有效的非小细胞肺癌治疗的基础nicholasthatcher2009csco年会

Building the foundations of effective NSCLC therapy Prof. Nicholas Thatcher Christie Hospital NHS Trust, U.K. AVASTIN FIRST LINE AVASTIN FIRST LINE IN ADVANCED NON SQUAMOUS NSCLCIN ADVANCED NON SQUAMOUS NSCLC Nick Thatcher, Christie Hospital, Manchester, England AVASTIN FIRST LINE NON-SQUAMOUS ADVANCED NSCLC Introduction, anti angiogenesis Phase III trials, E4599, AVAIL Phase IV trial, SAIL Future Conclusion ANGIOGENESIS INHIBITION THROUGH THE VEGF PATHWAY VEGF VEGF receptor-2 Antibodies inhibiting VEGF (e.g. Avastin) Antibodies inhibiting VEGF receptors Soluble VEGF receptors (VEGF-TRAP) Small molecules inhibiting VEGF receptors (TKIs) Ribozymes (Angiozyme) P P P P P P P P P P P P Migration, permeability, DNA synthesis, survival LymphangiogenesisAngiogenesis ANTI-VEGF THERAPY: MECHANISM OF ACTION EARLY EFFECTSCONTINUED EFFECTS Normalisation of remaining tumour vasculature5-8 Regression of existing tumour microvasculature1-7 Inhibition of new tumour vasculature1,2,9,10 References: 1. Baluk P et al. Curr Opin Genet Dev. 2005;15:102-111. 2. Inai T et al. Am J Pathol. 2004;165:35-52. 3. Erber R et al. FASEB J. 2004;18:338-340. 4. Tong RT et al. Cancer Res. 2004;64:3731-3736. 5. Jain RK. Nat Med. 2001;7:987-989. 6. Jain RK. Science. 2005;307:58-62. 7. Lee CG et al. Cancer Res. 2000;60:5565-5570. 8. Willett CG et al. Nat Med. 2004;10:145-147. 9. Gerber HP et al. Cancer Res. 2005;65:671-680. 10. Warren RS et al. J Clin Invest. 1995;95:1789-1797. Mancuso et al. J Clin Invest 2006 (Ellis and Haller J Clin Oncol 2008) EFFECTS OF VEGF INHIBITION: inhibition of recurrent vessel growth Revascularisation following discontinuation of anti- VEGF therapy UntreatedAnti-VEGF, 7 daysWithdrawal, 2 daysWithdrawal, 7 days PIVOTAL STUDIES OF AVASTIN IN COMBINATION WITH PLATINUM-CONTAINING CHEMOTHERAPY Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) no gross hemoptysis no therapeutic anticoagulation no brain metastases CP (n=444) Avastin 15mg/kg + CP (n=434) PD* PD Avastin E4599 (US) Sandler et al N Engl J Med 2006 *No cross over permitted; Dose of Avastin every 3 weeks CG = cisplatin/gemcitabine; CP = carboplatin/paclitaxel; PD = progressive disease PD PD PD* Avastin Avastin Placebo + CG (n=347) Avastin 15mg/kg + CG (n=351) Avastin 7.5mg/kg + CG (n=345) Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1,043) As above no evidence of tumour invading or abutting major blood vessels no spinal cord compression, ulceration, bone fractures or wound- healing complications AVAiL (Ex-US) Reck et al J Clin Oncol 2009 PHASE III TRIALS OF AVASTIN (E4599 VS. AVAIL): ELIGIBILITY CRITERIA AND SAFETY 1Sandler et al. N Engl J Med 2006; 2 Manegold et al. ASCO 2007 Abstract LBA 7514 E4599 1 and AVAiL2 evaluated Avastin in combination with CP and CG, respectively Inclusion/exclusion criteria were comparable, with additional considerations in AVAiL ECOG PS 0-1 ; Non-squamous cell no haemoptysis, 5% 479 187 BEVACIZUMAB PATHOLOGICAL SELECTION REDUCES BLEEDING RISK Grade 3 pulmonary haemorrhage Percentage 10 8 6 4 2 0 AVF0757g 7.5 or 15mg/kg + CP* E4599 Bevacizumab 15mg/kg + CP AVAiL Bevacizumab 7.5mg/kg + CG AVAiL Bevacizumab 15mg/kg + CG Johnson et al. JCO 2004 Sandler et al. NEJM 2006 Manegold et al ASCO 2007 Abstract LBA 7514 *Phase II trial including patients with squamous cell histology Restricting eligibility to patients with non- squamous histology and minimal baseline haemoptysis Additional exclusion of tumours abutting or invading major blood vessels SAFETY PROFILE OF AVASTIN IN NSCLC IS WELL-CHARACTERISED The side-effect profile of Avastin in patients with advanced NSCLC is generally consistent with that observed in other solid tumour types Hypertension and proteinuria were the most common side effects associated with Avastin in E4599 1 and AVAiL2 these events were generally manageable and did not require permanent discontinuation of Avastin Severe (grade 3) pulmonary haemorrhage uncommon and associated only with cavitation not location 3 1Sandler et al. N Engl J Med 2006; 2 Reck et al J Clin Oncol 2009 3 Sandler et al J Clin Oncol 2009 TRIAL DESIGN lPatient population Asian 15%, adenocarcinoma 86%, PS 2 6%,central tumour 26%; cardiovascular drugs 32%, anticoagulants 4% Thatcher et al WCLC 2009 abst C2.4 Locally advanced, metastatic or recurrent non-squamous NSCLC (n=2,166) SAiL (Safety of Avastin in Lung) PD Bevacizumab maintenance therapy *Platinum-based chemotherapy or standard-of-care, first-line, NSCLC chemotherapy regimen. This may include non-platinum doublets or single-agent chemotherapy if appropriate. Bevacizumab (7.5mg/kg or 15mg/kg) 3 weekly + chemotherapy* No increase in bleeding in patients on anticoagulation Griesinger et al ASCO 2008 abst 8049 Avastin safe in presence of brain metastases identified during therapy Dansin et al ASCO 2008 abst 8085 DISEASE CONTROL RATE IN SAIL STUDY lDCR was 88.7% for the overall population Response rates* (%) 100 50 0 2.8 48.0 37.9 88.7 DCRSDCRPR *Percentage is based on the number of patients with tumour assessment (n=1,956 90.3%) CR = complete response; PR = partial response; SD = stable disease Thatcher et al WCLC 2009 abst C2.4 TOLERABILITY OF AVASTIN-BASED THERAPY CONFIRMED Grade 3 AEs of special interest in E4599, AVAiL and SAiL E4599 Avastin 15mg/kg + CP AVAiL Avastin 15mg/kg + CG AVAiL Avastin 7.5mg/kg + CG SAiL Avastin 7.5 or 15mg/kg + chemotherapy Bleeding Incidence (%) 50 45 40 35 30 25 20 15 10 5 0 HypertensionProteinuriaFebrile neutropenia Arterial thrombosis 4 7 3.1 5.2 1.9 4 9 1 2 3 6 0.3 2 2.42.2 3.6 0.8 0 5.4 4.4 Extensive experience with Avastin-based therapy (350,000 patients treated in routine clinical setting across indications) Crino et al ASCO 2009 abst 8043 1Sandler et al. N Engl J Med 2006; 2Dansin et al. ASCO 2008 abs 8085 3Reck et al J Clin Oncol 2009 GETTING PATIENT ELIGIBILITY RIGHT: reduced grade 3 haemoptysis 1.5% Non-squamous cell histology only with no significant haemoptysis at baseline E45991 No tumour invasion of major blood vessels SAiL3 Same patients as in AVAiL 0.2% AVAiL2 Similar to baseline risk of lung cancer patients 2.3% SAFETY (AES OF SPECIAL INTEREST GRADE 3) FOR PATIENTS WITH HTN VERSUS THOSE WITHOUT HTN events (%) Patients without HTN event N=1,586 Patients with HTN event N=580 Safety population N=2,166 Grade 1-2098.426.4 Grade 3-501.60.4 AE (%) Bleeding Epistaxis Haemoptysis Pulmonary haemorrhage Other bleeding 0.6 0.6 0.3 0.6 0.9 0.0 0.0 0.2 0.7 0.4 0.2 0.5 Proteinuria0.00.30.1 Thromboembolism5.04.04.8 Congestive heart failure1.20.50.1 Gastrointestinal perforation1.10.30.9 CNS bleeding0.20.20.2 Thatcher et al WCLC 2009 abst C2.4 EFFICACY FOR PATIENTS WITH HTN VERSUS THOSE WITHOUT Patients without HTN event N=1,586 Patients with HTN event N=580 Survival Dead (%) 40.9233.79 censored patients (%) 59.0866.21 Median OS (LowerUpper limit) months 12.9 (12.414.6)18.8 (17.020.4) Progression Progressive disease (%) 56.0364.66 Censored patients (%) 43.9735.34 Median TTP (LowerUpper limit) months 7.2 (7.07.6)8.7 (8.39.2) Thatcher et al WCLC 2009 abst C2.4 OS IN THE OVERALL POPULATION AND BY CHEMOTHERAPY REGIMEN Median OS, months (95% CI) Overall population 15.3 (14.516.5) Patients with an event (%)39.0 Censored patients (%)61.0 Chemotherapy regimen Carboplatin doublets 14.6 (13.616.0) Cisplatin doublets 15.3 (14.017.3) Non-platinum doublets8.7 (5.7NR) Single-agent therapy14.7 (6.023.6) NR = not reached Laskin et al et al WCLC abst C2.5 SAFETY :ELDERLY vs. NON-ELDERLY PATIENTS (AES OF SPECIAL INTEREST GRADE 3 AND GRADE 5) Patients 65 years N=1,557 Patients 65 years N=609 Safety population N=2,166 AE, %Grade3 Grade 5Grade 3 Grade 5Grade 3 Grade 5 Bleeding Epistaxis0.4 0.11.500.70.1 Haemoptysis0.40.30.50.20.40.2 Pulmonary haemorrhage0.30.10.200.20.1 CNS bleeding0.100.30.20.20.1 Other bleeding0.30.11.00.20.50.1 Proteinuria0.1NR0.0NR0.1NR Thromboembolism4.60.85.10.74.80.7 Congestive heart failure1.20.40.70.31.10.4 Gastrointestinal perforation0.8NR1.0NR0.9NR Hypertension0.50.10.200.40.1 NR = not reported Griesinger et al WCLC abst C2.6 EFFICACY: ELDERLY VERSUS NON-ELDERLY PATIENTS Patients 65 years N=1,557 Patients 65 years N=609 Survival Median OS (LowerUpper limit) months 15.2 (14.216.5) 15.3 (12.918.8) Censored patients (%) 61.4059.93 Progression Median TTP (LowerUpper limit) months 7.6 (7.38.0) 8.3 (7.58.7) Censored patients (%) 38.9948.52 Griesinger et al WCLC abst C2.6 AVASTIN-BASED THERAPY AS THE FIRST- LINE THERAPY OF CHOICE: RESPONSE October 2007 before AvastinDecember 2007 during Avastin Martin Reck, Grosshansdorf Hospital, Germany Median OS (months) 15 10 5 0 12.3 13.4 13.6 15.3* Consistent OS in bevacizumab-treated patients 11.011.3 SAiL5AVAiL4 (7.5mg/kg) E45993AVAiL4 (15mg/kg) FLEX2 (note: includes squamous histology) JMDB1 AVASTIN BASED THERAPY OVERALL SURVIVAL COMPARED WITH OTHER FIRST-LINE REGIMENS IN NON-SQUAMOUS NSCLC *Preliminary OS HR=0.84HR=0.87HR=0.79HR=1.03HR=0.93 1. Scagliotti, et al. Oncologist 2009 2. Pirker, et al. Lancet 2009; 3. Sandler, et al. NEJM 2006 4. Manegold, et al. ESMO 2008; 5. Crin, et al. ASCO 2009 GOALS Non-PDPD Off Study Patel et al J Clin Oncol 2009 50 patients OR 55% PFS 7.8 mos MS 14.1 mos PHASE II STUDY OF CARBOPLATIN + PEMETREXED + BEVACIZUMAB Carboplatin AUC 6 i.v. day 1 Pemetrexed 500 mg/m2 i.v. day 1 Bevacizumab 15 mg/kg i.v. day 1 Cycles q3 weeks X 6 Chemotherapy-nave Stage IIIB/IV ECOG PS 0-1 Non-squamous histology No CNS metastases Pemetrexed 500 mg/m2 Bevacizumab 15 mg/kg Cycles q3 weeks until PD FURTHER TRIALS WILL EVALUATE AVASTIN IN ADDITIONAL PATIENT POPULATIONS Phase III ATLAS: in combination with first-line Tarceva as maintenance after Avastin plus chemotherapy in NSCLC 15mg/kg every 3 weeks (n=1,150) E1505: chemotherapy Avastin in the adjuvant setting in NSCLC 15mg/kg every 3 weeks for up to one year (n=1,500) Phase IIPhase I/II PASSPORT: in combination with first- or second-line chemotherapy or Tarceva in non-squamous NSCLC (with treated brain metastases) 15mg/kg every 3 weeks (n=110) MO18632: in combination with first-line Tarceva 15mg/kg every 3 weeks (n=46) BO20571: first-line Avastin with Tarceva or chemotherapy 15mg/kg every 3 weeks (n=200) BRIDGE: in combination with CP in squamous NSCLC 15mg/kg every 3 weeks (n=40) ABIGAIL(BO21015) : biomarker trial: first-line Avastin with GC/CP 7.5mg/15mg/kg every 3 weeks(n=300) RATIONALE FOR COMBINING TARCEVA AND AVASTIN Tumour InhibitorTarcevaAvastin Mechanism Inhibits tumour cell growth and blocks synthesis of angiogenic proteins (e.g. bFGF, VEGF, TGF-a) by tumour cells Binds to the angiogenic protein VEGF, and inhibits all of its functions bFGF VEGF TGF-a Endothelial cells Sandler AB, et al. Proc ASCO 2004;23:127 (Abs. 2000) Bevacizumab 15mg/kg + placebo Chemotherapy- nave stage IIIb/IV non- squamous NSCLC (n1,150) Non-PD Off study Bevacizumab 15mg/kg + Erlotinib 150mg/day PD (n800) 1:1 Bevacizumab 15mg/kg plus chemotherapy PD or significant toxicity ATLAS PHASE III STUDY OF BEVACIZUMAB ERLOTINIB IN MAINTENANCE NSCLC PD Bevacizumab Erlotinib or Erlotinib or Bevacizumab + salvage CT Optional post