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Abstracts 4005-8
Jordan Berlin, MD
Ingram Professor of Clinical Research
Co-Director, GI Oncology Program
Vanderbilt-Ingram Cancer Center
Disclosures
• With regards to these presentations:
– I have done an advisory board and have had
multiple trials with Amgen,
– Vanderbilt has trials open from Daiichi and
Arqule
The obvious groupings
•Abstracts 4005-7
–These abstracts address the use of Cmet
inhibition as a therapeutic target in GI cancers
•I will be reversing the order of these abstracts
•Abstract 4008
–This abstract addresses the oft ignored issue of trying to
reduce the discomforts caused by one of our therapeutic
options
First, and Foremost
• All 4 abstracts represent excellent work from
dedicated individuals who want to make a
difference in the lives of our patients
– All the authors should be congratulated for their
efforts.
– This does not mean I won’t be critical
cMet
• You have seen the pathway
• Key factor: Expression has been a prognostic marker
• Frequently dysregulated in a number of tumor types
including HCC and gastric cancers
– Gene amplification in the primary has been reported in a limited
number of diseases including colon and gastric primaries
• Overexpression has been found to be a potential
resistance mechanism to HER pathway inhibition, VEGF
inhibition and possibly IGF1R inhibition
• It does bad things: proliferation, survival, etc, etc
– We have all seen most of this rationale for almost any targeted
agent
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
Tivantinib (ARQ 197) vs Placebo in Patients (Pts) with
Hepatocellular Carcinoma (HCC) Who Failed One
Systemic Therapy:Results of a Randomized Controlled
Phase 2 Trial (RCT)
L Rimassa, C Porta, I Borbath, B Daniele, S Salvagni, JL Van
Laethem, H Van Vlierberghe,J Trojan, F Kolligs, A Weiss, N
Barahona, A Gasbarrini, M Lencioni, A Pande, M Lamar, Y
Chen, G Abbadessa, B Schwartz, A Santoro
Similarities
• Both are randomized phase II studies of -nibs that
are primarily cMet inhibitors studied in patients
with HCC
• Both study groups clearly understood the
difficulties of this disease and incorporated it into
study design
– Frequent stable disease, heterogeneous etiologies, etc
• Both studies had designs that encouraged
enrollment
• Both groups felt further study is warranted based
on their results
Significant differences
• Cabozantinib
– Has inhibitory effects on two key pathways:
cMet and VEGFR2
– Had a novel trial design (randomized
discontinuation)
• Recognized the frequent stability of this disease in
Child’s A patients and low platelets despite good PS
– Focused on PFS as well as tumor shrinkage
and AFP reduction
– Had a more heterogeneous patient population
• Number and type of prior therapies
Significant Differences
• Tivantinib
– Selective for cMet pathway inhibition
– Had a predefined biomarker analysis
incorporated into the design
– Clearly defined prior therapies
• (1 systemic therapy taken for at least 21 days)
– Primary endpoint was TTP, but looked at OS
and PFS
– Had two different doses of drug due to toxicities
in the first 57 patients randomized
Best Target Lesion Regression of Patients with
≥1 Post-Baseline Tumor Assessment (N=36)*
50
% Change from Baseline
Prior sorafenib
30
10
-10
-30
-50
-70
*per Original RECIST 1.0
‡ Confirmed PRs
No prior sorafenib
‡ ‡
Best AFP Time Point Response of Patients with
≥1 Post-Baseline Measurement (N=26)*
% Change from Baseline
100
+
+
+
Prior sorafenib
No prior sorafenib
80
60
40
20
0
-20
-40
-60
-80
-100
+ Increase >100% from Baseline
* Only Patients with AFP ≥ 20ng/mL at baseline are shown.
Cabozantinib Results
• There is reduction in AFP, change in tumor
measurements
• PFS over 4 months suggests some effect
and while 15 month survival is encouraging,
this is a highly selected patient group in a
small study
• Does it warrant further study?
– Further phase II planned is appropriate.
– Biomarkers should be considered based on the
other two abstracts I am discussing
Tivantinib Results
• First, cMet expression was prognostic
– OS 9 months for cMet low and 3.8 months for
cMet high (based on 28 patients)
• While tivantinib had no apparent effect in
cMet low patients,
• cMet high patients appeared to get benefit
Primary Endpoint: TTP (ITT Population)
Median TTP
Patients
Events
Tivantinib
6.9 wks
71
46
Placebo
6.0 wks
36
30
HR: 0.64 (90% CI: 0.43-0.94) Log Rank: P=0.04
•
•
•
•
Study powered to detect a treatment difference with a 1-sided type I error α = 0.05
PFS consistent with TTP: HR 0.67 (95% CI: 0.44-1.04) Log Rank: P=0.06
1 PR was observed in the 240mg BID group. Disease control rate: 44% on tivantinib (32-56) vs 31% (16-48)
Of 23 crossed-over patients, 11 showed best response of SD (3 ongoing at time of data cut-off), 8 PD, 4 non evaluable
ARQ 197-215
PRESENTED BY: LORENZA RIMASSA
Improved TTP in MET Diagnostic High Group
Median TTP
Patients
Events
Tivantinib
11.7 wks
22
14
Placebo
6.1 wks
15
13
HR: 0.43 (95% CI: 0.19-0.97) Log Rank: P=0.03
PFS: HR 0.45 (95% CI: 0.21-0.95) Log Rank: P=0.02
DCR: 50% on tivantinib (28-72) vs 20% (4-48)
ARQ 197-215
PRESENTED BY: LORENZA RIMASSA
Improved OS in MET Diagnostic High Group
Median OS
Patients
Events
Tivantinib
7.2 mos
22
17
Placebo*
3.8 mos
15
15
HR: 0.38 (95% CI: 0.18-0.81) Log Rank: P=0.01
*8 MET Dx High patients crossed-over, 5 remained on open-label tivantinib for at least 6 weeks (1 non-evaluable at cut-off date)
ARQ 197-215
PRESENTED BY: LORENZA RIMASSA
cMet in HCC: Conclusions
• Both studies demonstrated some benefit
• Both studies warrant further analysis
• A randomized phase II study for crizontanib is
appropriate
• A randomized phase III study for tivantinib seems
appropriate, and I laud the conviction to follow the
biomarker hypothesis, but
– A large, randomized trial is now being built on a subset
analysis of 37 patients out of a 107 patient study
– This scenario has been repeated multiple times in
pancreatic cancer and look where it has gotten us
– Do the randomized phase II in cMet high patients first
INTRIGUINGLY, SUPPORT FOR A
BIOMARKER APPROACH COMES
FROM ANOTHER DISEASE SITE
Evaluation of MET Pathway Biomarkers in a Phase
2 Study of Rilotumumab or Placebo in
Combination With
Epirubicin/Cisplatin/Capecitabine in Patients With
Locally Advanced or Metastatic Gastric or
Esophagogastric Junction Cancer
Kelly S. Oliner,1 Rui Tang,1
Abraham Anderson,1 Yun Lan,1
Timothy Iveson,2 Ross C. Donehower,3
Yizhou Jiang,1 Sarita Dubey,4 Elwyn Loh4
1Amgen
Inc., Thousand Oaks, CA, USA; 2Southampton General
Hospital, Southampton, UK; 3Johns Hopkins Cancer Center,
Baltimore, MD, USA; 4Amgen Inc., South San Francisco, CA, USA
Progression-Free Survival (%)
Clinical Efficacy in the Intent-to-Treat
Population*
100
Progression-Free Survival
60
40
20
HR†
(80% CI)
P Value
Rilotumumab + ECX (n = 82)
5.6 (4.9–6.9)
0.64 (0.48–0.85)
0.045
Placebo + ECX (n = 39)
4.2 (3.7–4.6)
Median Months
(80% CI)
HR†
(80% CI)
P Value
Rilotumumab + ECX (n = 82)
11.1 (9.5–12.1)
0.73 (0.53–1.01)
0.215
Placebo + ECX (n = 39)
8.9 (5.7–10.6)
HR 0.64
0
0
1
2
3
4
5
6
100
Overall Survival (%)
Median Months
(80% CI)
80
7 8 9 10 11 12 13 14 15 16
Time (months)
Overall Survival
80
60
40
HR 0.73
20
0
0
1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 16 17
Time (months)
*Results based on the updated analysis with data cutoff of April 1, 2011. †Adjusted for baseline randomization
stratification variables (ECOG status [0 or 1] and disease extent [locally advanced or metastatic]).
Iveson T, et al. European Multidisciplinary Cancer Congress, September 23-27, 2011,
Stockholm, Sweden; abstract #6504.
Selected Biomarkers to find a
better population for further study
– Biomarkers selected
– Tumor
 MET protein expression
 HER2 status
 MET gene copy number
– Circulating plasma total HGF/SF and soluble MET
– For Met protein expression, used similar methods to the
Brivantinib study
– Criteria chosen for clinical trial assay performed by a central lab:
– METHigh: > 50% of tumor cells with ≥ 1+ cytoplasmic staining
– METLow: ≤ 50% of tumor cells with ≥ 1+ cytoplasmic staining
– For Met expression ~75% of patients in each arm had
samples
Improved PFS and OS in METHigh Patients
Progression-Free Survival
Progression-Free
Survival (%)
100
80
Median Months
(80% CI)
HR*
(95% CI)
P Value
Rilotumumab + ECX (n = 27)
6.9 (5.1–7.5)
0.51 (0.24–1.10)
0.085
Placebo + ECX (n = 11)
4.6 (3.7–5.2)
Median Months
(80% CI)
HR+
(95% CI)
P Value
Rilotumumab + ECX (n = 27)
11.1 (9.2–13.3)
0.29 (0.11–0.76)
0.012
Placebo + ECX (n = 11)
5.7 (4.5–10.4)
60
40
20
0
HR 0.51
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
Time (Months)
Overall Survival
Overall Survival (%)
100
80
60
40
20
HR 0.29
0
0
1
2
3
4
5
6
• MET-evaluable OS HR, 0.95
7
8
9 10 11 12 13 14 15 16 17
Time (Months)
*HR adjusted for baseline disease extent and ECOG PS.
• ITT OS HR, 0.73
High Levels of Tumor MET May Be
Predictive and Prognostic
100
Overall Survival (%)
90
80
70
60
Median Months
(80% CI)
50
40
30
Placebo + ECX (METLow, n = 17)
NE (8.5–NE)
20
Placebo + ECX (METHigh, n = 11)
5.7 (4.5–10.4)
Logrank
P value
0.023
10
0
0
1
2
3
4
5
6
7
8
9
10 11
Time (Months)
12
13
14
15
16
17
• Patients with gastric tumors with high MET expression may have a poorer prognosis but may
receive more benefit from rilotumumab
Rilotumumab in Gastric Cancer
Conclusions
• Once again, Met expression was prognostic
• And predictive of drug effect
• It is good when these things are consistent
across tumor types
• Once again, the company is moving forward
with a phase III trial based on the data from
a subset analysis
• Once again, I would urge caution, and
prefer a less dramatic step
Last thing on cMet trials
• Thank you to the authors for calling the
toxicity profiles manageable.
• The most common phrase concluding
ASCO abstracts
– “This (drug, regimen, etc) was well-tolerated
and further study is warranted”
• Often, neither is true
Symptom Management
• We have spent millions of dollars,
man/woman-hours, and gigabytes of
memory on global quality of life
– This has been of limited utility
• Difficult to interpret
– Worsening disease negatively affects QOL, as can side
effects of drug
• Heterogeneity as to how we as individuals define
QOL
• We mostly use it to justify that it is okay to use
borderline effective agents
– Desperation will make patients “tolerate” a lot more side
effect
Safety events from first SHARP
presentation
Sorafenib
(n=297)
Placebo
(n=302)
• Treatment-emergent serious adverse events (SAE, %)
52
54
• Drug-related adverse events (%)
13
9
• Drug-related adverse events (%)
Diarrhea
Pain (abdomen)
Weight loss
Anorexia
Nausea
Hand-foot skin reaction
Vomiting
Alpecia
Liver dysfunction
Bleeding
All
39
8
9
14
11
21
5
14
<1
7
Grade 3/4
8
2
2
<1
<1
8
1
0
<1
<1
All
Grade 3/4
11
3
<1
3
8
3
3
2
0
4
2
<1
0
<1
1
<1
<1
0
0
<1/<1
CTC Version 3.0:
– Grade 2: Skin changes (e.g., peeling, blisters,
bleeding, edema) or pain, not interfering with
function
– Grade 3: Ulcerative dermatitis or skin changes
with pain interfering with function
– While we might not know how to measure
global quality of life in a meaningful way, we can
choose a symptom/side effect and address it
A Randomized Controlled Phase II Study of the
Prophylactic Effect of Urea-Based Cream on the
Hand-Foot Skin Reaction Associated with
Sorafenib in Advanced Hepatocellular Carcinoma
Zhenggang Ren1，Kangshun Zhu2, Haiyan Kang3, Minqiang Lu2,
Zengqiang Qu4, Ligong Lu5, Tianqiang Song6, Weiping Zhou4, Hui
Wang7, Weizhu Yang8, Xuan Wang9, Yongping Yang10, Lehua Shi4,
Yuxian Bai11, Sheng-Long Ye1*
1 Zhongshan Hospital, Fudan University, Shanghai, China; 2 The Third Affiliated Hospital of Sun Yatsen University, Guangdong, China; 3 301 Military Hospital, Beijing, China; 4 Eastern Hepatobiliary
Surgery Hospital of the Second Military Medical University, Shanghai, China; 5 Guangdong
Provincial People's Hospital, Guangdong, China; 6 Tianjin Cancer Hospital , Tianjin, China; 7 Jilin
Provincial Tumor Hospital, Jilin, China; 8 Union Hospital of Fujian Medical University, Fujian, China;
9 The 81 Hospital of the Chinese People's Liberation Army, Nanjing, China; 10 302 Military Hospital,
Beijing, China; 11 Heilongjiang Provincial Cancer Hospital, Heilongjiang, China
Incidence of Worst-grade HFSR
Prophylactic Ureabased Cream + BSC
Grade of HFSR*
(Arm A)
N=439 (%)
BSC
(Arm B)
N=432 (%)
Total
N=871
(%)
193(44.0)
114(26.4)
307(35.3)
246(56.0%)
318(73.6%)
564(64.8%)
1
155(35.3)
192(44.4)
347(39.8)
2
72(16.4)
98(22.7)
170(19.5)
3
19(4.3)
28(6.5)
47(5.4)
2/3
91 (20.7)
126(29.2)
217(24.9)
0
All Grade (%)
P Value
<.0001
0.004
•
Primary Endpoint: The incidence of all-grade HFSR was significantly lower in Arm A (p<0.0001)
•
Secondary Endpoint: The incidence of grade ≥ 2 HFSR was significantly lower in Arm A (p=0.004)
•
The incidence of HFSR by grade was lower in Arm A
•
More patients in Arm A did not develop HFSR
Prevalence of All-grade HFSR at Each Visit
60
50
Arm A
Arm B
%
40
30
20
10
0
Week 0
Arm A 1.16
Arm B 1.18
Week 2
31.4
36.1
Week 4
40.8
49.8
*EOS: 2 weeks after end of study
Week 6
36.2
52.1
Week 8 Week 10 Week 12
28.9
23.2
18.5
47.2
33.8
28.2
EOS*
13
17.8
%
Time to the first HFSR event
Secondary Endpoint
• The median time to the first HFSR event was 2.5 fold longer in
Arm A compared to Arm B (84 days vs. 34 days, p<0.0001)
HFSR Conclusions
• Urea-based hand creams helped
– Less severity
– Delay of onset
• This reduces the number of people who will
not get benefit from sorafenib who have to
endure this side effect
• It is worth a consideration for your patients
• More studies like this should be done to
alleviate the suffering brought on by our
treatments
Overall Conclusions
• We all have little tricks we do to help
ameliorate side effects of our drugs
– But Ren, et al showed that we can
systematically analyze what we are doing
– I would argue these types of studies that focus
on a symptom or side effect are more valuable
than all the QOL analyses we have ever done
• I cannot name one incidence where we changed our
therapies based on global QOL
• We have solely used it to justify what we wanted to
do anyhow