Micro-ambiente tumorale. Antiangiogenici e immunoterapia: miti e realtà Milano, 11 Ottobre 2016 Antiangiogenici in combinazione a chemioterapia in prima linea: bevacizumab Francesco Grossi U.O.S. Tumori Polmonari IRCCS Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro Genova
Bevacizumab and NSCLC: starving the enemy to survive Angiogenesis is the process of new blood vessel formation Angiogenesis is required for tumours to grow and metastasize Tumours generally cannot grow beyond 1 2 mm in diameter without an independent blood supply 1,2 Therefore, angiogenesis is an important process in the growth of malignant tumours Avascular tumour Vascularised tumour Growth factors e.g. VEGF Grossi F, Expert Opin Biol Ther 2007
Agenda Bevacizumab + CT in first-line: efficacy Bevacizumab + CT in first-line: safety Bevacizumab + CT in first-line: future perspectives
Agenda Bevacizumab + CT in first-line: efficacy Bevacizumab + CT in first-line: safety Bevacizumab + CT in first-line: future perspectives
E4599: trial design Trial commenced 2001 Previously untreated stage IIIB, IV or recurrent predominantly nonsquamous NSCLC (n=878) R 1 1 CP q3w x6 (n=444) Bevacizumab 15mg/kg + CP q3w x6 (n=434) Bevacizumab to progression PD* PD Primary endpoint overall survival (OS) *No crossover permitted; CP = carboplatin/paclitaxel Secondary endpoints objective response rate progression-free survival (PFS) duration of response safety Sandler A, NEJM 2006
Bevacizumab-based therapy until progression increases OS: E4599 Sandler A, NEJM 2006
E4599: pre-planned OS analysis in adenocarcinoma subgroup Sandler A, JTO 2010 & NEJM 2006
Algorithm for therapy of advanced NSCLC Proposed treatment algorithm EGFR mutation positive or ALK fusion positive Molecular Good PS Clinical (PS) Poor PS EGFR TKIs or Crizotinib Nonsquamous Histologic Squamous Single-agent chemotherapy Bevacizumab eligible Clinical Bevacizumab ineligible First line Platinum/pemetrexed (or other*) ± bevacizumab Platinum/pemetrexed (or other*) Platinum/gemcitabine (or other*) Progression Chemotherapy by algorithm Bevacizumab or erlotinib or pemetrexed Based on prior therapy End of first-line chemotherapy Pemetrexed or erlotinib Based on prior therapy Erlotinib Based on prior therapy Based on prior therapy Maintenance Second line *Docetaxel, paclitaxel, or vinorelbine. Adapted from Gandara DR, Clin Lung Cancer 2009
AVAiL: Study design 6 cycles Previously untreated stage IIIB/IV nonsquamous NSCLC (n=1043) R 2:1:1:2 Bevacizumab 15 mg/kg q3w + cisplatin + gemcitabine (n=351) Placebo 15 mg/kg a + cisplatin + gemcitabine (n=347) Placebo 7.5 mg/kg a + cisplatin + gemcitabine Bevacizumab 7.5 mg/kg q3w + cisplatin + gemcitabine (n=345) Bevacizumab 15 mg/kg q3w Placebo 15 mg/kg a Placebo 7.5 mg/kg a Bevacizumab 7.5 mg/kg q3w Treat to PD Primary endpoint: PFS Secondary endpoints: ORR, DoR, OS, safety Stratification factors: Region, disease stage, ECOG PS, sex a No crossover to bevacizumab permitted Reck M, JCO 2009
AVAiL: significant prolongation of PFS (primary endpoint) Reck M, JCO 2009
AVAiL: no significant benefit in OS* (secondary endpoint) Reck M, Ann Oncol 2010 *ITT (intent-to-treat) population
AVAiL: high proportion of patients received post-protocol therapies Post-protocol therapy* Placebo + CG % (n) Bev 7.5mg/kg + CG % (n) Bev 15mg/kg + CG % (n) Any treatment, % (n) 65 (224) 61 (210) 61 (214) Treatment/procedures, % (n) TKIs 41 (92) 48 (100) 42 (90) Chemotherapy 73 (164) 65 (137) 69 (147) Angiogenesis inhibitors <1 (2) <1 (2) <1 (3) Surgical and medical procedures 26 (60) 34 (71) 27 (57) *Total patients with 1 treatment % patients who received a post-protocol therapy Includes but not limited to radiotherapy, laser therapy and stent placement Reck M, Ann Oncol 2010
OS estimate AVAiL: improved OS in bevacizumab pts not receiving post-protocol therapies* 1.0 0.8 Median OS (95% CI) No 2nd-line Bev 8.7 (7.8 9.9) Placebo 7.3 (5.9 8.9) 0.6 HR (p value) Bev to placebo 0.84 (0.20) 0.4 0.2 Bev without 2nd-line Placebo without 2nd-line n=123 n=272 0 0 10 20 30 40 *Exploratory analysis Time (months) Reck M, Ann Oncol 2010
Meta-analysis of beva+ct vs CT in advanced NSCLC: OS and PFS OS PFS Costa Lima BC, PLOS ONE 2011
SAiL: trial design Trial commenced 2006 First-line, advanced non-squamous NSCLC (n=2,212) Bevacizumab 7.5mg/kg or 15mg/kg q3w + standard of care chemotherapy x6 Bevacizumab to progression PD Primary endpoint safety profile Secondary endpoints time to disease progression (TTP) overall survival safety in CNS metastases Crinò L, Lancet Oncol 2010
OS estimate SAiL: Efficacy consistent with 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 phase III data Bev + any chemotherapy (SAiL ITT population)* Bev + CP (E4599 adenocarcinoma analysis) CP (E4599 adenocarcinoma analysis) 0 6 12 18 24 30 36 42 Time (months) *86% of patients in SAiL had adenocarcinoma histology Crinò L, Lancet Oncol 2010 Crinò, et al. Lancet Oncol 2010; Sandler, et al. JTO 2010
Median OS (months) SAiL: Consistent efficacy across all chemotherapy backbones 18 14.6 12 14.6 14.3 14.7 6 0 n=2,212 Overall SAiL population n=1,087 n=829 Bevacizumab + carboplatin doublets Bevacizumab + cisplatin doublets Data for other groups (total n=296, including non-platinum doublets, single-agent chemotherapy and other chemotherapy combinations) are not statistically robust due to small patient numbers and are not reported Crinò, et al. Lancet Oncol 2010 Crinò L, Lancet Oncol 2010
ARIES: Avastin Registry: Investigation of Effectiveness and Safety Registry with 2000 first-line patients Bevacizumab combined with any standard of care chemotherapy Bevacizumab continued at physician s discretion Stage IIIB/IV non-squamous NSCLC (n 2,000) Bevacizumab (7.5 or 15 mg/kg) q3w + chemotherapy* Bevacizumab continued at physician s discretion Objectives: Safety and effectiveness of becvacizumab *Any standard-of-care first-line NSCLC chemotherapy Wozniak A, ASCO 2010
Efficacy and tolerance of frontline bevacizumab-based chemotherapy for advanced non-small cell lung cancer patients: a multicenter, phase IV study of the Hellenic Oncology Research Group (HORG): Study design First-line, advanced non-squamous NSCLC (n= 314) Bevacizumab (15 mg/kg) q3w + standard of care chemotherapy PD Primary endpoint safety profile Secondary endpoints ORR PFS overall survival (OS) safety in pts with CNS metastases. Matikas A, Cancer Chemother Pharmacol 2016
Efficacy: PFS and OS mpfs=7.7 mesi mos=17.6 mesi Matikas A, Cancer Chemother Pharmacol 2016
Median OS (months) Efficacy of first-line regimens: pre-planned OS analyses in adenocarcinoma patients 18 Cisplatin + pem (JMDB) 1 HR=0.84 Bevacizumab-based therapy (E4599) 2 HR=0.69 12 6 0 CG Cis/pem 1. Scagliotti G, Oncologist 2009 2. Sandler A, JTO 2010 CP Cross-trial comparisons should be interpreted with caution Bevacizumab + CP
Median PFS (months) Efficacy of first-line regimens: pre-planned PFS analyses in adenocarcinoma patients 18 Cisplatin + pem (JMDB) 1 HR=0.90 Bevacizumab-based therapy (E4599) 2 HR=0.65 12 6 0 CG Cis/pem 1. Scagliotti G, Oncologist 2009 2. Sandler A, JTO 2010 CP Cross-trial comparisons should be interpreted with caution Bevacizumab + CP
PRONOUNCE: Study Design Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m 2, Carboplatin AUC 6 (Pem+Cb) Paclitaxel 200 mg/m 2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev) Induction Phase q21d, 4 cycles Maintenance Phase q21d until PD Bev-Eligible Population Inclusion: - Chemo-naïve patients - PS 0/1 - Stage IV, nonsquam - Stable treated CNS mets Exclusion: - Uncontrolled effusions Stratified for: R 1:1 Pemetrexed (folic acid & vitamin B 12 ) + Carboplatin 180 patients each Paclitaxel + Carboplatin + Bevacizumab PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b) Pemetrexed (folic acid & vitamin B 12 ) Bevacizumab Zinner RG, JTO 2015
PRONOUNCE: primary objective Progression free survival without grade 4 AE (assuming HR of 0.75, there was 80% power to detect superiority of CBDCA+Pem over CBDCA+PAC+Bev with a 2-sided type I error of 0.10) Secondary objective: OS, PFS, RR, DCR, safety and tolerability Zinner RG, JTO 2015
PRONOUNCE: secondary endpoints (PFS, RR, DCR) Zinner RG, JTO 2015
PRONOUNCE: overall survival Zinner RG, JTO 2015
PRONOUNCE: secondary endpoints (toxicity) Zinner RG, JTO 2015
Agenda Bevacizumab + CT in first-line: efficacy Bevacizumab + CT in first-line: safety Bevacizumab + CT in first-line: future perspectives
Consensus on bevacizumab safety Exclusion factors for bevacizumab Squamous histology Haemoptysis grade 2 Invalid exclusion factors Central tumour location Cavitation Full-dose anticoagulation Elderly Major vessel invasion = individual assessment No clinical or radiological features (including cavitation and central tumour location) have been shown to be reliable predictive factors for severe PH in bevacizumab-treated patients. Major blood vessel infiltration and bronchial vessel infiltration, encasement and abutting, may predict PH. However, standardized radiological criteria for defining infiltration have not been established. Reck M, Ann Oncol 2011
Patients (%) Bevacizumab has a wellestablished safety profile 30 Grade 3 AEs of special interest E4599 1 (15mg/kg) AVAiL 2 (7.5mg/kg) AVAiL 2 (15mg/kg) 20 SAiL 3 ARIES 4 10 0 4,4 4.2 4.3 3,6 3,6 1,9 1,5 0,9 0,7 0,9 7.0 6.4 8.5 5,7 <5.0 Bleeding Pulmonary Hypertension Proteinuria (all types) haemorrhage 3.0 <1.0 1.2 3,1 NR 1. Sandler A, NEJM 2006; 2. Reck M, Ann Oncol 2010 3. Crinó L, Lancet Oncol 2010; 4. Wozniak A, ASCO 2010
Meta-analysis of beva+ct vs CT in advanced NSCLC: gr. 3-4 toxicities Costa Lima BC, PLOS ONE 2011
Agenda Bevacizumab + CT in first-line: efficacy Bevacizumab + CT in first-line: safety Bevacizumab + CT in first-line: future perspectives
OS estimate PFS estimate Continued VEGF suppression leads to improved clinical outcomes in NSCLC pts Retrospective analysis of electronic medical records of NSCLC patients (n=403) from community-based oncologists network in the USA 1.0 continued bevacizumab leads to more favourable clinical outcomes Bevacizumab to progression No bevacizumab to progression 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 10.2 20.9 6.5 10.3 0.0 0.0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months Nadler E, The Oncologist 2011
Bevacizumab to progression: SAiL experience SAiL methodology directed continuing bevacizumab until disease progression consistent with global product label maintaining precise inhibition of continuously expressed VEGF In SAiL, 1332 patients achieved disease control and continued to receive bevacizumab until disease progression Dansin, ESMO 2010
Median OS (months) 18.8 months median OS achieved in responding patients treated to progression 24 18 14.6 18.8 12 6 0 Dansin, ESMO 2010 n=2,212 Total study population n=1,332 Bevacizumab continued to PD in responding patients (CR/PR/SD)
SAiL: continuing bevacizumab to progression has limited impact on safety profile No maintenance population (n=880) Maintenance population (n=1,332) Patients (%) Grade 3 Grade 3 Overall bleeding Epistaxis PH/haemoptysis CNS bleeding 4.5 1.5 1.0 0.1 3.0 1.1 0.5 0.1 HTN 4.0 6.8 Proteinuria 2.2 3.6 Thromboembolism 11.9 5.0 Cerebral haemorrhage/haematoma Dansin, ESMO 2010
Randomize 1:1 AvaALL: trial design Global trial conducted in ~20 countries Primary endpoint: OS Stage IIIB/IV non-squamous NSCLC treated with platinumdoublet (4-6 cycles) + bevacizumab PLUS > 2 cycles of bevacizumab maintenance N=600 PD 1 Enroll SOC2* + bevacizumab PD 2 SOC3 + bevacizumab PD 3 SOC4 ± bevacizumab SOC2* SOC3 SOC4 * SOC2: Labelled agents for 2 nd -line treatment of NSCLC (erlotinib, pemetrexed and docetaxel) SOC3 and beyond: Choice of labelled agents in 3 rd -line and beyond is the Investigator s choice Bevacizumab dose must remain the same throughout the trial Beyond PD3, bevacizumab should be continued through subsequent lines of therapy at Investigator s discretion (in the absence of unacceptable toxicity or consent withdrawal)
AVAPERL1: phase III trial of bevacizumab ± pemetrexed maintenance AVAPERL1 trial design Previously untreated stage IIIB/IV nonsquamous NSCLC (N>400) Bevacizumab 7.5 mg/kg + Pemetrexed/Cisplatin q3w Bevacizumab 7.5 mg/kg + Pemetrexed q3w Bevacizumab 7.5 mg/kg q3w PD PD Induction: 4 cycles Maintenance therapy Primary objective: PFS Secondary objectives: OS, ORR, disease control rate, duration of response, duration of disease control, safety, QoL Barlesi F, ESMO 2011
Cisplatin + pemetrexed maintenance AVAPERL: PFS from induction Barlesi F, ESMO 2011
PointBreak: study design Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m 2 ; Carboplatin AUC 6; Bevacizumab 15 mg/kg Paclitaxel 200 mg/m 2 ; Carboplatin AUC 6; Bevacizumab 15 mg/kg Inclusion: - No prior systemic therapy for lung cancer - PS 0/1 - Stage IIIB-IV NS-NSCLC - Stable tx t brain mets Exclusion: - Peripheral neuropathy > Gr 1 - Uncontrolled pleural effusions R 1:1 Induction Phase q21d, 4 cycles Pemetrexed (folic acid & vitamin B 12 ) + Carboplatin + Bevacizumab 450 patients each Paclitaxel + Carboplatin + Bevacizumab Maintenance Phase q21d until PD Pemetrexed (folic acid & vitamin B 12 ) + Bevacizumab Bevacizumab Stratified for: PS (0 vs 1); sex (M vs F); disease stage (IIIB vs IV); measurable vs nonmeasurable disease Patel JD, CMLCC 2012
PointBreak: PFS and OS from randomization (ITT) Patel JD, CMLCC 2012
Examples of phase III anti-pd1/pd-l1 combination trials in 1 st -line advanced NSCLC
Phase 3 and 4 trials of bevacizumab at the first-line setting of NSCLC Matikas A, Cancer Chemother Pharmacol 2016
Grazie per l attenzione! francesco.grossi@hsanmartino.it