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

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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,

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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.

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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
f 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

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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.

0.0 0.2 0.4 0.6 0.8 1.0 Probability of OS No EGFR mutation EGFR mutation 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 No EGFR mutation: Median OS = 6.3yr (95%CI: 5.6 - 7.8) EGFR mutation: Median OS = 6.9yr (95%CI: 6.3 - NA) p (adj for stage) < 0.001

EGFR mut Prognostic in Resected NSCLC

HR= 0.51 (0.34 ‐ 0.76) p < 0.001

D’Angelo, J Thorac Oncol 7(12), 2012

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Months

||| | | |||| || || ||| ||||| ||| ||||| |||| |||| || | | | | |||| || || |||||| ||| || ||| ||||||| | | || | || | | | | || | | | | || | | || | | | | | | | | | | | | ||| | | | | |||| || | ||| || ||| | || | || || || | || ||| || | | | | | | ||

12 24 36 48 60 72 84 96 108 0.0 0.2 0.4 0.6 0.8 1.0 no g/e, n=202 g/e, n=56 adjusted HR: 0.48 (0.29, 0.80), p=0.005

Number at Risk no g/e g/e 159 74 94 58 46 39 22 18 14 8 11 2 6 4 1 no g/e g/e 159 74 94 58 46 39 22 18 14 8 11 2 6

Months

||| | | |||||| | || ||| || ||||| ||| |||| || || || ||| ||| ||| || ||| || ||| ||| || |||| ||| |||||| ||| | ||| ||| ||| || ||||| || || | ||| | | | | | ||||| || | | || | | || | || | || | | | | | | | | | | || | | | | | | | || | ||| || | || |||| || | ||| || ||| | || | || || ||| | || ||| || | | | | | | || | | | | || | ||

12 24 36 48 60 72 84 96 108 0.0 0.2 0.4 0.6 0.8 1.0 no g/e, n=202 g/e, n=56 Adjusted HR: 0.56 (0.27, 1.17), p=0.123

Number at Risk no g/e g/e 163 79 117 65 64 46 44 28 30 12 19 6 9 6 1 no g/e g/e 163 79 117 65 64 46 44 28 30 12 19 6 9

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

No TKI TKI No TKI TKI

D’Angelo, J Thorac Oncol 7(12), 2012

DISEASE FREE SURVIVAL OVERALL SURVIVAL

EGFR mut Predicts Benefit from Adjuvant TKI in Resected NSCLC

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

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Abst 7514: SELECT

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RADIANT Study

Stage IB‐IIIA NSCLC Surgery +/‐ Adj CTx Erlotinib Placebo

Kelly et al, ASCO 2014

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Presented By Karen Kelly at 2014 ASCO Annual Meeting

Prognostic (Point Estimate Death) Predictive (Point Estimate Death) Prospective 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 ? ‐‐

Molecular Prognostic/Predictive Factors for Adjuvant Therapy

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GIST tumors and adjuvant imatinib

Dematteo R et al. Lancet 2009; 373: 1097–104

Recurrence free survival

HR 0.35 (95% CI 0.22‐0.53), p<0.0001 No difference in overall survival

GIST tumors and duration adjuvant imatinib

Joensuu, JAMA. 2012 Mar 28;307(12):1265‐72.

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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

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