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Role of Induction and Adjuvant Therapy in Regionally Advanced / Resectable NSCLC

Role of Induction and Adjuvant Therapy in Regionally Advanced / Resectable NSCLC. Rodney J. Landreneau M.D. Professor of Surgery Department of CardioThoracic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania. Stage IIIA Non Small Cell Lung Cancer.

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Role of Induction and Adjuvant Therapy in Regionally Advanced / Resectable NSCLC

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  1. Role of Induction and Adjuvant Therapy in Regionally Advanced / Resectable NSCLC Rodney J. Landreneau M.D. Professor of Surgery Department of CardioThoracic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

  2. Stage IIIA Non Small Cell Lung Cancer A “heterogeneous” anatomic stage classification with difficult to interpret responses to therapy

  3. Stage IIIa Non-Small Cell Lung Cancer Heterogeneity Microscopic mediastinal disease prognosis compared to macroscopic disease. Single station mediastinal node involvement compared to multiple station involvement Minimal clinical nodal involvement vs. Bulky mediastinal node involvement

  4. Stage IIIa – “Bulky”

  5. Stage IIIa – “Minimal Involvement”

  6. Single Station IIIa Disease

  7. Induction Chemo-radiotherapy for Stage III-a non-small cell lung cancer Standard of Care ???

  8. Intergroup Trial 0139Chemo-radiation vs Chemo-radiation followed by surgical resection of Stage IIIa NSCLC Kathy Albain et al. Lancet. 2009 Aug 1;374:379-86

  9. LUNG INTERGROUP TRIAL 0139 STUDY DESIGN IIIA(PN2) STRATIFY KPS 70-80 vs 90-100 T1 vs T2 vs T3 RANDOMIZE RE-EVALUATERE-EVALUATE 2-4 weeks after 7 days before completion of RT completion of RT Cisplatin, 50 mg/m2 IV d1, 8, 29, 36 Etoposide, 50 mg/m2 IV d1-5, 29-33 Thoracic RT, 45 Gy (1.8 Gy/d), begin d1 Induction CT/RT

  10. LUNG INTERGROUP TRIAL 0139 STUDY DESIGN No progression at re-evaluation Surgical Resection Continue RT to 61 Gy without interruption CONSOLIDATION cisplatin plus etoposide X 2 cycles

  11. INTERGROUP 0139/RTOG 9309PROGRESSION-FREE SURVIVAL BY TREATMENT ARMS 100 Failed/Total 75 CT/RT/S 159/202 CT/RT 172/194 / 50 % Alive without Progression / / / / / 25 / / / / / / / / / / / / / / / / Logrank p = 0.017 Hazard ratio = 0.77 (0.62, 0.96) / / / / 0 0 12 24 36 48 60 Months from Randomization

  12. Criteria for Patient Eligibility for O139 Trial? “Any mediastinal node positive status by any means? No systemic sampling/ recording” – Kathy Albain - personal communication

  13. Adjuvant Chemotherapy in NSCLC: A new standard of care?

  14. N Engl J Med 2004;350:351-60

  15. 4% New Engl J Med 2004;350:351-60

  16. Chemotherapy better NEJM 2004;350:351-60

  17. "Fading" Benefit ? IALT: 7.5-Year Median Follow-Up 100% chemotherapy: 578 deaths - 495 deaths before 5 years 80% - 83 deaths after 5 years 60% HR: 0.91 (0.81-1.02, P = 0.10) 40% control 590 deaths - 534 deaths before 5 years 20% - 56 deaths after 5 years 0% 0 1 2 3 4 years 5 6 7 8 775 520 125 935 447 372 282 208 619 399 300 932 650 550 208 133 780 487 Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.

  18. ASCO 2004 CALGB 9633 NCIC BR 10 Chemotherapy Chemotherapy Observation Observation 69% 54% 71% 59% HR 0.7 p=0.012 HR 0.62 p=0.028 YRS 5yrs 4yrs

  19. ASCO 2006 (137/155 of Total Events) ABSTR #7007CALGB 9633 - OVERALL SURVIVAL 1.0 Observation Chemo 0.8 0.6 Probability 0.4 0.2 0.0 0 0 1 2 2 3 4 4 5 6 6 7 8 8 9 SurvivalTime (Years)

  20. ASCO 2005 ANITA : OS OBS. NVB + CDDP Median months 43.8 65.8 1.00 P-value 0.013 Hazard Ratio 0.79 [0.66 - 0.95] 0.75 0.50 Survival Distribution Function Obs 0.25 NVB + CDDP 0 0 20 40 60 80 100 120 months

  21. Review of Adjuvant Chemotherapy

  22. Adjuvant Platinum-Based Chemotherapy Negative trial result *Failed to complete goal enrollment. Positive trial result Initial positive result, later follow-up negative

  23. Perception or Reality???

  24. Adjuvant Chemotherapy for NSCLCLung Adjuvant Cisplatin Evaluation (LACE) Meta-analysis of adjuvant cisplatin trials performed since 1995 BLT, ALPI, IALT, JBR.10, ANITA Pooled individual patient data 4584 resected patients, 5 randomized trials – 7% Stage IA – 30% Stage IB – 36% Stage II – 27% Stage III Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.

  25. Adjuvant Chemotherapy for NSCLCLACE: Overall Survival No Deaths Hazard Ratio / No Entered Entered Trial Trial HR [95% CI] (95% CI) (Chemotherapy / Control) ALPI 569 / 1088 569 / 1088 0.95 0.95 [0.81;1.12] [0.81;1.12] ANITA 458 / 840 458 / 840 0.82 0.82 [0.68;0.98] [0.68;0.98] BLT 186 / 307 0.95 [0.71;1.27] IALT 980 / 1867 980 / 1867 0.91 0.91 [0.80;1.04] JBR10 197 / 482 197 / 482 0.71 0.71 [0.54;0.94] [0.54;0.94] Total Total 2390 / 4584 0.89 0.89 [0.82;0.96] (0.82;0.96] 0.0 0.0 0.5 0.5 1.0 1.0 1.5 1.5 2.0 2.0 | Chemotherapy better Control better Chemotherapy effect P = 0.005 Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.

  26. Adjuvant Chemotherapy for NSCLCLACE: Pooled Data Overall Survival 5.4% survival advantage at 5 years HR = 0.89 95% CI 0.82-0.96 P = 0.005 Chemotherapy 100 100 No chemotherapy 80 80 61.0 61.0 60 60 Survival (%) Survival (%) 48.8 48.8 57.1 57.1 40 40 43.5 43.5 20 20 0 0 0 0 1 1 2 2 3 3 4 4 5 5 ≥ 6 Time from Randomization (Years) Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.

  27. Adjuvant Chemotherapy for NSCLCLACE Analysis by Stage Adjuvant chemo has greatest benefit for stage II and III and may be detrimental for stage IA No No. Deaths Deaths Hazard Hazard Ratio Category Category HR HR [95% CI] [95% CI] (Chemotherapy / Control) (Chemotherapy / Control) / No. / No Entered Entered 104 / 347 Stage IA Stage IA 1.41 1.41 [0.96;2.09] [0.96;2.09] Stage IB Stage IB 515 / 1371 0.92 0.92 [0.78;1.10] [0.78;1.10] Stage II Stage II 893 / 1616 0.83 0.83 [0.73;0.95] [0.73;0.95] Stage III Stage III 878 / 1247 0.83 0.83 [0.73;0.95] [0.73;0.95] 0.5 0.5 1.0 1.0 1.5 1.5 2.0 2.0 2.5 2.5 Chemotherapy better Control better Test for trend: P = 0.051 Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.

  28. Adjuvant Chemo for Stage IB – III NSCLCAbsolute Benefit in 5-Year Survival Alive due to surgery Alive due to chemo Die despite chemo Stage IB Stage II Stage III Based on HR from LACE meta-analysis and 5YS from ANITA trial Chemotherapy = 4 months of cisplatin + vinorelbine Pignon JP et al. J Clin Oncol. 2006;24(18S). Abstract 7008; Douillard JY et al. Lancet Oncol. 2006:7;719-727.

  29. “NATCH” Trial

  30. Induction Chemotherapy for NSCLCOngoing Trial “(Neo)adjuvant TaxolCarboplatin Hope” (NATCH) Stages I and II (T3N1) NSCLC Goal = 600 patients Accrual complete - 624 Randomize Surgery - 212 Surgery - 211 Carboplatin/ Paclitaxel x 3 - 201(93%) Carboplatin/ Paclitaxel x 3 (65%) Surgery Rosell R, et al. Lung Cancer. 2001;34(suppl 3):S63-S74.

  31. “No” Differences 5 yr Disease Free Survival Surgery – 39% Induction/Surgery – 41% Surgery/ Adjuvant – 39% Felip E., et al. - ASC0 (abst #7500) -2009

  32. Adjuvant Chemotherapy in NSCLC: A new standard of care?

  33. Breaking the Sound Barrier

  34. Adjuvant ChemotherapyStandard of Care Good performance status patients with “R0” Anatomic Resection • Stages IIA-B • IIIA NSCLC • Maybe Larger IB???

  35. Future Directions Assay directed? Empiric therapy STD Patients with micrometastisis Responders to Chemotx

  36. ? Study Concept ? “Single Station IIIa NSCLC”

  37. Is There a Role for Surgery for N2 NSCLC?

  38. “Surprise” N2 Disease

  39. Specific Clinical Frequency of “Single Station” IIIa NSCLC Historically – 33% to 50% of patients in “IIIa” surgical series Mithos P - Ann Thor Surg 2008 Rae F – Lung Cancer 2004 Kang HC – Ann Thor Surg 2008

  40. “Single Station” Stage IIIa Proposal Randomized trial: Induction Chemotherapy followed by anatomic resection “less than” pneumonectomy compared toanatomic resection “less than” pneumonectomy with Adjuvant Chemotherapy [mediastinal staging accuracy evaluation]

  41. Small T1 Right Upper Lobe Cancer

  42. Small T1 Right Upper Lobe Cancer- Paratracheal Nodes Clinical Negative

  43. Small T1 Right Upper Lobe Cancer- PET Positive Single Station Paratracheal Nodes

  44. Phase III Randomized Study Design R A N D O M I Z E SINGLE STATION N2 Platinum based Chemotherapy x3 cycles SURGERY Platinum based chemotherapy x3 cycles SURGERY • Clinical Stage T1-3, N2 Single Station • Staging Procedures: Mediastinoscopy, EBUS, EUS, PET

  45. Surgical Management Single Station IIIa Proposal • RO anatomic resection (segmentectomy or lobectomy) • Mediastinal node dissection (including 4R, 10, 7 pockets on right and 5, 6, 10L, 7 on left) • Tissue acquisition for correlative studies

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