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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.

To access the following abstract, please visit our Select Publications page:

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