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Advanced NSCLC: treatment options for non-squamous, EGFR wildtype tumors

Advanced NSCLC: treatment options for non-squamous, EGFR wildtype tumors. Prof. Christian Manegold Interdisciplinary Thoracic Oncology Department of surgery Medical Center Mannheim – University Heidelberg. Disclosures.

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Advanced NSCLC: treatment options for non-squamous, EGFR wildtype tumors

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  1. Advanced NSCLC: treatment options for non-squamous, EGFR wildtype tumors Prof. Christian Manegold Interdisciplinary Thoracic Oncology Department of surgery Medical Center Mannheim – University Heidelberg

  2. Disclosures Consultancy: Hoffmann-La Roche, Pfizer, Eli Lilly, Merck-Serono, Novartis, Amgen, Boehringer Ingelheim, AstraZeneca Speaking: Hoffmann-La Roche, Eli Lilly, Merck-Serono, AstraZeneca Grant support: Merck-Serono, Sanofi-Aventis, Eli Lilly Travel Support: Hoffmann-La Roche, Merck-Serono, Eli Lilly, AstraZeneca

  3. NSCLC: Incidence of single driver mutations Mutation found in 54% (280/516) oftumours completely tested (CI 50-59%) Kris et al. J Clin Oncol 29: 2011 (suppl; abstr 7506)

  4. Treatment Strategiesfor NSCLC

  5. Advanced NSCLC: Treatment algorithm in 2012 Non-Squamous Squamous Mutatedtumours Platinum-Doublets (Pem!) plus Bev or Cet Platinum-Doublets (No Pem, no Bev) plus Cet EGFR-TKI; ALK-Inhibitor 1st-line Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Switch: Erlotinib Maintenance in case of non-PD/SD Single agent Non-cross resistant Single agent Non-cross resistant 2nd-line Dealer’s choice Dealer’s choice 3rd-line Dealer’s choice Dealer’s choice

  6. NSCLC: ASCO treatment recommendations for advanced disease • Chemotherapy prolongs survival and is most appropriate for individuals with good performance status (PS 0 or 1, and possibly 2). • Chemotherapy should be a platinum-based two-drug combination regimen. • Non-platinum containing regimens may be used as alternatives to platinum-based regimens. For elderly patients, or patients with PS 2, available data support the use of single-agent chemotherapy. • Chemotherapy should be stopped at 4 cycles in patients who are not responding to treatment, and should be administered for no more than six cycles . • If chemotherapy is to be given it should be initiated while the patient still has good PS. Azzoli et al. J Clin Oncol 29, 3825-3831, 2011

  7. First line Gemcitabine/Cisplatin combination therapy for advanced NSCLC: outcome plateau

  8. NSCLC: Pivotal phase III trails in stage IIIB/IV disease relevant for the treatment of non-mutated, non-squamous tumours

  9. AVAiL: Cis/Gem Advanced NSCLC: Bevacizumab plus Standard CT ECOG 4599: Carbo/Taxol CP PD Previously untreated stage IIIB/IV non-squamous NSCLC Bev every 3 weeks until progression Bev (15mg/kg) every 3 weeks + CP PD 2 Bevacizumab RANDOMISE Bev 7.5mg/kg + CG PD Previously untreated, stage IIIB/IV non-squamous NSCLC 1 Placebo + CG 1 PD Placebo + CG 2 Bevacizumab Bev 15mg/kg + CG PD

  10. Advanced NSCLC: Bevacizumab plus Standard CT Results by primary endpoints ECOG 4599: Carbo/Taxol AVAiL: Cis/Gem 6.7 m 6.1 m 12.3 m 10.3 m 6.5 m 6.1 m Time Months Sandler et al N Engl J Med 355, 2542-2550, 2006 Reck et al, Ann Oncol 21, 1804-1809, 2010 Reck et al, J Clin Oncol 27, 1227-1235, 2009

  11. NSCLC: Bevacizumab - EMA Registration • BEV at a dose of 7.5mg/kg or 15mg/kg, in combination with platinum-based chemotherapy, for the first-line treatment of patients with unresectable advanced, metastatic or recurrent NSCLC other than predominantly squamous cell histology • Removal of Bev- contraindication in patients with untreated CNS metastases (2008)

  12. NSCLC: Bevacizumab - Key eligibility criteria

  13. R JMDB: Pemetrexed vs Gemcitabine Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1 RandomizationFactors • Stage • PS • Gender • Histo vs cyto • Brain mets Each cycle repeated q3 weeks up to 6 cycles Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8 Vitamin B12, folate, and dexamethasone given in both arms Primaryendpoint: survival; non-inferioritydesign Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008

  14. JMDB: Pemetrexed vs Gemcitabine Squamous (n=473) Nonsquamous* (n=1252) HR=1.229 (95% CI: 1.00–1.51) p=0.051 HR=0.844 (95% CI: 0.74–0.96) p=0.011 Gemcitabine+Cisplatin Median OS: 10.8 mos Pemetrexed+Cisplatin Median OS: 11.0 mos Survival Probability Survival Probability Gemcitabine+Cisplatin Median OS: 10.1 mos Pemetrexed+Cisplatin Median OS: 9.4 mos Survival Time (months) Survival Time (months) Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008

  15. Treatment-by-Histology Interaction Analyses in Three Phase III Trials Show Superiority of Pemetrexed in Nonsquamous NSCLC Scagliotti J Thorac Oncol 6, 64–70, 2011

  16. FLEX: First-Line ErbituX in lung cancer Pirker et al. Lancet 373, 1525-1531, 2009

  17. Flex: Kaplan-Meier estimates of overall survival time in the intention-to-treat population Pirker et al. Lancet 373, 1525-1531, 2009

  18. FLEX: Stained tumour sections from study patients Pirker et al. Lancet Oncol 13: 33–42, 2012

  19. FLEX: Objective response rate by IHC score Pirker et al. Lancet Oncol 13: 33–42, 2012

  20. 44.4 10 30 40 50 20 20 10 40 50 30 32.6 29.6 28.1 0 0 FLEX: Response rate by EGFR-IHC expression Low EGFR expression (<200) n=776 (69%) High EGFR expression (≥200) n=345 (31%) Response rate (%) p=0.002 p=0.36 CT + cetuximab CT Treatment interaction test p=0.040 Pirker et al. Lancet Oncol 13: 33–42, 2012

  21. FLEX: Overall survival for patients according to treatment group and EGFR expression group Low EGFR High EGFR Pirker et al. Lancet Oncol 13: 33–42, 2012

  22. Advanced NSCLC: Treatment algorithm in 2012 Non-Squamous Squamous Mutatedtumours Platinum-Doublets (Pem!) plus Bev or Cet Platinum-Doublets (No Pem, no Bev) plus Cet EGFR-TKI; ALK-Inhibitor 1st-line Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Switch: Erlotinib Maintenance in case of non-PD/SD Single agent Non-cross resistant Single agent Non-cross resistant 2nd-line Dealer’s choice Dealer’s choice 3rd-line Dealer’s choice Dealer’s choice

  23. NSCLC – Erlotinib switch maintenance Erlotinib 150mg/day Stratification factors: • EGFR IHC (positive vs negative vs indeterminate) • Stage (IIIB vs IV) • ECOG PS (0 vs 1) • CT regimen (cis/gem vs carbo/doc vs others) • Smoking history (current vs former vs never) • Region PD Chemonaïve advanced NSCLC n=1,949 4 cycles of first-line platinum doublet chemotherapy* Non-PD n=889 1:1 Placebo PD Mandatory tumour sampling Co-primary endpoints: • PFS in all patients • PFS in patients with EGFR IHC+ tumours • Secondary endpoints: • OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

  24. NSCLC – Erlotinib switch maintenanceProgression free survival Progression free Survival Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

  25. NSCLC – Erlotinib switch maintenanceOverall survival Overall Survival Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

  26. NSCLC: Erlotinib switch maintenanceOverall survival by response Stable disease CR/PR 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 HR=0.72 (0.59–0.89) HR=0.94 (0.74–1.20) Log-rank p=0.0019 Log-rank p=0.6181 Overall Survival 9.6 11.9 12.0 12.5 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Time (months) Measured from time of randomisation into the maintenance phase Coudert et al.Ann Oncol 23, 388-394, 2012

  27. NSCLC: Erlotinib switch maintenanceOverall survival by response (subgroups) Coudert et al.Ann Oncol 23, 388-394, 2012

  28. NSCLC: Erlotinib switch maintenanceSurvival for SD in wild-type tumours Coudert et al.Ann Oncol 23, 388-394, 2012

  29. NSCLC – Erlotinib switch maintenance (registration) Erlotinib Maintenance : as single agent in patients with stable disease after 4 cycles of platinum based first-line chemotherapy EMA: 2010

  30. NSCLC – Pemetrexed switch maintenance • Stage IIIB/IV NSCLC • PS 0-1 • 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD • Randomization factors: • gender • PS • stage • best tumor response to induction • non-platinum induction drug • brain mets Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)* 2:1 Randomization Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N=222)* *B12, FOLATE, AND DEXAMETHASONE GIVEN IN BOTH ARMS Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

  31. NSCLC – Pemetrexed switch maintenancePFS by histology Squamous Non-squamous HR=1.03 (95% CI: 0.77-1.5) p=0.896 HR=0.47 (95% CI: 0.37-0.6) p <0.00001 Pemetrexed: 4.4 mos Placebo: 2.5 mos Progression-free Probability Placebo: 1.8 mos Pemetrexed: 2.4 mos Time (months) Time (months) Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

  32. NSCLC – Pemetrexed switch maintenanceOS by histology Non-squamous Squamous HR=0.70 (95% CI: 0.56-0.88) p=0.002 HR=1.07 (95% CI: 0.49-0.73) p=0.678 Overall Survival Pemetrexed: 15.5 mos Placebo: 10.8 mos Pemetrexed: 9.9 mos Placebo: 10.3 mos Time (months) Time (months) Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

  33. NSCLC – Pemetrexed continuation maintenance Non PD PARAMOUNT Pemetrexed 3qw bis PD Stadium IV Non-squamous SD nach 4-6x Induktions-CT Cisplatin/Pemetrexed Randomisation 2:1 Placebo 3qw bis PD Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011

  34. NSCLC – Pemetrexed continuation maintenance Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011

  35. NSCLC – Pemetrexed continuation maintenanceProgression free survival Progression free Survival Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011

  36. NSCLC – Pemetrexed continuation maintenanceProgression free survival (subgroups) Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011

  37. NSCLC – Pemetrexed continuation maintenanceAdverse events Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011

  38. NSCLC-maintenance: ASCO 2011 Azzoli et al. J Clin Oncol 29, 3825-3831, 2011 For patients with SD or response after 4 cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with non-squamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered (alternative to second-line therapy!)

  39. NSCLC – Pemetrexed switch and continuation maintenance (registration) Pemetrexed Maintenance : as single agent following platinum based therapy (predominantly other than squamous cell histology; non-progression after four cycles of chemotherapy) EMA: 2009 / 2011

  40. Advanced NSCLC: Treatment algorithm in 2012 Non-Squamous Squamous Mutatedtumours Platinum-Doublets (Pem!) plus Bev or Cet Platinum-Doublets (No Pem, no Bev) plus Cet EGFR-TKI; ALK-Inhibitor 1st-line Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Switch: Erlotinib Maintenance in case of non-PD/SD Single agent Non-cross resistant Single agent Non-cross resistant 2nd-line Dealer’s choice Dealer’s choice 3rd-line Dealer’s choice Dealer’s choice

  41. Advanced NSCLC - Medical Treatment Standard Approach In caseof PD In case of PD 3rd-line 2nd-line 1st-line Combination CT or single agent defined number of cycles (4-6) single agent , Non-cross-resistant until progression single agent, Non-cross-resistant until progression Erlotinib Gefitinib Docetaxel Pemetrexed Erlotinib Gefitinib

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