4/23/2015 Objectives Provide an algorithm that outlines the use - PDF document

4/23/2015 Objectives • Provide an algorithm that outlines the use of first-line treatment options based on histology and mutation status of metastatic non- small-cell lung cancer An overview of first-line treatments in • Review the main evidence supporting the role of chemotherapy metastatic non-small-cell lung cancer: regimens and targeted agents as first-line treatment options • • Summarize current clinical trials that may add new options in first- Summarize current clinical trials that may add new options in first A paradigm shift from chemotherapy to targeted agents line treatment Michelle Lui RPh BScPhm PharmD MSc (c) Pharmacy Oncology Fellow Odette Cancer Centre April 9, 2015 2 April 23, 2015 Disclosures From chemo to hero… 2009 – Mid 1990s – • Funding (honoraria): Boehringer Ingelheim, Amgen maintenance docetaxel, therapy with 2013 – paclitaxel, erlotinib 2004 – gefitinib afatinib vinorelbine and improves produces better approved for gemcitabine shown survival in responses in Stage IV to be effective when Stage IV some EGFR NSCLC combined with NSCLC treatment cisplatin mutations 1990 2000 2010 2020 1995 – cisplatin 2003 – 2004 – 2013 – chemo increases gefitinib erlotinib 2010 – crizotinib approved approved crizotinib found approved for survival in advanced for Stage for Stage to produce Stage IV NSCLC IV NSCLC IV NSCLC responses in NSCLC stage IV ALK+ treatment treatment treatment NSCLC http://www.cancerprogress.net/sites/cancerprogress.net/files/category-downloads/progress_against_lung_cancer_timeline.pdf 3 April 23, 2015 4 April 23, 2015 Algorithm of first-line treatments Chemotherapy • First line for squamous cell carcinoma: Platinum-containing doublet chemotherapy Non-small-cell lung cancer – Carboplatin/paclitaxel – Cisplatin/paclitaxel Squamous cell carcinoma Adenocarcinoma – Cisplatin/docetaxel – Cisplatin/gemcitabine Cisplatin/gemcitabine EGFR-mutant EGFR t t Wild-type ALK-mutant ROS-1 OS – Cisplatin/vinorelbine Exon 19 Exon 21 – Carboplatin/vinorelbine del L858R Doublet platinum Doublet platinum chemotherapy chemotherapy Leighl NB. Current Oncology. 2012; 19 (S1) Azzoli et al. JCO. 2011; 29(28): 3825-3831 Azzoli et al. JCO. 2011; 29(28): 3825-3831 5 April 23, 2015 6 April 23, 2015 1

4/23/2015 Chemotherapy Chemotherapy Parameters Schiller et al. (2002) - RCT Population Patients with malignant pleural/pericardial effusion or Stage IV NSCLC or recurrent disease (n=1207, median age = 63, ECOG = 1) ) 1) Cisplatin 75mg/m 2 + paclitaxel 135mg/m 2 q21 days for Interventions and 2) Cisplatin 100mg/m 2 + gemcitabine 1000mg/m 2 on days 1, 8, Comparators 15 q28 days 3) Cisplatin 75mg/m 2 + docetaxel 75mg/m 2 q21 days 4) Paclitaxel 225mg/m 2 + carboplatin AUC 6 q21 days Outcomes Primary: 1-year median survival Secondary: response rate, time to progression Schiller et al. NEJM. 2002; 346(2): 92-98 Schiller et al. NEJM. 2002; 346(2): 92-98 7 April 23, 2015 8 April 23, 2015 Chemotherapy • First line for adenocarcinoma wild-type: Carboplatin or cisplatin + pemetrexed Parameters Scagliotti et al. (2008) - RCT Population Patients with malignant pleural/pericardial effusion or Stage IV NSCLC or recurrent disease (n=1725, median age = 61, ECOG 0-1, 48% adenocarcinoma, 27% squamous) Interventions 1) Cisplatin 100mg/m 2 + gemcitabine 1000mg/m 2 on days 1, 8, and 15 q28 days 2) Cisplatin 75mg/m 2 + pemetrexed 500mg/m 2 on day 1 q21 Comparators days Outcomes Primary: overall survival (OS) Secondary: progression-free survival (PFS), time to progressive • CG= cisplatin/gemcitabine disease, time to treatment failure, ORR, duration of response, • CP = cisplatin/pemetrexed toxicity Scagliotti et al. JCO. 2008; 26: 3543-3551. Scagliotti et al. JCO. 2008; 26: 3543-3551 9 April 23, 2015 10 April 23, 2015 Why does pemetrexed only work in adenocarcinoma? • Adenocarcinoma cells seem to have lower thymidate synthase and dihydrofolate reductase than non-adenocarcinoma cells Scagliotti et al JCO 2008; 26: 3543-3551 Scagliotti et al. JCO. 2008; 26: 3543-3551 Chen et al. Lung Cancer. 2011; 74; 132-138. 11 April 23, 2015 12 April 23, 2015 2

4/23/2015 Algorithm of first-line treatments Maintenance therapy (pemetrexed) Parameters Paz-Ares et al (PARAMOUNT) – 2013 Non-small-cell lung cancer Population Patients with stage IIIB-IV non-squamous NSCLC, no prior chemo for lung cancer, ECOG 0-1 Squamous cell carcinoma Adenocarcinoma Interventions Phase I Placebo + BSC and and EGFR-mutant EGFR t t Wild-type ALK-mutant ROS-1 OS Cisplatin 75mg/m 2 + q3weeks Comparators All pemetrexed 500mg/m 2 Exon 19 Exon 21 patients q3weeks del L858R Pemetrexed 500mg/m 2 q3weeks Doublet platinum Cisplatin or chemotherapy carboplatin + Randomization 2:1 for pemetrexed and placebo arms, respectively pemetrexed Outcomes Primary outcome: OS and PFS Maintenance Maintenance Paz-Ares et al. JCO. 2013; 31. DOI: 10.1200/JCO.2012.47.1102 therapy therapy Leighl NB. Current Oncology. 2012; 19 (S1) 13 April 23, 2015 14 April 23, 2015 Azzoli et al. JCO. 2011; 29(28): 3825-3831 Maintenance therapy (erlotinib) Parameters Cappuzzo et al (SATURN) – 2010 Population Patients with stage IIIB-IV non-squamous NSCLC, no prior chemo for lung cancer, ECOG 0-1 Interventions Phase I and Placebo + BSC Comparators All All Doublet platinum Doublet platinum daily daily chemotherapy q3weeks patients Erlotinib 150mg daily Randomization 1:1 in each group Outcomes Primary outcome: PFS Secondary outcomes: OS, PFS according to different EGFR mutation statuses, tumour response, time to deterioration of symptoms, quality of life Paz-Ares et al. JCO. 2013; 31. DOI: 10.1200/JCO.2012.47.1102 Cappuzzo et al. Lancet Oncology. 2010; 11: 521-529. 15 April 23, 2015 16 April 23, 2015 Cappuzzo et al. Lancet Oncology. 2010; 11: 521-529. Cappuzzo et al. Lancet Oncology. 2010; 11: 521-529. 17 April 23, 2015 18 April 23, 2015 3

4/23/2015 Algorithm of first-line treatments Non-small-cell lung cancer Squamous cell carcinoma Adenocarcinoma EGFR EGFR-mutant t t Wild-type ALK-mutant ROS-1 OS Exon 19 Exon 21 del L858R Doublet platinum Cisplatin or EGFR tyrosine chemotherapy carboplatin + kinase inhibitors pemetrexed Erlotinib Erlotinib Pemetrexed Cappuzzo et al. Lancet Oncology. 2010; 11: 521-529. Leighl NB. Current Oncology. 2012; 19 (S1) 19 April 23, 2015 20 April 23, 2015 Azzoli et al. JCO. 2011; 29(28): 3825-3831 Erlotinib Parameters Rosell et al. (EURTAC) - 2012 Population Adult patients with metastatic EGFR mutant (exon 19 del or L858R mutations) NSCLC, treatment-naïve (all European patients) Interventions 1) Erlotinib 2) Doublet platinum chemotherapy -Cisplatin 75mg/m 2 + docetaxel 75mg/m 2 on day 1 and 150mg Comparators daily q3weeks -Carboplatin AUC6 + docetaxel 75mg/m 2 on day 1 q3weeks -Cisplatin 75mg/m 2 + gemcitabine 1250mg/m 2 on days 1 and 8 q3weeks -Carboplatin AUC5 + gemcitabine 1250mg/m 2 on days 1 and 8 q3weeks Outcomes Primary: PFS Secondary: OS, response rate Rosell et al. Lancet Oncology. 2012; 13:239-246 Rosell et al. Lancet Oncology. 2012; 13:239-246 21 April 23, 2015 22 April 23, 2015 Gefitinib Parameters Mok et al. (IPASS) - 2009 Population Adult patients with metastatic EGFR mutant NSCLC, treatment- naïve, ECOG 0-2 (East Asian patients) Interventions 1) Gefitinib 250mg 2) Carboplatin AUC5-6 + paclitaxel 200mg/m 2 and daily Comparators Comparators Outcomes Primary: PFS Secondary: OS, response rate, quality of life Mok et al. NEJM. 2009; 361(10):947-957 23 April 23, 2015 24 April 23, 2015 Rosell et al. Lancet Oncology. 2012; 13:239-246 4

4/23/2015 Mok et al. NEJM. 2009; 361(10):947-957 Mok et al. NEJM. 2009; 361(10):947-957 25 April 23, 2015 26 April 23, 2015 Afatinib Parameters Sequist et al. (LUX-LUNG 3) – 2013 Population Adult patients with metastatic EGFR mutant NSCLC, treatment- naïve, ECOG 0-1 (72% East Asian) 2) Cisplatin 75mg/m 2 + pemetrexed 500mg/m 2 Interventions 1) Afatinib and 40mg daily Comparators C t Outcomes Primary: PFS Secondary: OS, response rate, quality of life Mok et al. NEJM. 2009; 361(10):947-957 Sequist et al. JCO. 2013; 31:3327-3334 27 April 23, 2015 28 April 23, 2015 How do we choose between the EGFR- TKIs for EGFR-mutant NSCLC? • Cost/Provincial drug coverage • Toxicity profile • Efficacy Let’s take a quick poll! Sequist et al. JCO. 2013; 31:3327-3334 Yang et al. Lancet Oncology. 2015; 16:141-151 29 April 23, 2015 30 April 23, 2015 5