Download Report

A Phase 1b Study of the Anti-Cancer Stem Cell Agent Demcizumab, Pemetrexed and Carboplatin in Patients with
Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
1 Kotasek
3 Markman
M,
5
5
7.5
5
5
(Cohort1)
(Cohort2)
(Cohort3)
Expansion*
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
8
6
6
7
7
Total
2.5
5
5
7.5
5
5
(Cohort2)
(Cohort3)
Expansion
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
59.5
65.0
60.5
60.5
66.0
63.0
63.0
Male/Female
2/4
2/4
2/6
3/3
3/3
3/4
2/5
17/29
Prior Radiotherapy
2
* 3 of these patients received truncated dosing
-
1
J,
9Hughes
B
Spain; 5 Sir
1
-
5
2
-
2
-
1
2
3
4
2
1
8
6
6
7
7
46
Fatigue
3
3
5
3
1
3
4
22 (48%)
Nausea
1
2
6
5
3
3
1
21 (46%)
Hypertension/Blood
Pressure Increased
2
4
5
1
2
4
3
21 (46%)
Vomiting
1
2
3
3
2
1
1
13 (28%)
Neutropenia
2
1
3
2
-
2
1
11 (24%)
Edema
-
-
7
1
1
1
1
11 (24%)
BNP Increased
1
-
5
1
-
3
1
11 (24%)
Anemia
1
-
3
1
1
2
-
8 (17%)
Dyspnea
3
-
1
-
-
2
2
8 (17%)
Diarrhea
2
-
1
1
1
2
-
7 (15%)
Thrombocytopenia
-
-
2
2
-
3
-
7 (15%)
Reversible Cardiopulmonary Toxicity
(Grade 3*)
% Immune
Cells
2.5
5
5
7.5
5
5
(Cohort1)
(Cohort2)
(Cohort3)
Expansion*
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
*
Total
N
6
6
8
6
6
7
7
46
Pulmonary
hypertension(Reversible)
-
-
2**
-
-
-
-
2 (4%)
1
LEGEND: Patients with CONTINUOUS DEM dosing received 6 cycles of demcizumab, carboplatin and pemetrexed followed by demcizumab
maintenance. Excludes 3 patients from cohort 4.
* Six patients without long-term survival follow-up (i.e., beyond their study termination date) were assumed to have died at the date that they were
last known to be alive thus, this was a WORST CASE ANALYSIS. ** mOS could be underestimated since this a worst case analysis.
16
FFPE tumors from truncated patients were evaluated for % immune cells/tumor area, % TILs/tumor area , % PDL-1 positivity
(membrane plus cytoplasm) on infiltrating immune cells and % PDL-1 positivity on tumor cells.
Exploration of Death Hazard Before & After 300 Days
Survival – Truncated Demcizumab Patients
(Cohorts 5-7)
Progression-Free Survival
Continuous Demcizumab Patients (Cohorts 1-4)
Follow Up
Cohort
Congestive heart failure
(Reversible)
-
-
1**
-
-
-
-
1 (2%)
Right-sided
heart failure (Reversible)
-
-
1**
-
-
-
-
1 (2%)
% PD-L1
on Tumor
Green=high
Red=low
50th cut-off
One of the patients with 100% reduction in their target lesion size did not have a CR, as there was residual non-target disease
5
% TILs
% PD-L1 on
Immune Cells
On-Study Data Only
Includes Off-Study Data
mPFS (95% CI) = 5.3 mos (3.3-6.3)
Group
Days
Events
P-value
Median (95% CI) Survival = 8.1 mos (5.8-NR)
Continuous Dosing*
(N=23)
mPFS (95% CI) = 5.6 mos (3.7-19.1)
<300 Days
1446
7
<0.05
>300 Days
7969
2
* No cases of Grade 4 or 5 toxicity. ** Occurred following >160 days of treatment and reversible following the discontinuation of demcizumab
and medical management. Events occurred in the same two patients
Survival Probability
* Patients with CONTINUOUS DEM dosing received 6 cycles of demcizumab, carboplatin and pemetrexed followed by demcizumab maintenance. Excludes 3 patients
from cohort 4.
Effect on Notch Pathway Gene Expression
In Whole Blood (By DEM Dose Cohort)
Notch pathway genes show clear modulation
in truncated and non-truncated cohorts and
at Phase 2 dose (5.0 mg/kg Q3W)
Probability
NOTCH1
LEGEND: An exploratory statistical analysis was performed to assess the plateau at the tail of the Kaplan-Meier survival curve treated with
continuous DEM.. This analysis suggests that there is a difference in survival event rate before and after 300 days on study. A separate
analysis (data not shown) assessed the event rate of the plateau at the tail of the OS curve compared to the expected event rate in the first
300 days from Ph3 NSCLC chemo trials, and the result remained significant
Summary
• This was a Phase 1b dose escalation study of demcizumab, a first-in-class monoclonal
antibody targeting DLL4 with anti-CSC, anti-tumor angiogenesis and immune modulation
properties, plus PEM & Carbo in 1st-line stage IIIb/IV NSCLC pts.
PD modulation observed up to ~77 days
post last infusion in some patients
NOTCH2
LEGEND: Patients with TRUNCATED DEM dosing received 4 cycles of demcizumab, carboplatin and pemetrexed followed by pemetrexed
maintenance. Includes 3 patients from cohort 4 who received truncated dosing.
Control
LEGEND: Patients received 6 cycles of demcizumab, carboplatin and pemetrexed followed by demcizumab maintenance.
Excludes 3 patients from cohort 4 who received truncated dosing.
MAML3
Progression-Free Survival
Truncated Demcizumab Patients (Cohorts 5-7)
Legend: Fold change from baseline shown. * and ** on the bars denote
the days since last dosing: beyond 21 days and 42 days, respectively.
Biomarkers are not significantly down-regulated blood from control
subjects. Control genes (e.g., ACTB) are not changed.
RECIST Best Overall Response (n=46)
2.5
5
5
7.5
5
5
Total
(Cohort1)
(Cohort2)
(Cohort3)
Expansion*
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
(40 Evaluable)
• Intra-tumoral stained vessels evaluated for CD31 & DLL4 by IHC
• % DLL4 positive vessels/ total vessels (CD31 positive plus DLL4 positive vessels)
• Scoring performed by a board-certified clinical anatomic pathologist
mPFS (95% CI) = 5.8 mos (3.3-11.0)
High
• The truncated DEM treatment and patient monitoring with BNP and ECHO appears to
prevent the onset of late cardiopulmonary toxicity.
OS
PFS
• One of the 40 (3%) evaluable patients had a RECIST complete response, 19 (48%) had a
partial response and 15 (38%) had stable disease. The clinical benefit rate was 88%.
• The Kaplan-Meier estimated mPFS for the continuous and truncated DEM patients using the
on-study data were and 5.3 and 5.8 mos, respectively. The KM estimated mPFS for the
continuous and truncated DEM patients using both on-study and additional off-study data
were and 5.6 and 5.8 mos, respectively.
• The Kaplan-Meier estimated mOS for the continuous ‘worst-case’ and the truncated DEM
subjects was 6.3 & 8.1 mos, respectively.
Complete
Response
-
-
-
1
-
-
-
1 (3%)
Partial Response
2
4
2
-
4
3
4
19 (48%)
Stable Disease
2
2
4
2
1
2
2
15 (38%)
Clinical Benefit
(SD + PR + CR)
4
6
6
3
5
5
6
35 (88%)
Progressive
Disease
-
-
1
2
1
-
1
5 (13%)
Not Evaluable
2
-
1
1
-
2
-
6
* 3 of these patients received truncated dosing
• The regimen of DEM, PEM & Carbo was generally well-tolerated with fatigue, nausea and
manageable hypertension being the most common DEM-related toxicities. Two cases of
reversible Grade 3 pulmonary hypertension and heart failure occurred in patients receiving 5
mg/kg for > 160 days. Subsequently, truncated DEM used (i.e., 63 days of treatment).
• The Phase 2 dose of DEM at 5mg/kg Q3W shows sustained pharmacodynamic modulation of
the Notch pathway in patient samples.
DLL4 IHC
Includes Off-Study Data
mPFS (95%CI) = 5.8 mos (3.3- NR)
5
Exploratory DLL4 Expression Biomarker Analyses
Truncated Patients (N =12)
• The continuous DEM PFS and OS Kaplan-Meier curves reveal prolonged tails that suggest
there is a subset of DEM treated subjects that have prolonged PFS and OS. A statistical
analysis of the plateau at the tail of the continuous demcizumab OS curve suggested that
there is a change in the hazard starting at 10 months. Data from the truncated DEM subjects
is less mature.
DLL4
Levels
7
4
Overall Survival Exploratory Biomarker Analyses
Truncated Patients (n = 12)
mOS (95%CI) = 6. 3 mos (3.2-NR)**
6
Dose Level- mg/kg
Copies of this poster obtained through Quick Response (QR) code are for personal
use only and may not be reproduced without written permission from ASCO and the
authors of this poster.
Total
6
46
66.5
-
E,
8Dupont
Survival Probability
5
(Cohort1)
N
Dose Level mg/kg
Median age (years)
Prior Neo-adjuvant/
Adjuvant Therapy
AM,
8Holmgren
Survival – Continuous Demcizumab Patients
Worst Case Analysis* (Cohorts 1-4)
Probability
2.5
-
R,
8Kapoun
4 CNIO-CIOCC-START,
On-Study Data Only
5
-
D,
% Change in Tumor Size
Dose Level – mg/kg
Patient Demographics (n=46)
Prior Surgery
M,
8Stagg
% Change in RECIST Target Lesion Size
Probability
This is an ongoing open-label Phase 1b dose escalation study of demcizumab plus
pemetrexed and carboplatin in chemotherapy naïve patients with stage IIIb or IV
NSCLC. Prior to enrollment, patients underwent screening to determine study
eligibility. The study endpoints included the determination of the safety profile,
maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, antitumor activity
and biomarkers of Notch signaling and CSCs in blood. Patients received demcizumab
(2.5 or 5 mg/kg), pemetrexed 500 mg/m2 and carboplatin (AUC = 6) every 3 weeks for
6 cycles followed by maintenance demcizumab (first 4 cohorts: CONTINUOUS
DOSING) or demcizumab (5 or 7.5 mg/kg), pemetrexed 500 mg/m2 and carboplatin
(AUC = 6) every 3 weeks for 4 cycles followed by pemetrexed every 3 weeks (5-7
cohorts: TRUNCATED DOSING) until disease progression. Folic acid, vitamin B12
and dexamethasone were administered as pemetrexed pre-medication. Dosing of
patients in the 1st cohort was paused due to emerging evidence of cardiotoxicity
secondary to demcizumab in other ongoing studies. The protocol was subsequently
amended to include a risk mitigation plan which included cardiac monitoring using Btype natriuretic peptide (BNP) testing and echocardiography. In addition, a
cardioprotective medication (i.e., an angiotensin-converting enzyme inhibitor or
carvedilol) was administered to patients with rising BNPs.
As reversible
cardiopulmonary toxicity occurred in 2 patients in the 3rd cohort receiving 5 mg/kg who
were dosed for more than 168 days, the subjects in the 5th-7th cohorts received
truncated dosing of demcizumab (i.e. 5 or 7.5 mg/kg for 4 courses or 63 days of
therapy). A DSMB reviewed the data from each dose cohort after the last subject in
that cohort had been on study for 56 days to decide if it was safe to proceed to the
next dose cohort. Data through March 1, 2015 for cohorts 1-7 are presented. A
randomized Ph2 trial (DENALI) in 1st line non-squamous NSCLC has been initiated.
6
M,
7Harris
3 Monash
Related AEs (All Grades) ≥15% of Pts
by Dose Level (mg/kg)
Methods
6
M,
6Jameson
Line
Adelaide Cancer Centre, Adelaide,
of Auckland, Auckland, New Zealand,
Cancer Centre and Monash University, Melbourne, Australia;
Madrid,
Charles Gairdner Hospital, Perth,
Australia; 6 Waikato Hospital, Hamilton, New Zealand; 7 Christchurch Hospital, Christchurch, New Zealand; 8 OncoMed Pharmaceuticals, Inc., Redwood City, CA; and 9The Royal Brisbane and Woman’s Hospital, Brisbane, Australia.
There is accumulating evidence that the cell types within tumors are heterogeneous
and that a subset of the cells retain the property to self-renew and give rise to more
differentiated progeny. These cells, called cancer stem cells (CSCs) or tumor
initiating cells drive tumor growth and metastasis and are more resistant to
chemotherapy and radiotherapy than the remaining bulk tumor cells. The ability to
characterize the CSCs through surface markers and functional limiting tumor dilution
assays, using minimally passaged human tumors, has enabled the identification of
novel agents that specifically target the CSC population. One pathway which
appears critical for the CSCs is the Notch pathway (Wang J, et al. Notch signaling in
cancer stem cells Adv Exp Med Biol 727:174-85; 2012). The pathway is comprised
of 4 Notch receptors (1-4) and 5 ligands, Jagged (1-2) and delta-like ligand (DLL1, 3
and 4). DLL4 ligand contributes to CSC self-renewal and vascular development.
Additionally, the Notch pathway has been characterized as a regulatory pathway for
immune system function (Mukherjee, et al J.Immunol; 182 (12):7381-8). The
Demcizumab is a humanized IgG2 antibody that blocks DLL4. In minimally
passaged human tumor xenografts, demcizumab was observed to have activity
against a variety of tumors including colorectal cancer, breast cancer, lung cancer,
pancreatic cancer, melanoma and ovarian cancer. The impact of treatment on the
frequency of tumorigenicity was assessed using a limiting dilution assay. In several
models, using different chemotherapeutic agents, while the chemotherapy alone
decreased tumor volume, the frequency of tumor initiating cells was increased in the
residual tumor. In contrast, demcizumab alone decreased the frequency of CSCs
and the greatest reduction was observed when demcizumab was combined with
chemotherapy.
N
B,
5Millward
Australia; 2University
Background
Dose Level –
mg/kg
4Hidalgo
Probability
1
D,
2McKeage
st
1
On study
Low
LEGEND: Patients with TRUNCATED DEM dosing received 4 cycles of demcizumab, carboplatin and pemetrexed followed by pemetrexed
maintenance. Includes 3 patients from cohort 4 who received truncated dosing.
Alive
• An exploratory biomarker analyses performed on baseline tumor specimens from 12 of the
truncated patients suggest a possible relationship between % TILs and survival outcome.
• A randomized Phase 2 trial (DENALI) of demcizumab with carboplatin and pemetrexed in 1st
line non-squamous NSCLC has been initiated and is enrolling subjects in Europe, Australia,
and the United States and this randomized control trial will further explore the effect of DEM,
PEM & Carbo in patients with NSCLC.