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Department of Thoracic/Head & Neck Medical Oncology Management of EGFR-Mutant NSCLC Resistant to EGFR-TKI therapy Anne S. Tsao, M.D. Associate Professor

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Text of Department of Thoracic/Head & Neck Medical Oncology Management of EGFR-Mutant NSCLC Resistant to...

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  • Department of Thoracic/Head & Neck Medical Oncology Management of EGFR-Mutant NSCLC Resistant to EGFR-TKI therapy Anne S. Tsao, M.D. Associate Professor The University of Texas MD ANDERSON CANCER CENTER Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program
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  • EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Outline: Long-term management EGFR mutated NSCLC patients Current EGFR TKI Resistance Management Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686 MetMAb (onartuzumab) Met inhibition
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  • EGFR mutations Found in 10% - 15% of all lung cancer patients and 85% who clinically respond to EGFR TKIs Found more commonly in never-smokers, adenocarcinomas, BAC, women, Asians Predominantly located in EGFR exons 19 - 21 EGFR mutations are not the same. There are sensitive mutations and acquired resistance mutations (T790M). 85% of EGFR mutations are either deletion exon 19 or L858 mutation. Pao, Miller. J Clin Oncol. 2005;23:2556-2568; Wu et al. J Thorac Oncol. 2007;2:430-439.
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  • 12-00 12-02 Patient with EGFR mutation deletion exon 19
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  • Newly diagnosed 3-16-07 3 months of erlotinib 6-18-07 Patient with L858 EGFR mutation
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  • The relative frequencies of the various mechanisms of acquired resistance. Yu H A et al. Clin Cancer Res 2013;19:2240-2247
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  • EGFR T790M: Frequently Found in Tumor Cells From Patients With Acquired Resistance to EGFR TKIs Pao W, et al. PLoS Med. 2005;2:e73; Balak MN, et al. Clin Cancer Res. 2006;12:6494-6501.
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  • T790M blocks erlotinib binding and leads to a resistant phenotype Michalczyk et al. Bioorganic & Medicinal Chemistry 16 (7): 3482; April 2008
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  • EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Outline: Long-term management EGFR mutated NSCLC patients Current EGFR TKI Resistance Management Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686 MetMAb (onartuzumab) Met inhibition
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  • EGFR mutant on TKI develops oligometastatic PD Continue EGFR TKI Utilize radiation therapy or surgical resection Close monitoring Several studies demonstrate additional PFS benefit (6.2- 10 months) and possibly OS (41 months) benefit with this strategy. Weickhardt et al. JTO 7: 1807-1814, 2012; Yu et al. ASCO 2012 abstract 7527, JCO 30, 2012
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  • Weickhardt et al. JTO 7: 1807-1814, 2012 EGFR mutation and ALK mutation patients with oligo- progressive disease + local therapy have PFS benefit
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  • EGFR Mutant Disease Progression on EGFR TKI Molecular: -Unknown (other pathways) -MET -PIK3CA -SCLC -HER2 Clinical PD appearance: - Rapid disease PD globally -Slow growth globally -Growth in several areas, but not all
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  • Flare of Disease after EGFR TKI discontinuation in acquired resistance Rapid disease acceleration leading to hospitalization and/or death after EGFR TKI cessation occurs in up to 23% (n=14) of patients in MSKCC series (n=61). Riely et al. Clinical Cancer Research 2007, Chaft et al. CCR 17 (19): 6298-6303, 2011
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  • Current Options in EGFR TKI resistant patient with EGFR mutation Chemotherapy Chemotherapy + EGFR TKI combination Chemotherapy Chemotherapy with intermittent EGFR TKI EGFR TKI
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  • Chemo is safe Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe Chemotherapy Chemotherapy + EGFR TKI combination Chemotherapy Chemotherapy with intermittent EGFR TKI EGFR TKI SATURN INTACT I, II TRIBUTE, TALENT FAST ACT
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  • *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel. 1:1 Chemotherapy- nave advanced NSCLC N=1949 No PD N=889 4 cycles of first-line platinum doublet chemotherapy* Placebo PD Erlotinib 150 mg/day PD Mandatory tumor sampling SATURN: Treatment Schema Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) Chemotherapy regimen (cisplatin/gemcitabine vs carboplatin/docetaxel vs others) Smoking history (current vs former vs never) Region Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumors Secondary endpoints: OS in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC tumors, biomarker analyses, safety, time to symptom progression, and QOL Cappuzzo. ASCO. 2009 (abstr 8001).
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  • SATURN: PFS by EGFR Mutation Status About 50% of all tumors were able to be sequenced for EGFR mutation Time (Weeks) Patients Without Progression (%) PFS: Wild-Type EGFR PFS: Mutated EGFR HR=0.78 (0.63-0.96) P=0.0185 HR=0.10 (0.04-0.25) P
  • Continuing EGFR TKI +/- Chemo may have benefit TrialPatients Continued EGFR TKI + chemo Goldberg et al.34 chemo + E 44 chemo RR improved No PFS or OS difference Faehling et al.27 chemo + EGFR TKI 14 chemo Improved OS Yoshimura et al.27 pemetrexed + EGFR TKIORR 26%, DCR 78% Median PFS 7 months Median OS 11.4 months Delayed additional therapy Oxnard et al.42 EGFR TKI45% > 3 months 19% > 12 months Goldberg et al. ASCO 2012 Abstract 7524, Yoshimura N. et al. JTO 8 (1):96-101, 2013; Faehling et al. ASCO 2012 Abstract 7572; Oxnard et al. ASCO 2012 Abstract 7547 ASPIRATION Phase II Asian multicenter trial for NSCLC EGFR mutation patients using continuation erlotinib beyond PD1 Enrollment: April 2011 Dec 2014 Plan 207 patients
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  • 2 Trials to compare ongoing EGFR TKI for Acquired Resistance
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  • Chemo is safe Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe Chemotherapy Chemotherapy + EGFR TKI combination Chemotherapy Chemotherapy with intermittent EGFR TKI EGFR TKI SATURN INTACT I, II TRIBUTE, TALENT FAST ACT
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  • Potential Antagonism Chemo + EGFR TKI There are concerns over combining erlotinib-chemo as erlotinib arrests the cancer cells in the G1 checkpoint and chemo usually works best in the mitotic phase. Solit et al, Clin Can Res 2005; Davies A et al. CLC 7 (6): 385-388, 2006; Encyclopedia of Science Cell Biology http://www.daviddarling.info/encyclopedia/C/cell_cycle.html
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  • First-Line Asian Sequential Erlotinib plus chemo Trial (FASTACT) 1:1 Untreated NSCLC IIIB/IV No prior EGFR TKI Platinum (d1) Gemcitabine (d1, 8) + Placebo D15-28 Q4weeks x 6 cycles Placebo Platinum (d1) Gemcitabine (d1, 8) + Erlotinib D15-28 Q4weeks x 6 cycles Erlotinib 1 o endpoint: 8-week non-PD rate 2 nd : PFS, 16-week non-PD rate, ORR, TTP, OS Lee J et al. ASCO 2012 Abstract 8031 n=154
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  • FAST ACT 1 PFS favored GC-erlotinib Lee J et al. ASCO 2012 Abstract 8031
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  • FAST ACT-2 Mok T et al. ASCO 2012
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  • FAST ACT II: ITT PFS favors erlotinib-GC Critique: FAST ACT 2 has a maintenance portion with the EGFR TKI and this affects clinical outcomes SATURN maintenance trial proves PFS benefit in EGFR mutant patients
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  • Tsao Summary on Acquired Resistance For local oligo-PD, continue EGFR TKI and apply local therapy. For more global PD: 4 options until future trials elaborate on acquired resistance Chemo Chemo + EGFR TKI Chemo then EGFR TKI Chemo intercalated with EGFR TKI Ultimately Re-biopsy and molecular profile will determine the optimal therapy
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  • EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Outline: Long-term management EGFR mutated NSCLC patients Current EGFR TKI Resistance Management Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686 MetMAb (onartuzumab) Met inhibition
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  • Novel agents targeting EGFR TKI resistant disease AgentInhibitor typePreclinical benefit against T790M Clinical Trial phase Dacomitinib (Pfizer) Irreversible TKI of EGFR, HER2, HER 4 yesII, III Afatinib (Boehringer Ingelheim) Irreversible TKI of EGFR, HER2, HER4 yesII, III CO-1686 (Clovis) Selective covalent inhibitor EGFR mutations yesI/II (T790M selection) AZD9291Irreversible TKI to mutant EGFR yesI Onartuzumab (Genentech) Monoclonal antibody that targets MET receptor n/aII, III Tivantinib (ArQule)MET-R TKIn/aII, III Volitinib (AZ)cMET TKIn/aI Ariad 26113EGFR, ALK, ROS1I
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  • [TITLE] Yang et al. ASCO 2012 Abstract LBA7500
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  • Phase III Lung LUX-3 Trial 1269 screened, 452 EGFR mutation (+) => 345 randomized
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  • [TITLE] Yang et al. ASCO 2012 Abstract LBA7500
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  • ORR favored afatinib Yang et al. ASCO 2012 Abstract LBA7500
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  • PFS favored afatinib Yang et al. ASCO 2012 Abstract LBA7500
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  • PFS Independent Review Subgroup Analysis Ya

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