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Slide 1 ___________________________________ ___________________________________ New Cytotoxics in Lung Cancer: An Update ___________________________________ Primo N. Lara, Jr., MD Professor of Medicine University of California Davis Cancer

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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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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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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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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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p<0.0001 Adenocarcinoma Squamous P<0.001 Relative expre. levels Relative expre. levels 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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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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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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  • 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 reductase Krug LM, et al. Clin Cancer Res. 2000; Azzoli CG, et al. ECCO/ESMO 2009.

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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 Randomization PRALATREXATE

190 (initially 230) mg/m2 IV push Days 1 & 15 (28-day cycle) ERLOTINIB 150 mg/day

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PDX-012 ITT Population

Efficacy 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)

Pralatrexate Censored Pral Patients Erlotinib Censored Erl Patients Pralatrexate Censored Pral Patients Erlotinib Censored Erl Patients

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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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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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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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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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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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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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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

Percent Responses

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

(n = 521) (n = 531)

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…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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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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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

10 20 30 40 50 60 70 80 90 100 200 400 600 800 1000 1200 Time (days) Percent disease free P=0.004 10 20 30 40 50 60 70 80 90 100 200 400 600 800 1000 1200 1400 Time (days) Percent disease free P=0.002 β3T(+) β3T(-)

PFS OS

β3T(+) β3T(-)

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

β3T IHC

200 400 600 800 1000 41 51 69 90 111 131 Days post-tumor implant Median tumor weight (mg)

Antitumor efficacy

Control Paclitaxel (24 mg/kg, IV, Q2Dx5) Ixabepilone (10 mg/kg, IV, Q4Dx3) Years

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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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 Randomize βT3 stratification 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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β3T IHC Assay and Scoring

Score Description of staining None 1+ Weak 2+ Moderate = internal control (endothelial cells) 3+ Strong β3T status Score % tumor cells Negative 0, 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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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 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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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 Thrombocytopenia 71.1 11.1 4.4 52.7 1.1 Leukopenia 82.2 31.1 3.3 69.9 16.1

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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  • No. of patients at risk:

Ixa + Carb 98 76 52 22 15 4 2 Pac + Carb 99 75 57 26 11 4 1 1

PFS in All Patients

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

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  • No. of patients at risk:

Ixa + Carb 53 40 28 11 6 1 1 Pac + Carb 51 39 29 15 7 1 1 1 HR= 1.04 (80% CI, 0.78-1.41); P=0.85

PFS in β3T(+) Patients

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Eribulin (E7389): A Synthetic Analog

  • f Halichondrin B

1Image available at http://www.shimoda.tsukuba.ac.jp/~hassei/image/H.%20okadai.jpg 2Eisai, 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 H Me O O Me H H O O Me O O O O O O H H O Me HO H HO HO H O Me O O O O O O 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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Growing microtubule Shortening microtubule

Spindle Pole

Tubulin depolymerization Tubulin polymerization

Eribulin has no measurable effect on microtubule shortening Eribulin Eribulin 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

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Taxanes, & epothilones (stabilize microtubules, inhibit depolymerization

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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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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

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Spira, ASCO 2007

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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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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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