New Strategies on Horizon Tony Mok MD Dept of Clinical Oncology The Chinse University of Hong Kong.

New Strategies on Horizon

Tony Mok MD

Dept of Clinical Oncology

The Chinse University of Hong Kong

TKI is foreverTKI is forever

Addressing the

difference

Addressing the

differenceNovel TargetNovel Target

TKI is foreverTKI is forever

5cm5cm

PR at 2cmPR at 2cm

RECIST PDAt 2.6cm

RECIST PDAt 2.6cm

6m0m 12m 18m

5cm5cm

PR at 2cmPR at 2cm

Symptomatic PD at 4cm


6m0m 12m 18m

5cm5cm

PR at 2cmPR at 2cm

RECIST PDAt 2.6cm

RECIST PDAt 2.6cm



MolecularresistanceMolecularresistance

6m0m 12m 18m

ASPIRATION: To optimize treatment duration

Advance stageNSCLC with

EGFR Mutation


EGFR Mutation

EGFR TKIEGFR TKI

PDBy RECIST

PDBy RECIST

PDBy doctor

Discretion*

PDBy doctor

Discretion*

PFS 1PFS 1

PFS 2 PFS 2

*Doctor Discretion: Symptomatic progression, multiple progressionThreat to major organ…etc*Doctor Discretion: Symptomatic progression, multiple progressionThreat to major organ…etc

EGFR TKIEGFR TKI

PI: K Park

TKI Resistance after ASCO 2012

Oncogenic driven cancer with tumor response to TKI

Oligo-ProgressionSystemic

Progression

Local therapy + continuation of TKI

Systemic therapy

Targeting the resistant

gene

Chemotherapy

Chemotherapy + TKI

Treatment of TKI ResistanceOncogenic driven cancer with tumor response to TKI


Progression


Systemic therapy


gene

Chemotherapy

Chemotherapy + TKI

Local Therapy in Acquired Resistance: MSKCC

• 18/184 pts/7+ yrs underwent local therapy for extracranial PD – CNS PD excluded

• From time of local therapy– Median TTP: 10 months– Median time to new systemic Rx: 22 months – Median OS: 41 months

Yu, ASCO 2012, Abst#7527

Local treatment to oligo-progression plus continuation of TKI

• Colorado University collection of 65 patients with oncogenic driven cancer (EGFR mutation or ALK positive)

• All received EGFR TKI or Crizotinib• PFS 1 defined as <4 sites of progression

– Local ablative therapy offered to all sites of involvement and continue TKI

• PFS 2 defined as from time of local therapy to second progression

ASCO 2012 Abst 7526

Ϯ Includes 3 patients who progressed systemically (eCNS) and simultaneously within the CNS

Site of first progression

Number of patients

PFS1(months)(95% CI)

PFS2(months)(95% CI)

Site of 2nd progression

CNS 1010.9

7.3 – 18.37.1

1.7 – 11.3

2 (20%) no prog3 (30%) CNS5 (50%) eCNS

eCNSϮ 159.0

6.5 – 13.84.0

2.7 -7.4

4 (27%) no prog3 (20%) CNS8 (53%) eCNS

All patients 259.8

8.8 – 13.86.2

3.7 – 8.0

6 (24%) no prog7 (28%) CNS

12 (48%) eCNS

PFS of patients treated with LAT and continuation of TKI therapy

Future Prospective Study?Oncogenic driven cancer with tumor response to TKI

PD by RECIST <4 sites of PD


Chemotherapy

Randomized

Primary endpoint: PFSSecondary endpoint: OS, RR, QOL

Treatment of TKI ResistanceOncogenic driven cancer with tumor response to TKI


Progression


Systemic therapy


gene

Chemotherapy

Chemotherapy + TKI

Chemo/Erlotinib vs. Chemo Alone at Progression after Acquired Resistance

• N = 78 retrospective review of outcomes – chemo alone (N = 44) or– chemo/erlotinib (N = 34)

• RR 18% (chemo) vs. 41% with chemo/erlotinib)

• No differences in PFS or OS between these two strategies

Goldberg, ASCO 2012, Abst#7524

IMPRESS: Chemotherapy with or with gefitinib at progression


EGFR Mutation


EGFR Mutation

GefintinibGefintinib

PDBy RECIST

PDBy RECIST

Gefitinib +Alimta/Platinum

Gefitinib +Alimta/Platinum

Alimta/PlatinumAlimta/Platinum

Primary endpoint: PFSPrimary endpoint: PFS

Co-PI: Soria J; Mok T

Addressing the

difference

Addressing the

difference

Classic concept of cancer

Cancer cell division

Fourth orlater mutation

Third mutation

Second mutation

First mutation

Uncontrolled growth

Cell Suicide or Apoptosis

Cell damage—no repair

Normal cell division

What if the cancer is not homogenous?

Early finding of intratumor heterogeneity in lung cancer

• Twenty-one patients with recurrent EGFR mutation positive lung cancer

• Surgical specimens were retrieved from archive

• Using laser capture microdissection and analyzed 50–60 areas from each tissue

• Fifteen tissues consisted only of cells with EGFR mutations

• Six tissues contained both mutated and non-mutated cells.

Taniguchi K, Cancer Sci, 2008 May;99(5):929-35

Combination strategy for heterogeneous tumor

• Chemotherapy is standard cytotoxic for adenocarcinoma

• Adenocarcinoma has a higher incidence of harboring driver oncogene, especially among the non-smoker adenocarcinoma

• Cancer patient may have heterogeneous mix of tumor with or without the driver oncogenes

• We need a rational approach to “Chemotherapy + Targeted Therapy”

Intercalated combination ofChemotherapy + EGFR TKI

NVALT-10:Design

Patients

Locally advanced or metastatic NSCLC(IIIB-IV)

Failed first line platinum therapy

WHO PS 0-2

Combinationtherapy

Monotherapy

Squamous

Erlotinib 150mg p.o. day 2-16+ Docetaxel 75 mg/m2 day 1 q3 weeks

Non- Squamous

Erlotinib 150mg p.o. day 2-16+ Pemetrexed 500 mg/m2 day 1 q3 weeks

Squamous and Non Squamous

Erlotinib 150mg p.o. daily

Chemotherapy planned 4 cyclesErlotinib until disease progression Aerts et al ESMO 2012

Primary endpoint: PFS

PFS and OS

Adjusted for stratification factors: p=0.09, HR=0.78 (0.59-1.04)

Adjusted for stratification factors: p=0.02, HR=0.67 (0.50 – 0.93)

Improvement in patients with or without EGFR mutation?

Improvement limited to non-squamous cell carcinoma

• Lack of improvement in squamous cell carcinoma– No improvement in

EGFR wild type

• Slight improvement in non-squamous cell carcinoma– May imply benefit in a

small portion of patients with EGFR mutations

For a population dominated by EGFR wild type, control arm should be Alimta

Placebo

Erlotinib 150mg/day

Previously untreated stage IIIB/IV NSCLC,

PS 0/1(n=451)

R

PD

Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin

75mg/m2 (d1) + placebo (d15–28); q4wks x 6 cycles

GC-placebo (n=225)

Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin

75mg/m2 (d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles

GC-erlotinib (n=226)

PD

Study treatment Maintenance phaseScreening

Erlotinib 150mg/dayPrimary endpoint: PFS with IRC confirmation

Secondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL

FASTACT-2 (MO22201; CTONG0902) study design

NSCLC = non-small cell lung cancer; PS = performance status; PD = disease progression; AUC = area under the curve; q4wks = every 4 weeks; IRC = independent review committee; OS = overall survival; ORR = objective response rate; TTP = time to progression; NPR = non-progression rate; QoL = quality of life

1:1; stratified by stage, histology, smoking status and chemo regimen

EGFR mutation status in FASTACT-2

9797

210 patients in the study had unknown EGFR mutation status

136136

Erlotinib n=49

Placebo n=48

Erlotinib n=69

Placebo n=67

500

400

300

200

100

0

451

241

All patients Tested for EGFR mutation

EGFR mutation-positive (Mut+)EGFR wild-type (WT)Single resistance mutation

300

250

200

150

100

50

0EGFR mutation status

**

* n=8: one with T790M (received placebo); one with S768I (received placebo); six with exon 20 mutations (two received erlotinib, four received placebo)* n=8: one with T790M (received placebo); one with S768I (received placebo); six with exon 20 mutations (two received erlotinib, four received placebo)

PFS in ITT population (22 Jun 2012)P

FS

pro

babi

lity

Time (months)

1.0

0.8

0.6

0.4

0.2

00 3836343230282624222018161412108642

6.0 7.6


GC-placebo (n=225)

HR=0.57 (95% CI 0.47–0.69) p<0.0001

E 226 192 162 136 102 81 70 59 52 45 39 32 24 17 12 6 1 0 0 0P 225 185 156 114 57 31 22 15 12 9 7 6 4 3 3 2 1 1 1 0

CI = confidence intervals

OS in ITT population (22 Jun 2012)

15.2 18.3


GC-placebo (n=225)

HR=0.79 (95% CI 0.64–0.99) p=0.0420

OS

pro

babi

lity

Time (months)

1.0

0.8

0.6

0.4

0.2

00 3836343230282624222018161412108642

E 226 219 202 191 176 165 154 138 129 114 98 85 68 52 39 23 9 6 1 0 P 225 218 206 185 168 156 138 120 103 92 78 68 53 37 24 13 6 4 0 0

PFS and OS in EGFR WT subgroup (22 Jun 2012)

1.0

0.8

0.6

0.4

0.2

0

Time (months)

PF

S p

roba

bilit

y

1.0

0.8

0.6

0.4

0.2

0

Time (months)

0 8 12 16 20 24 28 40

OS

pro

babi

lity

0 4 8 12 16 20 24 28 3632 40

5.9 6.7 12.2 14.9

GC-erlotinib (n=69)

GC-placebo (n=67)

HR=0.77 (0.53–1.11)p=0.1612

GC-erlotinib (n=69)

GC-placebo (n=67)HR=0.97 (0.69–1.36)p=0.8467RR: 26.1% vs 19.4%

PFS OS

4 32 36

E 69 60 49 43 30 19 12 6 4 0 0P 67 57 43 34 23 15 7 3 2 1 0

E 69 45 15 7 5 3 2 1 0 0 0P 67 46 16 5 3 2 1 1 1 1 0

PFS and OS in EGFR Mut+ subgroup (22 Jun 2012)

1.0

0.8

0.6

0.4

0.2

0

Time (months)

PF

S p

roba

bilit

y

1.0

0.8

0.6

0.4

0.2

0

Time (months)

OS

pro

babi

lity

0 4 8 12 16 20 24 28 32 0 4 8 12 16 20 24 28 32 36

6.9 16.8 20.6 31.4

GC-erlotinib (n=49)

GC-placebo (n=48)

HR=0.48 (0.27–0.84)p=0.0092

GC-erlotinib (n=49)GC-placebo (n=48)

HR=0.25 (0.16–0.39)p<0.0001RR: 83.7% vs 14.6%

PFS OS

E 49 46 42 33 25 19 11 6 0P 48 35 16 5 4 2 2 1 0

E 49 48 46 45 41 33 24 15 3 0P 48 48 43 36 26 24 14 6 0 0

Novel TargetNovel Target

MET PathwaysTarget HGFAMG 102AVEO299

Target HGFAMG 102AVEO299

Target Met receptorMetMab

Target Met receptorMetMabTarget TK

ARQ197, XL184 + many

Target TKARQ197, XL184

+ many

Phase 2 Study Design: Ficlatuzumab + Gefitinib in NSCLC in the First Line

Stratification:•ECOG PS•Smoking history•Gender

Stratification:•ECOG PS•Smoking history•Gender

Ficlatuzumab+ gefitinib(n=94)

Ficlatuzumab+ gefitinib(n=94)

Early discontinuations, nonresponders, or patients

who do not want to participate in crossover

Early discontinuations, nonresponders, or patients

who do not want to participate in crossover

Crossover permitted:gefitinib + ficlatuzumab

(progressive disease after initial response, partial response or

stable disease >3 months)

Crossover permitted:gefitinib + ficlatuzumab

(progressive disease after initial response, partial response or

stable disease >3 months)

R1:1R

1:1

Key entry criteria:•Stage IIIB/IV NSCLC•Treatment naïve•Adeno histology•Asian, nonsmoker or light former smoker

Key entry criteria:•Stage IIIB/IV NSCLC•Treatment naïve•Adeno histology•Asian, nonsmoker or light former smoker

Gefitinib(n=94)

Gefitinib(n=94)

Study Endpoints:Primary: ORRSecondary: PFS, OS

Enrollment initiated in May 2010 & completed in May 2011

Treatment:Gefitinib: 250 mg qd Ficlatuzumab: 20 mg/kg q2w in 28-day cycles

Mok et al ESMO 2012 (Poster)

Biomarker Analyses

144 (77%) tissue samples collected

Biomarkers

EGFR mutation(n=125)

c-Met IHC level(n=123)

Tumor HGF IHC level

(n=114)

Stroma HGF level

(n=99)

SM+ SM- High* Low High LowS-HGF high

S-HGF low

Definition

TKI sensitiv

e mutatio

n

No or insensitiv

e mutation

Score 2-3+distribution:

> 75%

Remaining

Score 2-3+

distribution:

> 25%

Remaining

Score: strong

moderate

Score: weak

negative

n, (% known)

71 (57) 54 (43) 78 (63)45

(37)64 (56) 50 (44) 17 (17) 82 (83)

188 patients enrolled

May 2010 – May 2011

188 patients enrolled

May 2010 – May 2011


PFS and OS (c-Met Low)


40

Tivantinib (ARQ 197)/Erlotinib Combination in Non-Small Cell Lung Cancer (Study 209)

a Based on investigator assessment. PFS defined by histology, molecular profile, and other prognostic characteristics.b Patients in the control arm will be allowed to crossover to receive ARQ 197. Abbreviations: BID, twice daily; EGFR, epidermal growth factor receptor; LA, locally advanced; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; TKI, tyrosine kinase inhibitor.Schiller JH, et al. J Clin Oncol. 2010;28(18 suppl II):954s. Abstract LBA7502.

Endpoints 1° PFSa

2° ORR, OS Subset analyses Crossover: ORR

Accrual complete Archival tissue evaluated for EGFR /

c-MET / K-Ras status in pre-planned subset analyses

RANDOMIZE

NSCLC N =154 Age ≥18 years Inoperable LA/

metastatic disease ≥1 prior chemo

(no prior EGFR TKI)

bArm A: Tivantinib

(ARQ 197)360 mg PO BID

Erlotinib150 mg PO QD+

Arm B: Erlotinib150 mg PO QD

PlaceboPO BID +

Sequist et al JCO 29:3307, 2011

PFS and OS (ITT population and Non-squamous cell)

42

Study 302: MET Inhibitor ARQ 197 Plus Erlotinib vs Erlotinib Plus Placebo in Non-Squamous NSCLC (MARQUEE)

Abbreviations: BID, twice daily; EGFR, epidermal growth factor receptor; FACT-L, functional assessment of cancer therapy-lung; ITT, intent-to-treat; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; wt, wild type; QOL, quality of life; TKI, tyrosine kinase inhibitor.http://clinicaltrials.gov/ct2/show/NCT01244191.

Phase 3 in NSCLC Inoperable locally adv/metastatic

disease Non-squamous histology 1-2 regimens prior chemo (no prior

EGFR TKI) Prior platinum-based doublet

therapy required

RANDOMIZE

Endpoints1° OS (ITT population)2°/Exploratory:

- PFS (ITT population)- OS and PFS in EGFR wt patients- Safety and toxicity- QOL/FACT-L- Biologic sub-group analysis

988 patients Stratification by EGFR and KRAS

mutation status (tissue required) Interim analysis performed at 50% of

events

Arm A: Tivantinib(ARQ 197)

360 mg PO BID

Erlotinib150 mg PO QD

+

Arm B: Erlotinib150 mg PO QD

PlaceboPO BID

+

Early termination at interim analysis (2012)

Early termination at interim analysis (2012)

http://clinicaltrials.gov/ct2/show/NCT01244191

OAM4558g: A Phase II randomized, placebo controlled study testing erlotinib +/- MetMAb in 2nd/3rd line NSCLC

*128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010

Arm AErlotinib (150 daily) + MetMAb (15 mg/kg IV q3w)

** Must be eligible and treated with

MetMAb

Arm BTarceva (150 daily) + Placebo (IV q3w)

RANDOMIZATION

1:1

Key eligibility:

• Stage IIIB/IV NSCLC• 2nd/3rd-line NSCLC• Tissue required• PS 0–2

n=137*n=69

n=68

ADD** MetMAb

Progressivedisease

n=27

Co-primary objectives:

• PFS in ‘Met DiagnosticPositive’ patients (est 50%)

• PFS in overall ITT population

Other key objectives:

• OS in ‘Met Diagnostic Positive’ patients

• OS in overall ITT patients

• Overall response rate

• Safety/tolerability

Stratification factors:

• Tobacco history

• Performance status

• Histology

Spiegel et al ASCO 2011Spiegel et al ASCO 2011

MetMAb plus erlotinib leads to a better outcome than erlotinib alone in Met Diagnostic Positive NSCLC patients

Time to progression (months)

0 3 6 9 12 15 18

Pro

bab

ilit

y o

f p

rog

ress

ion

fre

e

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

3.8

26

MetMAb +erlotinib

12.60.37

(0.19–0.72)0.002

16

Median (mo)HR(95% CI)Log-rank p-valueNo. of events

Overall survival (months)

0 3 6 9 12 15 18 21P

rob

abil

ity

of

surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

1.5

27

MetMAb +erlotinib

2.90.53

(0.28–0.99)0.042

20

Median (mo)HR(95% CI)Log-rank p-valueNo. of events

The addition of MetMAb in this population resulted in a 2-fold reduction in therisk of progression and a near 3-fold reduction in the risk of death

PFS: HR=0.53 OS: HR=0.37

Met Dx Negative

Development of Met IHC for use as a companion diagnostic

• Technical metrics– Tissue was obtained from 100% of patients.– 95% of patients had adequate tissue for evaluation of Met by IHC

• Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories

• Met diagnostic status was assessed after randomization and prior to unblinding– ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining

intensity52% patients enrolled were ‘Met Diagnostic Positive’

Negative (0) Weak (1+)

Moderate (2+) Strong (3+)

Met Dx Negative

Met Dx Positive

MET IHC score

1 2 30

1

10

100

1000

0

Met Dx Positive

ME

T m

RN

A (

2-c

t )

Phase III study design

Registeredpatients

Registeredpatients

Centralized lab (Met IHC or T-score)


Met DiagnosticPositive


Met DiagnosticNegative

Met DiagnosticNegative

Erl +MetMab

Erl +MetMab ErlErl Erl +

MetMabErl +

MetMab ErlErl

Marker-by-treatment-interaction DesignMarker-by-treatment-interaction Design

Registeredpatients

Registeredpatients





Met DiagnosticNegative excluded

Met DiagnosticNegative excluded

Erl +MetMab

Erl +MetMab ErlErl

Marker-based Strategy DesignMarker-based Strategy Design

Mandrekar SJ et al J Biopharm Stat 19:530, 2009Mandrekar SJ et al J Biopharm Stat 19:530, 2009

Summary• TKI is forever

– Redefine TKI resistance. RECIST criteria may not be applicable

• Addressing the difference– Intercalated combination of chemotherapy and EGFR

TKI may potentially improve treatment outcome

• Novel targets– C-MET is a promising target but we are still in search

of a biomarker

Old Strategy New Strategy

New Strategies on Horizon Tony Mok MD Dept of Clinical Oncology The Chinse University of Hong Kong.

Documents

tki slide

egfr mutation egfr tki

prior egfr tki nsclc

daily tki

prior egfr tki b arm

daily egfr

pfs itt population os

poster slide