Adjuvant and Neoadjuvant Chemotherapy for NSCLC Gregory J. Riely October 14, 2012

1. Adjuvant and Neoadjuvant Chemotherapy for NSCLCGregory J. RielyOctober 14, 2012

2. Disclosures Consulting Chugai Ariad Tragara Daiichi Novartis Abbott Foundation Medicine Celgene Research Funding Novartis Chugai Glaxo SmithKline BMS Infinity Pfizer Merck

3. Cancer in the United States, 2012 Siegel, R. Cancer Statistics, 2012; Cancer 2012: 62:10-29

4. Stage at Diagnosis: Women Percent (%) Siegel, R. Cancer Statistics, 2012; Cancer 2012: 62:10-29

5. Enrollment: September, 2002 – February, 2004 Observation through 2009 Annual “low dose” CT N=50,000 Current, or formerheavy cigarette smoker (>1ppd x 30 years) If quit, <15 years agoAge 55-74 1 2 3 Stop Annual chest x-ray Primary endpoint: Mortality due to lung cancer

6. National Lung Screening Trial 24% CT scans “abnormal” (>4mm solid nodule or enlarged nodes) 7% of CXR were “abnormal” NLST, NEJM 2011

7. National Lung Screening Trial 24% CT scans “abnormal” (>4mm solid nodule or enlarged nodes) 7% of CXR were “abnormal” NLST, NEJM 2011

8. CT Screening for Lung Cancer NLST results announced by NCI, October, 2010 NLST results published in NEJM, June, 2011

9. Estimated American Smokers at Risk CDC sponsored National Health and Nutrition Examination Survey (NHANES) 9,762 Americans polled in 2007-08 Data Courtesy of Peter Bach

10. Cancer in the United States, 2012 Siegel, R. Cancer Statistics, 2012; Cancer 2012: 62:10-29

11. Lung Cancer Staging, AJCC 7th Edition Detterbeck F C et al. Chest 2009;136:260-271

12. Lung Cancer Staging, AJCC 7th Edition Detterbeck F C et al. Chest 2009;136:260-271

13. Lung Cancer Staging, AJCC 7th Edition Detterbeck F C et al. Chest 2009;136:260-271

14. Lung Cancer Staging, AJCC 7th Edition Detterbeck Chest 2009;136:260-271

15. Surgery for NSCLC Surgically resected patients, 1990 – 2000 No adjuvant chemotherapy 8988 / 15952 : TOTAL Overall Survival 3 7 9 5 1 Goldstraw, et al. J Thorac Oncol. 2007;2:706-714.

16. Adjuvant Chemotherapy for NSCLCIALT: Cisplatin + a Vinca or Etoposide 100% Surgery + chemo Surgery 80% N = 1867 60% Proportion Surviving 40% HR = 0.86; 95% CI 0.76 – 0.98; P < 0.03 20% 0% 3 5 4 0 1 2 Years Arriagada R et al. N Engl J Med. 2004;350:351-360.

17. IALT Longer Follow-up P=0.10 Arriagada R et al. JCO 2010;28:35-42

18. JBR.10: IB – II only, “split-dose” Cisplatin ____ Adjuvant Vin / Cis ____ Observation N = 482 Proportion Surviving Median survival Vin / Cis 94 months vs observation 73 months HR = 0.69; 95% CI 0.52 – 0.91; P = 0.04 Years Winton T et al. N Engl J Med. 2005;352:2589-2597.

19. JBR.10: Longer Follow-up Butts C A et al. JCO 2010;28:29-34

20. JBR.10: Longer Follow-up Butts C A et al. JCO 2010;28:29-34

21. JBR.10: “Elderly” patients ≤ 65 years, n = 327 > 65 years, n = 155 Despite 20% lower chemotherapy dose delivery, the older group experienced similar benefit Pepe C et al. J Clin Oncol. 2007;25:1553-1561

22. 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 • 4585 resected patients, 5 randomized trials • 38% Stage I • 35% Stage II • 27% Stage III Pignon JP et al. J Clin Oncol 2008 Jul 20;26(21):3552-9

23. Adjuvant Chemotherapy for NSCLCLACE: Pooled Data Overall Survival 5.3% survival benefit at 5 years HR = 0.89, 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 Jul 20;26(21):3552-9

24. Benefit of Adjuvant Cisplatin+Vinorelbine LACE, N=4584 Pignon , JCO 2008;26 Death by year 5 Saved by Chemo Alive at year 5 HR 0.92 5Y risk 36% N=1371 HR 0.83 5Y risk 61% N=1616 HR 0.83 5Y risk 74% N=1247

25. Benefit of Adjuvant Cisplatin+Vinorelbine LACE, N=4584 Pignon , JCO 2008;26 Number Needed to Treat 1 / absolute risk reduction HR 0.92 5Y risk 36% 1 / 3% = 33patients Stage IB N=1371 1 / 10% = 10patients HR 0.83 5Y risk 61% Stage II N=1616 1 / 13% = 8patients HR 0.83 5Y risk 74% Stage III N=1247

26. The Stage “IB” Dilemma: CALGB 9633 Stage IB TUMORS TUMORS > 4cm Strauss G M et al. JCO 2008;26:5043-5051

27. The Stage “IB” Dilemma: JBR.10 Butts C A et al. JCO 2010;28:29-34

28. The Stage IB Dilemma: 7th-Edition TNM Staging July, 2009 IIA Node-negative tumors >5cm are now stage II

29. LACE-Bio evaluation of KRAS as a prognostic Shepherd et al ASCO 2012

30. Pronostic Value of KRAS Mutation on OS and DFS (BothArmsCombined) Overall Survival Disease-Free Survival Logrank p=0.82 Logrank p=0.44 KRAS wild-typeKRAS mutated KRAS wild-typeKRAS mutated Shepherd et al ASCO 2012

31. Different ways to treat "resectable" Stage IIIA (N2)

32. Resectable IIIA(N2): role of surgeryINT 0139 NSCLC Stage IIIA (pN2) R A N D O M I Z E Complete Resection n = 202 Same chemo x 2 cycles Cisplatin 50 mg/m2 days 1, 8, 29, 36 Etoposide 50 mg/m2 days 1-5 & 29-33 Induction RT 45 Gy Continue RT to 61 Gy n = 194 Same chemo x 2 cycles If no progression and remained medically healthy Albain KS, et al. Lancet. 2009;374:379-386.

33. Resectable IIIA(N2): role of surgeryINT 0139 CT / RT / S CT / RT HR 0.87 P = 0.24 CT / RT / S CT / RT HR 0.77 P = 0.017 Overall Survival Progression-Free Survival 27% surgical mortality in patients undergoing pneumonectomy Albain KS, et al. Lancet. 2009;374:379-386.

34. Resectable IIIA(N2): role of surgery?INT 0139 Subset analysis matched by clinical prognostic variables (T stage, gender, KPS) LOBECTOMY GOOD PNEUMONECTOMY BAD Albain KS, et al. Lancet. 2009;374:379-386.

35. Stage IIIA-IIIB: Does XRT improve surgery? NSCLC Stage IIIA - IIIB, n=558 R A N D O M I Z E Cisplatin + Etoposide x 3 Carbo + Vindesine + XRT (bid) XRT if Unresectable or Positive Margin Surgery Cisplatin + Etoposide x 3 • Rates of surgery 54% in pre-op XRT, 59% in pre-op chemo • Of resected, complete resection 37% pre-op XRT, 32% in pre-op chemo • Rates of pneumonectomy were the same in both groups (35%), but mortality was higher in patients who received pre-op XRT (14% vs. 6%) Thomas M, et al. Lancet Oncology. 2008; 9:636-648.

36. Stage IIIA-IIIB: Does XRT improve surgery? OVERALL SURVIVAL PROGRESSION-FREE SURVIVAL COMPLETE RESECTION IS GOOD Thomas M, et al. Lancet Oncology. 2008; 9:636-648.

37. Different ways to treat "resectable" Stage IIIA (N2)

38. Induction Chemotherapy for NSCLCMeta-analysis Dautzenberg Roth Rosell Depierre JCOG 9209 Sorenson SWOG 9900 Overall HR = 0.82 (95% CI 0.69 – 0.97) • Burdett S et al. J Thorac Oncol. 2006;1:611-621.

39. Significant Controversy Martins et al JNCCN 2012

40. Perioperative Chemotherapy for NSCLCConclusions • Adjuvant cisplatin chemotherapy improves survival in patients with resected stage II-III NSCLC • Matters of debate • Adjuvant vs. Neoadjuvant ? • Benefit in IB patients ? • Little data for patients > 75 years of age • Which agents work best ? • Molecular markers for selection of therapy ?

41. Adjuvant Chemotherapy for NSCLCConclusions • Adjuvant cisplatin chemotherapy improves survival in patients with resected stage II-III NSCLC • Matters of debate • Adjuvant vs. Neoadjuvant ? • Benefit in IB patients ? • Little data for patients > 75 years of age • Which agents work best ? Where do we go from here?

42. Addition of Bevacizumab Improves Overall Survival in Metastatic NSCLC Paclitaxel carboplatin bevacizumab ----Paclitaxel carboplatin P = 0.003 Medians: 10.3, 12.3 months Sandler et al NEJM 2004

43. E1505: Phase 3 Adjuvant Chemotherapy  Bevacizumab • Resected IB (>4cm) – IIIA • Adequate MLND sampling • All pts: level 7 • Left: level 5 or 6 • Right: level 4 RANDOM I ZE Chemotherapy* x 4 cycles Chemotherapy* x 4 cycles + bevacizumab x 1 year N = 1500 • Cisplatin and vinorelbine • Cisplatin and docetaxel • Cisplatin and gemcitabine • Cisplatin and pemetrexed Primary endpoint: overall survival Results anticipated in 2016.

44. Lung Adenocarcinomas 35% Unknown 2012

45. EGFR TKIs are better than Cisplatin doubletin patients with EGFR mutations Maemondo et al NEJM 2010, Rosell et al Lancet Oncol 2012

46. EGFR mutation is Prognostic in ResectedNSCLC HR= 0.51 (0.34 - 0.76) p < 0.001 D’Angelo, J Clin Oncol 28:15s, 2010 (suppl; abstr 7011)

47. MSKCC Retrospective Data:Adjuvant EGFR TKI for Resected NSCLC with EGFR mutation DISEASE FREE SURVIVAL OVERALL SURVIVAL No TKI TKI Adjusted HR: 0.48 (0.29-0.80), p=.005 No TKI TKI Adjusted HR: 0.56 (0.27-1.17), p=.123 Janjigian, J Thorac Oncol. 2011 Mar;6(3):569-75; update July, 2011

48. RADIANT trial Placebo x 2 years 1 Resected stage I-IIIA NSCLC -EGFR IHC (+) or FISH (+)* -n=945 2 Erlotinib x 2 years 1° endpoint: Disease-Free Survival * EGFR and KRAS mutations will be assessed in retrospect clinicaltrials.gov NCT 00373425

49. NCI Personalized Adjuvant Trial, “PAT” Resected NSCLC Tested positive for EGFR activating / sensitizing mutation N=400 RANDOM I ZE Erlotinib for 2 years Placebo for 2 years

50. Perioperative Chemotherapy for NSCLC • CT screening will increase the incidence of early-stage NSCLC • For stage I-III NSCLC, pre-op staging is fundamental for assignment of neoadjuvant vs. adjuvant chemotherapy • Trials underway which require post-op molecular testing • Molecular markers which are both prognostic of survival, and predictive of benefit from chemotherapy, are still lacking for the majority of patients (smokers!)