Safety
• This cohort was investigated as part of a Phase 2 randomized discontinuation trial (RDT)

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/mm3; 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 (%)

19 (46) 1 22 (54)

Etiology of disease, n (%)

Hepatitis B 10 (24) Hepatitis Ca 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 (%)

8 (20) 1-2 33 (80)

Prior anticancer therapy, n(%)

Prior TKI 23 (56) Sorafenib 21 (51) Surgical resection 17 (42) Locoregional therapya 16 (39)

aLocoregional therapy includes transarterial embolization, percutaneous ethanol injection

radiofrequency ablation, radiotherapy applied to extrahepatic metastatic lesions

Patient Disposition

Open Label Extension > Week 12 n = 7 (17%) Randomized at Week 12 n = 22 (54%) Off-Treatment ≤ Week 12 n = 12 (29%) Active 1 Discontinued 6 Disease Progression 9 (22%) Adverse Event 0 (0%)

Patients Enrolled N =41

Cross-over to cabozantinib Othera 3 (7%) Active Discontinued 10

a Patient request other than AE (n=2; investigator decision (n=1)

12

Week 12

Death 0 (0%)

Most Frequently Reported Adverse Events During Lead-In Stage Regardless of Causality (N = 41)

Adverse Event All Grades, n (%) Grade ≥ 3a, 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)

• aNo 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*

*includes patients with >1 post-baseline lab Proportion Progression-Free

Platelets (109 / L)

S c r e e n i n g W e e k 4 W e e k 8 W e e k 1 2 W e e k 1 5 W e e k 2 1 W e e k 2 7 W e e k 3 3 W e e k 3 9 100 200 300

( n = 4 ) ( n = 9 )

400 500 600

≈

20 x 109 / L

Summary of Response by Original RECIST 1.0

Original RECIST response evaluable, N 41a Objective response rate, n (%) Confirmed partial response 2 (5) Stable disease 32 (78) Progressive disease 3 (7) Week 12 DCRb, n (%) 27 (66) AFP response evaluablec 26c 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

2 4 6 8 10 12 14 0.00 0.25 0.50 0.75 1.00

Sorafenib-Pretreated (n=21) Sorafenib-Naive (n=20)

PFS per RECIST (months) Proportion Progression-Free

Duration of PFS Not Affected By Sorafenib Pretreatment Status* (N = 41)

Median PFS 5.2 months 4.2 months

Overall median PFS: 4.4 months

* Method described by Ratain et al, J. Clin. Oncol. v24 p2505 (2006)

Overall Survival (N = 41)

Median OS (95% CI) # Events 15.1 months (8.9, 18.3) 26

Proportion Progression-Free

5 10 15 20 25 30 0.00 0.25 0.50 0.75 1.00

OS (months) Proportion Overall Survival

Best Target Lesion Regression of Patients with ≥1 Post-Baseline Tumor Assessment (N=36)*

*per Original RECIST 1.0

‡ ‡

Prior sorafenib No prior sorafenib Confirmed PRs

‡

Best AFP Time Point Response of Patients with ≥1 Post-Baseline Measurement (N=26)*

+ Increase >100% from Baseline

* Only Patients with AFP ≥

20ng/mL at baseline are shown. Prior sorafenib No prior sorafenib

+ + +

AFP Response in Patient Randomized to Placebo

200 400 600 800 1000 1200 1400 2 / 9 / 2 1 1 3 / 9 / 2 1 1 4 / 9 / 2 1 1 5 / 9 / 2 1 1 6 / 9 / 2 1 1 7 / 9 / 2 1 1 8 / 9 / 2 1 1 9 / 9 / 2 1 1 1 / 9 / 2 1 1 1 1 / 9 / 2 1 1 1 2 / 9 / 2 1 1 AFP μg/L AFP

Randomized to placebo Start cabozantinib Unblinded, re‐started cabozantinib

Increases in Hemoglobin Over Time in Patients With Hb <11 g/dL at Baseline (N = 13)

The median maximum rise in Hb was 3.1 g/dL (range 1.3 to 7.8)

2 4 6 8 10 12

• 1

1 2 3 4 5 6 7 8

Study Week Change in Hb from Baseline (g/dL)

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 2nd line HCC

planned

Acknowledgments

• We thank the patients and their families
• XL184-203 investigators and staff