1 / 76

Keeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual Meeting

Keeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual Meeting. Introduction. Overview of Targeted Therapies and Focus on Monoclonals. Karen Kelly, MD Professor of Medicine Department of Medical Oncology University of Colorado at Denver Aurora, Colorado.

KeelyKia
Télécharger la présentation

Keeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual Meeting

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. Keeping Pace with Targeted Therapies in Lung CancerHighlights from the ASCO 2006 Annual Meeting

  2. Introduction

  3. Overview of Targeted Therapies and Focus on Monoclonals Karen Kelly, MD Professor of Medicine Department of Medical Oncology University of Colorado at Denver Aurora, Colorado

  4. FDA-Approved Agents BeingInvestigated for Lung Cancer Treatment VEGF = vascular endothelial growth factor; CRC = colorectal cancer; EGFR = epidermal growth factor receptor; TK = tyrosine kinase; NSCLC = non–small-cell lung cancer; PDGFR = platelet-derived growth factor receptor; RCC = renal cell carcinoma; GIST = gastrointestinal stromal tumor;RXR = retinoid X receptor.

  5. Examples of Novel Targeted Agents Being Investigated for Lung Cancer Treatment EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; PDGFR = platelet-derived growth factor receptor; TGF = transforming growth factor.

  6. ASCO 2006 UpdateBevacizumab in NSCLC Paclitaxel + carboplatin ± bevacizumab (updated results from randomized phase III trial E4599) • Sandler AB, et al.1 • Brahmer JR, et al.2 • Dowlati A, et al.3 1. Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4. 2. Brahmer JR, et al. 42nd ASCO;June 2-6, 2006. Abstract 7036. 3. Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.

  7. Paclitaxel/Carboplatin ± Bevacizumab Previously Reported ECOG 4599 Results *As percent of patients with measurable disease, n = 350 for the PC arm and n = 357 for PCB arm. ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab; PFS = progression-free survival; OS = overall survival. Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4.

  8. Paclitaxel/Carboplatin ± BevacizumabPossible Gender Differences in Overall Survival • Unplanned subgroup analysis of ECOG 4599 • Key finding: compared with males, females did not appear to gain same overall survival benefit from addition of bevacizumab ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab. Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.

  9. Paclitaxel/Carboplatin ± Bevacizumab No Gender Differences in Overall Survival • Females on PCB arm had higher response rate and progression-free survival compared with females in the PC arm P = paclitaxel; C = carboplatin; B = bevacizumab; CR = complete response; PR = partial response. Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.

  10. Paclitaxel/Carboplatin ± Bevacizumab Perspective on Unplanned Analysis by Gender • Treatments at time of disease progression were not different, except that in the PCB arm, females were slightly less likely than males to get chemotherapy as 2nd-line therapy • Reasons for observed differences in overall survival are unclear, possibilities include • Random chance • Pitfalls of unplanned subgroup analysis • These results contrast with results in CRC trials where no gender differences reported in overall survival • PCB remains ECOG reference treatment in NSCLC PCB = paclitaxel/carboplatin/bevacizumab; CRC = colorectal cancer; ECOG = Eastern Cooperative OncologyGroup; NSCLC = non–small-cell lung cancer. Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036. Laskin JJ. 42nd ASCO; June 2-6, 2006. Lung Cancer I Poster Discussion. Discussant.Hurwitz H, et al. N Engl J Med. 2004;350:2335. Genentech data on file

  11. Prospective Correlative Assessment of Biomarkers from ECOG 4599 Biomarkers studied • Endothelial leukocyte adhesion molecule-1 (E-selectin) • Expressed only on endothelial cell after activation by inflammatory cytokines • Elevated E-selectin seen in disorders characterized by endothelial cell apoptosis and malignancies • Intercellular adhesion molecule-1 (ICAM-1; CD54) • Expressed on endothelial, epithelial, lymphocytes, monocytes, hepatocytes, and hemapoietic cells • Elevated levels seen in many malignancies and alterations seen with vascular targeting and antiangiogenic agents • Vascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF) • Well-known angiogenic factors Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.

  12. Prospective Correlative Assessment of Biomarkers From ECOG 4599—Results • Baseline plasma ICAM may be prognostic for response and survival in advanced NSCLC • This might be useful stratification factor in future trials • Low levels indicate a 2-fold increase in likelihood of response to chemotherapy (unclear if this is prognostic or predictive) • Future trials are needed to determine if these will be better markers for clinical outcome than conventional radiographic response assessment Survival by Baseline ICAM 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0.0 - <260.5 (62 deaths/75 cases)>260.5 (70 deaths/75 cases) P = .000050 Probability 1 y 60% 1 y 25% 0 10 20 30 40 Months Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027. Reprinted with permission from Dr. Dowlati. Hirsch F. 42nd ASCO; June 2-6, 2006. Lung Cancer III. Discussant.

  13. Risk Factors for Pulmonary Hemorrhage (PH) in Bevacizumab-Treated Patients Retrospective study of ECOG 4599 data examining association between baseline clinical factors and incidence of early onset (< 150 d from initial treatment) PH • Grade  3 PH occurred in 2.3% of patients • Of 10 cases identified, 6 met criteria for early onset PH related to bevacizumab • Pretreatment cavitation may be associated with increased risk of PH • Hemoptysis was predicative of possible future PH Sandler AB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7068.

  14. ASCO 2006 Update on Cetuximab in NSCLC • SWOG 0342 phase II trial of chemotherapy + cetuximab vs chemotherapy followed by cetuximab1 • FLEX phase III trial of cisplatin/vinorelbine ± cetuximab2 1. Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. 2. Von Pawl, J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.

  15. Paclitaxel/ carboplatin + cetuximab × 4 cycles (n = 106) Cetuximab weekly × 1 year Randomize stage IIIB/IVNSCLC Cetuximab weekly × 1 year Paclitaxel/ carboplatin × 4 cycles (n = 119) Preliminary Results of SWOG 0342 Phase II Trial of Paclitaxel/Carboplatin + Cetuximab Primary objectives • Compare response rate and toxicity of concurrent vs sequential platinum-based chemotherapy + cetuximab regimens as 1st-linetreatment for advanced NSCLC • Select regimen for future trials based on overall survival Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.

  16. Phase II Trial ofPaclitaxel/Carboplatin + CetuximabPreliminary Efficacy Results *Patients evaluable for response: 71 in the chemo + cetuximab arm and 87 in the chemo-only arm. Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.

  17. SWOG 0342—Phase II Trial of Paclitaxel/Carboplatin + CetuximabPreliminary Safety Results Adverse Events (grade 3/4) 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - 67 55 Grade 3/4 AE (>5%) on Chemo (+/-C) N=101 N=94 % of Evaluable Patients Sequential Concurrent 27 20 N=20 N=22 Chemo +/- C Post-Chemo C Rash (grade 3/4) 14 - 12 - 10 - 8 - 6 - 4 - 2 - 0 - 12 10 N=94 N=20 N=22 No new cases concurrent ann % of Evaluable Patients Sequential Concurrent 1 N=101 Chemo = paclitaxel/carboplatin; C = cetuximab. Chemo +/- C Post-Chemo C Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.

  18. Phase II Trial ofPaclitaxel/Carboplatin + CetuximabPreliminary Conclusions • Concurrent cetuximab + chemotherapy arm met predetermined 10-month minimal median survival requirement • Trend toward higher response rate in concurrent arm • Rash only significant additional toxicity seen with concurrent administration of cetuximab + chemotherapy • Biomarker correlative studies ongoing • New trials with this concurrent regimen + bevacizumab planned Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.

  19. Phase III Trial ofCisplatin/Vinorelbine ± CetuximabPreliminary Safety Report • Stage IIIB with documented malignant pleural effusion or stage IV previously untreated NSCLC • Epidermal growth factor receptor expression by immunohistochemistry • Patients recruited from 166 centers in 29 countries in Europe, Asia, Australia, and South America • Primary objective: overall survival • Preplanned analysis by Data Safety Monitoring Board (DSMB) of baseline and safety data from 365 patients • Results • Recruitment completed in February 2006 • 1125 patients randomized • Trial continues Von Pawl J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.

  20. SWOG S0339—Phase II Trial of Bortezomib + Gemcitabine/Carboplatin • Design • Primary endpoint: OS (goal 10 month median OS to rule out null hypothesis) • Stage IIIB (with pleural effusion) or IV NSCLC, chemotherapy-naive • PS = 0 or 1 • Results • N = 121 accrued (116 eligible) • Median age: 64 years (range, 28–78) • 11% stage IIIB, 86% stage IV • Median follow-up: >15 months • Median number of cycles: 3.6 SWOG = Southwest Oncology Group; OS = overall survival; PS = performance status. Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.

  21. Phase II Trial of Bortezomib+ Gemcitabine/ CarboplatinEfficacy and Safety Results • Overall survival 11 months (95% CI 8.2–13 months) • 1-year survival 47%; 2-year survival 14% • Results above predetermined statistical endpoint to proceed to a phase III trial ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease;PD = progressive disease; AST = aspartate aminotransferase; ALT = alanine aminotransferase. Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.

  22. Summary • Clarification with regards to carboplatin/paclitaxel ± bevacizumab phase III trial ECOG 4599 • Bevacizumab does have some differential gender effect on overall survival, but not clinically meaningful • Potential predictive or prognostic biomarkers • Risk factors for bevacizumab-associated pulmonary hemorrhage • Promising results from phase II trials • Cetuximab + carboplatin/paclitaxel • Cetuximab + cisplatin/vinorelbine • Bortezomib + gemcitabine/carboplatin • Data from phase III trials needed for cetuximab and bortezomib

  23. Focus on Small Molecules and Investigational Agents Roy S. Herbst, MD, PhD Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology University of Texas M.D. Anderson Cancer Center Houston, Texas

  24. Tyrosine kinase inhibitors with FDA approvals Sunitinib Sorafenib Erlotinib Gefitinib Investigational agents Vatalanib ZD6474 ABI-007 AMG706/panitumumab Biomarkers Osteopontin EGF, Her2, p-Akt RXR-beta, pPARy Update on Small Molecule and Investigational Agents

  25. Tyrosine Kinase Inhibitors Target Both the Tumor and Endothelial Cells Growth Factor Receptor VEGFR/PDGFR EGFRRAS-RAF VEGFRNRP1 VEGFR 1,2,3PDGFR Nucleus Nucleus Tumor Cell Endothelial Cell VEGF PDGF Endothelial Cell Pericytes

  26. Similarities and Differences in Targets for TKIs and Monoclonals Inhibitor Erlotinib Bevacizumab Mechanism Inhibits tumor cell growth and blocks synthesis of angiogenetic proteins(eg, bFGF, VEGF, TGF-by tumor cells Inhibits endothelial cells from responding to the angiogenic protein VEGF bFGF VEGF TGF- Tumor Endothelial cells Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from theAmerican Society of Clinical Oncology.

  27. Sunitinib Phase II Trial in Previously Treated Advanced NSCLC • Open-label, single-arm, 2-stage multicenter trial • Patients had recurrent stage IIIB/IV NSCLC that had failed 1 or more chemotherapy regimens (with/out EGFR inhibitor) • Sunitinib given at 50 mg/d for 4 wk followed by 2 wk off treatment before next 6-week cycle • Primary endpoint: overall confirmed objective response rate (ORR) • Enrollment • 63 patients • 64% had adenocarcinoma, 90% had stage IV disease • 43% had 1 prior regimen, 44% had 2 prior regimens, 13% had 3 or more prior regimens • 33% had received prior EGFR inhibitor Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.

  28. Sunitinib Phase II Trial inPreviously Treated Advanced NSCLCSafety Results • Most toxicities were grade 1 or 2 • 3 hemorrhage-related deaths on study: 2 (a pulmonary hemorrhage and a cerebral hemorrhage) were considered study-drug related Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.

  29. Sunitinib Phase II Trial inPreviously Treated Advanced NSCLCEfficacy Results Best Response forTarget Lesions by Patient 100 80 60 40 20 0 -20 -40 -60 -80 -100 Partial Responses by RECIST Stable Disease/Progressive Disease Change from Baseline (%) • Median duration of response: 12.2 weeks (range, 4.3–30.1+ weeks) • Median PFS: 11.3 weeks (95% CI 10.0–15.7) • Median OS: 23.9 weeks (95% CI 17.0–28.3) ORR = overall response rate; PR = partial response; SD = stable disease; PD = progressive disease;RECIST = response evaluation criteria in solid tumors. Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001. Reprinted with permission from Dr. Socinski.

  30. Phase II Trial of Sorafenib in Advanced NSCLC • Primary objective: tumor response by RECIST of sorafenib 400 mg BID in previously treated pts • Eligibility • 1–2 prior treatments • No prior gefitinib • Asymptomatic brain metastases permitted • Enrollment • 52 patients • Median age 62 years (range, 26–85) • 85% ECOG PS = 1 • 54% adenocarcinoma, 31% squamous cell carcinoma • 94% stage IV • 67% 1 prior chemotherapy; 29% 2 prior chemotherapy RECIST = response evaluation criteria in solid tumors; ECOG = eastern cooperative oncology group;PS = performance status. Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.

  31. Phase II Trial of Sorafenib in Advanced NSCLCEfficacy Results Maximum Percentage Reduction of Target Lesion by Patient (N = 48)† 60 40 20 0 -20 -40 -60 SD Patients PD Patients • Tumor cavitation in 4 patients • Median PFS: 2.7 mo; median OS: 6.7 mo • SD patients: median PFS 5.5 mo • 2 patients treated for > 2 years with ongoing treatment SD = stable disease; PD = progressive disease; PFS = progression-free survival; OS = overall survival. *Patients died prior to tumor assessment. †48 patients with postbaseline tumor measurements available. Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.

  32. Safety No grade 4 events Grade 3 events: hand-foot skin reactions (20%), hypertension (4%), diarrhea (2%), fatigue (2%), headache (2%) 4 patients had sorafenib-related bleeding events (3 epistaxis, 1 fatal pulmonary hemorrhage 30 days after stopping sorafenib) Biomarker analysis Plasma biomarkers evaluated by ELISA High VEGF at baseline correlated with shorter survival (P < .05) Phase II Trial of Sorafenib in Advanced NSCLCSafety and Biomarker Analysis Results 1.0 0.5 0.0 Low VEGF High VEGF Survival Fraction 300 0 100 200 400 500 600 700 Time to Death (Days) ELISA = enzyme-linked immunosorbent assay; VEGF = vascular endothelial growth factor. Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.

  33. Phase II Trial of Sorafenib in Advanced NSCLC Conclusions • Sorafenib has some activity in NSCLC • Historical comparisons show that 59% stable disease is in same range as other targeted agents in NSCLC • Agent generally well tolerated, with low incidence of bleeding • Deterioration of quality of life not seen • Shorter median overall survival correlated with high baseline VEGF and greater decreases in plasma VEGF during sorafenib treatment • Phase III study of carboplatin/paclitaxel ± sorafenib is currently accruing patients Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.

  34. Randomized Phase II Trial of Chemotherapy ± Bevacizumab vs Erlotinib + Bevacizumab • Phase II, multicenter 3-arm randomized trial • Arm 1: chemotherapy (docetaxel or pemetrexed) + placebo • Arm 2: chemotherapy (docetaxel or pemetrexed) + bevacizumab • Arm 3: erlotinib + bevacizumab • Arms 1 and 2 were double-blinded • Patients stratified by ECOG performance status and smoking history • Eligibility: recurrent unresectable NSCLC • Primary endpoint: safety and preliminary efficacy Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062.

  35. Phase II Chemotherapy ± Bevacizumab vs Erlotinib + BevacizumabEfficacy *Adjusted by randomization stratification factors (ECOG PS, smoking history). HR = hazard ratio; NA = not applicable; CR = complete response; PR = partial response; SD = stable disease. Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.

  36. Phase II Chemotherapy ± Bevacizumab vsErlotinib + BevacizumabSafety Percent of Patients Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.

  37. Phase II Trial of Erlotinib vs Carboplatin/Paclitaxel in NSCLC • Primary endpoint: PFS (treatment worthy of further evaluation if PFS  3.5 months) • Study design • Eligibility: stage IIIB or IV no prior chemotherapy • Performance status 2 • No prior treatment with any EGFR inhibitor; no uncontrolled brain metastases • Optional cross-over to erlotinib • Enrollment: 103 patients • Arms well balanced in demographics and baseline characteristics PFS = progression-free survival; EGFR = epidermal growth factor receptor. Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.

  38. Phase II Trial of Erlotinib vs Carboplatin/ Paclitaxel (CP) in NSCLCEfficacy Results Progression-Free Survival (PFS) 1.0 - 0.9 - 0.8 - 0.7 - 0.6 - 0.5 - 0.4 - 0.3 - 0.2 - 0.1 - 0.0 - Group N Median(M) 95% Cl Erlotinib 52 1.91 (1.28, 2.69) PC 51 3.52 (1.48, 4.87) PFS Probability 0 6 12 18 24 36 PFS (Months) Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022. Reprinted with permission from Dr. Lilenbaum.

  39. Phase II Trial of Erlotinib vsCarboplatin/Paclitaxel in NSCLCConclusions • Single-agent erlotinib treatment did not meet progression-free survival endpoint to warrant further evaluation • Results in erlotinib-treated patients who developed grade 2+ rash were “in closer range to chemotherapy” • Sample size too small to make significant correlation between biomarkers analyzed and outcome • Quality of life parameters similar between 2 treatment arms • Development of erlotinib in 1st-line NSCLC centers on • Molecular selection of patients • Combination with other targeted agents • Dosing optimization Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.

  40. Molecular Predictors of Outcome with Erlotinib in Bronchioloalveolar Cell Carcinoma (BAC) • Results of a prospective phase II trial • Objective: compare clinical, pathologic, and molecular characteristics of tumor specimens associated with response, PFS, and OS • Marker analysis: EGFR (mutations, amplification, polysomy, chromogenic in situ hybridization [CISH]), KRAS (mutations) Molecular Characteristics and Outcome Outcome of Patients Treated with Erlotinib Median PFS Median OS n RR(%) P (mo) P (mo) P EGFR mut + 18 83 <.01 13 <.01 23 .65 EGFR wt 64 7 2 17 CISH ≥ 4 24 43 <.01 9 <.01 25.38 CISH < 4 53 13 2 16 IHC ≥ 1 25 20 .99 4 .76 19 .60 IHC 0 39 21 4 16 KRAS mut + 19 0 <.01 4 .25 13 .24 KRAS wt 62 32 5 21 n Median PFS Median OS (mo) (mo) All 102 4 17 CR+PR 22 15 24 Stable disease 38 6 29 Progression 36 1 8 Not evaluable 6 1 1 P < .01 Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003. Adapted with permission from Dr. Miller.

  41. Molecular Predictors of Outcomewith Erlotinib in BACConclusions • Erlotinib resulted in 23% overall response rate (ORR) and 17 mo median overall survival (OS) in BAC • Presence of EGFR mutation associated with an 83% ORR, 13 mo progression-free survival (PFS) and 22 mo OS • EGFR amplification in BAC rare • EGFR polysomy predictive of improvement in PFS • KRAS exon 2 mutation associated with no responses and poorer OS • Patients with EGFR mutation + CISH  4 had ORR 90%, PFS 15 mo, OS 35 mo • Patients with wild type EGFR + CISH < 4 had ORR 4%, PFS 2 mo, OS 15 mo Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003.

  42. Phase II Trial 1st-Line Erlotinib in Patientswith NSCLC and EGFR Mutations • Primary endpoint: time to progression • Eligibility • Stage IIIB/IV NSCLC + mutated EGFR • No prior chemotherapy • No prior EGFR targeted agents Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020.

  43. Response Predictors ORR P-value PS .662 0 8 (73%) 1 18 (86%) 2 5 (83%) Histology .754 Adeno 23 (79%) BAC 4 (100%) Other 4 (80%) Stage 1.0 IIIB 4 (100%) IV 27 (79%) ORR P-value EGFR Mutation .038 Exon 19 19 (95%) Exon 21 12 (67%) Smoking .038 Never 24 (90%) Former 7 (70%) Current 0 (0%) Gender .203 Female 22 (88%) Male 9 (69%) Phase II Trial 1st-Line Erlotinib in NSCLCwith EGFR MutationsResults TTP According to Mutational Status Log Rank P =.06Breslow P =.06 TTP According to Smoking Habits Log Rank P =.12Breslow P =.02 Conclusions • Most benefit: Exon 19 deletions, patients who never smoked, visceral site other than lung • Phase III trial planned (erlotinib vs platinum-based chemotherapy in EGFR-mutated NSCLC) Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. Reprinted with permission from Dr. Paz-Ares.

  44. Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLCPart A Results Individual Changes in Size of Target Lesions from Baseline: Part A Primary Endpoint in Part A:Progression-Free Survival ZD6474 Hazard ratio = 0.6995% Cl = 0.50 to 0.96Two-sided P-value = .025 Probability of RemainingProgression-Free Median PFS ZD6474 = 11.0 Gefitinib = 8.1 weeks Best Confirmed Change from Baselinein Target Lesion Size (%) Gefitinib Final data cut-off, July 2005 Progression-free survival in Part A (months) Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.

  45. Randomized Phase II Trial of ZD6474 vsGefitinib in Advanced NSCLCPart B Results Secondary Endpoint:Overall Survival Median PFS ZD6474 then gefitinib = 6.1 months Gefitinib then ZD6474 = 7.4 months Probability of Remaining Alive Hazard ratio = 1.19(95% Cl = 0.84 to 1.68)Two-sided P-value = .34 Time to Death (months) Final data cut-off, July 2005 Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.

  46. Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLC: Adverse Events *AEs are all CTC grade 1 or 2 except where noted. Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.

  47. Randomized Phase II Trial of ZD6474 vsGefitinib in Advanced NSCLCConclusions • Part A met primary endpoint of prolonging progression-free survival (PFS) • ZD6474 prolonged PFS by 45% compared with gefitinib • PFS prolongation did not result in overall survival advantage in Part B • Why? Not clear, maybe optional switchover confounded survival assessment • Adverse events (AEs) for both agents mostly mild • Slight differences in AE profiles Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000.

  48. Novel Targeted Agents UnderInvestigation for Lung Cancer TreatmentHighlights of ASCO 2006 CP = carboplatin/paclitaxel.

  49. Mack PC, et al1 Elevated osteopontin plasma levels may have prognostic value in advanced NSCLC Osteopontin is a secreted glycoprotein involved in induction of urokinase (uPA) and increased cell migration Toschi L, et al2 FISH or IHC analysis of samples from 190 consecutive patients treated for advanced NSCLC EGFR, HEr2, and p-Akt status are not predictors of sensitivity to chemotherapy EGFR FISH + and/or HER2 FISH+ patients seemed to benefit more from nonplatinum vs platinum-based combinations (but N small) In EGFR FISH+ patients, RR and TTP after EGFR-TKI used as 2nd-line treatment were at least equal to 1st-line chemotherapy Other Searches for Useful Biomarkers in NSCLC—ASCO 2006 Mack PC, et al. 42nd ASCO, June 2-6, 2006. Abstract 7198. Toschi L, et al. 42nd ASCO, June 2-6, 2006. Abstract 7111.

  50. Summary • First-generation TKIs (gefitinib, erlotinib) the search continues for • Molecular markers for patient selection • Optimal combinations • Improved dosing • Multitargeted TKIs currently on the market (sorafenib, sunitinib) • Some promising, but not yet conclusive results • Investigational multitargeted TKIs (vatalanib, ZD6474, AMG706, AZ2171) • Need data from randomized trials • Some differences in adverse event profiles • General areas of need • Surrogate markers for evaluation of agents • Biomarkers for patient selection • Optimization of clinical trial design

More Related