Vecchi e nuovi antiangiogenetici Cesare Gridelli Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy) cgridelli@libero.it

Proangiogenic Ligands and their Receptors Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

First-Line Treatment of A-NSCLC EGFR-mutation ALK analysis Non-squamous cell carcinoma Metastatic NSCLC, PS 0-2 Squamous cell carcinoma EGFR mutation (del 19 or L858R in exon 21) EGFR wild type (or not done) EGFR-TKI Radiotherapy CNS Central airways Bone Soft tissue Platinum plus Pemetrexed or gemcitabine or taxanes or vinorelbine OR Platinum combination plus Bevacizumab* (PS 0,1) Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly) Gemcitabine or taxane or vinorelbine 3 ALK positive 2 Crizotinib 1 2

First-Line Treatment of Advanced NSCLC Adenocarcinoma Large cells NSCLC NOS Squamous cell carcinoma EGFR mutation and ALK negative EGFR mutation positive ALK positive PS 0-1 PS 2 PS 3-4 Gefitinib Erlotinib Afatinib Crizotinib Doublet chemotherapy (category 1) OR Cetuximab/vinorelbine/ cisplatin (category 2B) Chemotherapy Best supportive care Bevacizumab + chemotherapy (if criteria met) Cisplatin/pemetrexed (category 1) (if criteria met) Cetuximab/vinorelbine/cisplatin (category 2B) Best supportive care only

Proangiogenic Ligands and their Receptors Bevacizumab Bevacizumab Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

Overall Survival, % Month 100 Hazard ratio, 0.79; P=0.003 80 BPC group (305 events in 417 patients) 60 Overall Survival, % 40 PC group (344 events in 433 patients) 20 6 12 18 24 30 36 42 Month BPC, bevacizumab-paclitaxel-carboplatin; PC, paclitaxel-carboplatin. The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab versus 10.3 months in the chemotherapy-alone group. Sandler A, et al. N Engl J Med. 2006;355(24):2542-2550.

Duration of OS (months) 0.8 0.6 0.4 0.2 Avastin-based therapy (n=602) extends OS to 14.2 months 31% reduction in the risk of death (HR=0.69) Avastin + CP (n=300) CP (n=302) Probability of OS 10.3 14.2 0 6 12 18 24 30 36 42 48 Duration of OS (months) 7

Antiangiogenic Drugs as Chemosensitizing Agents Recently, in Cancer Cell an artcile suggest that a subset of chemotherapeutic agents (such as paclitaxel) induce CEP mobilisation and act like VDA agent whereas other agent such as gemcitabine do not present this effect. This VDA propertie of chemotherapy could explain the clinical benefit to adding anti-VEGF-VEGFR therapies with chemotherapy. Paclitaxel induces rapid chemotherapy-induced acute endothelial progenitor cell mobilization (CEP), indicating synergy with bevacizumab. Gemcitabine does not induce CEP. Shaked Y et al, Cancer Cell 14, 263-273, 2008

Does the Chemo Partner Make a Difference Does the Chemo Partner Make a Difference?: Taxane Versus Non-Taxane Regimens N=29 studies N=5890 pts. Median OS: 14.4 vs. 13.7 m, P=0.5 Behera et al, J Thorac Oncol, 2015

First-Line Treatment of Advanced NSCLC Adenocarcinoma Large cells NSCLC NOS Squamous cell carcinoma EGFR mutation and ALK negative EGFR mutation positive ALK positive PS 0-1 PS 2 PS 3-4 Gefitinib Erlotinib Afatinib Crizotinib Doublet chemotherapy (category 1) OR Cetuximab/vinorelbine/ cisplatin (category 2B) Chemotherapy Best supportive care Bevacizumab + chemotherapy (if criteria met) Cisplatin/pemetrexed (category 1) (if criteria met) Cetuximab/vinorelbine/cisplatin (category 2B) Best supportive care only

Presented By Terufumi Kato at 2014 ASCO Annual Meeting Study design Presented By Terufumi Kato at 2014 ASCO Annual Meeting

Primary endpoint: PFS by independent review Presented By Terufumi Kato at 2014 ASCO Annual Meeting

BEVERLY : STUDY DESIGN R Control arm Erlotinib 150 mg orally once daily Experimental arm Bevacizumab 15 mg/kg iv every 21 days NSCLC Non-squamous Activating EGFR mutation Stadio IIIB o IV PS 0-2 R 1:1 Treatment in both arms will be given until disease progression or unacceptable toxicity or patient’s or physician’s motivated decision to stop Strata: PS (0-1 vs 2) Type of mutation (exon19 del vs 21 L858R mut vs others) Primary endpoints: investigator-assessed and blinded, indipendent centrally-reviewed PFS Sample size: 200 pts Centres involved: about 60 PI: C. GRIDELLI

treated with platinum- AvaALL: Trial design Global trial conducted in ~20 countries Enroll Primary endpoint: OS PD1 SOC2* + bevacizumab SOC3† + bevacizumab SOC4 ± bevacizumab SOC2* SOC3† SOC4 PD3 Randomize 1:1 PD2 Stage IIIB/IV non-squamous NSCLC treated with platinum- doublet (4-6 cycles) + bevacizumab PLUS > 2 cycles of bevacizumab maintenance N=500 * SOC2: Labelled agents for 2nd-line treatment of NSCLC (erlotinib, pemetrexed and docetaxel) † SOC3 and beyond: Choice of labelled agents in 3rd-line and beyond is the Investigator’s choice PI: C. Gridelli

Proangiogenic Ligands and their Receptors Ramucirumab Bevacizumab VEGFR TKI Bevacizumab Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

Treatment until disease progression or unacceptable toxicity REVEL: Study Design 1:1 R A N D O M I Z E Ramucirumab 10 mg/kg + Docetaxel 75 mg/m2 q3wks N=628 Stage IV NSCLC after one platinum- based chemo +/- maintenance Prior Bev allowed All histologies PS 0 or 1 No major blood vessel invasion, or cavitation Treatment until disease progression or unacceptable toxicity Placebo + Docetaxel 75 mg/m2 q3wks N=625 Stratification factors: ECOG PS 0 vs 1 Gender Prior maintenance East-Asia vs. ROW Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes Pérol, ASCO 2014; Garon, Lancet 2014

Overall Survival ITT Population 20 40 60 80 100 Overall Survival (%) RAM+DOC PL+DOC Number at risk 3 6 9 12 15 18 21 24 27 30 33 527 501 415 386 329 306 231 197 156 129 103 86 70 56 45 36 23 11 2 Survival Time (months) 628 625 Censored Median (95% CI) Censoring Rate RAM+DOC RAM+DOC vs PL+DOC: 10.5 (9.5-11.2) 31.8% PL+DOC 9.1 (8.4-10.0) 27.0% Stratified HR (95% CI) = 0.857 (0.751-0.979) Stratified log-rank P = .0235 Pérol, ASCO 2014; Garon, Lancet 2014

Survival Time (months) Survival Time (months) OS by Histology Nonsquamous OS Squamous OS Stratified HR (95% CI) = 0.84 (0.71-0.98) RAM+DOC PL+DOC 11.1 (9.9-12.3) 9.7 (8.5-10.6) 35.5% 29.3% Median (95% CI) Censoring Rate vs PL+DOC Stratified HR (95% CI) = 0.89 (0.70-1.15) RAM+DOC PL+DOC 9.5 (8.0-10.8) 8.2 (6.3-9.4) 21.7% 19.9% Median (95% CI) Censoring Rate vs PL+DOC 3 6 9 12 15 18 21 24 27 30 33 36 100 80 60 Overall Survival (%) 40 20 Survival Time (months) 465 447 RAM+DOC PL+DOC Number at risk 401 362 311 282 251 226 182 144 125 94 64 54 39 10 5 1 Censored RAM+DOC PL+DOC Censored 100 80 60 Overall Survival (%) 40 20 3 6 9 12 15 Survival Time (months) 18 21 24 27 30 33 36 157 171 Number at risk 124 132 103 99 78 75 49 48 31 23 16 14 8 2 5 1 4 Pérol, ASCO 2014; Garon, Lancet 2014

Presented By Maurice Perol at 2014 ASCO Annual Meeting Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm Presented By Maurice Perol at 2014 ASCO Annual Meeting

Proangiogenic Ligands and their Receptors Ramucirumab Bevacizumab Nindetanib PDGFR TKI FGFR TKI VEGFR TKI Nindetanib Bevacizumab Nindetanib Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

LUME-Lung 1: Randomised Phase III Study Nintedanib 200 mg BID po, Days 2–21 + docetaxel 75 mg/m2 IV, Day 1, 21-day cycles (n=655) Placebo BID po, Days 2–21, + docetaxel 75 mg/m2 IV, Day 1, 21-day cycles (n=659) N=1314 RANDOMISE 1:1 PD Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy Stage IIIB/IV* or recurrent NSCLC patients after first-line chemotherapy (all histologies) The LUME-Lung 1 trial was a global randomised controlled Phase III trial Patients with Stage IIIB/IV or recurrent NSCLC (all histologies) who had failed prior first-line chemotherapy were recruited to the study In total, 1773 patients were recruited and 1314 patients were subsequently randomised to treatment: Nintedanib + docetaxel: nintedanib 200 mg twice daily orally + docetaxel 75 mg/m2 by intravenous infusion on Day 1 Placebo + docetaxel: oral placebo + docetaxel 75 mg/m2 by intravenous infusion on Day 1. Oral placebo tablet was given in order to maintain blinding of the trial patients and the treating physicians to treatment The number of docetaxel cycles was not restricted, and patients were able to continue monotherapy with either nintedanib/placebo or docetaxel after they had received 4 cycles of combination therapy; patients could receive any treatment until progression (combination therapy or either of the agents as monotherapy) The primary endpoint and key secondary endpoints are shown Additional notes: Docetaxel was administered every 3 weeks until unacceptable AEs or disease progression Nintedanib 100 mg or placebo capsules (×2) were taken each morning and evening after a meal (Boehringer Ingelheim, data on file) Prior to randomisation, patients were stratified by ECOG PS (0 vs 1), previous bevacizumab treatment (yes vs no), histology (squamous vs non-squamous), and presence of brain metastases (yes vs no) The study was conducted at 211 centres in 27 countries (23 European countries, plus China, South Korea, India and South Africa) Patients were enrolled into the study between 23 December 2008 and 9 February 2011   Primary Endpoint: PFS by independent central review Key Secondary Endpoint: OS, prespecified hierarchical analyses of patients with adenocarcinoma who progressed in <9 months after start of first-line therapy, all patients with adenocarcinoma, and ITT population Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs. no) Histology (squamous vs. non-squamous) Brain metastases (yes vs. no) Regions: Europe/Asia/South Africa Accrual: 23 Dec 2008 to 09 Feb 2011 Reck M, et al. Lancet Oncol. 2014;15:143-55.

All histology

Grade ≥3 AEs in Patients with Adenocarcinoma* Lume Lung 1: Grade ≥3 AEs Grade ≥3 AEs in Patients with Adenocarcinoma* In patients with adenocarcinoma histology, the most frequently observed AEs of grade ≥3 that occurred in more than twice as many patients in the nintedanib + docetaxel arm than the placebo + docetaxel arm were liver enzyme elevations (ALT and AST increase) and asthenia; grade ≥3 diarrhoea was also more common with nintedanib + docetaxel than with placebo + docetaxel The rate of haematological grade ≥3 AEs was not increased by the addition of nintedanib to docetaxel Boehringer Ingelheim data on file: Rate of asthenia   Reck M, et al. Lancet Oncol. 2014;15:143-55.

Approved by EMA on November 21, 2014 VARGATEF® (nintedanib) is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy On November 21, 2014, the European Commission granted approval to Vargatef® (nintedanib) in combination with docetaxel for use in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. This approval was based on the data from LUME-Lung 1 Phase III trial.

LUME-Columbus Phase III Study: 2-line NSCLC Key inclusion criteria Stage IIIB/IV NSCLC of adenocarcinoma histology 1 prior treatment line ≥1 measurable target lesion ECOG PS 0 or 1 EGFR-mutation negative Alk translocation negative Key exclusion criteria Prior VEGFR inhibitors (except bevacizumab) or docetaxel Active brain metastases RANDOM I ZE Nintedanib: 200 mg BID + Docetaxel * PD 1 * 75 mg/m2 IV, on Day 1 of every 3-week cycle - No restriction of number of courses 1 Placebo: 200 mg BID + Docetaxel * PD N = 800 Stratification Time since start 1st line (<9mo vs. ≥9mo) ECOG PS (0 vs. 1) Co- Primary Endpoints: OS and PFS (by independent review; 6 weeks CT-schedule) Secondary Endpoints: OR, DC, HRQOL Study Start Date: September 2014 Accrual Completed Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Chairmen F. de Marinis C. Gridelli Panelists F. Ciardiello L. Crinò J.Y. Douillard F. Griesinger D. Lambrechts M. Perol S. Ramalingam E. Smit

Which selection criteria for antiangiogenetic treatment? Non-squamous PS 0-1 No serious cardio-vascular comorbidities No cavitation No major vessel invasion No previous hemoptysis No recent thromboembolic disease or hemorrhage No severe or uncontrolled hypertension No recent major surgery (< 4 weeks) No recent thoracic radiation, including the mediastinum

Any predictive biomarker for antiangiogenetic treatment ? So far, no biomarker for NSCLC patient selection (as well as other cancers) has been validated for clinical practice.

Advanced NSCLC: Old Algorythm (just yesterday) for Second- and Third-line therapy 1 ° Progression of disease Squamous NOS Nonsquamous EGFR WT/UNK EGFR mutated EGFR mutated EGFR WT/UNK ALK Negative/UKN ALK positive Gefitinib or Erlotinib Crizotinib Docetaxel or Erlotinib Pemetrexed or Docetaxel or Erlotinib 2° Progression of disease Erlotinib (if not previously administered)

NEW TREATMENT ALGORITHM IN ADVANCED SQUAMOUS NSCLC Platin + GEM/TXT/TAX/VNR Squamous 1st Line Nivolumab 2nd Line Pembrolizumab (PD-L1 > 50%) Docetaxel ± Ramucirumab 3rd Line Afatinib > Erlotinib 4rd Line

NEW TREATMENT ALGORITHM IN ADVANCED NON SQUAMOUS NSCLC Non Sq WT P/Pem P-based CTx + BEVA 1st Line Pem Maintenance BEVA until PD Nivolumab Pembrolizumab PD-L1 >50% 2nd Line Docetaxel ± Nindetanib Docetaxel ± Ramucirumab 3rd Line Erlotinib Pemetrexed 4rd Line Erlotinib 5rd Line

Consensus for clinical research Issue Priority Identification, validation and clinical performance of biomarkers High How incorporate immunotherapy and antiangiogenic treatment in the overall strategy Efficacy of the combination of antiangiogenic drugs and TKI for EGFR and other mutation NSCLC Efficacy of Ramucirumab for 1° line squamous NSCLC (including maintainance) Efficacy of Bevacizumab beyond progression Medium Efficacy of new antiangiogenic drugs plus Docetaxel after immunotherapy Develop rationale combinations among antiangiogenic drugs Optimize dose, schedule and timing of antiangiogenic drugs