Olaparib and temozolomide in SCLC · 2018. 5. 8. · PARP inhibition in SCLC. • PARP1 regulates base excision repair, homologous recombination, and non-homologous end joining. Inhibition

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


Dose level 3:

• O 200 mg PO BID


Dose level 4:

• O 200 mg PO BID


Olaparib tablets + Temozolomidedosed days 1-7 of each 21-day cycle


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


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


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

*

*


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

*

*


Phase 2 expansion

Dose level 1:

• O 100 mg PO BID


Dose level 2:

• O 100 mg PO BID


Dose level 3:

• O 200 mg PO BID


Dose level 4:

• O 200 mg PO BID



20 Patient

expansion

Primary EP: ORRSecondary EPs: PFS, OS

Phase 2 expansion

Dose level 1:

• O 100 mg PO BID


Dose level 2:

• O 100 mg PO BID


Dose level 3:

• O 200 mg PO BID


Dose level 4:

• O 200 mg PO BID



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


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


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


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


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


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

Documents

Olaparib and temozolomide in SCLC · 2018. 5. 8. · PARP inhibition in SCLC. • PARP1 regulates base excision repair, homologous recombination, and non-homologous end joining. Inhibition