Transcript Research To Practice

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Novel Strategies for Targeting
the EGFR Pathway
Pasi A. Jänne, M.D., Ph.D.
Lowe Center for Thoracic Oncology
Dana Farber Cancer Institute
EGFR Targeted Therapies
• First generation TKIs
– Erlotinib, gefitinib, lapatinib
• Second generation TKIs
– Neratinib, afatinib (BIBW2992), dacomitinib
(PF299804)
• Third generation
– WZ4002 – preclinical only
• Combinations
– Afatinib/cetuximab
Use of Novel EGFR Therapies
• When erlotinib fails
– Afatinib phase III trial
– Afatinib/cetuximab
• Instead of erlotinib
– Second line – dacomitinib vs. erlotinib
– First line – afatinib or dacomitinib instead of
erlotinib
LUX-Lung 1: Trial Design
Patients with:
• Adenocarcinoma of the lung
• Stage IIIB/IV
• Progressed after one or two lines of chemotherapy (incl. one platinum-based
regimen) and ≥12 weeks of treatment with erlotinib or gefitinib
• ECOG 0–2
N=585
Randomization 2:1
(Double Blind)
Oral afatinib 50 mg once daily
plus BSC
Oral placebo once daily
plus BSC
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL (LC13 & C30), safety
• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter
• Exploratory biomarkers:
Archival tissue testing for EGFR mutations (optional; central lab)
Serum EGFR mutational analysis (all patients)
Primary Analysis: Overall Survival
OS
• Placebo, deaths = 114 (58.5%), median = 11.96 months
(95% CI: 10.15-14.26)
• Afatinib, deaths = 244 (62.6%), median = 10.78 months
(95% CI: 9.95-11.99)
– Hazard ratio (afatinib vs placebo) - 1.077 (0.862, 1.346)
– Log-rank test p-value (one-sided) - 0.7428
• Afatinib RR: 7%
• PFS: Afatinib 3.3 months; placebo 1.1 months
– HR 0.38, 95% CI 0.31 to 0.48, p < 0.0001
Miller et al. ESMO 2010
Combination of BIBW2992 and Cetuximab
Is Effective against EGFR T790M
"The combination of both agents together
induced dramatic shrinkage of erlotinib-resistant
tumors harboring the T790M mutation, because
together they efficiently depleted both
phosphorylated and total EGFR."
Regales et al. JCI 2009
Phase Ib Study of Afatinib & Cetuximab
Dose escalation schema 3–6
patients per cohort
Pathology confirmed
NSCLC with
EGFR mutation1
OR
SD 6 months
on erlotinib/gefitinib
OR
Partial or complete
response
to erlotinib/gefitinib
ECOG PS 0-2
Age ≥ 18 years
1EGFR
Disease
progression2
Stop erlotinib/
gefitinib for
≥72 hours3
Afatinib p.o. daily + escalating
doses of i.v. cetuximab q 2 weeks
Dose levels starting at:
afatinib 40 mg +
cetuximab 250 mg/m2
Predefined maximum dose:
afatinib 40 mg +
cetuximab 500 mg/m2
MTD cohort expanded up to 80 EGFR
mutation-positive patients4:
40 T790M+ and 40 T790M–
G719X, exon 19 deletion, L858R, L861Q; 2Progression of disease (Response Evaluation Criteria in Solid Tumors
v1.1) on continuous treatment with erlotinib or gefitinib within the last 30 days; 3Amended from original 14-day interval;
4Acquisition of tumor tissue after the emergence of acquired resistance was mandated.
i.v.=intravenous; MTD=maximum tolerated dose; NSCLC=non-small cell lung cancer; SD=stable disease.
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Groen JL et al. Proc IASLC 2011;Abstract O19.07.
Randomized Phase 2 Study of
Dacomitinib (PF299804) vs. Erlotinib
Key Eligibility:
-Advanced NSCLC
-12 prior chemotherapies
-ECOG PS 0‒2
-Available tumor tissue
-No prior EGFR TKI
Stratification:
Non-smokers vs smokers
Adeno vs Non-adeno
East Asian vs non-East Asian
Boyer et al. WCLC 2011
R
A
N
D
O
M
I
Z
E
D
PF299804
45 mg QD
N=94
Recruited 11/08 – 10/09
47 Centres, 12 countries
Treated till PD, death or
unacceptable toxicity
Erlotinib
150 mg QD
N=94
Primary endpoint: PFS
Secondary endpoints: OS, response,
safety, patient reported outcomes
128 PFS events to show 45% improvement,
with 80% power, a=0.1 (1-sided)
Progression-Free Survival (PFS) PF299804 vs
Erlotinib: All and KRAS WT (both 12% Censored)
2-sided
p-value
PF299804
Erlotinib
Stratified HR
PFS, all
patients
(n=94)
12.4 weeks
8.3 weeks
0.66 (95% CI:
7.9-11.7)
0.012
PFS, KRAS
WT (n=57)
16.1 weeks
8.3 weeks
0.50 (95% CI:
0.33-0.78)
0.002
Boyer et al. WCLC 2011
First-Line Phase II Trial of PF299804
Patients clinically selected:
Endpoints:
Never-* or former lightsmoker †; Asian or KRAS
WT non-Asian
Primary
•PFS rate at 4 months
OR
Known EGFR mutation
PF299804
45 mg QD
(amended to
30 mg)
Secondary:
•PFS
•OS
•ORR
•Safety
Additional inclusion criteria:
Exploratory:
•Serial tissue- and
blood-based
biomarkers (T790M)
• Adenocarcinoma histology
• Chemotherapy naϊve
• ECOG PS 0/1
Data cut-off: July 28, 2010
*Never-smoker: <100 cigarettes, cigars, or pipes over lifetime, and none in 12 months
†Former light-smoker: ≤15 years since last cigarette, and less than 10 pack-years of prior cigarette smoking
Mok et al. ESMO 2010
Best Tumor Change in Target Lesions:
Overall Population Treated with PF299804
40
Best change from baseline (%)
20
0
–20
–40
–60
–80
–100
45 mg, RDI ≥70%
45 mg, RDI <70%
30 mg, RDI ≥70%
30 mg, RDI <70%
N=71
With permission from Mok et al. ESMO 2010
First-Line Therapy with SecondGeneration EGFR TKIs
• Dacomitinib (PF299804) –
– High RR (~60% in EGFR mutants)
– PFS – ASCO 2012
• Afatinib1
– RR 64%; PFS 14.7 months
• Afatinib vs. chemotherapy
– ASCO 2012
1Yang
et al. ASCO 2010
Saturday, February 11, 2012
Hollywood, Florida
Co-Chairs
Rogerio C Lilenbaum, MD
Co-Chair and Moderator
Neil Love, MD
Mark A Socinski, MD
Faculty
Chandra P Belani, MD
John Heymach, MD, PhD
Pasi A Jänne, MD, PhD
Thomas J Lynch Jr, MD
Heather Wakelee, MD