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Adjuvant chemotherapy in patients with resected NSCLC Current status & perspectives

Adjuvant chemotherapy in patients with resected NSCLC Current status & perspectives Robert Pirker, MD Vienna, Austria Novel Clinical Strategies in NSCLC Policlinico Umberto I, Rome May 9-10, 2019. Conflict of Interest. Honoraria for Advisory Board/Consulting

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Adjuvant chemotherapy in patients with resected NSCLC Current status & perspectives

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  1. Adjuvant chemotherapy in patients with resected NSCLC Current status & perspectives Robert Pirker, MD Vienna, Austria Novel Clinical Strategies in NSCLC Policlinico Umberto I, Rome May 9-10, 2019

  2. Conflict of Interest • Honoraria for Advisory Board/Consulting • AstraZeneca Boehringer Ingelheim • Jansen Oncology Takeda • Speaker‘s fee • AstraZeneca Boehringer Ingelheim • Honoraria for Data Safety Monitoring Board • Gedeon Richter Genmab • Merck Sharp Dohme Regeneron

  3. Adjuvant chemotherapy of NSCLC • Survival benefit of absolute 5% at 5 years (p=0.08) NSCLC Collaborative Group BMJ 311, 899, 1995 • IALT, JBR.10 & ANITA: 5-year survival rates increased by 4-15% • LACE meta-analysis confirmed improved cure rate: HR 0.89 (0.82-0.96), p=0.005; 5-year survival increase of 5.4% Pignon JP et al . JCO 2008, 26, 3552 • LACE vinorelbine meta-analysis: HR 0.8 (0.70-0.91), p=0.0007; 5-year survival increase of 8.9%Douillard JY et al. JTO 2010, 5, 220 • NSCLC Meta-analysis Collaborative Group: HR 0.86 (0.81-0.92), p<0.0001 Lancet 2010, 375, 1267

  4. LACE Meta-Analysis Pignon JP et al. JCO 2008, 26, 3552 4584 patients: IALT, JBR.10, ANITA, ALPI-EORTC & BLT Overall survival Disease-free survival HR 0.89 (0.82-0.96), p=0.005 HR 0.8 (0.78-0.9), p<0.001 5-y survival increased by 5.4% ± 1.6%

  5. Adjuvant Chemotherapy in resected NSCLCRecommendations for daily practice • Patients with • stage II & III, selected IB (6th TNM classification) • good performance status • adequate organ functions • rapid postoperative recovery • informed consent • Cisplatin-based chemotherapy • preferably cisplatin/vinorelbine, based on phase III trials • 4 cycles • begin 4-8 weeks after surgery • Advice & support for smoking cessation

  6. Strategies to improve outcome of adjuvant therapy • Optimization of chemotherapy • Treat study. Kreuter M et al. Ann Oncol 2013, 24, 986 • Predictive biomarkers remain experimental. • IALT-Bio, LACE-Bio • Customized chemotherapy remains experimental. • ITACA trial is ongoing.

  7. ITACA Trial Pharmacogenomics: Yes or No? Taxanes High Profile 4 Control TS Pem Low Profile 3 High Control Cis/Gem ERCC1 High Profile 2 Control Low TS Cis/Pem Low Profile 1 Control Control = investigators’ choice of cisplatin-based doubletPrimary endpoint: survival; HR pharmacogenomic arm = 0.7; Trial Status as of ASCO 2012: 312/700 patients Courtesy G. Scagliotti

  8. Strategies to improve outcome of adjuvant therapy • Optimization of chemotherapy • Treat study. Kreuter M et al. Ann Oncol 2013, 24, 986 • Predictive biomarkers remain experimental. • IALT-Bio, LACE-Bio • Customized chemotherapy remains experimental. • ITACA trial is ongoing. • Integration of targeted therapies • Bevacizumab added to chemotherapy failed (E1505). • EGFR tyrosine kinase inhibitors

  9. Adjuvantchemotherapy ± bevacizumab (E1505)Overall survivalWakelee H et al. Lancet Oncol 2017, 18, 1610 Intent-to-treatpopulationEligiblepatients

  10. EGFR TKIs as adjuvant therapy in resected NSCLC • Gefitinib in unselected patients (NCIC CTG BR19 Study) Goss GD et al. JCO 2013, 31, 3320 • Erlotinib in patients with EGFR-positive tumors (RADIANT) Kelly K et al. JCO 2015, 33, 400 • Patients with EGFR mutation-positive tumors • Subgroup analyses (NCIC CTG BR19; RADIANT) • Icotinib studies • SELECT (Phase 2)Pennell NA et al. ASCO 2014 • Phase 3 trials ADJUVANT (CTONG1104; NCT01405079) WJOG6410L ALCHEMIST ADAURA

  11. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II–IIIA (N1–N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104) Wen-Zhao Zhong et al. Lancet Oncol 2018; 19: 139–48

  12. ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial

  13. Adjuvant EGFR TKIs in patients with EGFR mutation-positive tumors: phase 3 trial • ADAURA (NCT02511106) • Osimertinib versus placebo after complete resection ± adjuvant chemotherapy in NSCLC IB-IIIA • 700 patients with EGFR mutations (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M • Disease-free survival

  14. Strategies to improve outcome of adjuvant therapy • Optimization of chemotherapy • Treat study. Kreuter M et al. Ann Oncol 2013, 24, 986 • Predictive biomarkers remain experimental. • IALT-Bio, LACE-Bio • Customized chemotherapy remains experimental. • ITACA trial is ongoing. • Integration of targeted therapies • Bevacizumab added to chemotherapy failed (E1505). • EGFR tyrosine kinase inhibitors • Gefitinib compared to chemotherapy increases PFS in EGFR mutation-positive NSCLC Wen-Zhao Zhong et al. Lancet Oncol 2018; 19: 139–48 • Immunotherapy • MAGE-A3 vaccine failed (MAGRIT). • Immune checkpoint inhibitors

  15. MAGE-A3 cancer immunotherapeutic in resected NSCLC (MAGRIT)Vansteenkiste J et al. Lancet Oncology 2016, 17, 822

  16. Lessons learnt from MAGRIT • Large phase 3 trials can be done in the adjuvant setting. • It is difficult to improve outcome of patients with resected NSCLC. • Phase 2 trials often do not predict phase 3 results. • The development of the MAGE-A3 cancer immunotherapeutic was discontinued. • Cisplatin-based doublets remain standard of care.

  17. Immune checkpoint inhibitors as adjuvant therapy

  18. Immune checkpoint inhibitors in the adjuvant treatment of resected NSCLC: phase 3 trials * OS overall survival; DFS disease-free survival

  19. Challenges of adjuvant therapy trials in resected NSCLC • Large sample sizes are required because of moderate benefits. • Long trial duration and high costs • Selection of drugs is based on efficacy in the advanced setting. • Most appropriate endpoint: Overall survival, disease-free survival (progression-free survival), time-to-disease progression • Novel trial designs • Focus on patients with high risk of recurrence • Surrogate endpoints for survival • Residual disease assessed by circulating tumor DNA * * Dasari A et al. JCO 2018, 36, 3437

  20. Pre-operative chemotherapy for NSCLC: Meta-AnalysisNSCLC Meta-analysis Collaborative Group . Lancet 2014, 383, 2014 Hazard ratio 0.87; p=0.007

  21. Pre-op CT + Surg vs. Surg + adj CT vsSurgFelip H et al. JCO 2010

  22. Immune checkpoint inhibitors as neo-adjuvant therapy

  23. Immune checkpoint inhibitors as neo-adjuvant therapy Phase 2 trials

  24. CheckMate 816 (NCT02998528): phase 3 trialFelip E et al. WCLC 2018, P2.16-03

  25. Adjuvant versus pre-operative chemotherapy of NSCLC • Adjuvant chemotherapy is preferred. • No delay in curative surgery • Patients want cancers to be removed as quickly as possible. • More tumor material for histological & molecular analyses • More accurate tumor stage • Pre-operative chemotherapy is an option in selected patients. • Patients with marginally resectable tumors • Patients with large tumors • Patients with more advanced tumor stage • Waiting list for surgery

  26. Adjuvant therapy of resected NSCLCSummary • Adjuvant chemotherapy with cisplatin-based doublet is established as • standard. • Predictive biomarkers & customized chemotherapy remain experimental. • Several major trials failed to improve outcome. • E1505 (bevacizumab), BR19 & RADIANT (EGFR TKIs), MAGRIT (MAGE-A3 vaccine) • Among EGFR mutation-positive patients, gefinitibimproved disease-free • survival and further trials are ongoing. • Immune checkpoint inhibitors are evaluated within phase 3 trials. • ANVIL, PEARLS, CCTG ADJUVANT • Induction (neo-adjuvant) therapy is an option for selected patients.

  27. Benefits of stopping smoking: United Kingdom Million Women Study Jha P & Peto R. NEJM 2014, 370, 60

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