Ignyta 8-K Ignyta Announces Interim Data from

Filippo G. De Braud

1

, Lorenzo Pilla

1

, Monica Niger

1

, Silvia

Damian

1

, Benedetta Bardazza

1

, Antonia Martinetti

1

, Giuseppe

Pelosi

1

, Giovanna Marrapese

2

, Laura Palmeri

2

, Giulio Cerea

2

,

Emanuele Valtorta

2

, Silvio Veronese

2

, Andrea Sartore-Bianchi

2

,

Elena Ardini

3

, Marcella Martignoni

4

, Antonella Isacchi

3

, Arturo

Galvani

3

, David Luo

5

, Litain Yeh

5

, Adrian Senderowicz

5

,

and Salvatore Siena

2

1

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;

2

Ospedale Niguarda Ca' Granda, Milan, Italy;

3

Nerviano Medical Sciences, Nerviano, Italy;

4

CLInical Organization for Strategies & Solutions (CLIOSS), NMS

Group, Nerviano, Italy;

5

Ignyta, Inc., San Diego, CA

Phase 1 Open Label, Dose Escalation

Study of RXDX-101, an Oral Pan-Trk,

ROS1, and ALK Inhibitor, in Patients with

Advanced Solid Tumors with Relevant

Molecular Alterations

Exhibit 99.2

Abstract

2

Background:  RXDX-101 is a small molecule inhibitor of TrkA, TrkB, TrkC, ROS1 and ALK, with high

potency and selectivity. RXDX-101 demonstrated potent pharmacological activity in preclinical studies

and is potentially first-in-class against the Trk family of kinases. This study aims to determine MTD, PK,

PD and anti-tumor activity in patients with advanced cancer and applicable molecular alterations.

Methods:  Phase 1 dose escalation in patients with advanced solid tumors. RXDX-101 was dosed orally

once/day in a 4 day on, 3 day off schedule for 3 weeks, followed

by a 7 day rest period, in continuous

28-day cycles (Schedule A); once/day in continuous 28-day cycles (Schedule B); and once/day in a 4

day on, 3 day off schedule without interruption in continuous 28-day cycles (Schedule C). Minimum of 3

patients were enrolled at each dose level. Endpoints include safety, PK, and tumor response by RECIST.

Results:

19

patients

have

been

treated

at

6

dose

levels

(100,

200,

400,

800,1200

and

1600

mg/m

)

in

Schedule

A;

3

patients

at

one

dose

level

(200

mg/m

)

in

Schedule

B;

and

3

patients

at

one

dose

level

(400

mg/m

)

in

Schedule C.  RXDX-101 has been well tolerated to date; the MTD has not been reached.  No DLT has

been seen at any dose level in any dosing schedule. The most common AEs (mainly grade 1-2)

considered possibly treatment-related included paresthesia, nausea, diarrhea, asthenia, myalgia,

vomiting, arthralgia, and dysgeusia.  There was one possibly treatment-related grade 3 AE of asthenia.

No treatment-related serious adverse events have been reported.

A patient with colorectal carcinoma (TrkA+) had a PR and progressed after cycle 4.  One patient with

NSCLC (ROS1+) has achieved CR, and three patients with NSCLC (2 ROS1+; 1 ALK+) have achieved

PRs, and all remain on treatment. An additional patient with neuroblastoma (ALK+) has a PR and is

currently in cycle 21. Two patients have had prolonged stabilization of their disease: a patient with

NSCLC (ALK+) in cycle 19 who remains on treatment and a patient with pancreatic cancer (ROS1+) who

progressed in cycle 11.

PK analysis shows maximum concentrations of RXDX-101 were generally achieved within 2 to 4 hours

following dosing and exposure increased in an approximate dose proportional manner up to doses of

800

mg/m

with

minimal

accumulation

following

multiple

doses.

Mean

plasma

half-life

was

17

to

44

hours and steady state reached within 4 days.

Conclusions: RXDX-101 intermittent and continuous dosing schedules have been well tolerated in

patients with advanced solid tumors.  Early responses in patients with 3 different relevant molecular

alterations are promising.  A global phase I/II trial was recently initiated.

2

2

2

2

Introduction

RXDX-101 is a potent, selective, orally available inhibitor of the tyrosine kinases TrkA

(coded by the gene NTRK1), TrkB (coded by the gene NTRK2), TrkC (coded by the gene

NTRK3),

ROS1

(coded

by

the

gene

ROS1),

and

ALK

(coded

by

the

gene

ALK).

Molecular

alterations to these targets are present in several different tumor types, including non-small

cell lung cancer (NSCLC), colorectal cancer (CRC), papillary thyroid cancer, pancreatic

cancer, and neuroblastoma, among others.

Potent in vitro and in vivo antitumor effects have been observed

in several TRK, ROS1 and

ALK-dependent tumor models. Antitumor effects in the preclinical models were associated

with

apoptosis

and

downstream

signaling

effects,

leading

to

MAPK

and

AKT

modulation.

RXDX-101 is currently being evaluated in ALKA-372-001, a First-in-Human (FIH) study that

began in October 2012 and is being conducted in Italy. ALKA-372-001 is an ongoing,

Phase 1, open-label study evaluating the safety, pharmacokinetics, and antitumor activity of

RXDX-101 in patients with advanced/metastatic solid tumors that harbor a TrkA, ROS1, or

ALK molecular alteration.

RXDX-101 is also being evaluated in RXDX-101-01, a new Phase 1/2a study, also referred

to as STARTRK-1 (Study

Targeting

ALK,

ROS1 and

TRKA/B/C), that was initiated in July

2014 and is being conducted in the U.S. The data presented are from ALKA-372-001 only. 

3

Methods

Patient

population:

Patients

with

locally

advanced

or

metastatic

solid

tumors,

with

TrkA,

ROS1

or

ALK

molecular

alterations

Dosing

schedules

and

cohorts

(see

Table

1):

To

date,

three

different

schedules

of

administration

of

RXDX-101

have been assessed. A total of 26 patients have been enrolled, and 25 dosed in the 3 schedules.

4

Schedule

Cohort

Daily Dose Level

# of Patients Treated

A

1

100 mg/m

3

2

200 mg/m

3

3

400 mg/m

4

4

800 mg/m

3

5

1200 mg/m

3

6

1600 mg/m

3

B

1

200 mg/m

3

C

1

400 mg/m

3

Primary

objectives:

DLT,

MTD,

RP2D

Secondary

objectives:

safety,

PK,

antitumor

activity

by

RECIST

Table 1

Schedule A evaluated ascending oral doses of RXDX-101 once daily (fasted state) in a 4-day on, 3-day off schedule for 3 weeks,

followed by a 7-day rest period, in continuous 28-day cycles. Dose escalation was conducted according to the standard ‘3 + 3’

scheme (see Figure 1a). Enrollment has been completed (n = 19) for Schedule A.

Schedule B is evaluating ascending oral doses of RXDX-101 once daily (fed state) without rest, in continuous 28-day cycles (see

Figure

1b).

Enrollment

is

ongoing

(n

=

3).

Schedule C is evaluating ascending oral doses of RXDX-101 once daily (fed state) in a 4-day on, 3-day off schedule for 4 weeks

without rest, in continuous 28-day cycles (see Figure 1c). Enrollment is ongoing (n = 3).

2

2

2

2

2

2

2

2

Figure 1. Dosing Schedules

5

1

2

3

4

Week

Figure 1a. Schedule A

1

2

3

4

Week

Figure 1c. Schedule C

1

2

3

4

Week

Figure 1b. Schedule B

Dose

Dose

Dose

Break

Break

n = 25

Age, mean (range) years

51 (22-75)

Female, n (%)

15 (60)

Race, %

White

100

Histology, n (%)

NSCLC

Neuroblastoma

CRC

Pancreatic

Leiomyosarcoma

GBM

16 (64)

4 (16)

2 (8)

1  (4)

1  (4)

1 (4)

Performance status (ECOG)

0

1

2

12

12

1

Prior systemic therapy

1

2   

3 or more

3

5

17

Table 2. Demographics and Baseline Characteristics

6

Primary Diagnosis

Molecular Alteration

N

NSCLC

ALK       rearrangement

ROS1    6 rearrangements

1 deletion

1 copy number gain

8*

8

CRC

TrkA      rearrangement

ROS1     deletion

1

1

Neuroblastoma

ALK        mutation

ROS1     rearrangement

TrkA      overexpression

2

1

1

Glioblastoma

None**

1

Pancreatic

ROS1     deletion

1

Leiomyosarcoma

ALK        deletion

1

Table 3. Histology and Molecular Alteration

7

* 7 had prior treatment w/ crizotinib

** Patient had false positive TrkA IHC result

Results

A total of 25 patients have been treated in ALKA-372-001 (see Table 1)

Schedule

A

was

terminated

at

1600

mg/m

/day

due

to

a

plateau

of

RXDX-101

exposure

and the data were presented previously (ASCO 2014 oral presentation)

RXDX-101 has been well tolerated in all dosing schedules tested thus far (both on an

intermittent and daily continuous basis). Most AEs

<

Grade 2 (see Table 4)

Only

1

possibly

drug-related

Grade

>3

AE

has

been

observed:

asthenia

(1200

mg/m

,

Schedule

A),

that

subsided

with

dose

reduction

to

800

mg/m

/day

No DLTs or drug-related SAEs have been reported in any dosing schedule 

1 complete response has been observed in this trial (see Figure 2)

5 partial responses have been observed in this trial (see Figures 2, 3, 4 and 5)

2 prolonged stable diseases have been observed: a patient with NSCLC with brain

metastases (18 cycles) and a patient with pancreatic adenocarcinoma (11 cycles)

Exposure to RXDX-101 increased in an approximate dose proportional manner up to

doses of 800 mg/m2 with mean plasma half-life of 17 to 44 hours (see Figure 6)

Responders tend to have higher exposure than non-responders throughout the entire

dosing cycle in Schedule A (see Figure 7)

8

2

2

2

Results (cont’d)

9

Complete Response

NSCLC patient (N=1)

Partial Responses

-

46 year old female, ROS1 rearrangement, s/p 2 cycles of chemotherapy, achieved CR after 2 cycles of RXDX-101 (400

mg/m2/day, Schedule C). CR is ongoing (pt currently in cycle 2).

-

63 year old female with metastatic adenocarcinoma, ALK rearrangement, s/p 4 cycles of chemotherapy, crizotinib,

achieved PR after 4 cycles of RXDX-101 (1200 mg/m²/day, Schedule A). PR is ongoing (pt currently in cycle 11) (see

Figure 3).

-

44 year old female with metastatic disease (CNS metastases), ROS1 rearrangement, s/p 3 cycles of chemotherapy,

erlotinib, s/p surgery/XRT to brain, achieved PR after 2 cycles of RXDX-101 (1200 mg/m²/day, Schedule A). PR is ongoing

(pt currently in cycle 10).

-

63 year old male, ROS1 rearrangement, s/p 3 cycles of chemotherapy, achieved PR after 1 cycle of RXDX-101 (400

mg/m²/day, Schedule C). PR is ongoing (pt currently in cycle 3) (see Figure 4).

-

75

year

old

female

with

metastatic

CRC,

TrkA

rearrangement,

s/p

3

cycles

of

chemotherapy,

cetuximab,

achieved

PR

after 1 cycle of RXDX-101 (1600 mg/m², Schedule A). PR lasted for 4 cycles before PD (see Figure 5).

-

22 year old female with metastatic NB, ALK mutation, s/p 4 cycles of chemotherapy, achieved PR after 12 cycles of

RXDX-101 (started at 200 mg/m²/day and had subsequent dose escalations to1200 mg/m²/day, Schedule A). PR is

ongoing (pt currently in cycle 21).

NSCLC patients (N=3)

CRC (N=1):

Neuroblastoma (N=1)

Adverse Event

G1 (%)

G2 (%)

Total (%)**

Nausea

14 (56)

2 (8)

16 (64)

Paresthesia

14 (56)

0 (0)

14 (56)

Asthenia

9 (36)

3 (12)

13 (52)

Vomiting

7 (28)

2 (8)

9 (36)

Diarrhea

6 (24)

2 (8)

8 (32)

Myalgia

6 (24)

1 (4)

7 (28)

Abdominal pain

4 (16)

2 (8)

6 (24)

Back Pain

5 (20)

1 (4)

6 (24)

Arthralgia

3 (12)

3 (12)

6 (24)

Headache

6 (24)

0 (0)

6 (24)

Dyspnea

2 (8)

1 (4)

6 (24)

Pyrexia

6 (24)

0 (0)

6 (24)

Dysgeusia

6 (24)

0 (0)

6 (24)

Cough

4 (16)

1 (4)

5 (20)

* Frequency >

20%, all dosing schedules

Table 4. Most Common* Adverse Events (n=25)

** Total includes one possibly drug-related G3 asthenia AE (4%) and three unrelated G3 dyspnea AEs (12%)

-

Overall, one G4 (increased lipase) and one G5 (respiratory failure) AE have been

reported (both unrelated)

Figure 2. Clinical Antitumor Activity in Each of

TrkA, ROS1 and ALK Patients

Tumor type

(Alteration)

Dose

(mg/m²)

Treatment Cycles / Months

Best

Response

2

4

6

8

10

12

14

16

18

20

22

24

Neuroblastoma

(ALK)

200  

400

800  

1200

PR

NSCLC

(ALK)

200 

400

800

SD

Pancreatic

(ROS1)

400

800

SD

NSCLC

(ALK)

1200

800

PR

NSCLC

(ROS1)

1200

PR

CRC

(TrkA)

1600

PR

NSCLC

(ROS1)

400**

PR

NSCLC

(ROS1)

400***

CR*

PD at C11

PD at C4

11

*  Unconfirmed

**

All

PRs

were

in

Schedule

A

except

1

patient

with

ROS1+

NSCLC

in

Schedule

C

***  CR was in Schedule C

Timing of PR

Timing of CR

Figure 3. Patient 15, NSCLC ALK+

Schedule A, 1200 mg/m²

Baseline, 11/2013

Week 8, 1/2014

Week 20, 5/2014

12

2

Baseline, 7/2014

Week 4, 8/2014

Figure 4. Patient 22, NSCLC ROS1+

Schedule C, 400 mg/m²

13

2

Baseline, 3/2014

Week 4, 4/2014

Figure 5. Patient 20, CRC TrkA+

Schedule A, 1600 mg/m²

14

2

•

Exposure to RXDX-

101 increased in an

approximate dose

proportional manner

up to doses of 800

mg/m

•

Mean plasma half-life

was 17 –

44 hours

3

3

4

3

3

3

n

Figure 6.

RXDX-101 Schedule A Steady State PK Profile

15

100 mg/m

200 mg/m

400 mg/m

800 mg/m

1200 mg/m

1600 mg/m

2

2

2

2

2

2

100

1000

10000

Time (Day)

4

5

2

Figure 7. Responders Tend to Have Higher Exposure than

Non-Responders Throughout the Entire Dosing Cycle

16

Note:

Analysis

includes

patients

in

the

800,

1200

and

1600

mg/m

cohorts;

mean

is

represented

by

square,

and

standard error of the mean is represented by error bars

1

2

3

4

Week

Non-responders

(n = 6)

Responders

(n = 3)

Day 18, T

96h

RXDX-101 Exposure Levels of

Responders and Non-Responders

Intermittent Dosing Schedule (Schedule A, fasted)

(4 days on, 3 days off, 1 week break)

The following may further increase

RXDX-101 exposure:

Additional PK Optimization

Dose

Break

Fed (vs. fasted) state

New formulation

Continuous dosing schedules

without breaks

•

•

•

2

Conclusions and Future Directions

A total of 25 patients have been evaluated across 3 different dosing schedules in this First-in-Human trial of RXDX-

101

There was 1 complete response and 5 partial responses across multiple tumor types (NSCLC, CRC, and

neuroblastoma) in patients with TrkA, ROS1, and ALK molecular alterations; three of them were prolonged (> 9

cycles) and two of them are too early to determine. There were also two patients with prolonged stable disease:

NSCLC with brain metastases (18 cycles) and pancreatic adenocarcinoma (11 cycles)

RXDX-101 has been well tolerated in all dosing schedules tested to date, including intermittent and daily

continuous administration

-

Most common AEs (mainly grade 1-2) considered possibly drug-related were paresthesia, nausea, diarrhea,

asthenia, myalgia, vomiting, arthralgia, and dysgeusia

-

Only 1 possibly drug-related Grade

>3 AE has been observed: asthenia (Grade 3 in one patient)

-

No DLTs or drug-related SAEs have been reported in any dosing schedule

In preliminary PK analysis (day 18, T

96h

), it appears that responders have higher RXDX-101 median Cmin

concentrations vs. non-responders

STARTRK-1, a global Phase 1/2a trial, is ongoing

STARTRK-2

study

will

begin

as

soon

as

RP2D

is

established

in

these

Phase

1

studies

Ignyta is developing a proprietary companion diagnostic for patient selection into RXDX-101 clinical studies

17