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Adjuvant TKI Therapy for Driver Mutations in Early Stage NSCLC Suresh - PDF document

Adjuvant TKI Therapy for Driver Mutations in Early Stage NSCLC Suresh S. Ramalingam, MD Professor Director, Division of Medical Oncology Emory University Winship Cancer Institute Disclosures Advisory board Amgen, Aveo, Ariad, Astra Zeneca,


  1. Adjuvant TKI Therapy for Driver Mutations in Early Stage NSCLC Suresh S. Ramalingam, MD Professor Director, Division of Medical Oncology Emory University Winship Cancer Institute Disclosures • Advisory board – Amgen, Aveo, Ariad, Astra Zeneca, Biodesix, Boehringer Ingelheim, Celgene, Lilly, Gilead, Genentech, Novartis. 1

  2. Early Stage NSCLC • The goal of treatment is to cure patients • Surgery provides excellent local control • Adjuvant chemotherapy provides modest improvement in cure rate • Despite the use of adjuvant therapy, majority of patients with stage II and III NSCLC will still experience recurrent disease Chemotherapy Works Better in Early Stage NSCLC • HR for Cisplatin ‐ based chemotherapy in advanced NSCLC is 0.86 (compared to BSC) • HR for cisplatin ‐ based adjuvant chemotherapy is 0.69 – Winton et al, NEJM, 2005 • Most likely related to lower tumor burden 2

  3. How Much Does Chemotherapy Contribute to Cure in Early Stage NSCLC? • Stage IB ‐ 3% • Stage II ‐ 10% • Stage III ‐ 13% LACE Meta ‐ analysis, Pignon et al, JCO. EGFR mut Prognostic in Resected NSCLC 1.0 0.8 Probability of OS 0.6 0.4 No EGFR mutation: Median OS = 6.3yr (95%CI: 5.6 - 7.8) EGFR mutation: Median OS = 6.9yr (95%CI: 6.3 - NA) 0.2 p (adj for stage) < 0.001 HR= 0.51 (0.34 ‐ 0.76) No EGFR mutation p < 0.001 0.0 EGFR mutation 0 1 2 3 4 5 6 7 8 Years After Surgery No. At Risk No EGFR mutation 896 778 517 293 160 104 65 26 10 EGFR mutation 222 204 133 91 55 33 18 7 4 D’Angelo, J Thorac Oncol 7(12), 2012 3

  4. EGFR mut Predicts Benefit from Adjuvant TKI in Resected NSCLC DISEASE FREE SURVIVAL OVERALL SURVIVAL 1.0 1.0 ||| ||| | | | | || | | | |||||| ||| || | || |||| || | ||| || | || ||| | | || ||||| ||| | | |||| || || ||| |||| || || || ||| ||| ||| || ||| || ||||| ||| ||| ||| ||| | ||||| | |||| ||| || || | || || ||| | || ||| |||||| | | ||| | ||| ||| |||| |||| || | ||| | | | | |||| || | ||| || ||||| || 0.8 0.8 ||| || || || | ||| | | ||| | | || | || | | | | ||||| || | | | | | | | | | || | | | | || |||| || || || || |||||| || | | ||| | || || || ||| ||| ||||||| | | || 0.6 0.6 | || | | || | || | | | | | || | | | | || | | | | | | || | | | | | || | | 0.4 | | | || 0.4 | | | || | | | | | | | || 0.2 0.2 No TKI | No TKI no g/e, n=202 no g/e, n=202 TKI TKI g/e, n=56 g/e, n=56 adjusted HR: 0.48 (0.29, 0.80), p=0.005 Adjusted HR: 0.56 (0.27, 1.17), p=0.123 Adjusted HR: 0.48 (0.29 ‐ 0.80), p=.005 Adjusted HR: 0.56 (0.27 ‐ 1.17), p=.123 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Months Months Number at Risk Number at Risk No TKI No TKI no g/e no g/e 159 159 94 94 46 46 22 22 14 14 11 11 6 6 4 1 no g/e no g/e 163 163 117 117 64 64 44 44 30 30 19 19 9 9 6 1 TKI TKI g/e g/e 74 74 58 58 39 39 18 18 8 8 2 2 0 0 0 0 g/e g/e 79 79 65 65 46 46 28 28 12 12 6 6 0 0 0 0 D’Angelo, J Thorac Oncol 7(12), 2012 Adjuvant Erlotinib at MSKCC • Stage I ‐ III NSCLC • EGFR Mutation +ve • N=167 patients • 33% received an EGFR TKI peri ‐ operatively • 2 ‐ DFS was 89% with TKI compared to 72% without TKI Janjigian et al, J Thoracic Oncol, 2011 4

  5. Abst 7514: SELECT 5

  6. Slide 20 RADIANT Study Erlotinib Surgery Stage IB ‐ IIIA NSCLC +/ ‐ Adj CTx Placebo Kelly et al, ASCO 2014 6

  7. Slide 22 Presented By Karen Kelly at 2014 ASCO Annual Meeting Molecular Prognostic/Predictive Factors for Adjuvant Therapy Prognostic Predictive Prospective (Point Estimate Death) (Point Estimate Death) Validation “Occult” LN by CK IHC HR = 1.5 ? ‐‐ EGFR mutation HR = 0.5 * EGFR TKI HR = 0.5 * ‐‐ KRAS mutation ‐‐ ‐‐ ‐‐ ALK rearrangement ? in stage IV NSCLC ‐‐ ERCC1 IHC ? ? ‐‐ P27 IHC ? ? ‐‐ MSH2 IHC MSH2 high HR = 0.7 MSH2 low and cisplatin ‐‐ BAX IHC BAX high tend worse BAX high and cisplatin ‐‐ TUBB3 IHC High TUBB3 HR = 1.3 ‐‐ ‐‐ p53 ‐‐ p53+ IHC and cisplatin ‐‐ Gene sets by Affychip HR 2 ‐ 4 Canada, and Texas signature ‐‐ Gene sets by RT ‐ PCR HR 2 ‐ 4 Canada, and Texas signature ‐‐ Methylated genes HR 2 ‐ 4 ? ‐‐ 7

  8. GIST tumors and adjuvant imatinib Recurrence free survival HR 0.35 (95% CI 0.22 ‐ 0.53), p<0.0001 No difference in overall survival Dematteo R et al. Lancet 2009; 373: 1097–104 GIST tumors and duration adjuvant imatinib Joensuu, JAMA. 2012 Mar 28;307(12):1265 ‐ 72. 8

  9. Adjuvant Trastuzumab in Breast Cancer Gianni et al, Lancet Oncol, 2011 Conclusions • EGFR TKI as adjuvant therapy improved DFS in early stage NSCLC • Impact on survival is not known • Improved DFS has served as the basis for FDA approval of targeted agents in other diseases • The results of the the definitive randomized studies will not be available for another 8 years 9

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