Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana Farber Cancer Institute
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Transcript of Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana Farber Cancer Institute
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Pasi A. Jänne, M.D., Ph.D.Lowe Center for Thoracic Oncology
Dana Farber Cancer Institute
Novel Strategies for Targeting
the EGFR Pathway
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
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)
• 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)
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
Primary Analysis: Overall Survival
Miller et al. ESMO 2010
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
Regales et al. JCI 2009
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."
Phase Ib Study of Afatinib & Cetuximab
1EGFR 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.
Stop erlotinib/ gefitinib for ≥72 hours3
Disease progression2
Pathology confirmed NSCLC with
EGFR mutation1
OR
SD 6 monthson erlotinib/gefitinib
OR
Partial or complete response
to erlotinib/gefitinib MTD cohort expanded up to 80 EGFR mutation-positive patients4:
40 T790M+ and 40 T790M–
Dose escalation schema 3–6 patients per cohort
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
ECOG PS 0-2Age ≥ 18 years
Research To Practice could not obtain permission to reproduce this slide at the time of publication.
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Groen JL et al. Proc IASLC 2011;Abstract O19.07.
Randomized Phase 2 Study of Randomized Phase 2 Study of Dacomitinib (PF299804) vs. ErlotinibDacomitinib (PF299804) vs. Erlotinib
Stratification:
Non-smokers vs smokers
Adeno vs Non-adeno
East Asian vs non-East Asian
Primary endpoint: PFS
Secondary endpoints: OS, response, safety, patient reported outcomes
128 PFS events to show 45% improvement, with 80% power, =0.1 (1-sided)
Key Eligibility: Advanced NSCLC 12 prior chemotherapies ECOG PS 0‒2 Available tumor tissue No prior EGFR TKI
Recruited 11/08 – 10/0947 Centres, 12 countriesTreated till PD, death or unacceptable toxicity
Erlotinib150 mg QD
N=94
PF29980445 mg QD
N=94
RANDOMIZED
Boyer et al. WCLC 2011
Progression-Free Survival (PFS) PF299804 vs Erlotinib: All and KRAS WT (both 12% Censored)
Boyer et al. WCLC 2011
PF299804 Erlotinib Stratified HR2-sided p-value
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
Patients clinically selected:
Never-* or former light-smoker †; Asian or KRAS WT non-Asian
OR
Known EGFR mutation
Additional inclusion criteria:
• Adenocarcinoma histology• Chemotherapy naϊve• ECOG PS 0/1
First-Line Phase II Trial of PF299804First-Line Phase II Trial of PF299804
PF29980445 mg QD
(amended to 30 mg)
*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
Endpoints:
Primary•PFS rate at 4 months
Secondary:•PFS•OS•ORR•Safety
Exploratory: •Serial tissue- and blood-based biomarkers (T790M)
Data cut-off: July 28, 2010
Mok et al. ESMO 2010
Best Tumor Change in Target Lesions: Overall Population Treated with PF299804
40
20
0
–20
–40
–60
–80
–100
40
20
0
–20
–40
–60
–80
–100
Best
chang
e f
rom
base
line (
%)
Best
chang
e f
rom
base
line (
%)
45 mg, RDI ≥70%
45 mg, RDI <70%
30 mg, RDI ≥70%
30 mg, RDI <70%
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 Second- Generation 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, 2012Hollywood, Florida
Faculty
Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD
Co-Chair and ModeratorNeil Love, MD
Chandra P Belani, MDJohn Heymach, MD, PhDPasi A Jänne, MD, PhD
Thomas J Lynch Jr, MDHeather Wakelee, MD