Desmoid tumor trial using a gamma secretase inhibitornirogacestat (PF-03084014)

Victor M. Villalobos, M.D., Ph.D.Assistant Professor

Director, Sarcoma Medical OncologyDirector, Molecular Oncology Therapeutic Team

Division of Medical Oncology

Disclosures

• Advisory capacity:• Lilly, Novartis, Janssen, Springworks, Ignyta, Abbvie

Gamma secretase inhibition in desmoid

• Gamma secretase is an integral membrane protein that cleaves multiple different transmembrane protein complexes including:• NOTCH• E-CADHERIN• Amyloid Precursor Protein• others

• Nirogacestat is a noncompetitive, reversible, targeted agent that selectively inhibits gamma secretase

• Activation of WNT pathway through B-Cat or APC mutations appears to be primary driver in desmoid tumors

• Hypothesis that cooperativity exists between WNT pathway activation and active NOTCH signaling.

• Inhibition of NOTCH may reverse activation of B-catenin due to mutations in Bcat or APC. Hughes, D. P. M. et al. , Clinical Cancer Research 21, 7–9 (2015).

Prior studies in desmoid have shown drugs with efficacy

• Azzarelli et al. – Vinblastine & methotrexate (adults)• 40% Partial Response rate no CR, n = 30

• PFS @ 2 years 84%

• Skapek et al. - COG ARST0321 – Tamoxifen + Sulindac• 8% Partial Response + Complete Response rate (1 CR /4 PR), n = 59

• Progression Free Survival @ 2 years 36%

• Gounder et al. – sorafanib• 25% Partial Response rate, n = 24

• Messersmith et al. – PF-03084014 (GSI)• 72% Partial Response rate, n=7

• 85% Progression Free Survival @ 5 years

Azzarelli, A. et al. Cancer 92, 1259–1264 (2001).Skapek, S. X. et al. Pediatr. Blood Cancer 60, 1108–1112 (2012).Gounder, M. M. et al. Clinical Cancer Research 17, 4082–4090 (2011).Messersmith, W. A. et al. Clinical Cancer Research 21, 60–67 (2015).

A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oralg-Secretase Inhibitor PF-03084014 (nirogacestat)

• 64 patients (solid tumors) enrolled in 3+3 dose escalation design.

• MTD: 220 mg BID orally (n=16)

• RP2D was 150 BID orally (n=23)

• A total of 9 desmoid patients were enrolled (7 at UC Denver)

Messersmith, W. A. et al. Clinical Cancer Research 21, 60–67 (2015).

Patient# Sex Location of tumor

Initial RECIST

dimension

(cm)

Initial WHO

dimension

(cm2)

Age at

Start of

Trial

1 F Pelvis 22.3 109.1 29

2 M Abdomen/Mesentery 14.9 76.4 45

3 M LowerExtremity 10.5 33.2 35

4 M Abdomen 23.9 181.8 28

5 F Trunk 33.7 350.6 35

6 M LowerExtremity 2.7 49.6 46

7 F ProximallowerExtremity 13.3 100.3 32

BaselineCharacteristics

Desmoid tumor patients at CU Denver

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

- 12 24 36 48 60 72 84

RESPONSESONGAMMASECRETASEINHIBITORPF03084014INDESMOIDTUMORS(months)

Known germlineAPCmutationSpontaneousdesmoid▲ 80 mgBID▲ 100mgBID▲ 130mgBID

● 150mgBID

◼ 220mgBID

Arrows:Patientsstoppedtherapy,maintaineddiseasestabilitydespite nofurtherintervention

Patientwasbiopsiedatendofstudyandpathologyshowedpaucicellulartissuewithprominentcollagenousfibrosis

Nirogacestat in Desmoid tumors

• 7 desmoids accrued at UCD (9 total)

• Overall RECIST response rate of 71.4%

• Median TTP – Not met

• Median DOR – 49.8+ mo. (47.9-67+ mo.)

• Mean time to response -8.7 mo.

• Effective even at low doses (80 mg BID)

T1 post 6 weeks after starting

T1 post Pretreatment

T1 post 4 years after starting

T2 pre 6 weeks after starting

T2 pre Pretreatment

T2 pre4 years after starting

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

- 12 24 36 48 60 72 84

RESPONSESONGAMMASECRETASEINHIBITORPF03084014INDESMOIDTUMORS(months)

▲ 80 mgBID▲ 100mgBID▲ 130mgBID

● 150mgBID◼ 220mgBID

Treatment effects

• Even in absence of RECIST response, there were considerable treatment effects

• Arrow – came off study at 42 months due to patient preference

2 monthsPretreatment 4 months

6 months 10 months 14 months

36 months 48 months 54 months

Off

Th

erap

y

2012 Biopsy prior to treatment 2015 End of treatment biopsy

Pathologic response to therapy

Paucicellular fibroconnective tissue with prominent collagenous fibrosis

Desmoid fibromatosis

0 1 2 3 4 5 6 7 8 9 10 11 12

1

2

3

4

5

6

7

Timetotreatmentfailureineachpatientinchronologicorder(weeks)

Treatmentduration(years)

PF-03084014(GSI)

OffRx FreeofProgressionTamoxifen/SulindacSurgeryMethotrexate/VinblastineVinorelbineImatinibIndomethacinLiposomal Doxorubicin

Time to treatment failure of therapies (chronologic)42

54

9.5

15

15 47

53 13

78

78

0 1 2 3 4 5 6 7 8 9 10 11 12

1

2

3

4

5

6

7

Timetotreatmentfailureineachpatientinchronologicorder(weeks)

Treatmentduration(years)

PF-03084014(GSI)

OffRx FreeofProgressionTamoxifen/SulindacSurgeryMethotrexate/VinblastineVinorelbineImatinibIndomethacinLiposomal Doxorubicin

Time to treatment failure of therapies (chronologic)

42

54

9.5

15

15 47

53 13

78

78

4/28/11 baseline

Week 63Taken off study for patient protocol violation

10/8/14 Week 142

5/12/16 Week 262

RECIST 17cm% Change ----WHO 171.7 cm2% Change -----

RECIST 11.7 cm% Change -31%WHO 34.6 cm2% Change -80%

RECIST 12cm% Change -30%WHO 24.7 cm2% Change -85%

RECIST 12.3 cm% Change +5%WHO 27.1 cm2% Change + 10%

Kummar, S. et al. JCO.2016.71.199–11 (2017).

NCI experience with nirogacestat

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

0 52 104 156 208

%change

Weeks

Patient6

RECIST

WHO

T1postratio

T2ratio

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

- 52 104 156 208

%change

Weeks

Patient7

RECIST

WHO

T1postratio

T2RATIO

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

- 52 104 156 208

%change

Weeks

Patient3

RECIST

WHO

T1postratio

T2preratio

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

- 12 24 36 48 60 72

%change

Weeks

Patient5

RECIST

WHO

T1postratio

T2ratio

Different methods for measuring efficacy

• Consider using MRI enhancement changes.

• Unable to use enhancement as it is unitless

• Can create a ratio of enhancement of tumor to muscle to normalize data.

• Rapid changes may foretell RECIST response

Changes in CT density (Hounsfield Units)

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

- 52 104 156 208 260 312

%change

Weeks

Patient4

RECIST

WHO

DENSITYCT

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

- 52 104 156 208 260 312 364

%change

Weeks

Patient2

RECIST

WHO

DensityCT

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

- 52 104 156 208 260 312 364

%change

Weeks

Patient1

RECIST

WHO

DensityCT

Time to response

RECIST 1.0 WHO MER -T1

post contrast

MER - T2

pre contrast

CT - density

(houndsfield

units)

Mean time to response (mo.) 11.9 13.5 3.5 1.6 3.7

95% Confidence interval (mo.) (-1.7 - 25.1) (-3.1 - 30.1) (1.1 - 5.9) (1.0 - 2.2) (-1.8 - 9.2)

n 5 5 3 3 3

Response cutoff -30%

2-axes

-30

1-axis

-30%

Tumor/muscle

ratio

-30%

Tumor/muscle

ratio

+20% tumor

density HF

Conclusions – nirogacestat gamma secretase inhibitor

• Exciting potential for use in desmoid patients

• 72% RECIST response rate

• Active at even low doses (as low as 80mg BID)

• Tolerable side effect profile (primarily diarrhea, hypophosphatemia)

• Clinical benefit in 100% of patients (only patient with progression had mild regression lasting 12 months)

• Even if no response by size criteria, evidence of tumor activity on pathology

• Working on further clinical development

Acknowledgements

• Phase I team• Wells Messersmith MD

• Antonio Jimeno MD, PhD

• Lia Gore MD

• Sarcoma Team • Anthony Elias MD

• Brianna Hoffner NP

• Pfizer

• Springworks