Slide 1

New Cytotoxics in Lung

Cancer: An Update

Primo N. Lara, Jr., MD

Professor of Medicine

University of California Davis Cancer Center

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Slide 2 Cytotoxics:

Everything old is new again

• Antimetabolites

– Fluoropyrimidines (S1)

– Anti-folates (Pralatrexate)

• Antimicrotubule agents

– Tubulin binders (Nab-paclitaxel, Ixabepilone, Eribulin)

• Topoisomerase inhibitors

– Anthracyclines (Amrubicin)

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Slide 3

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Slide 4 Cytotoxics:

Everything old is new again

• Antimetabolites

– Fluoropyrimidines (S1)

– Anti-folates (Pralatrexate)

• Antimicrotubule agents

– Tubulin binders (Nab-paclitaxel, Ixabepilone, Eribulin)

• Topoisomerase inhibitors

– Anthracyclines (Amrubicin)

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Slide 5 Fluoropyrimidines

S-1 (or TS-1): oral fluoropyrimidine: Tegafur, 5-chloro-2,4-

dihydroxypyridine, and potassium oxonate (molar ratio 1:0.4:1)

Nakayama, The Oncologist 2010

MOA:

5-FU converts to 5-FdUMP, which inhibits thymidylate syntase

5-FU converts to 5-FUTP, incorporated into RNA thus inhibiting RNA processing.

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Slide 6

p<0.0001

Adenocarcinoma Squamous

P<0.001

Rel

ativ

e ex

pre

. lev

els

Rel

ativ

e ex

pre

. lev

els

P<0.001

Squamous cell carcinoma has higher mRNA and protein

levels for thymidylate synthase (TS)

Ceppi et al. Cancer 2006

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Slide 7 TS in Lung Cancer : a Japanese Large-

Scale Study (N=2,651)

Conclusion: “Lower TS expression in

adenocarcinoma of the lung was confirmed” in this

large-scale study.

Tanaka F. et al. Ann. Oncol. 2011

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Slide 8 S1 in NSCLC

ASCO 2011: OS Update

Overall

Carbo/S1 15.2 mos

Carbo/Pac 13.1 mos

HR 0.96 (0.79, 1.15)

Squamous subset

Carbo/S1 14 mos

Carbo/Pac 10.5 mos

HR 0.71 (0.48, 1.07)

Owamoto, JCO 2010, Hirashima ASCO 2011 #7552

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Slide 9

• Antifolate with preferential uptake and retention by tumor cells

• TARGET: DHFR

• Phase 1 study with vitamin supplementation allowed for higher dosing and confirmed activity in NSCLC

- ORR 10% (4/39; 95% CI: 0.7%-20%); 2 CRs (TTP 26+, 21+ mo)

- Safety profile consistent with prior studies, RD for Phase 2 with vitamin supplementation was 190 mg/m2 q2wks

Pralatrexate: Folate Antagonist

RFC, reduced folate carrier

FPGS, folylpolyglutamyl synthetase

DHFR, dihydrofolate reductaseKrug LM, et al. Clin Cancer Res. 2000; Azzoli CG, et al. ECCO/ESMO 2009.

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Slide 10

Stratification based on smoking history

Light smoker: > 100 lifetime cigarettes; ≤ 15 pack-year history

Heavy smokers: > 15 pack-year history

PDX-012: Phase 2b Study in Advanced NSCLC (N=201)

1:1

Ran

do

miz

atio

n

PRALATREXATE

190 (initially 230) mg/m2

IV push Days 1 & 15 (28-day cycle)

ERLOTINIB

150 mg/day

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Slide 11 PDX-012 ITT PopulationEfficacy Outcomes

RESPONSE & DISEASE CONTROL RATE*Pralatrexate

230 & 190 mg/m2

Erlotinib

150 mg

Response rate 2% 7%

DCR: ITT 36% 43%

DCR: Patients with Response Assessment 53% 54%

Overall Survival, ITT*

Pralatrexate (N= 100) Erlotinib (N=101)

Median (month) 6.7 7.0

HR (95% CI)*: 0.84 (0.61, 1.14)

Progression-free Survival, ITT*

Pralatrexate (N= 100) Erlotinib (N=101)

Median (month) 3.4 2.8

HR (95% CI)*: 0.91(0.63, 1.32)

PralatrexateCensored Pral Patients

ErlotinibCensored Erl Patients

PralatrexateCensored Pral Patients

ErlotinibCensored Erl Patients

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Slide 12 PDX-012 Safety Summary

COMMON AEs &

GRADE 3/4 AEs

IN ≥5% OF PATIENTS

Pralatrexate

230 & 190 mg/m2

(n = 97)

Erlotinib

150 mg

(n = 101)

All

Grades Gr 3 Gr 4

All

Grades Gr 3 Gr 4

Non-Heme AEs

Stomatitis 66 (68) 19 (20) 3 (3) 5 (5) 0 (0) 0 (0)

Fatigue 39 (40) 7 (7) 2 (2) 24 (24) 5 (5) 0 (0)

Dyspnea 12 (12) 4 (4) 2 (2) 23 (23) 8 (8) 0 (0)

Rash 16 (16) 1 (1) 0 (0) 64 (63) 8 (8) 0 (0)

Diarrhea 15 (15) 1 (1) 0 (0) 33 (33) 3 (3) 0 (0)

Heme AEs based on lab values

Anemia 34 (35) 5 (5) 0 (0) 33 (33) 6 (6) 2 (2)

Thrombocytopenia 22 (23) 3 (3) 2 (2) 11 (11) 0 (0) 1 (1)

Neutropenia 18 (19) 4 (4) 2 (2) 5 (5) 1 (1) 1 (1)

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Slide 13 PDX-012 Landmark Analysis:

Patients remaining on treatment at 30 Days

Pralatrexate (n=60) Erlotinib (n=85)

Median OS 9.7 6.8

HR (95% CI): 0.61 (0.42, 0.90)

Pralatrexate

Erlotinib

Censored Pralatrexate Patients

Censored Erlotinib Patients

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Slide 14 Cytotoxics:

Everything old is new again

• Antimetabolites

– Fluoropyrimidines (S1)

– Anti-folates (Pralatrexate)

• Antimicrotubule agents

– Tubulin binders (Nab-paclitaxel, Ixabepilone, Eribulin)

• Topoisomerase inhibitors

– Anthracyclines (Amrubicin)

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Slide 15 Anti-microtubule agents

Taxanes, Epothilones– Decreases dissociation of αβ-tubulin heterodimer

subunits, stabilizes microtubules

– Examples: Nab-paclitaxel, cabazitaxel, ixabepilone

Halichondrin B Analogs– Inhibits microtubule polymerization

– Example: Eribulin

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Slide 16 Novel Taxanes

Tesetaxel (Genta) – not being developed in NSCLC

BMS-184476 (Bristol Myers) – studied in phase II

second line setting; not developed further

Cabazitaxel (Sanofi Aventis) – approved for

prostate cancer, no formal trials in NSCLC

Larotaxel (Sanofi Aventis)

– studied in combination with gemcitabine*,

cisplatin*, and carboplatin** in NSCLC

–no clear advantages; not pursued further

Camps, Ann Oncol 2005; *Zatloukal, JTO 2008; Robert, **Cancer Chemo Pharm 2009

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Slide 17 Phase III nab-P/C vs P/C

Study Design

Chemo-naive

PS 0-1

Stage IIIb/IV

NSCLC

N = 1,050

Stratification factors:

Stage (IIIb vs IV)

Age (<70 vs >70)

Sex

Histology (squamous vs nonsquamous)

Geographic region

nab-Paclitaxel 100 mg/m2 d1, 8 15

Carboplatin AUC 6 d1

No Premedication

n = 525

1:1

Paclitaxel 200 mg/m2 d1

Carboplatin AUC 6 d1

With Premedication of

Dexamethasone + Antihistamines

n = 525

Socinski, ASCO 2009

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Slide 18

33%

37%

25%

30%

0%

10%

20%

30%

40%

Independent

Radiologic Review

Investigator

Assessment

nab-P/C

P/C

Response Ratio = 1.31

(1.082 – 1.593)

P = 0.005

Response Ratio = 1.26

(1.060 – 1.496)

P = 0.008

Perc

en

t R

esp

on

ses

Response rate was higher in nab-P/C arm….

(n = 521)

(n = 531)

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Slide 19 …but PFS was no better than paclitaxel!

Socinsky, ASCO 2011 #7551

“Interim PFS analysis with 47% events revealed no

significant differences between the 2 arms.”

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Slide 20 Ixabepilone

Microtubule stabilizing epothilone B analog

FDA-approved for metastatic breast

cancer (MBC)

Activity in βIII-tubulin expressing, taxane-

resistant tumors (MBC)1.

Modest activity in previously platinum

treated advanced NSCLC

Perez, J Clin Oncol, 2007

Vansteenkiste, J Clin Oncol, 2007

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Slide 21

Sève P, Mol Cancer Ther, 2005

Dumontet C . Mol Cancer Ther, 2009

βIII-Tubulin (β3T) Expression is Associated with

Poor Response to Taxanes in Advanced NSCLC

High β3T levels associated with shorter PFS and OS in retrospective study of patients with advanced NSCLC treated with taxane

0

10

20

30

40

50

60

70

80

90

100

0 200 400 600 800 1000 1200

Time (days)

Perc

en

t d

isease f

ree

P=0.004

0

10

20

30

40

50

60

70

80

90

100

0 200 400 600 800 1000 1200 1400

Time (days)

Pe

rce

nt

dis

ea

se

fre

e

P=0.002

β3T(+)

β3T(-)

PFS OS

β3T(+)

β3T(-)

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Slide 22 Ixabepilone Exhibits Sensitivity to Lung

Tumors Overexpressing βIII Tubulin

Lung Tumor Model

Antitumor Efficacy (LCK)

Ixabepilone Docetaxel Vinorelbine

H1155 4.2 0.2 0.1

LX-1 2.6 0.5 0.1

LCK, log cell kill; MTD, maximum tolerated dose.

• Two lung tumor xenografts overexpressing βIII tubulin

were resistant to docetaxel and vinorelbine at their MTD

• In contrast, ixabepilone was active in all of them

Milross CG, J Natl Cancer Inst, 1996

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Slide 23

Ixa & Taxol were tested head-to-head for efficacy at their maximum

tolerated doses

β3T IHC

0

200

400

600

800

1000

41 51 69 90 111 131

Ixabepilone (10 mpk, IV, Q4Dx3) Taxol (24 mpk, IV, Q2Dx5) ControlDays post-tumor implant

Med

ian

tu

mo

r w

eig

ht

(mg

)

Antitumor efficacy

Control

Paclitaxel

(24 mg/kg,

IV, Q2Dx5)

Ixabepilone

(10 mg/kg,

IV, Q4Dx3)

Years0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

Pat-21

(Triple Negative

Breast Tumor)

ADR + CMF (10 cycles) Taxol + Dexverapamil (4 cycles)

Biopsied

Ixabepilone Preclinical Activity

in β3T Over-expressing Tumors

Pat-21: established xenograft from a primary patient breast tumor that was resistant to taxol

Immunohistochemical analysis

demonstrates strong bIII expression

in the Pat-21 tumor in vivo [Pgp over-

expression not found in Pat-21 tumor

line]

Dumontet et al Mol Cancer Ther 2009; 8:17-25

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Slide 24 Ixabepilone/Carboplatin First-line Phase II

Study Stratified by βIII Tubulin Expression

Primary Endpoint: PFS in βIII tubulin- positive subgroup

Secondary Endpoints: PFS in all comers; ORR; OS

n = 104 βIII tubulin-positive

197 treated pts overall

Ra

nd

om

ize

βT

3 s

tra

tifi

ca

tio

n

Paclitaxel 200 mg/m2

+ Carboplatin AUC 6

Ixabepilone 32 mg/m2

+ Carboplatin AUC 6

Stage IIIB/IV

NSCLC

Stratify

• β3T status (+/-)*

• Tumor stage (IIIB/ IV)

• Brain mets (yes/no)

• Study site

Edelman, Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL.2010

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Slide 25 β3T IHC Assay and Scoring

Score Description of staining

0 None

1+ Weak

2+ Moderate = internal control

(endothelial cells)

3+ Strong

β3T status Score% tumor

cells

Negative0, 1+ ≥ 50%

2+, 3+ < 50%

Positive 2+, 3+ ≥ 50%

Staining intensity scores

C. Roach et al. Poster #186

2010 Multidisciplinary Symposium in

Thoracic Oncology, Chicago, IL.

Immunohistochemistry (IHC)

assay for bIII-tubulin

- Used monoclonal antibody (TUJ-1)

- Optimized assay conditions (Dako)

Multiple cut-offs for β3T positivity were explored

NSCLC, 2 +

arrow = endothelial cell

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Slide 26

β3T(+) Patients β3T(-) Patients Overall Population

Ixa/Carb

(N=53)

Pac/Carb

(N=51)

Ixa/Carb

(N=45)

Pac/Carb

(N=48)

Ixa/Carb

(N=98)

Pac/Carb

(N=99)

Response rate1, % 17.0 29.4 26.7 27.1 21.4 28.3

Disease control rate2, % 77.4 76.5 77.8 77.1 77.6 76.8

Tumor Response, %

Complete response (CR) 1.9 3.9 0 0 1.0 2.0

Partial response (PR) 15.1 25.5 26.7 27.1 20.4 26.3

Stable disease (SD) 60.4 47.1 51.1 50.0 56.1 48.5

Progressive disease (PD) 18.9 13.7 8.9 14.6 14.3 14.1

ND 3.8 9.8 13.3 8.3 8.2 9.1

ND=not determined due to unavailability of data, early discontinuation, death, or because the patient

was never treated in the study; 1CR+PR/number of patients; 2CR+PR+SD/number of patients

Tumor Response Rates

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Slide 27

Ixa/Carb

(N=90)

Pac/Carb

(N=93)*

Abnormality, %All

Grades

Grade 3 Grade 4 All

Grades

Grade 3 Grade 4

Neutropenia 82.2 21.1 38.9 79.3 31.5 23.9

Anemia 98.9 12.2 4.4 90.3 0 0

Thrombocytopenia 71.1 11.1 4.4 52.7 1.1 0

Leukopenia 82.2 31.1 3.3 69.9 16.1 0

Hematologic Adverse Events

Febrile Neutropenia: 2 patients in each treatment arm reported febrile neutropenia (as a grade

3/4 adverse event)

*N=92 for neutropenia

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Slide 28

No. of patients at risk:

Ixa + Carb 98 76 52 22 15 4 2 0 0

Pac + Carb 99 75 57 26 11 4 1 1 0

PFS in All Patients

HR= 0.92 (80% CI, 0.73-1.15); P=0.63

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Slide 29

No. of patients at risk:

Ixa + Carb 53 40 28 11 6 1 1 0 0

Pac + Carb 51 39 29 15 7 1 1 1 0

HR= 1.04 (80% CI, 0.78-1.41); P=0.85

PFS in β3T(+) Patients

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Slide 30 Eribulin (E7389): A Synthetic Analog

of Halichondrin B

1Image available at http://www.shimoda.tsukuba.ac.jp/~hassei/image/H.%20okadai.jpg2Eisai, Inc. Data on File.2Zhang Z-Y, et al. Cancer Chemother Pharmacol 2008; 62: 707-716.

Marine sponge Halichondria okadaii1

30

“Right Half”

O

H

H

O

O

H

H

O

O

H

HMe

O

O

MeH

H

O

O

Me

O

OO

O

OO

H

H

O

Me

HO

HHO

HOH

O

Me

O

OO

O

OO

H

H

O

H

O

OMe

H2N

OH

Halichondrin B Eribulin

Pharmacokinetics2

– 49 - 65% protein binding

– T1/2 distribution = 0.43 hours

– T1/2 elimination = 39 hours

– Large Vss = 1.81 L/hr/m2

– ~7% renal excretion

– Dose proportional over 0.25 -1.4 mg/m2

– No accumulation on weekly schedule

Tissue distribution in animals1

• High concentrations in the lung

• Low concentrations in the brain

Primarily metabolized by CYP3A42

First in humans trial showed activity in

NSCLC

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Slide 31

Growing

microtubule

Shortening

microtubule

Spindle

Pole

Tubulin

depolymerization

Tubulin

polymerization

Eribulin has no measurable effect on microtubule shortening

EribulinEribulin inhibits

microtubule growth

1

Eribulin leads to nonproductive tubulin aggregates

Nonproductive

tubulin

aggregates

Jordan MA & Kamath K. Current Cancer Drug Targets. 2007; 7:730-742.1Jordan MA, et al. Mol Cancer Ther. 2005;4:1086 -1095.

Eribulin: Microtubule Dynamics Inhibitor

Vincas, block polymerization,

(promote depolymerization)

Eribulin

3

Eribulin

2

31

Taxanes, & epothilones

(stabilize microtubules,

inhibit depolymerization

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Slide 32 Eribulin in NSCLC: Phase II

Platinum- and taxane-pretreated NSCLC (n=41)– TS: Taxane sensitive (PD > 90 days after taxane, n=20)

– TR: Taxane resistant (PD during or < 90 d after taxane, n=21)

Eribulin 1.4 mg/m2 D1 & 8, q 21 days

Response rate = 15% (3 pts, all TS)

Stable disease = 60% in TS, 24% in TR

mPFS = 6.3 months in TS, 1.2 months in TR

Conclusion: Active in taxane sensitive cohort

Gitlitz, ASCO 2009

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Slide 33 Eribulin in NSCLC: Another Phase II

Prior platin-treated NSCLC (N=103)

– Taxane naïve (n=83)

– Taxane pre-treated (n=20)

Eribulin 1.4 mg/m2 d1, 8, 15 q28 days

– Later changed to d1, 8 q 21 days

Response rate = 10%

Disease control rate = 53%

Median OS = 9.6 months

33

Spira, ASCO 2007

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Slide 34 Combination Eribulin Trials in

NSCLC

Eribulin + Carboplatin (1st line Phase Ib)

complete

Eribulin + erlotinib (phase II) complete

Eribulin + pemetrexed (relapse; Phase

Ib/II), enrolling

Eribulin + gemcitabine v. cisplatin +

gemcitabine (phase III), planned for Asia

Aisner, Targeted Therapies Santa Monica 2011

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Slide 35 Conclusions:

New Cytotoxics in NSCLC

Cytotoxic chemotherapy is a cornerstone of

therapy

However, efficacy has plateaued

New cytotoxics are in development

Early results show only modest activity

Need to optimize patient selection based on

biology

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