miami, fl december 19, 2009 speaker: pasi a. jänne md, phd files/syllabus files fall...miami, fl...
TRANSCRIPT
1
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
3
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.
4
• Therapeutic choices for relapsed NSCLC– Supportive care– Chemotherapy– Erlotinib– Participation in a clinical trial
Management of Relapsed NSCLC
5
Management of Relapsed NSCLC
• Considerations for offering treatment for relapsed NSCLC– Performance status– Recovery from first-line therapy– Patient preferences
6
• FDA-approved agents for relapsed NSCLC– Docetaxel– Pemetrexed– Erlotinib
Management of Relapsed NSCLC
2
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
8
Chemotherapy for Relapsed NSCLC
Management of 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
Management of Relapsed NSCLC
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)
Management of Relapsed NSCLC
11 Data from Fossella FV, et al. J Clin Oncol. 2000;18:2354-2362.
Docetaxel vs Vinorelbine or IfosfamidePatient Characteristics
• Relapsed IIIB/IV NSCLC
• 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
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
3
13
Pemetrexed vs DocetaxelPatient Characteristics
• Relapsed IIIB/IV NSCLC
• 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
Management of Relapsed NSCLC
14 Data from Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
Management of Relapsed NSCLC
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
Data from Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
Pemetrexed vs Docetaxel: Toxicity
Management of Relapsed NSCLC
16
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 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
17
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 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
18
• Strategies to improve efficacy of chemotherapy for relapsed NSCLC– Alternative administration schedules of currently
approved agents– Alternative agents– Combination approaches– Patient selection methods
Management of Relapsed NSCLC
4
19
• Strategies to improve efficacy of chemotherapy for relapsed NSCLC– Alternative administration schedules of currently
approved agents– Alternative agents– Combination approaches– Patient selection methods
Management of Relapsed NSCLC
20
Docetaxel every 3 wks vs docetaxel weeklyPatient Characteristics
• Relapsed IIIB/IV NSCLC
• 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%
Management of Relapsed NSCLC
21
Docetaxel every 3 wks vs docetaxel weekly
Data from Schuette W, et al. J Clin Oncol. 2005;23:8389-8395.
Time to progression Survival
Management of Relapsed NSCLC
22
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
Data from Schuette W, et al. J Clin Oncol. 2005;23:8389-8395.
Management of Relapsed NSCLC
23
• 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.
Management of Relapsed NSCLC
24
• Strategies to improve efficacy of chemotherapy for relapsed NSCLC– Alternative administration schedules of currently
approved agents– Alternative agents– Combination approaches– Patient selection methods
Management of Relapsed NSCLC
5
25
Docetaxel vs Oral TopotecanPatient Characteristics
• Relapsed IIIB/IV NSCLC
• 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.
Management of Relapsed NSCLC
26 Data from Ramlau R, et al. J Clin Oncol. 2006;24:2800-2807.
P = 0.0568; log rank test
Docetaxel vs Oral Topotecan
Management of Relapsed NSCLC
27
Docetaxel vs Paclitaxel poliglumexPatient Characteristics
• Relapsed IIIB/IV NSCLC
• 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%
Management of Relapsed NSCLC
28
Docetaxel vs Paclitaxel poliglumex
Data from Paz-Ares L, et al. Brit J Cancer. 2008;98:1608–1613.
Management of Relapsed NSCLC
29
• Strategies to improve efficacy of chemotherapy for relapsed NSCLC– Alternative administration schedules of currently
approved agents– Alternative agents– Combination approaches– Patient selection methods
Management of Relapsed NSCLC
30
Randomized phase II trial of chemotherapy +/- bevacizumab
Data from Herbst RS, et al. J Clin Oncol. 2007;25:4743-4750.
Patient Characteristics
• Relapsed IIIB/IV NSCLC
• 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
Management of Relapsed NSCLC
6
31
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%
Data from Herbst RS, et al. J Clin Oncol. 2007;25:4743-4750.
Randomized phase II trial of chemotherapy +/- bevacizumab
Management of Relapsed NSCLC
32Data from Herbst RS, et al. J Clin Oncol. 2007;25:4743-4750.
Randomized phase II trial of chemotherapy +/- bevacizumab
Management of Relapsed NSCLC
33Data from Herbst RS, et al. J Clin Oncol. 2007;25:4743-4750.
Randomized phase II trial of chemotherapy +/- bevacizumab
Management of Relapsed NSCLC
34 Data from Heymach JV, et al. J Clin Oncol. 2007;25:4270-4277.
Randomized phase II study of Docetaxel +/- Vandetanib
Patient Characteristics
• Relapsed IIIB/IV NSCLC
• PS 0-1
• No prior EGFR or VEGFR inhibitors or docetaxel
Management of Relapsed NSCLC
VandetanibEGFR & VEGFR TKI
35
Docetaxel(n = 41)
Docetaxel/Vandetanib100 (n = 42)
Docetaxel/Vandetanib300 (n = 44)
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)
Management of Relapsed NSCLC
36 Data from Heymach JV, et al. J Clin Oncol. 2007;25:4270-4277.
Randomized phase II trial of docetaxel +/- vandetanib
Management of Relapsed NSCLC
7
37
Docetaxel(n = 41)
Docetaxel/Vandetanib100 (n = 42)
Docetaxel/Vandetanib300 (n = 44)
Diarrhea 1 0 7Rash 0 0 8Nausea/Vomit 2 1 4HTN 1 1 4Dizziness 0 0 0
Randomized phase II trial of docetaxel +/- vandetanib
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.
Management of Relapsed NSCLC
38
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
Management of Relapsed NSCLC
39
• 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
Management of Relapsed NSCLC
40
• Strategies to improve efficacy of chemotherapy for relapsed NSCLC– Alternative administration schedules of currently
approved agents– Alternative agents– Combination approaches– Patient selection methods
Management of Relapsed NSCLC
41
Patient Selection Methods: Histology
Management of Relapsed NSCLC
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”
Management of Relapsed NSCLC
8
43
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
Data from Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
Management of Relapsed NSCLC
FDA label change for “non-squamous”histology
44
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
45
Audience Response Question
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
46
Patient Selection Methods: Molecular Characteristics
Management of Relapsed NSCLC
47
Management of Relapsed NSCLC
Epidermal Growth Factor Receptor Inhibitors and EGFR mutations
48
• 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
Management of Relapsed NSCLC
9
49
Cetuximab
Panitumumab
KK
EGFR EGFR
GefitinibErlotinibLapatinib
TKI
Matuzumab
EGFR Targeted Agents
Management of Relapsed NSCLC
50
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
Management of Relapsed NSCLC
51
EGFR TKI vs Placebo
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
54
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.
Management of Relapsed NSCLC
10
55
• 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
Management of Relapsed NSCLC
56
Management of Relapsed NSCLC
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
57
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.
Management of Relapsed NSCLC
58
EGFR TKI vs Chemotherapy
Management of Relapsed NSCLC
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.
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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%
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
65
Data from Herbst RS, et al. J Clin Oncol. 2005;23:2544-2555.
Management of Relapsed NSCLC
66
Patients (n = 40)RR 20.0%
PFS months 7.0
OS months 12.61-year survival 54.2%
Data from Herbst RS, et al. J Clin Oncol. 2005;23:2544-2555.
No unexpected side-effects were observed
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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.
Management of Relapsed NSCLC
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.
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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Management of Relapsed NSCLC
EML4-ALK Translocations
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Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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
Management of Relapsed NSCLC
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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
Management of Relapsed NSCLC
PF-0231066
ALK inhibitor is clinically very effective in EML4-ALK NSCLC.
Response rate: 59%Shaw et al. IASLC 2009.
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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
Management of Relapsed NSCLC
Randomized phase III trial of PF-02341066 vschemotherapy in previously treated EML4-ALK NSCLC
Primary endpoint: PFS
Secondary endpoint: ORR
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• 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
Management of Relapsed NSCLC
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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
Management of Relapsed NSCLC
Summary of randomized phase III results inrelapsed NSCLC
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Audience Response Question
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?
?
1.1. DocetaxelDocetaxel2.2. PemetrexedPemetrexed3.3. ErlotinibErlotinib4.4. Pemetrexed/bevacizumabPemetrexed/bevacizumab5. Erlotinib after testing for EGFR mutation
Thank you for attendingMaster Class for Oncologists
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Questions & Answers
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