Miami, FL December 19, 2009 Speaker: Pasi A. Jänne MD, PhD Files/Syllabus Files Fall...Miami, FL...

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Master Class for Oncologists

Welcome to

Miami, FL

December 19, 2009

Improved Strategies for Relapsed NSCLC: New Regimens, New

Combinations, and Targeted Therapies

Speaker:

Pasi A. Jänne MD, PhD

Session 3: 2:45 PM - 3:30 PM

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Presenter Disclosure Information

The following relationships exist related to this presentation:

• Dr Jänne serves as a consultant for Roche and BoehringerIngelheim Pharmaceuticals, Inc.; and AstraZeneca LP. He also receives royalties from Genzyme.

Off Label/Investigational DiscussionIn accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

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• Therapeutic choices for relapsed NSCLC– Supportive care– Chemotherapy– Erlotinib– Participation in a clinical trial

Management of Relapsed NSCLC

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• Considerations for offering treatment for relapsed NSCLC– Performance status– Recovery from first-line therapy– Patient preferences

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• FDA-approved agents for relapsed NSCLC– Docetaxel– Pemetrexed– Erlotinib


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Audience Response Question

Mr. T., a 68 yo 40 pack year current smoker, presented in March 2008 with seizures and was found to have stage IV NSCLC with brain and bone metastases. Following whole brain radiation, he was treated with carboplatin/paclitaxel which was complicated by febrile neutropenia. He achieved a partial response after 6 cycles of treatment but in September 2008 had new liver metastases. His PS is 0. How would you treat him?

?

1. Docetaxel 75 mg/m2 every 3 weeks2. Pemetrexed 500 mg/m2 every 3 weeks3. Weekly docetaxel4. Enrollment in a clinical trial5. Supportive care alone

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Chemotherapy for Relapsed NSCLC


9 Data from Shepherd, F A, et al. J Clin Oncol. 2000;18:2095-2103.

Docetaxel vs Supportive CarePatient Characteristics

• Relapsed IIIB/IV NSCLC

• PS 0-2

• No prior paclitaxel therapy

BSC 100 pts vs docetaxel (2 doses) 104 pts.

Docetaxel BSCRR 5.8% 0%TTP (weeks) 10.6* 6.7OS (months) 7.0 4.6

1-year survival 29% 19%

Outcome Measures

*P = 0.001


10 Data from Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.

Only docetaxel 75 mg/m2 associated with a survival benefit

Median OS: 7.5 (D) vs 4.6 months (BSC) (P = 0.01; log rank test)

1-year survival: 37% (D) vs 12% (BSC) (P = 0.03; X2 test)


11 Data from Fossella FV, et al. J Clin Oncol. 2000;18:2354-2362.

Docetaxel vs Vinorelbine or IfosfamidePatient Characteristics


• PS 0-2

• Prior paclitaxel allowed

Docetaxel 100 mg/m2 (125 pts) vs docetaxel 75 mg/m2 (125 pts) vs Vin/Ifos (123 pts)

Docetaxel 100 Docetaxel 75 Vin/Ifos

RR 10.6% 6.7% 0.8%TTP (weeks) 8.4* 8.5 7.9 *P = 0.044OS (months) 5.5 5.7 5.6 P = NSyear Survival 21% 32%* 19% * P = 0.025


12Data from Fossella, FV, et al. J Clin Oncol. 2000;18:2354-2362. *Shepherd F, et al. Semin Oncol. 2001 Feb;28(1 Suppl 2):4-9 and **Leighl NB. et al. J Clin Oncol. 2002;20:1344-52.

• Patients treated with prior paclitaxel also benefited from docetaxel.

• Docetaxel treatment was associated with improvement in quality of life.*

•Cost-effectiveness of docetaxel 75 mg/m2: $31,766 per/year of life gained**

Docetaxel 75 mg/m2


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13

Pemetrexed vs DocetaxelPatient Characteristics


• PS 0-2

Pemetrexed 500 mg/m2 (n = 283) vs docetaxel 75 mg/m2 (n = 288)

Non-inferiority statistical design

Data from Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

Pemetrexed DocetaxelRR 9.1% 8.8%TTP (months) 3.4 3.5OS (months) 8.3 7.91-year survival 29.7% 29.7%

No differences in quality of life measures between

pemetrexed and docetaxel


14 Data from Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.


15

ToxicityPemetrexed

(n = 265)Docetaxel(n = 276) P-value

Grade 3/4 neutropenia 5.3% 40.2% < 0.001

Febrile neutropenia 1.9% 12.7% < 0.001

Neutropenia with infection 0% 3.3% 0.004

> 1 hospitalization for neutropenic event

1.5% 13.4% < 0.001

G-CSF/GM-CSF 2.6% 19.2% < 0.001


Pemetrexed vs Docetaxel: Toxicity


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Mr. T., a 68 yo 40 pack year current smoker, presented in March 2008 with seizures and was found to have stage IV NSCLC with brain and bone metastases. Following whole brain Radiation, he was treated withcarboplatin/paclitaxel which wascomplicated by febrile neutropenia. He achieved a partial response after 6cycles of treatment but in September 2008 had new liver metastases. His PS is 0. How would you treat him?

?

1.1. DocetaxelDocetaxel 75 mg/m75 mg/m22 every 3 weeksevery 3 weeks2.2. PemetrexedPemetrexed 500 mg/m500 mg/m22 every 3 weeksevery 3 weeks3.3. Weekly Weekly docetaxeldocetaxel4.4. Enrollment in a clinical trialEnrollment in a clinical trial5.5. Supportive care aloneSupportive care alone

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Mr. J. is a 57 yo former 80 pack year smoker who presented with hemoptysisin June 2008. He was found to have a central cavitary lesion and liver metastases. Bronchoscopy was performed and confirmed squamous cell cancer. He was treated with chest radiation and with 6 cycles ofcarboplatin/paclitaxel, which finished in December of 2008. He tolerated the treatment well and had a partial response. In March 2009 his follow-up CT revealed new lung nodules. His PS is 1. How would you treat him?

?

1. Pemetrexed 500 mg/m2

2. Pemetrexed 500 mg/m2 & bevacizumab 15 mg/kg 3. Erlotinib/bevacizumab4. Docetaxel 75 mg/m2

5. Supportive care alone

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• Strategies to improve efficacy of chemotherapy for relapsed NSCLC– Alternative administration schedules of currently

approved agents– Alternative agents– Combination approaches– Patient selection methods


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Docetaxel every 3 wks vs docetaxel weeklyPatient Characteristics


• PS 0-2

Docetaxel 75 mg/m2 every 3 weeks (n = 103) vs docetaxel 35 mg/m2 days 1,8,15 every 28 days (n = 105)

25% of patients in each arm had prior paclitaxel

Statistical design – difference in 1-year survival rate

Data from Schuette W, et al. J Clin Oncol. 2005;23:8389-8395.

Docetaxel q 3 wks Docetaxel weeklyRR 12.6% 10.5%TTP (months) 3.4 3.3OS (months) 6.3 9.21-year survival 26.9% 39.5%


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Docetaxel every 3 wks vs docetaxel weekly


Time to progression Survival


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ToxicityDocetaxel q 3 wks (n = 102)

Docetaxel q week (n = 105) P-value

Anemia 5.9 % 1 % < 0.05

Leukopenia 27.5 % 1 % < 0.0001

Neutropenia 20.6 % 4.8 % < 0.001

Febrile Neutropenia 2.0 % 1.0 % NS

Infection 2.9 % 2.9 % NS

Docetaxel q 3 wks vs weekly: Grade 3/4 Toxicities



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• Other studies of docetaxel q 3 wks vs weekly– Gridelli, et al.: Docetaxel 75 mg/m2 q 3 wks (n = 110) vs 33

mg/m2 (n = 110) days 1,8,15,22, 29, 36 q 8 weeks.• No differences in response rate or median OS• Docetaxel q 3 wks associated with more leukopenia, neutropenia

and febrile neutropenia– Camps, et al.: Docetaxel 75 mg/m2 q 3 wks (n = 129) vs 36

mg/m2 (n = 125) days 1,8,15,22, 29, 36 q 8 weeks• No difference in response rate, TTP, or OS• Docetaxel q 3 wks associated with more febrile neutropenia• Docetaxel weekly associated with more mucositis

Gridelli C, et al. Br J Cancer. 2004;91:1996-2004. Camps C, et al. Ann Oncol. 2006;17:467-472.


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Docetaxel vs Oral TopotecanPatient Characteristics


• PS 0-2

Docetaxel 75 mg/m2 (n= 415) vs oral topotecan (n = 414) 2.3 mg/m2/d days 1-5

Non-inferiority statistical design; OS primary endpoint

Docetaxel Oral Topotecan P-valueRR 5% 5%TTP (weeks) 13 11 0.02OS (weeks) 31 28 0.05681-year survival 29 % 25 %

Data from Ramlau R, et al. J Clin Oncol. 2006;24:2800-2807.


26 Data from Ramlau R, et al. J Clin Oncol. 2006;24:2800-2807.

P = 0.0568; log rank test

Docetaxel vs Oral Topotecan


27

Docetaxel vs Paclitaxel poliglumexPatient Characteristics


• PS 0-2

Docetaxel 75 mg/m2 q 3 wks (n = 422) vs paclitaxel poliglumex (n = 427) 210 mg/m2

(175 mg/m2 for PS 2 pts) q 3 wks

Primary endpoint: OS improvement over docetaxel

Data from Paz-Ares L, et al. Brit J Cancer. 2008;98:1608–1613.

Docetaxel PPX P-valueRR 12% 8%TTP (months) 2.6 2.0 0.075OS (months) 6.9 6.9 0.261-year survival 29% 25%


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Docetaxel vs Paclitaxel poliglumex

Data from Paz-Ares L, et al. Brit J Cancer. 2008;98:1608–1613.


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Randomized phase II trial of chemotherapy +/- bevacizumab

Data from Herbst RS, et al. J Clin Oncol. 2007;25:4743-4750.

Patient Characteristics


• PS 0-2

• No hemoptysis or other bleeding conditions

• 1:1:1 randomization

Docetaxel: 75mg/m2 q 3wks

Pemetrexed: 500 mg/m2 q 3 wks

Bevacizumab: 15 mg/kg q 3wks


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Chemotherapy(n = 41)

Chemotherapy/bev(n = 40)

Erlotinib/bev(n = 39)

ChemotherapyDocetaxel 63.4% 50% N/APemetrexed 36.6% 50% N/AEfficacyRR 12.2% 12.5% 17.9%PFS (months) 3.0 4.8 4.4OS (months) 8.6 12.6 13.71-year survival 33.1% 53.8% 57.4%




32Data from Herbst RS, et al. J Clin Oncol. 2007;25:4743-4750.



33Data from Herbst RS, et al. J Clin Oncol. 2007;25:4743-4750.



34 Data from Heymach JV, et al. J Clin Oncol. 2007;25:4270-4277.

Randomized phase II study of Docetaxel +/- Vandetanib

Patient Characteristics


• PS 0-1

• No prior EGFR or VEGFR inhibitors or docetaxel


VandetanibEGFR & VEGFR TKI

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Docetaxel(n = 41)

Docetaxel/Vandetanib100 (n = 42)


RR 12% 26% 18%PFS (weeks) 12.0 18.7 17.0OS (months) 13.4 13.1 7.9

Randomized phase II trial of docetaxel +/- vandetanib

Data from Heymach, JV, et al. J Clin Oncol. 2007;25:4270-4277.

HR for PFS of docetaxel/vandetanib 100 mg vs docetaxel = 0.64 (P = 0.037)


36 Data from Heymach JV, et al. J Clin Oncol. 2007;25:4270-4277.



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37

Docetaxel(n = 41)



Diarrhea 1 0 7Rash 0 0 8Nausea/Vomit 2 1 4HTN 1 1 4Dizziness 0 0 0


Grade 3/4 Toxicities

Six patients experienced hemoptysisDocetaxel (n = 3; CTC grade 1/3/4)Docetaxel + Vandetanib 100 mg (n = 2; CTC grade 1/2)Docetaxel + Vandetanib 300 mg (n = 1; CTC grade 1)

Data from Heymach JV, et al. J Clin Oncol. 2007;25:4270-4277.


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Placebo +

Docetaxel 75 mg/m2

every 21 days

Van 100 mg/day +

Docetaxel 75 mg/m2

every 21 daysLocally advanced or metastatic (stage III–IV) NSCLC after failure of

1st-line therapy (n = 1240 patients)

Dis

ease

pro

gres

sion

• Randomized in 1:1 ratio • Primary endpoint: progression-free survival• Secondary endpoints: overall survival and response rate• Statistics: 25% prolongation in PFS• All histologies enrolled


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• Other ongoing/completed phase III trials in relapsed NSCLC– Pemetrexed vs pemetrexed / vandetanib 100 mg

• Completed accrual– Docetaxel or pemetrexed vs docetaxel / cetuximab or pemetrexed /

cetuximab• Accrual ongoing

– Docetaxel vs docetaxel/oblimersen (Bcl-2 antisense oligonucleotide)• Completed accrual

– Docetaxel vs docetaxel/exisulind• Completed accrual• “Did not meet primary endpoint” – press release 11/04

– Docetaxel vs vinflunine• No difference in PFS or OS; vinflunine more toxic.

– Docetaxel vs docetaxel/aflibercept (VEGF Trap)• Accrual ongoing


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41

Patient Selection Methods: Histology


42 Data from Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

Breakdown by Histology: Cis/Pem vs Cis/Gem

“Non-Squamous”

“Squamous”


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Retrospective analysis of impact of histology in second line treatment: pemetrexed vs docetaxel

Pemetrexed Docetaxel HRAll patients 8.3 7.9 0.99

“Non-Squamous” 9.3 8.0 0.778 Squamous 6.2 7.4 1.563



FDA label change for “non-squamous”histology

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Audience Response Question Mr. J. is a 57 yo former 80 pack year smoker who presented with hemoptysisin June 2008. He was found to have a central cavitary lesion and liver metastases. Bronchoscopy was performed and confirmed squamous cell cancer. He was treated with chest radiation and 6 cycles of carboplatin/paclitaxel, which finished in December of 2008. He tolerated the treatment well and had a partial response. In March 2009 his follow-up CT revealed new lung nodules. His PS is 1. How would you treat him?

?

1.1. PemetrexedPemetrexed 500 mg/m500 mg/m22

2.2. PemetrexedPemetrexed 500 mg/m500 mg/m2 2 & & bevacizumabbevacizumab 15 mg/kg 15 mg/kg 3.3. Erlotinib/bevacizumabErlotinib/bevacizumab4.4. DocetaxelDocetaxel 75 mg/m75 mg/m22

5.5. Supportive care aloneSupportive care alone

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Mrs. G. is a 54 yo female, life-long never smoker, who inApril 2007 was diagnosed with stage IV NSCLC. At the time of diagnosis she had liver and bone metastases. She was treated with carboplatin/paclitaxel/bevacizumab with a good partial response. She now has disease progression in her liver. Her PS is 1.What therapy would you choose next?

?

1. Docetaxel2. Pemetrexed3. Erlotinib4. Pemetrexed/bevacizumab5. Erlotinib after testing for EGFR mutation

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Patient Selection Methods: Molecular Characteristics


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Epidermal Growth Factor Receptor Inhibitors and EGFR mutations

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• Rationale for developing EGFR inhibitors:– EGFR is expressed in the majority of NSCLC and in limited normal

tissues.– EGFR is associated with a poor prognosis.

DAKO EGFR PharmaDxTM Kit


9

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Cetuximab

Panitumumab

KK

EGFR EGFR

GefitinibErlotinibLapatinib

TKI

Matuzumab

EGFR Targeted Agents


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Agent Study Patients RR%

Gefitinib1 IDEAL 1 209 18-19%

Gefitinib2 IDEAL 2 216 9-12%

Erlotinib3 57 12%

Data from 1Fukuoka M, et al. J Clin Oncol. 2003;21:2237-2246. 2Kris M, et al. JAMA. 2003;290:2149-2158. 3Perez-Soler R, et al. J Clin Oncol. 2004;22:3238-3247.

Phase II studies of EGFR kinase inhibitors in Chemotherapy treated NSCLC patients


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EGFR TKI vs Placebo


52SD, stable disease; PD, progressive disease;* 2:1 randomization.

Stratified by:• Center• Performance status

(0/1 vs 2/3)• Response to prior Rx

(CR/PR:SD:PD)• Prior regimens

(1 vs 2)• Prior platinum

(Yes vs no)

Erlotinib150 mg daily

Placebo150 mg daily

RANDOM I ZE*

2

1

BR.21 – Randomized phase III trial of erlotinib vs placebo


53

0

20

40

60

80

100

0.0 10.0 20.0Months

Pro

porti

on S

urvi

ving

0

20

40

60

80

100

0.0 10.0 20.0Months

0

20

40

60

80

100

0.0 10.0 20.0Months

Pro

porti

on S

urvi

ving 9%

36%

38%

17%

PRNE

PD SD

Response rate: 9%

Median survival: 6.7 vs 4.7

HR: 0.71; P < 0.0001

Data from Shepherd, et al. N Engl J Med. 2005;352:123-132.

BR.21 – Randomized phase III trial of erlotinib vs placebo


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0

20

40

60

80

100

0.0 10.0 20.0Months

Pro

porti

on S

urvi

ving

0

20

40

60

80

100

0.0 10.0 20.0Months

0

20

40

60

80

100

0.0 10.0 20.0Months

Pro

porti

on S

urvi

ving

Response rate: 9%

Median survival: 6.7 vs 4.7

HR:0.71; P < 0.0001

All patients (n = 731)

0

25

50

75

100

Months0 5 10 15 20 25

Placebo (n=42)

Erlotinib (n=104)

Pro

porti

on S

urvi

ving

0

25

50

75

100

Months0 5 10 15 20 25

Placebo (n=42)

Erlotinib (n=104)

Pro

porti

on S

urvi

ving

Response rate: 24.7%

Median survival: ~6 vs ~ 12 months

HR:0.42; P < 0.001

Never smokers (n = 146)

Data from Shepherd et al. N Engl J Med. 2005;353:123-132.


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• Somatic• Found in 10-15% of Caucasians; 30-40% of

Asians with NSCLC1

• Found more commonly in never or light cigarette smokers2

• Oncogenic in NIH3T3 cells and in mice3,4

• Exquisite sensitivity to EGFR TKIs

1Shigematsu H, et al. J Natl Cancer Inst. 2005;97:339-346. 2Pham D, et al. J Clin Oncol. 2006;24:1700-1704. 3Greulich H, et al. PLoS Med. 2005;2:e313. 4Ji H, et al. Cancer Cell. 2006;9:485-495.

EGFR mutations


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CI

F

N

O NH

N

O

O

N

NH

N

O

O

N

CI

F

N

O NH

N

O

O

N

NH

N

O

O

N

NH

N

O

O

N

O

O

H3C

H3CO

O

NH

N

NO

O

H3C

H3CO

O

NH

N

N

Quinazoline type EGFR inhibitors

Gefitinib Erlotinib

Located in TK domain

Exon 19 and 21 most common

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Author # screened EGFR mutations Agent RR TTP

Chemotherapy Naïve – EGFR mutantInoue 99 16 Gefitinib 75% 9.7 mosPaz-Ares 1047 43 Erlotinib 82% 13.3 mos

Tamura 118 32 Gefitinib 75% 11.5 months

Sequist 98 31 Gefitinib 55% 11.4 mos

Second Line Therapy – EGFR mutant

Sutani 107 23 Gefitinib 74% 9.4 mosSecond Line Therapy - UnselectedThatcher N/A N/A Gefitinib 8% 3.0 mosShepherd N/A N/A Erlotinib 9% 2.0 mos

Prospective Phase II clinical trials of EGFR TKIs in EGFR mutant NSCLC

Inoue et al., JCO 2006; Paz-Ares et al., ASCO 2006; Tamura et al., Br J Cancer 2008; Sequist et al., JCO 2008; Sutani et al., Br J Cancer 2006; Thatcher et al., Lancet 2005; Shepherd et al. NEJM 2005.


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EGFR TKI vs Chemotherapy


59

723593 (82.0%)

710576 (81.1%)

NEvents

Primary Cox analysis without covariates

HR (96% CI) = 1.020 (0.905, 1.150)

Median OS (months)1-year survival

7.632%

8.034%

Gefitinib Docetaxel

Conclude non-inferiorityin the overall PP population

723 336 225 131 83 50 31 14 0 0710 339 228 139 89 46 24 7 0 0

518503

0 4 8 12 16 20 24 28 32 36 40

0.0

0.2

0.4

0.6

0.8

1.0

Months

Probabilityof survival

At risk :GefitinibDocetaxel

Douillard et al. ASCO 2008.


INTEREST: Phase III Gefitinib vs Docetaxel

60

13

7.59

15.8

42.1

6.6

0

9.67.4

10.1 11 9.8

3.76.1

21.1

11.9

0

10

20

30

40

50GefitinibDocetaxel

EGFR gene copy number EGFR protein expression

EGFR mutation

P = 0.0361 P = 0.3720P = 0.2741P = 0.6560P = 0.2688P = 0.0387 P = NC P = 0.6292

OR

R (%

)

Positive NegativeHigh Low Positive Wild-typeK-RAS mutation

Positive Wild-type


INTEREST: Response Rate by Genotype

11

EGFR mutation

Prob

abili

ty o

f PFS

GefitinibDocetaxel

EGFR wild-type

Prob

abili

ty o

f PFS

GefitinibDocetaxel

1.0

0.8

0.6

0.4

0.2

0.00 4 8 12 16 20 24 28 32 36 40

Months

1.0

0.8

0.6

0.4

0.2

0.00 4 8 12 16 20 24 28 32 36 40

Months

HR (95% CI) = 1.24 (0.94, 1.64) p = 0.1353Median PFS (mo): gefitinib 1.7, docetaxel 2.6

HR (95% CI) = 0.16 (0.05, 0.49) p = 0.0012Median PFS (mo): gefitinib 7.0, docetaxel 4.1

Douillard et al. ASCO 2008

INTEREST: PFS by Genotype


62

Phenotype EGFR Mutation

All NSCLC patients 10-15%

Elderly NSCLC patients 10-15%

PS2 patients 10-15%

Caucasian never smokers ~ 35%

Asian never smokers ~ 65-70%


Selection by phenotype is not a great surrogate for EGFR mutations.

63

• Strategies to improve efficacy of erlotinib for relapsed NSCLC– Patient selection methods

• EGFR mutation testing – Commercially available through Genzyme

– Combination therapeutic approaches for all patients


64

Tumor

Inhibitor Erlotinib BevacizumabMechanism Inhibits tumor cell growth

and blocks synthesis of angiogenic proteins (e.g. bFGF, VEGF, TGF-α) by tumor cells

Inhibits endothelial cells from responding to the angiogenic protein VEGF

bFGFVEGFTGF-α

Endothelial cells


65



66

Patients (n = 40)RR 20.0%

PFS months 7.0

OS months 12.61-year survival 54.2%


No unexpected side-effects were observed


12

67

RANDOMIZE

Arm 1Erlotinib + bevacizumab placebo

Arm 2Erlotinib + bevacizumab

Arm 1: Erlotinib 150 mg/d + bevacizumab placebo 15 mg/kg q3wk Arm 2: Erlotinib 150 mg/d + bevacizumab 15 mg/kg q3wk

Previously treated

Non–squamouscell NSCLC

(N = 650)

Primary endpoint: OSSecondary endpoints: PFS, safety, QOL, EGFR markers to outcomes

Erlotinib vs erlotinib/bevacizumab: BETA lung trial


68

HR is estimated using stratified Cox model; P-value is based on stratified log-rank test. Stratification factors are ECOG PS, smoking status, and sex.

Data from Hainsworth. IASLC. 2008.


Erlotinib Erl/Bev

mPFS 1.7 mos 3.4 mos

RR % 6.2 12.6

69HR is estimated using stratified Cox model. P-value is based on stratified log-rank test. Stratification factors are ECOG PS, smoking status, and sex.


Data from Hainsworth. IASLC. 2008. 70

• Other ongoing phase III trials of erlotinib in relapsed NSCLC:– Erlotinib vs pemetrexed

• Accrual ongoing– Erlotinib vs vandetanib

• Accrual completed– Erlotinib vs erlotinib/CP-751,871 (IGF-1R antibody)

• Accrual ongoing– Erlotinib vs erlotinib/sunitinib

• Accrual ongoing


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EML4-ALK Translocations

72


Soda M, et al. Nature. 2007;448:561-566. Koivunen JP, et al. Clin Cancer Res. 2008;14:4275-4283.

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• NSCLC patients with EML4-ALK translocations:– Never or limited smokers– Adenocarcinoma– Do not harbor concurrent EGFR or KRAS mutations– Clinically resistant to erlotinib

• Clinical/molecular characteristics can be used to identify NSCLC patients with EML4-ALK. – Never/limited smoker; EGFR/KRAS WT

• ~20% - 30% will harbor EML4-ALK


Shaw AT, et al. J Clin Oncol. 2009;27:4247-4253.74

EML4ALKEML4ALK

Examples of EML4-ALK positive NSCLCs

FISH

IHC

FISH – Charles Lee – BWH IHC – Scott Rodig - BWH


75

Tumor Size Change and Treatment Duration (weeks)

-100

-80

-60

-40

-20

0

20

40

3 10 7 6 22 2 16 15 20 16 11 10 19 30 17 21 16 8 41 11 26 41 46 19

Green - PR Blue - SD Black - PD

% o

f bes

t cha

nge

from

bas

elin

e

ON

N

Cl

F

Cl

NN

N


PF-0231066

ALK inhibitor is clinically very effective in EML4-ALK NSCLC.

Response rate: 59%Shaw et al. IASLC 2009.

76

Key Entry Criteria• Positive for ALK gene

translocation• Brain mets allowed• 1 prior chemo

(platinum-based)

RANDOMIZE

N = 318

PF-02341066

Pemetrexed orDocetaxel

N = 159

N = 159


Randomized phase III trial of PF-02341066 vschemotherapy in previously treated EML4-ALK NSCLC

Primary endpoint: PFS

Secondary endpoint: ORR

77

• Beyond second line– Erlotinib only agent FDA-approved for 3rd-line therapy– No standard of care beyond 3rd line

• Commonly used chemotherapy in 3rd-line therapy– Vinorelbine– Gemcitabine

• Clinical trials ongoing– Second generation EGFR inhibitors

• BIBW 2992 vs placebo– Vandetanib

• Vandetanib vs placebo


78

Agent NResponse

Rate MedianSurvival

1-YearSurvival

Docetaxel 55 7% 8 mo 37%

Docetaxel 121 7% 6 mo 32%Docetaxel 288 9% 8 mo 30%Pemetrexed** 283 9% 8 mo 30%Gefitinib* 1129 8% 6 mo 27%Erlotinib* 488 9% 7 mo 31%

*Includes 2nd (50%) and 3rd (50%) line patients**Approved only for adenocarcinoma and large cell carcinoma


Summary of randomized phase III results inrelapsed NSCLC

14

79


Mrs. G. is a 54 yo female, life-long never smoker, who inApril 2007 was diagnosed with stage IV NSCLC. At the time of diagnosis, she had liver and bone metastases. She was treated with carboplatin/paclitaxel/bevacizumab with a good partial response. She now has disease progression in her liver. Her PS is 1.What therapy would you choose next?

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1.1. DocetaxelDocetaxel2.2. PemetrexedPemetrexed3.3. ErlotinibErlotinib4.4. Pemetrexed/bevacizumabPemetrexed/bevacizumab5. Erlotinib after testing for EGFR mutation

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Miami, FL December 19, 2009 Speaker: Pasi A. Jänne MD, PhD Files/Syllabus Files Fall...Miami, FL...

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