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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)
1McKeage
2
M, Kotasek
1University
D,
3 Markman
B,
4Hidalgo
Zealand; 2
M,
5Millward
M,
6Jameson
M,
7Harris
D,
8Stagg
Australia; 3 Monash
R,
8Kapoun
8Holmgren
A,
4 CNIO-CIOCC-START,
E,
8Dupont
J,
9Hughes
st
1
Line
B
Spain; 5 Sir
of Auckland, Auckland, New
Adelaide Cancer Centre, Adelaide,
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.
Related AEs (All Grades) ≥15% of Pts
by Dose Level (mg/kg)
5
7.5
5
5
(Cohort1)
(Cohort2)
(Cohort3)
Expansion*
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
6
8
6
6
7
7
46
Median age (years)
66.5
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 Surgery
-
-
1
2
-
2
2
7
Prior Neo-adjuvant/
Adjuvant Therapy
-
-
-
-
-
3
1
4
Prior Radiotherapy
2
* 3 of these patients received truncated dosing
4
Total
(Cohort2)
(Cohort3)
Expansion
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
On-Study Data Only
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*)
Pulmonary
hypertension(Reversible)
5
2.5
5
5
7.5
5
5
(Cohort1)
(Cohort2)
(Cohort3)
Expansion*
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
1
mPFS (95% CI) = 5.7 mos (3.3-11.0)
LEGEND: Patient demographics and laboratory parameters were assessed to determine which factors were associated with the prolonged
survival tail on the KM curve BLUE curve: High values or male gender; BLACK curve: Low Values and female gender. The variables
were: Age (> < 65); Gender: Male/female; Stage at diagnosis: III/IV; ECOG 0/1; Serum albumin >< 4; Eosinophils >< 0.1; Carcinoembryonic
antigen (CEA): >< 4. Across all these patient variables the survival tail on the Kaplan-Meier curves remains evident.
*
* One of the patients with 100% reduction in their target lesion size did not have a CR, as there was residual non-target disease
Dose Level- mg/kg
Includes Off-Study Data
mPFS (95%CI) = 5.8 (3.3- 11.0) mos
8
Patient Subset Analyses: Survival (All Pts)
Survival Probability
(Cohort1)
6
LEGEND: Patients with TRUNCATED DEM dosing received 4 cycles of demcizumab, carboplatin and pemetrexed followed by pemetrexed
maintenance. Includes 3 patients from cohort 4.
Exploration of Death Hazard Before & After 300D
6
6
8
6
6
7
7
46
-
-
2**
-
-
-
-
2 (4%)
-
-
1**
-
-
-
-
1 (2%)
Right-sided
heart failure (Reversible)
-
-
1**
-
-
-
-
1 (2%)
Dose Level mg/kg
5
2.5
5
5
7.5
5
5
Total
(Cohort1)
(Cohort2)
(Cohort3)
Expansion*
Truncated
Truncated
Truncated
(Cohort4)
(Cohort5)
(Cohort6)
(Cohort7)
(40 Evaluable)
1
-
-
-
Complete
Response
-
Partial Response
2
-
-
Follow Up
Cohort
Group
Continuous Dosing*
(N=23)
<300 Days
2
-
4
3
4
2
2
4
2
1
2
2
15 (38%)
Clinical Benefit
(SD + PR + CR)
4
6
6
3
5
5
6
35 (88%)
P-value
1446
7
7969
2
* Patients with CONTINUOUS DEM dosing received 6 cycles of demcizumab, carboplatin and pemetrexed followed by demcizumab maintenance. Excludes 3 patients
from cohort 4.
19 (48%)
Stable Disease
Events
<0.05
>300 Days
4
Days
mOS (95%CI) = 6. 3 mos (3.2-NR)**
1 (3%)
* 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
Effect on Notch and Angiogenesis Related
Gene Expression in Whole Blood (All Cohorts)
Survival – Continuous Demcizumab Patients
Worst Case Analysis* (Cohorts 1-4)
RECIST Best Overall Response (n=46)
Total
Congestive heart failure
(Reversible)
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
Fold Change from Baseline: 95%CI
Progressive
Disease
-
-
1
2
1
-
1
5 (13%)
Not Evaluable
2
-
1
1
-
2
-
6
• 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.
• 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).
* 3 of these patients received truncated dosing
Control
Subjects
Progression-Free Survival
Continuous Demcizumab Patients (Cohorts 1-4)
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.
Survival – Truncated Demcizumab Patients
(Cohorts 5-7)
Includes Off-Study Data
On-Study Data Only
mPFS (95% CI) = 5.3 (3.2-6.3) mos
Effect on Notch Pathway Gene Expression
In Whole Blood (By DEM Dose Cohort)
Total
6
1
5
mPFS (95% CI) = 5.6 (3.7-19.1) mos
NOTCH2
Median (95% CI) Survival = 8.1 months (5.8-NR)
• The truncated DEM treatment and patient monitoring with BNP and ECHO appears to
prevent the onset of late cardiopulmonary toxicity.
• The Ph2 dose of DEM at 5mg/kg Q3W shows sustained pharmacodynamic modulation of
the Notch pathway in patient samples.
• 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 5.7 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.
Survival Probability
5
2
5
Survival Probability
2.5
5
7.5
Survival Probability
5
1
5
LEGEND: Notch and angiogenesis genes are significantly modulated in the whole blood of NSCLC patients treated by DEM+SOC
(Pemetrexed and Carboplatin). The biomarkers are not significantly regulated in control subjects not treated by DEM. They are also are not
significantly change in PDX models treated by the SOC alone, but are regulated in PDX models by DEM treatment.
Patient Demographics (n=46)
N
5
6
N
Dose Level –
mg/kg
2.5
N
Methods
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.
5
Survival Probability
Dose Level – mg/kg
Progression-Free Survival
Truncated Demcizumab Patients (Cohorts 5-7)
Survival Probability
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.
% Change in RECIST Target Lesion Size
% Change in Tumor Size
Background
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Notch pathway genes show clear modulation in truncated and
non-truncated cohorts and at Phase 2 dose (5.0 mg/kg Q3W)
PD modulation observed up to ~77 days post last infusion in
some pts
• 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.
NOTCH1
• Worst case analysis suggests that the plateau at the tail of the continuous DEM survival
curve is not due to selective reporting of survival. The forest plot assessing patient factors
suggests that the tail is not due to selective enrollment. A review of off-study meds and the
observed plateau at the tail for PFS suggests that this plateau is not caused by treatment
received off of study (data not shown).
MAML3
LEGEND: Patients received 6 cycles of demcizumab, carboplatin and pemetrexed followed by demcizumab maintenance.
Excludes 3 patients from cohort 4.
16
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.
LEGEND: Patients with TRUNCATED DEM dosing received 4 cycles of demcizumab, carboplatin and pemetrexed followed by pemetrexed
maintenance. Includes 3 patients from cohort 4.
Corresponding Author: Jakob Dupont
email: [email protected]
• 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 in patients with NSCLC.