Ignyta 8K Regulation FD Disclosure | SEC 18 Apr 16

Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor

in TKI-naïve patients with advanced solid tumors

harboring gene rearrangements

Exhibit 99.1

Alexander Drilon, Filippo

G. De Braud, Salvatore Siena, Sai-Hong I. Ou,

Manish Patel, Myung-Ju

Ahn, Jeeyun

Lee, Todd M. Bauer, Anna F. Farago,

Stephen

Liu,

Natasha

Reddinger,

Rupal

Patel, David Luo,

Edna Chow Maneval, Pratik

S. Multani, Robert C. Doebele, Alice T. Shaw

Disclosures

•

Honoraria: Ignyta, Exelixis, Genentech/Roche

•

Consulting/Advisory Role: Exelixis, Genentech/Roche, AstraZeneca

•

Speaker’s Bureau: Ignyta

•

Research Funding: Foundation Medicine

•

Travel/Accomodations: Ignyta, Exelixis, Genentech/Roche, AstraZeneca

Recurrent Gene Rearrangements

•

Oncogenic drivers across a variety of

cancers

Upstream partner can provide

dimerization domains

ligand-

independent signaling

Activation of downstream pathways

•

Detectable in the clinic

FISH

RNAseq

DNA-based NGS

•

Select fusions are clinically-actionable

responses can be dramatic and durable

Farago et al, J Thorac Oncol. 2015 Dec;10(12):1670-4.

Recurrent Gene Rearrangements

•

NTRK1/2/3, ROS1, and ALK fusions are identified across multiple cancers

lower prevalence in more common cancers

10%

15%

20%

NTRK1

NTRK2

NTRK3

ROS1

ALK

Recurrent Gene Rearrangements

•

NTRK1/2/3, ROS1, and ALK

fusions are identified across multiple cancers

high prevalence events in rare adult and pediatric cancers

Drilon et al, Ann Oncol, 2016 Feb 15. PMID:

26884591

MASC (Mammary Analogue

Secretory Carcinoma)

20%

40%

60%

80%

100%

MASC

Breast

Secretory CA

Congenital

Mesoblastic

Nephroma

Congenital

Fibrosarcoma

NTRK3

5’

3’

Chromosome 12

Chromosome 15

NTRK3

ETV6

RTK

Entrectinib

(RXDX-101)

•

Highly-potent, orally-available, ATP-competitive

tyrosine kinase inhibitor

Low to sub-nanomolar

efficacy against 5 kinases

Results in decreased downstream effector activity

PLC

MAPK

and

PI3K/AKT

pathways

•

Active in vitro and in vivo

NTRK1/2/3-rearranged cancers

ROS1-rearranged cancers

ALK-rearranged cancers

Kinase

IC50 (nM)

TrkA

1.7

TrkB

0.1

TrkC

0.1

ROS1

0.2

ALK

1.6

Entrectinib

(RXDX-101)

•

Active against potential Trk

inhibitor resistance

mutations at clinically achievable exposures

NTRK1

F589L (gatekeeper)

NTRK1

V573M

NTRK1

G667S

TrkA

Kinase domain

Phe589

Val573

Gly667

Mutation in

TrkA

LOXO-101

(nM)

Entrectinib

(nM)

Entrectinib

Human Exposure

Equivalent (nM)

F589L

959.4

9.7

58.2

V573M

534.5

24.2

145.2

G667S

185.3

14.6

87.6

Wildtype

15.0

2.3

13.8

AACR Abstract 2136, Data generated by Ignyta

Phase I Development

STARTRK-1 and ALKA-372-001

Entrectinib: Phase I Studies

STARTRK-1 (n=65)

•

Dosing: continuous

•

NTRK/ROS1/ALK

alterations

•

US, EU, Asia

•

Ignyta

initiated in July 2014

ALKA-372-001 (n=54)

•

Dosing:

intermittent

continuous

•

NTRK/ROS1/ALK

alterations

•

Italy

•

FIH study: Nerviano

Medical Sciences in

October 2012

Ignyta

assumed

responsibility in November 2013

•

RP2D: 600 mg PO once daily, continuous

•

Total clinical experience: n=119 patients

•

Updated safety and efficacy data

•

Data cut-off: March 7, 2016

ALKA-372-001

(n=54)

STARTRK-1

(n=65)

TOTAL

(n=119)

Age, years,

median (range)

53 (46-63)

57 (46-66)

55 (46-66)

Sex,

male/female (%)

44/56

48/52

46/54

ECOG performance

status, n

(%)

30 (56)

22 (34)

52 (44)

21 (39)

41 (63)

62 (52)

2 (4)

2 93)

4 (3)

Unknown

1 (2)

1 (1)

Prior Cancer Therapies, n (%)

6 (9)

6 (5)

1 -2

(23)

15 (13)

3 -

3 (6)

25 (39)

28 (24)

51 (94)

19 (29)

70 (59)

Tumor type,

n (%)

NSCLC

35 (65)

36 (56)

71 (60)

Gastrointestinal Tract

9 (17)

9 (14)

18 (15)

CNS

4 (7)

1 (2)

5 (4)

Head & Neck

1 (2)

4 (6)

5 (4)

Other

(e.g.,

sarcomas,

breast,

melanoma,

RCC,

ovarian)

5 (9)

15 (23)

20 (17)

Baseline Characteristics

Safety

All patients in dose escalation and expansion phases

-advanced solid tumor

-NTRK1/2/3-,

ROS1-,

ALK

alteration

Treatment-Related Adverse Events

•

AEs were classified via CTCAE v4.0; all reversible with dose modifications

•

No evidence of cumulative hepatic

or renal toxicity, or QTc prolongation

•

Only

DLTs

occurred

(STARTRK-1):

grade

cognitive

disturbance,

grade

idiopathic

eosinophilic

myocarditis

Adverse Events (AEs) in >10% of Patients at Any Dose Level (n=119)

Adverse Event

Term, n (%)

Grades 1-2

Grade 3

Total

Fatigue/Asthenia

47 (40)

5 (4)

52 (44)

Dysgeusia

49 (41)

Paresthesia

33 (28)

Nausea

29 (24)

Myalgia

(22)

Diarrhea

22 (19)

1 (1)

23 (19)

Dizziness

19 (16)

Arthralgia

17 (14)

(1)

(15)

Vomiting

18 (15)

Constipation

14 (12)

Adverse Events (AEs) in >10% of Patients at the RP2D (n=45)

Adverse Event

Term, n (%)

Grades 1-2

Grade 3

Total

Dysgeusia

21 (47)

Fatigue/Asthenia

17 (38)

1 (2)

18 (40)

Constipation

10 (22)

Weight Increased

8 (18)

1 (2)

9 (20)

Diarrhea

7 (16)

1 (2)

9 (18)

Nausea

8 (18)

Myalgia

7 (16)

Paresthesia

7 (16)

Dizziness

6 (13)

Peripheral

Sensory Neuropathy

4 (9)

2 (4)

6 (13)

Anemia

2 (4)

3 (7)

5 (11)

Dysphagia

4 (9)

1 (2)

5 (11)

Vomiting

5 (11)

Treatment-Related Adverse Events

Efficacy

Phase 2-Eligible Population

Population

“Phase 2-Eligible Population” (n=25)

NTRK1/2/3-, ROS1-, or ALK-rearranged solid tumor

TKI treatment-naïve

treated at or above RP2D

Molecular Testing: local testing performed

FISH

next-generation sequencing

Response Evaluation

RECIST v1.1, locally assessed and confirmed (n=24)

volumetric assessment (n=1; primary brain tumor*)

* RECIST criteria not validated in primary brain tumors (FDA-AACR Brain Tumor Endpoints Workshop 2006)

Fusion

Confirmed

Responses (n)

ORR (%)

NTRK1/3

3/3

100%

ROS1

12/14

86%

ALK

4/7

57%

Antitumor Activity

Best Response in TKI Treatment-Naïve NTRK-, ROS1-, and ALK-rearranged Tumors (n=24)

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

Fusion

Confirmed

Responses (n)

ORR (%)

NTRK1/3

3/3

100%

1 additional patient with NTRK+ astrocytoma

•

SD by RECIST (not validated

for primary

brain tumors)

•

45% by exploratory 3-D volumetric

assessment

Antitumor Activity

Best Response in TKI Treatment-Naïve NTRK-, ROS1-, and ALK-rearranged Tumors (n=24)

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

NSCLC

MASC

NSCLC

Astrocytoma

RCC

NSCLC

Melanoma

NSCLC

Unknown Primary

CRC

NSCLC

CRC

NSCLC

Time on Study (months)

X = off study

= progression by RECIST, continued due to clinical benefit

Duration of Clinical Benefit

NTRK

ALK

ROS1

= time to response

TKI Treatment-Naïve NTRK-, ROS1-, and ALK-rearranged Tumors (n=25)

•

Response achieved in 100% of tumors

–

Rapid (within 1 month of treatment) and

prolonged ( ~1 year, ongoing) responses

were observed

•

Response achieved in a variety of

histologies and fusion types

–

CRC:

LMNA-NTRK1

–

Astrocytoma:

BCAN-NTRK1

–

NSCLC: SQSTM1-NTRK1

–

MASC: ETV6-NTRK3

NTRK-Rearranged Cancers

3-D volumetric assessment

(courtesy

Brastianos

MD,

MGH)

SD by RECIST v1.1

Best Response in TKI Treatment-Naïve NTRK-rearranged Tumors (n=4)

RECIST v1.1

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

CRC

Astrocytoma

NSCLC

MASC

Response to Entrectinib

34/F with metastatic ETV6-

NTRK3-rearranged

MASC

Resected stage III disease and

post-operative RT in 2006

Recurred in 2011 and treated

with 3 lines of cytotoxic

chemotherapy and RT

NGS revealed an ETV6-NTRK3

rearrangement

Enrolled onto STARTRK-1 in

2015

durable PR, 10 months

entrectinib

treatment

Images: Drilon, MSKCC

baseline

9 weeks on therapy

CNS Activity

CNS Disease in Cancer

Brain metastases

-20-40% of all patients

with cancer

-lung

(up to 50%)

-breast

-melanoma

Primary brain tumors

-astrocytoma (NTRK2

fusions: 3%)

-glioblastoma (NTRK1

fusions: 1-2%)

-pediatric gliomas (NTRK3 fusions: 7%)

Optimal therapy would address both systemic and CNS disease

CNS Activity of Entrectinib

•

Entrectinib

was designed to cross

the blood brain barrier

Blood/brain ratios

Mouse

0.4

Rat

0.6 –

1.0

Dog

1.4 –

1.2

•

Preclinical CNS activity

–

cells injected intracranially

–

treated

with

entrectinib

orally

vehicle for 10 days

EML4-ALK

rearranged

NCI-H228

Response to Entrectinib

46/M with metastatic SQSTM1-NTRK1-rearranged NSCLC

–

Diagnosed in November 2013 with widely metastatic disease

–

4 prior therapies including anti-PD-1: carboplatin/pemetrexed, pembrolizumab,

docetaxel, vinorelbine

–

Poor

baseline

performance

status

(ECOG

2),

supplemental

and

hospice

–

Enrolled in STARTRK-1 March 2015

Farago et al, J Thorac Oncol. 2015 Dec;10(12):1670-4.

Extracranial Response to Entrectinib

Baseline

Day 26: -

47% response

Day 317: -

79% response

Images: Farago and Shaw, MGH

Intracranial Response to Entrectinib

Baseline

Day 26: complete response

Day 317: complete response

Images: Farago and Shaw, MGH

Remains on entrectinib and clinically progression-free > 12 months

•

57/M with low-grade

astrocytoma harboring a BCAN-

NTRK1

gene rearrangement

–

Unresectable

pontine tumor

–

SD by RECIST (not validated for primary

brain tumors)

–

Exploratory 3-Dimensional volumetric

tumor assessment performed showed a

45% decrease in tumor burden

–

Improvements in clinical symptoms of

ataxia and diplopia

entrectinib initiated

Non-Enhancing

Volume

(cm³)

Enhancing

Volume

(cm³)

11.66

cm³

6.45

cm³

Tumor 3-D volumetric assessments courtesy of P. Brastianos

MD (MGH)

Jul 2015

Feb 2016

Primary Brain Tumor Response to Entrectinib

•

20 month-old boy with recurrent, metastatic infantile fibrosarcoma harboring

an ETV6-NTRK3 gene rearrangement

–

Presented at birth with left leg mass, requiring through-the-knee amputation

•

Age

months,

large

metastases

left

lung

identified

24-weeks

chemotherapy

•

Age

months,

large

right

frontal

intracranial

tumor

identified

resected,

followed by 5 cycles of salvage chemotherapy

•

Recurrent CNS disease with lesions in the right frontal and temporal lobes, as well

as leptomeningeal involvement

–

Received entrectinib starting February 2016

Response to Entrectinib

Response to Entrectinib

massive peritumoral edema, midline shift,

transtentorial herniation, progressive lethargy

decreased tumor and edema, patient with

increased alertness, resumed eating and crawling

ETV6-NTRK3 gene rearranged metastatic fibrosarcoma in 20-month old

Summary

•

Entrectinib

is a potent TrkA/B/C Inhibitor

–

Large safety experience (119 patients)

–

Rapid and durable responses

•

Response in 100% (5/5) of patients achieved

in a variety of histologies and fusion types

–

CRC:

LMNA-NTRK1

–

Astrocytoma:

BCAN-NTRK1

–

Infantile

fibrosarcoma:

ETV6-NTRK3

–

NSCLC: SQSTM1-NTRK1

–

MASC: ETV6-NTRK3

•

Dramatic intracranial activity in 100% of

patients with CNS disease (3/3)

–

3/5 of patients treated in Phase 1 setting had

primary or metastatic CNS disease

–

only Trk

inhibitor with demonstrated CNS

activity

thus far

NTRK-Rearranged Cancers

3-D volumetric assessment

(courtesy of P. Brastianos

MD, MGH)

estimated from radiology assessment

RECIST v1.1

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

mCRC

Astrocytoma

Fibrosarcoma

NSCLC

MASC

Response in TKI Treatment-Naïve

NTRK-rearranged Tumors (n=5)

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

ROS1-Rearranged Cancers

•

Response achieved in 86% (12/14) of

TKI-naïve tumors

–

Two complete responders

–

Rapid (within 1 month of treatment) and

prolonged responses were observed

–

In NSCLC, ORR of 85% (11/13 patients)

–

One additional response in melanoma

–

Longest ongoing response approaching

2 years and 3+ months

Best Response in TKI Treatment-Naïve

ROS1-rearranged Tumors (n=14)

Conclusions

•

Entrectinib

is safe and well-tolerated.

–

119 patients have been treated: 45 patients at the RP2D of 600 mg daily

–

therapy duration: 19 patients > 6 months (11 patients > 1 year, including 3 patients > 2 years)

•

Entrectinib

is an active targeted therapy for NTRK-, ROS1-,

and ALK-rearranged cancers.

–

confirmed responses observed in 19/24 (79%) patients with extracranial solid tumors; in addition,

evidence of tumor shrinkage observed in a patient with NTRK+ astrocytoma

–

brisk (within 4 weeks) and durable (up to 2 years and 3+ months) responses were achieved

–

NTRK-rearranged tumors

•

response achieved in 5 different histologies in both adult and pediatric patients

•

Entrectinib

is highly CNS-penetrant.

–

durable responses in both primary brain tumors and metastatic disease

–

complete response observed in the CNS

Current Directions

STARTRK-2

Open-Label,

Multicenter,

Global

Phase

Basket

Study

Entrectinib

for

the

Treatment

Patients

with

Locally

Advanced

Metastatic

Solid

Tumors

that

Harbor

NTRK1/2/3,

ROS1,

ALK

Gene

Thank You

Ignyta Inactive 8-KRegulation FD Disclosure