This document summarizes evidence for adjuvant and neoadjuvant chemotherapy in non-small cell lung cancer (NSCLC). Meta-analyses show adjuvant cisplatin-based chemotherapy improves 5-year survival by 4-5% after surgery for stages II-III NSCLC. Individual trials also found benefits, though some only for certain stages. Neoadjuvant chemotherapy may improve survival by 5% at 5 years for resectable stage IIIA NSCLC. Ongoing trials aim to personalize chemotherapy based on biomarkers and add targeted therapies.

1. Adjuvant / Neo-adjuvant Systemic Therapy of NSCLC Tanja Cufer, MD, PhD University Clinic Golnik Medical Faculty Ljubljana, Slovenia ESO Masterclass, Dubrovnik 2011

2. Does Chemo Work for Stage IV NSCLC? Yr Median Survival, Mos 1-Yr Survival, % 2-Yr Survival, % 1980s 4-6 10 -- 2000 8 30-35 10-15 2005 (adeno, no brain mets) 12 50 20

3. What After Radical Loco-regional Therapy in Operable NSCLC ?

4. Meta-Analysis on the Role of Chemotherapy in NSCLC Absolute benefit with cisplatin containing regimens Non-Small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899 . S ± CT S + RT ± CT 2 years 3% 2% 5 years 5% 2%

5. Are the Results Consistent ? Trial N HR (95% CI) P 5-Year Benefit IALT 1867 0.86 (0.76 – 0.98) .03 4% ALPI 1076 0.94 (0.79 – 1.12) .6 3% NCI-C 482 0.69 (0.52 – 0.91) .03 15% CALGB 344 0.80 (0.60 – 1.07) .10 3% ANITA 01 840 0.79 (0.66 – 0.95) .017 8% UFT overview 2003 0.77 (0.63 – 0.94) .001 5%

6. Lung Adjuvant Cisplatin Evaluation (LACE): a Pooled Analysis of 5 Randomized Trials Pignon JP, et al. J Clin Oncol, 2008;26:3552. Absolute benefit of 5.4% at 5 years Absolute benefit of 5.8% at 5 years

8. LACE: Stage and OS

9. LACE: Combined Drugs and OS

12. Overall Survival (S +/- Ct) Patients at Risk Surg alone Surg+chemo 4068 3585 3043 2539 2034 1548 779 358 103 4079 3607 3074 2584 2137 1665 835 389 108 % Survival 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Survival Time, years 0 1 2 3 4 5 6 7 8 HR: 0.87 (0.81-0.93), P <.0000001 Absolute benefit at 5 years 4%, from 60% to 64% Surg alone Surg + chemo

13. Survival by Stage Exploratory analysis STAGE I 717/2659 881/2694 II 311/652 353/654 IIIA 428/710 398/652 IIIB / IV 21/39 25/50 [no. events/no. entered ] Surg+chemo Surg alone Hazard Ratio (Fixed) Analysis prespecified in protocol When 89 IIIb/IV patients removed, trend p=0.178 Trend P = .05 Trend P = .208 STAGE IA 185/1028 228/982 IB 450/1308 519/1353 IIA 59/136 62/119 IIB 290/573 337/613 IIIA 239/394 218/341 IIIB / IV 15/28 23/40 Surg+chemo Better Surg alone Better 0 1 2 0.5 1.5

14. Overall Survival (S + Rt +/- Ct) Patients at risk CT 1315 711 385 203 84 Control 1345 660 376 202 85 % Survival Survival Time, years HR = 0.89 (95%CI: 0.81-0.97), P = .009 0.0 0.2 0.4 0.6 0.8 1.0 0 2 4 6 8 CT Control Absolute benefit at 5 yrs 4% , from 29% to 33%

16. R Chemotherapy Control  Thoracic Radiotherapy  60 Gy (optional, predefined according to N stage) Stratified by center, stage and type of surgery Long-Term Results of the International Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected NSCLC IALT Trial Design

17. Overall Survival 935 775 619 520 447 372 282 208 125 932 780 650 550 487 399 300 208 133 0% 20% 40% 60% 80% 100% 0 1 2 3 4 5 6 7 8 years Chemotherapy: 578 deaths - 495 deaths before 5 years - 83 deaths after 5 years Control 590 deaths - 534 deaths before 5 years - 56 deaths after 5 years HR = 0.91 [0.81-1.02] P = .10 Le Chevalier T, et al. J Clin Oncol . 2008;26(May 20 Suppl): Abstract 7507.

18. IALT: Causes of Mortality Arrigada et al, et al. J Clin Oncol . 2010;28

19. JBR.10 Design R Platinum / vinorelbin Control No Thoracic Radiotherapy RESECTED NSCLC Stratified by center, stage and type of surgery Butts CA, et al. J Clin Oncol . 2010, vol 28 Long-Term Results of the JBR.10 Trial Evaluating Adjuvant Chemotherapy with Cisplatin / Vinorelbin

20. Long-term OS JBR.10

22. J BR.10: Causes of Mortality Butts CA, et al. J Clin Oncol . 2010, vol 28

23. Meta-analysis of Neoadjuvant Chemotherapy in Resectable NSCLC Crino et al, Ann Oncol 2010; 21:103 Twelve per cent relative survival benefit with the addition of neoadjuvant chemotherapy (1507 patients; HR = 0.88; P = 0.07), equivalent to an absolute improvement in survival of 5% at 5 years.

26. Randomized Trials on “Adding Surgery to Induction Therapy” in Functionally Operable Stage IIIA No statistical difference in survival 1. Albain KS, et al. J Clin Oncol. 2005;23(16S): Abstract 7014. 2. van Meerbeeck JP, et al. J Natl Cancer Inst. 2007;99 (6):442-450. 3. Improved local control with surgery, and improved survival in patients opted for lobectomy ! Trial Treatment Patients Median Survival, Months 5-Yr Survival % Intergroup 1 R+C S C R+C C 202 194 23.6 22.2 27.2 20.3 EORTC 2 C Resp R S 165 167 17.5 16.4 14 15.7

29. ERCC1 negative Adjusted HR = 0.65, 95%CI [0.50-0.86], P = .002 Effect of Adjuvant Chemotherapy According to ERCC1 Status , IALT Bio ERCC1 positive Adjusted HR = 1.14, 95%CI [0.84-1.55], P = .40 Olaussen K, et al. N Engl J Med. 2006;355(10):983-991 .