Systemic therapy in early stage NSCLC Christian Manegold, MD Professor of Medicine, Heidelberg University Interdisciplinary Thoracic Oncology Department of Surgery University Medical Center Mannheim, Germany 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 1
Chemotherapy in early stage NSCLC Stage I III operable Chemotherapy adjuvant / postoperative Stage I-III III inoperable ChemoRadiotherapy sequential Chemotherapy neoadjuvant/ preoperative ChemoRadiotherapy concomitant Expected outcome following surgical resection in operable NSCLC Pisters and Le Chevallier, J Clin Oncol 23, 3270-3278, 2005 2
Neo-adjuvant chemotherapy Adjuvant chemotherapy ESMO - clinical practice guidelines Neo-adjuvant cisplatin-based chemotherapy is recommended in stage IIIA/N2 - radically resected NSCLC Crino et al. Ann Oncol 21 (Suppl 5), 103-115, 2010 3
Early NSCLC: advantages of neoadjuvant chemotherapy Early treatment t t of distant t micrometatstases t t Local-regional cytoreduction preoperatively Better patient acceptance Better tolerability and dose delivery Pisters et al. J Thor Cardiovasc Surg 119, 429,2000 Early NSCLC neoadjuvant chemotherapy (phase II) EORTC 08955 1 EORTC 08958 2 EORTC 08984 3 SAKK 4 Tampa 5 Cis Carbo / Cis / Cis / Pemetrexed/ /Gemcitabine Paclitaxel Docetaxel Docetaxel Gemcitabine Pts 47 40 40 90 45 CR 6.3% - 2.5% 8% 2% PR 63.8% 59% 42.5% 58% 31% SD 6.3% 18% 35% 25% 56% PD 4.2% 23% 2.5% 9% 7% 1 van Zandwijk et al J Clin Oncol 18,2658-2664, 2000; 2 O Brien et al Proc ASCO 18 (Abstr. 1898), 1999; 3 Betticher et al J Clin Oncol 21, 1752-59, 2003; 4 Bisma et al EJC 42, 1399-1406,2006; 5 Bepler et al J Clin Oncol 24, (18S), 396 (Abstr. 7129), 2006 4
NSCLC - neoadjuvant chemotherapy: metaanalysis surgery/ct vs. surgery alone Gilligan et al. Lancet 369: 1929-1937, 2007 Burdett et al. J Thorac Oncol 1: 611-621, 2006 Chemotherapy benefit in early NSCLC Neoadjuvant chemotherapy: HR 0.88 (95%CI: 0.76-1.01) corresponding with an absolute survival benefit of 5.4 % at 5 years Gilligan et al. Lancet 369: 1929-1937, 2007 5
Neo-adjuvant chemotherapy Adjuvant chemotherapy ESMO - clinical practice guidelines Adjuvant chemotherapy is recommended in stage II - III radically resected NSCLC Crino et al. Ann Oncol 21 (Suppl 5), 103-115, 2010 6
NSCLC- adjuvant chemotherapy: summary of recent trials N HR (95%CI) Stage Year BMJ meta 1394 0.87 (0.74-1.02) I-III 1995 IALT 1867 0.86 (0.76-0.98) I-III 2004 ALPI 1209 0.94 (0.79-1.12) I-IIIA 2003 ECOG3590 488 0.93 (0.74-1.18) II-IIIA 2000 BLT 381 1.02 (0.77-1.35) I-III 2004 BR.10 482 0.70 (0.62-0.92) II 2005 ANITA 840 0.79 (0.66-0.95) IB-IIIA 2006 BMJ meta update 8147 0.86 (0.81-0.93) I-III 2007 French meta 2660 0.89 (0.81-0.97) I-IIIA 2007 CALGB9633 344 0.83 (0.64-1.08) IB 2008 LACE meta 4584 0.89 (0.82-0.96) IA-IIIB 2008 Early NSCLC adjuvant chemotherapy (LACE- metaanalysis): effect on OS and DFS HR: 0.89; 95% CI: HR: 0.84; 95% CI: 0.82-0.96; 0.96; p=.005 0.78-0.91; 0.91; p<.001 11% reduction in risk of death; absolute benefit of 5.4% at 5 years 16% reduction in risk of disease progression; absolute benefit of 5.8% at 5 years Pignon et al J Clin Oncol 26: 3552-3559, 2008 7
NSCLC adjuvant chemotherapy: metaanalyses Adding CT to surgery: absolute survival increase of 4% at 5 years Adding CT to surgery/rt: absolute survival increase of 4% at 5 years NSCLC-metaanalysis collaborative group: Lancet 375, 1267-1277, 2010 Early NSCLC - adjuvant chemotherapy: LACE-metaanalysis Efficacy by stage OS Pts. HR [95% CI] Stage IA 347 1.40 [0.95;2.06] Stage IB 1371 0.92 [0.78;1.10] Stage II 1616 0.83 [0.73;0.95] Stage III 1247 0.83 [0.73;0.95] Pignon et al J Clin Oncol 26, 3552-3559, 2008 8
Elderly patients and adjuvant chemotherapy NSCLC adjuvant chemotherapy in the elderly: SEER database/ Ontario cancer registry Platinum-based chemotherapy improves survival (with or without t RT) Chemotherapy did not improve survival in pts. 80 years Tolerability appeared similar between pts. <70 years versus 70 years Chemotherapy was associated with increased SAE Wisnivesky et al, BMJ 14; 343: d4013. doi: 10.1136/bmj.d4013, 2011 Cuffe et al. J Clin Oncol 30, 1813-1821, 2012 9
Type / duration of adjuvant chemotherapy NSCLC - adjuvant chemotherapy: type / duration in randomized clinical trials Study Pts. Type of CT Author (no. of cycles) ALPI 474 Cisplatin-based (3) Scagliotti (2003) BLT 192 Cisplatin-based (3) Waller (2003) IALT 932 Cisplatin-based (3/4) Olaussen (2004) CALGB 9623 124 Carboplatin/Tax (4) Strauss (2008) ANITA 367 Cisplatin/Vin (4) Douillard (2006) BR10 233 Cisplatin/Vin (4) Winton (2005) 10
Chemotherapy benefit in early NSCLC Adjuvant chemotherapy: HR 0.89 (95%CI: 0.82-0.96) corresponding with an absolute survival benefit of 5% at 5 years Pignon et al J Clin Oncol 26: 3552-3559, 2008 Compliance and adjuvant chemotherapy 11
NSCLC - adjuvant chemotherapy : compliance in randomized clinical trials Study Pts. Compliance Author ALPI 474 69% Scagliotti (2003) BLT 192 64% Waller (2003) IALT 932 74% Olaussen (2004) CALGB 9623 124 84% Strauss (2008) ANITA 367 50% Douillard (2006) BR10 233 50% Winton (2005) Adjuvant chemotherapy followed by adjuvant radiotherapy 12
Early NSCLC adjuvant CT / RT (ANITA): survival according to lymph node status Best survival in stage III/N2 for adjuvant CT followed by RT Douillard et al. Lancet Oncol 7: 719-727, 2006 NSCLC - adjuvant radiotherapy: Cancer Care Ontario/ASCO - Guidelines Pisters et al. J Clin Oncol 25:5506-5518, 2007 13
Pemetrexed and adjuvant chemotherapy NSCLC - adjuvant chemotherapy (TREAT - phase II): Cis/Pemetrexed vs. Cis/Vinorelbine Cis/Pemetrexed is similar effective Cis/Pemetrexed less toxic Cis/Pemetrexed with superior dose delivery Cis/Pemetrexed with higher dose density Kreuter et al. J Clin Oncol 29 (suppl 15), 453, (abstr 7002), 2011 14
NSCLC: adjuvant chemotherapy - Pemetrexed containing regimens/trials - Japan UMIN000006737 Phase III China NCT01533727 Phase II USA ECOG1505- NCT00324805 Phase III Carbo- Gem/Pac/Pem Platin- Pem/Vin Cis- Vin/Doc/Gem/Pem +/- Killer cells Dentritic cells +/- Killer cells (CIK) N=800 Stage II-IV resected N=222 Stage IB-IIIA +/- Bevacizumab N=1500 Stage IB-IIIA Pharmocogenomics and adjuvant chemotherapy 15
NSCLC (ITACA phase III): International Tailored (ERCC1/TS) adjuvant chemotherapy High Profile 4 Taxane PE: overall survival High TS Control* Pemetrexed completely resected stage II-IIIA ECOG 0/1 n=700 *Investigators choice of a platinum-based doublet ERCC1 Low Low Profile 3 High TS Low Profile 2 Profile 1 ERCC1: Excision repair cross complementing group 1 gene TS: Thymidilate Synthase Control* Cis/Gem Control* Cis/Pem Control* NSCLC - chemotherapy: potential predictive molecular markers for response Gene Abnormality Drug Response p53 Mutation Multiple K-ras Mutation Multiple tubulin Increased Isotype 3 Taxanes RRM 1 Increased Expression Gemcitabine ERCC 1 Increased Expression Platinum TS Increased Expression Antifolates EGFR Mutation EGFR-TKI BRCA 1 Increased Expression Anti - microtubulins BRCA 1 Increased Expression Platinum 16
NSCLC (TASTE trial): tailored (ERCC1, EGFR mut.) adjuvant Therapy TAilored Post-Surgical Therapy in Early Stage NSCLC Phase II/III Stage II-IIIA complete resection, EGFR mut ERCC1 Control arm EGFR WT EGFR mutant www.clinicaltrials.gov; NCT00775385 Cis/Pem ERCC1 high ERCC1 low Erlotinib No treatment Cis/Pem NSCLC (BR19): adjuvant therapy by Gefitinib - overall survival Overall population Sensitizing i mutation ti 100 80 Placebo Gefitinib Percentage 60 40 20 0 at Risk 0 Placebo 40 Gefitinib 36 1 38 29 2 32 26 3 4 Time (Years) 30 26 21 17 5 6 7 6 1 0 Goss et al. J Clin Oncol 28 (suppl 15), 516 (abstr 7005), 2011 17
NSCLC (SELECT): tailored (EGFR mut.) adjuvant therapy by Erlotinib Phase II Stadium II-IIIA nach kompletter Resektion EGFR- Mutation + Erlotinib 150 mg/d 2 Jahre N=36: 2-years DFS 94% (95% CI, 80%-99%) Expansion to 100 pts. to permit analysis by stage Pennell et al. J Clin Oncol 29 (Suppl, Abstr. TPS209) 2011 Neal et al. J Clin Oncol 30 (Suppl, Abstr. 7010) 2012 NSCLC (WJOG6410L): tailored (EGFR mut.) adjuvant therapy - Gefitinib vs. CT WJOG 6410L, Impact study 18
NSCLC (SWOG 0720): tailored (ERCC1, RRM1) adjuvant Chemotherapy Phase II Stage IA- IB complete resection, RRM1 ERCC1 ERCC1 > 65 RRM1 > 40 ERCC1 < 65 RRM1 < 40 No treatment Cis/Gem www.clinicaltrials.gov; NCT00792701 NSCLC (SCAT): tailored (BRCA1) adjuvant chemotherapy Spanish customized adjuvant treatment according BRCA1 Phase III Stage II-IIIA complete resection mrna BRCA1 level High level Taxane No Platinum Low level Platinum based CT Massuti J Clin Oncol 29 (Suppl, Abstr. TPS208) 2011 Trials in progress Poster 19
Systemic therapy in early stage NSCLC Adjuvant chemotherapy is recommended in stage II - III radically resected NSCLC Cisplatin-based chemotherapy improves OS and DFS Benefit is greatest in stage II and III, and in PS 0-1 There is no significant interaction between CT and type of surgery, histology, age, gender, or planned RT Current trials investigate the role of pharmacogenomics Neo-adjuvant cisplatin-based chemotherapy is recommended in stage IIIA/N2- radically resected NSCLC Benefit similar to adjuvant therapy 20