1 / 17

Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana Farber Cancer Institute

morrison
Download Presentation

Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana Farber Cancer Institute

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

  2. Novel Strategies for Targeting the EGFR Pathway Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana Farber Cancer Institute

  3. 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

  4. 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

  5. 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)

  6. 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

  7. 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

  8. Phase Ib Study of Afatinib & Cetuximab Pathology confirmed NSCLC with EGFR mutation1 OR SD 6 months on erlotinib/gefitinib OR Partial or complete response to erlotinib/gefitinib 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 Stop erlotinib/ gefitinib for ≥72 hours3 Disease progression2 MTD cohort expanded up to 80 EGFR mutation-positive patients4: 40 T790M+ and 40 T790M– ECOG PS 0-2 Age ≥ 18 years 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.

  9. 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.

  10. Randomized Phase 2 Study of Dacomitinib (PF299804) vs. Erlotinib PF299804 45 mg QD N=94 RANDOMIZED • Key Eligibility: • Advanced NSCLC • 12 prior chemotherapies • ECOG PS 0‒2 • Available tumor tissue • No prior EGFR TKI Recruited 11/08 – 10/09 47 Centres, 12 countries Treated till PD, death or unacceptable toxicity Erlotinib 150 mg QD N=94 Stratification: Non-smokers vs smokers Adeno vsNon-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, a=0.1 (1-sided) Boyer et al. WCLC 2011

  11. Progression-Free Survival (PFS) PF299804 vs Erlotinib: All and KRAS WT (both 12% Censored) Boyer et al. WCLC 2011

  12. First-Line Phase II Trial of PF299804 • 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 • Endpoints: • Primary • PFS rate at 4 months • Secondary: • PFS • OS • ORR • Safety • Exploratory: • Serial tissue- and blood-based biomarkers (T790M) PF299804 45 mg QD (amended to 30 mg) 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

  13. Best Tumor Change in Target Lesions: Overall Population Treated with PF299804 40 20 0 –20 –40 –60 –80 –100 Best change from baseline (%) 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

  14. 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

  15. Saturday, February 11, 2012Hollywood, Florida Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Faculty Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD

More Related