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Strategies to overcome resistance in NSCLC with driver mutations Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy.

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Presentation on theme: "Strategies to overcome resistance in NSCLC with driver mutations Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy."— Presentation transcript:

1 Strategies to overcome resistance in NSCLC with driver mutations Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy

2 First-line therapy for metastatic NSCLC in 2012 Stratification for EGFR, ALK and histology EGFR mutatedEGFR WT non- squamous EGFR WT squamous EGFR-TKI Platinum + pemetrexed +/- bevacizumab Platinum- based doublet ALK+ Crizotinib

3 Mut+ NSCLC: EGFR-TKI Acquired Resistance Baseline Tumor regression (RR up to 90%) Progression (median 9 months) Disease Flare: Hospitalization and/or death attributable to disease progression after discontinuation of gefitinib or erlotinib and before initiation of study drug

4 Risk of disease flare in EGFR mut+ NSCLC with acquired resistance: Chaft J et al. (O 19.05) Characteristic: Total patients=61N (% or range) Male sex – N (%)13 (21) Age at diagnosis (years) Median (range)58 (26-78) EGFR mutation – N (%) Exon 19 deletion Exon 18 G719A Exon 21 L858R 41 (67) 1 (2) 19 (31) Time on gefitinib or erlotinib (months) Median (range)19 (7-78) Age in years - Median (Range)61 (27-80) Karnofsky Performance Status (%) 90% 80% 70% 13 (21) 37 (61) 11 (18) 14 of 61 patients (23%, 95% CI 14-35%) had a disease flare (hospitalization or death) – Flare & no flare group – same 30 day pretrial hospitalization rate Median time from last TKI to flare was 8 days (range 3-21 days) 3 patients went on to trial treatment

5 Changes in Tumor Diameter (RECIST) After Discontinuation and Re-introduction of EGFR TKI -30% 0% 20% 50% EGFR TKI stop re-start 3 weeks Change from baseline Riely et al, CCR 2007

6 Mechanisms responsible for EGFR-TKI resistance Sequist et al, Science Transl Med 2011

7 EGFR-TKI resistance A B

8 T790M Mutation causes drug resistance by increasing affinity for ATP Yun PNAS 2008

9 T790M mutations in EGFR-TKI naive NSCLC Present in up to 50% of NSCLC with EGFR-TKI acquired resistance Rare event in EGFR-TKI naive NSCLC (<3%) using low sensitive methods Detected in up to 40% of EGFR-TKI naive patients using high sensitive methods

10 Presence of T790M mutation predicts poor outcome to EGFR-TKI Su et al. JCO 2012; Rosell et al. Clin Cancer Res 2011;

11 T790M mutation and acquired resistance to gefitinib therapy Kobayashi et al. NEJM, 352, , 2005 Irreversible EGFR-TKI are still effective

12 Afatinib: Dual irreversible EGFR-HER2 inhibitor Orally bioavailable, small molecule tyrosine kinase inhibitor (TKI) Designed to irreversibly bind to the ATP binding pocket of EGFR and HER2 Highly specific for EGFR and HER2 EGFR IC 50 : 0.50 nM HER2 IC 50 : 14 nM EGFR or HER2 ATP binding pocket Afatinib +

13 Afatinib: active against resistance mutation BIBW2992 but not erlotinib is active against cells expressing T790M EGFR mutation: Li et al. Oncogene. 2008;27:4702–4711 NCI-H1975

14 Afatinib + cetuximab as the best option in presence of EGFR T790M mutation Regales et al. JCI 2009

15 Afatinib + cetuximab for metastatic NSCLC: Study Design 1 EGFR G719X, exon 19 deletion, L858R, L861Q; 2 Progression of disease (Response Evaluation Criteria in Solid Tumors v1.1) on continuous treatment with erlotinib or gefitinib within the last 30 days; 3 Amended from original 14-day interval; 4 Acquisition of tumor tissue after the emergence of acquired resistance was mandated. i.v.=intravenous; MTD=maximum tolerated dose; NSCLC=non-small cell lung cancer; SD=stable disease. Phase Ib, open-label, multicenter trial in the US and The Netherlands Stop erlotinib/ gefitinib for ≥72 hours 3 Disease progression 2 NSCLC with EGFR mutation 1 OR SD  6 months with erlotinib/gefitinib OR Partial or complete response to erlotinib/gefitinib MTD cohort expanded up to 80 EGFR mutation-positive patients 4 : 40 T790M+ and 40 T790M– Dose escalation schema 3–6 patients per cohort Afatinib p.o. daily + escalating doses of i.v. cetuximab q 2 weeks Dose levels starting at: afatinib 40 mg + cetuximab 250 mg/m 2 Predefined maximum dose: afatinib 40 mg + cetuximab 500 mg/m 2

16 Tumor Regression by T790M Mutation Status at Recommended Dose 39 patients with proven EGFR T790M mutation: confirmed RR=31%

17 Acquired resistance to EGFR-TKIs Acquired drug resistance is almost inevitable (~10 months) Mitsudomi, et al. Cancer Sci., 2007 About 30% of resistant mechanisms are unknown.

18 Resistant mechanisms in 33 tumors from 6 patients with EGFR-TKI acquired resistance Number of Tumors MET gene copy numbers (folds) Tumors with T790M Tumors without T790M < < % 8% 80% Suda et al. Clin Cancer Res 2010

19 Inhibition of both EGFR and MET is necessary for growth inhibition of HCC827 GR cells Irreversible EGFR inhibitors have no effect on HCC827 GR MET shRNA restores sensitivity to gefitinib Engelman et al. Science Gefitinib PHA Gefitinib/PHA Drug Concentration ( μ M) % of control

20 EML4-ALK fusion oncogene in NSCLC 3–7% of patients with NSCLC have an EML4-ALK gene fusion 1 detection test available mainly seen in adenocarcinomas (mutually exclusive with EGFR mutations) 2 phase I/II trial of crizotinib, oral c-MET and ALK inhibitor in selected patients: DCR = 70% 3 further potential for personalising therapy in NSCLC 1. Koivunen, et al. Clin Cancer Res Shaw, et al. ASCO 2009; 3. Bang, et al. ASCO 2010

21 ALK secondary mutations and crizotinib resistance Sasaki et al. Cancer Res 2011

22 New ALK inhibitors TAE684 and AP26113 overcome crizotinib resistance in H3122 CR cell line Katayama et al. PNAS 2011

23 Cell lines with ALK secondary mutation and ALK and EGFR co-dependency Sasaki et al. Cancer Res 2011

24 ALK amplification or ALK FISH loss as mechanisms of crizotinib resistance Katayama et al. PNAS 2011, Katayama et al Science Transl Med 2012, Doebele et al. Clin Cancer Res 2012

25 Several mechanisms responsible for crizotinib resistance: clinical implications Doebele et al. Clin Cancer Res 2012

26 Conclusions Different mechanisms are responsible for acquired resistance to novel targeted therapies So far no proven efficacy of irreversible EGFR-TKIs in NSCLC with acquired resistance to reversible agents No clinically available strategies for crizotinib resistant patients New drugs and new strategies are under investigation

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