olaparib and temozolomide in sclc · 2018. 5. 8. · parp inhibition in sclc. • parp1 regulates...
TRANSCRIPT
Olaparib and temozolomide in SCLC
Anna Farago, MD, PhD and Benjamin Drapkin, MD, PhD
March 16, 2018
Disclosures
Farago:
• Consulting fees from: PharmaMar, AbbVie, Takeda, Merrimack, Loxo Oncology
• Honorarium from: Foundation Medicine
• Research funding (to institution) from: AstraZeneca, AbbVie, Novartis, PharmaMar, LoxoOncology, Ignyta, Merck, Bristol-Myers Squibb
Drapkin:
• Research funding (to institution) from: AstraZeneca, AbbVie, Novartis
Bedside to Bench… and Back
PARP inhibition in SCLC
• PARP1 regulates base excision repair, homologous recombination,
and non-homologous end joining. Inhibition of PARP enzymatic
activity blocks PARP-mediated DNA repair.1
• PARP1 is highly expressed in SCLC compared to other cancers.2, 3
• SCLC cell lines are sensitive to PARP inhibitors. PARP sensitivity
is not associated with BRCA1/2 mutations or HR defects.4,5
• “Trapping” of PARP complexes to sites of DNA single stranded
breaks by PARP inhibitors can cause failure of repair and induction
of double strand breaks.6
• PARP inhibitors synergize with agents that increase prevalence of
single stranded breaks in tumor models, including SCLC models.7,8
1. Sonnenblick et al., 20152. Byers et al., 20123. Cardnell et al., 20134. Stewart et al., 20175. George et al., 20156. Hopkins et al., 20157. Murai et al., 20148. Lok et al., 2016
Farago et al., Presented at AACR annual meeting 2017
Rationale for olaparib + temozolomide in relapsed SCLC
• Catalytic inhibitor of PARP1 and
PARP2
• Moderate PARP-trapping activity1
• FDA-approved as monotherapy for
patients with BRCA-mutated
advanced ovarian cancer and for
patients with germline BRCA-mutated
breast cancer
Olaparib Temozolomide• Alkylating agent that induces
single strand DNA breaks
• FDA-approved in newly
diagnosed glioblastoma
multiforme and refractory
anaplastic astrocytoma
• Single agent activity in SCLC2
• STOMP UK trial: Maintenance olaparib vs placebo following first-line chemotherapy. No
PFS or survival benefit.
• SCLC second-line phase 2 study: temozolomide + veliparib vs temozolomide + placebo.
Improved response rate with combo, but no significant difference in 4-month PFS.4
1. Hopkins et al., 20152. Pietanza et al., 20123. Pietanza et al., ASCO
Abstract # 8512, 2016
PARP inhibitors are not created equally
Veliparib Olaparib Niraparib Talazoparib
• Olaparib + temozolomide greater PARP trapping than veliparib + temozolomide
• PARP inhibitors have varying PARP trapping activity in vitro
Schematic only, not drawn to scale
Murai et al., 2014Hopkins et al., 2015Murai et al., 2012
Less PARP trapping More PARP trapping
Phase 1 study schema: olaparib tablets and temozolomide in SCLC
• Histologically confirmed SCLC, not a
candidate for potentially curative
therapy
• Radiographic progression after one
platinum based chemotherapy
regimen (with any additional number
of subsequent therapies allowed)
• ECOG PS 0-2
• Treated and stable brain metastases
are allowed. Asymptomatic brain
mets < 1 cm are allowed.
• Primary objective: Determine RP2D of combination olaparib and temozolomide
• Secondary objectives: Safety and tolerability, exploratory biomarker analyses
• Dose limiting toxicities (DLTs) monitored during cycle 1
• Disease assessment Q6 weeks, RECIST 1.1
NCT02446704
Dose level 1:
• O 100 mg PO BID
• T 50 mg/m2 PO QPM
Dose level 2:
• O 100 mg PO BID
• T 75 mg/m2 PO QPM
Dose level 3:
• O 200 mg PO BID
• T 75 mg/m2 PO QPM
Dose level 4:
• O 200 mg PO BID
• T 100 mg/m2 PO QPM
Olaparib tablets + Temozolomidedosed days 1-7 of each 21-day cycle
Farago et al., Presented at AACR annual meeting 2017
Phase 1 Patient characteristics
N=13
Age, years, median (range) 66.3 (39.2 – 85.2)
Sex, male/female (%) 4 (31) / 9 (69)
ECOG performance status, n (%)
0 0
1 12 (92)
2 1 (8)
Prior cancer therapies, n (%)
1 3 (23)
2 4 (31)
3 1 (8)
>3 5 (38)
Prior response to platinum-based therapy*
Sensitive (%) 8 (62)
Resistant (%) 5 (38)
* Based on time from completion of first-line therapy to start of second-line therapy.
Sensitive: ≥ 90 days Resistant: < 90 days
Farago et al., Presented at AACR annual meeting 2017
Phase 1 Treatment emergent adverse events related to study drugs
Adverse Event Term, n (%) Grade 1 Grade 2 Grade 3 All Grades
Anemia 4 (31) 1 (8) 3 (23) 8 (62)
Nausea 5 (38) 3 (23) 0 8 (62)
Thrombocytopenia 2 (15) 4 (31) 2 (15) 8 (62)
Neutropenia 0 0 5 (38) 5 (38)
Fatigue 2 (15) 2 (15) 0 4 (31)
WBC count decreased 1 (8) 3 (23) 0 4 (31)
Vomiting 2 (15) 0 1 (8) 3 (23)
Diarrhea 1 (8) 1 (8) 0 2 (15)
AST elevation 2 (15) 0 0 2 (15)
Listed are adverse events that were reported in at least 2 of the patients and that were deemed by the investigators to be
possibly, probably, or definitely related to study drug(s). For each patient, only the highest grade of each AE is included.
There were no DLTs, SAEs or grade 4 or 5 AEs.
Data cut off: Feb 6, 2017
Farago et al., Presented at AACR annual meeting 2017
Phase 1 Efficacy
Best responseDose level
1
Dose level
2
Dose level
3
Dose level
4
All dose
levels (%)
Partial response 2 1 2 1 6 (46)
Stable disease 1 1 1 2 5 (38)
Progressive disease 0 1 1 0 2 (15)
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
Be
st O
bje
ctiv
e R
esp
on
se, R
ECIS
T 1
.1
Objective response rate
all confirmed responses46%
Shown are responses for all patient treated in the phase 1 portion (N=13)
Patient with 0% response, progressive disease (new lesion)
* Patients still on treatment as of data cutoff, Feb 6 2017
*
*
Farago et al., Presented at AACR annual meeting 2017
Phase 1 Efficacy by platinum sensitivity
Best responseDose level
1
Dose level
2
Dose level
3
Dose level
4
All dose
levels (%)
Partial response 2 1 2 1 6 (46)
Stable disease 1 1 1 2 5 (38)
Progressive disease 0 1 1 0 2 (15)
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
Be
st O
bje
ctiv
e R
esp
on
se, R
ECIS
T 1
.1
Objective response rate
all confirmed responses46%
Shown are responses for all patient treated in the phase 1 portion (N=13)
Patient with 0% response, progressive disease (new lesion)
* Patients still on treatment as of data cutoff, Feb 6 201711
Platinum sensitive
Platinum resistant
*
*
Farago et al., Presented at AACR annual meeting 2017
Phase 2 expansion
Dose level 1:
• O 100 mg PO BID
• T 50 mg/m2 PO QPM
Dose level 2:
• O 100 mg PO BID
• T 75 mg/m2 PO QPM
Dose level 3:
• O 200 mg PO BID
• T 75 mg/m2 PO QPM
Dose level 4:
• O 200 mg PO BID
• T 100 mg/m2 PO QPM
Olaparib tablets + Temozolomidedosed days 1-7 of each 21-day cycle
20 Patient
expansion
Primary EP: ORRSecondary EPs: PFS, OS
Phase 2 expansion
Dose level 1:
• O 100 mg PO BID
• T 50 mg/m2 PO QPM
Dose level 2:
• O 100 mg PO BID
• T 75 mg/m2 PO QPM
Dose level 3:
• O 200 mg PO BID
• T 75 mg/m2 PO QPM
Dose level 4:
• O 200 mg PO BID
• T 100 mg/m2 PO QPM
Olaparib tablets + Temozolomidedosed days 1-7 of each 21-day cycle
20 Patient
expansion
Further expansion underway
with additional dosing
strategies planned
Primary EP: ORRSecondary EPs: PFS, OS
New patient-derived xenograft (PDX) models of SCLC
CTC-iChip
Treatment
Repeat as above
Relapse
Biopsy
(if available)
NSG mouse
Latency
PDX Samples:
• Fix for IHC/IF
• Snap freeze
• Cryopreserve
P0 P1 P2
In collaboration with Shyamala Maheswaran and Daniel Haber
1. Library of PDX models, including OT trial patients
2. Model responses mirror patient responses
3. Molecular determinants of sensitivity to OT
Library of SCLC PDX models
Patient Course
MGH1505
MGH1506
MGH1508
MGH1512
MGH1515
MGH1517
MGH1520
MGH1521
MGH1522
MGH1523
MGH1524
MGH1501
Model #
MGH1504
MGH1514
MGH1518
Patient Course
MGH1545
Model #
MGH1529
MGH1528
MGH1534
MGH1536
MGH1541
MGH1543
MGH1535
MGH1537
MGH1525
MGH1538
MGH1542
Platinum/etoposide (EP)
Other treatment
CTC-derived
Biopsy-derived
Models initiated June 2014 – June 201634 models from 27 patients
Update as of December 2017 44 models from 32 patients
PDX Take Rate
(P0 / attempts, monitored 365 days)
CTC (iChip) 38% (16/42)
CTC (RosetteSep/Ficoll) 1/4
Biopsy (Bx.) 89% (16/19)
Effusions (Eff.) 1/3
Pathologic Fidelity
Model H&E + IHC
c/w SCLC
32/34 models
Model H&E ≈ Patient 14/14 models
Model IHC ≈ Patient 12/13 models
Drapkin et al., Cancer Discovery 2018
Comparative whole exome sequencing between tumor biopsy and
xenografts shows genomic fidelity of PDX models
Patient
biopsy PDX P0 PDX P1 PDX P2
vs.
1 3 5 7 9 11 13 15 17 19 21
2 4 6 8 10 12 14 16 18 20 22
Integral Copy Number (iCN)
< 0.3 >6.02.0
Model Source
MGH1504-1 CTC
MGH1512-1 biopsy
MGH1514-1 CTC
MGH1515-1 CTC
MGH1518-1 biopsy
MGH1525-1 CTC
MGH1528-1 CTC
281 159110
308 194
MGH1515-1
MGH1518-1
MGH1525-1
MGH1504-1 MGH1512-1 MGH1514-1
21 116
In collaboration with Roman Thomas and Julie George
Drapkin et al., Cancer Discovery 2018
Currently expanding these models for distribution at early passage
Sensitivity of the PDX library to first-line chemotherapy
vs.Naïve (12) Relapsed (18)
30 PDX trial with EP
MGH1518 EP
0 14 28 42 56 70 0 14 28 42 56 70
100
200
0
% IT
V
Days
PDX population trial approach
1. Dosing regimen that distinguishes serial models
2. Apply regimen across PDX panel
TTP (2x ITV)
Response (%ITV)
Tumor Metrics
0 14 28 42 56 70
100
200
0
% IT
V
Cis 7 mpk d1
Etop 10 mpk d1-3
d14-28 response
assessment window
Days
Drapkin et al., Cancer Discovery 2018
PDX model response to EP reflects
patient treatment history
-120%
-90%
-60%
-30%
0%
30%
60%
90%
120%
150%
MG
H15
18-3
M
GH
151
2-1
B
MG
H15
41-1
M
GH
15
34-2
M
GH
1512
-1A
M
GH
15
34-1
M
GH
15
34-3
M
GH
1546
-1A
M
GH
151
4-2
B
MG
H15
35-1
M
GH
15
25-1
M
GH
15
14-1
M
GH
15
57-1
M
GH
15
23-1
M
GH
1514
-2A
M
GH
1518
-1C
M
GH
151
8-1
B
MG
H1
546
-2A
M
GH
15
20-1
M
GH
15
24-1
M
GH
15
15-1
M
GH
153
8-1
B
MG
H15
04-1
M
GH
15
46-2
M
GH
15
48-1
M
GH
15
43-1
M
GH
15
37-1
M
GH
1545
-1A
M
GH
15
22-1
M
GH
15
42-1
Be
st R
esp
on
se
(%
ITV
)
+100
0
-100
p = 0.0065
Be
st R
esp
on
se
(%
ITV
)
Treatment-
naïve
Post-
relapse
Drapkin et al., Cancer Discovery 2018
100
50
0
Pe
rce
nt <
2x IT
V
Log-rank p = 0.047
TTP (fold-increase in doubling time)
2 4 6 8 10
PDX model response to EP reflects
patient treatment history
-120%
-90%
-60%
-30%
0%
30%
60%
90%
120%
150%
MG
H15
18-3
M
GH
151
2-1
B
MG
H15
41-1
M
GH
15
34-2
M
GH
1512
-1A
M
GH
15
34-1
M
GH
15
34-3
M
GH
1546
-1A
M
GH
151
4-2
B
MG
H15
35-1
M
GH
15
25-1
M
GH
15
14-1
M
GH
15
57-1
M
GH
15
23-1
M
GH
1514
-2A
M
GH
1518
-1C
M
GH
151
8-1
B
MG
H1
546
-2A
M
GH
15
20-1
M
GH
15
24-1
M
GH
15
15-1
M
GH
153
8-1
B
MG
H15
04-1
M
GH
15
46-2
M
GH
15
48-1
M
GH
15
43-1
M
GH
15
37-1
M
GH
1545
-1A
M
GH
15
22-1
M
GH
15
42-1
Be
st R
esp
on
se
(%
ITV
)
+100
0
-100
p = 0.0065
Be
st R
esp
on
se
(%
ITV
)
Treatment-
naïve
Post-
relapse
Drapkin et al., Cancer Discovery 2018
MYC regulon vs. EP response
0 20
20
EP
Re
sp
on
se
(ra
nk)
Regulon (rank)In collaboration with Camilla Christensen and Ruben Dries
ρ = - 0.78
Serial PDX models derived before and after
olaparib + temozolomide (OT)
Baseline Day 89: Nadir Day 158: Progression
OTECMGH1528 Clinical Course:
MGH1528-1 MGH1528-2MGH1528
CTC-derived
models
0 14 28 42 56 70Days
% I
TV
200
100
00 14 28 42 56 70Days
200
100
0
% I
TV
Days 1-5:
Ola 50 mpk bid
TMZ 25 mpk qd
Vehicle ctrl.
tumor volume
Drapkin et al., Cancer Discovery 2018
Conclusions
• OT is tolerable and shows promising clinical activity
– Phase I with 6/13 responses from pre-treated SCLC patients
– Phase II expansion underway with additional dosing strategies planned
• Efficient generation of SCLC PDX’s from biopsies, effusions or CTCs
• Genomic alterations retained, and few changes with passaging
• PDX responses reflect patient clinical course
– Sensitivity to EP reflects donor patient history
– Sensitivity to OT reflects trial patient responses
• Ongoing experiments to assess biomarkers and mechanism of OT activity in
PDX models.
Acknowledgements
Nick Dyson
Marcello Stanzione
Sarah Phat
David Myers
Jun Zhong
Peter Igo
Vashine Kamesan
Roxana Azimi
Jane Bailey Grinnell
Dyson LabIoannis Sanidas
Ana Guarner-Peralta
Badri Krishnan
Katerina Fella
Haber/Maheswaran LabDaniel Haber
Shyamala Maheswaran
Joseph Licausi
Dana Farber
Camilla Christensen
Ruben Dries
Kwok-Kin Wong
University of Cologne
Roman Thomas
Julie George
Martin Peifer
Nima Abedpour
MGH Cancer CenterMari Mino-Kenudson
Aaron Hata
Cyril Benes
Lee Zou
MGH Thoracic Oncology
Alice Shaw
Lecia Sequist
Jerry Azzoli
Rebecca Heist
Justin Gainor
Zosia Piotrowska
Jennifer Temel
Inga Lennes
Funding
U24 for SCLC
V Foundation
Lung Cancer Research Foundation
ASCO YIA
Novartis-MGH Alliance