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Department of Thoracic/Head & Neck

Management of EGFR-Mutant NSCLC Resistant to EGFR-TKI therapy. Anne S. Tsao, M.D. Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program. Associate Professor. The University of Texas. Department of Thoracic/Head & Neck. MD ANDERSON. Medical Oncology. CANCER CENTER.

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Department of Thoracic/Head & Neck

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  1. Management of EGFR-Mutant NSCLC Resistant to EGFR-TKI therapy Anne S. Tsao, M.D. Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program Associate Professor The University of Texas Department of Thoracic/Head & Neck MD ANDERSON Medical Oncology CANCER CENTER

  2. Outline: Long-term management EGFR mutated NSCLC patients EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI Current EGFR TKI Resistance Management Met inhibition MetMAb (onartuzumab) Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686

  3. 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.

  4. 12-02 12-00 Patient with EGFR mutation deletion exon 19

  5. Newly diagnosed 3-16-07 3 months of erlotinib 6-18-07 Patient with L858 EGFR mutation

  6. The relative frequencies of the various mechanisms of acquired resistance. Yu H A et al. Clin Cancer Res 2013;19:2240-2247

  7. EGFR T790M: Frequently Found inTumor 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.

  8. T790M blocks erlotinib binding and leads to a resistant phenotype Michalczyk et al. Bioorganic & Medicinal Chemistry 16 (7): 3482; April 2008

  9. Outline: Long-term management EGFR mutated NSCLC patients EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI Current EGFR TKI Resistance Management Met inhibition MetMAb (onartuzumab) Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686

  10. 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

  11. EGFR mutation and ALK mutation patients with oligo-progressive disease + local therapy have PFS benefit Weickhardt et al. JTO 7: 1807-1814, 2012

  12. EGFR Mutant Disease Progression on EGFR TKI Clinical PD appearance: - Rapid disease PD globally • Slow growth globally • Growth in several areas, but not all Molecular: • Unknown (other pathways) • MET • PIK3CA • SCLC • HER2

  13. 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

  14. Current Options in EGFR TKI resistant patient with EGFR mutation Chemotherapy Chemotherapy EGFR TKI Chemotherapy + EGFR TKI combination Chemotherapy with intermittent EGFR TKI

  15. Chemo is safe Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe Chemotherapy Chemotherapy EGFR TKI SATURN INTACT I, II TRIBUTE, TALENT Chemotherapy + EGFR TKI combination Chemotherapy with intermittent EGFR TKI FAST ACT

  16. SATURN: Treatment Schema Erlotinib 150 mg/day PD Chemotherapy-naïve advanced NSCLC N=1949 4 cycles of first-line platinum doublet chemotherapy* 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 No PD N=889 1:1 Placebo PD Mandatory tumor sampling 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 *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel. Cappuzzo. ASCO. 2009 (abstr 8001).

  17. SATURN: PFS by EGFR Mutation Status PFS: Mutated EGFR PFS: Wild-Type EGFR 100 100 HR=0.10 (0.04-0.25) P<0.0001 HR=0.78 (0.63-0.96) P=0.0185 80 80 60 60 Patients Without Progression (%) Patients Without Progression (%) Erlotinib (N=199) 40 Erlotinib (N=22) 40 Placebo (N=189) Placebo (N=27) 20 20 0 0 0 8 0 8 48 16 64 48 24 16 64 56 24 32 40 56 32 40 Time (Weeks) Time (Weeks) • About 50% of all tumors were able to be sequenced for EGFR mutation Cappuzzo. ASCO. 2009 (abstr 8001).

  18. Chemo is safe Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe Chemotherapy Chemotherapy EGFR TKI SATURN INTACT I, II TRIBUTE, TALENT Chemotherapy + EGFR TKI combination Chemotherapy with intermittent EGFR TKI FAST ACT

  19. Continuing EGFR TKI +/- Chemo may have benefit ASPIRATION Phase II Asian multicenter trial for NSCLC EGFR mutation patients using continuation erlotinib beyond PD1 Enrollment: April 2011 – Dec 2014 Plan 207 patients 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

  20. 2 Trials to compare ongoing EGFR TKI for Acquired Resistance

  21. Chemo is safe Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe Chemotherapy Chemotherapy EGFR TKI SATURN INTACT I, II TRIBUTE, TALENT Chemotherapy + EGFR TKI combination Chemotherapy with intermittent EGFR TKI FAST ACT

  22. 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

  23. First-Line Asian Sequential Erlotinib plus chemo Trial (FASTACT) Platinum (d1) Gemcitabine (d1, 8) + Erlotinib D15-28 Q4weeks x 6 cycles Erlotinib Untreated NSCLC IIIB/IV No prior EGFR TKI 1:1 Placebo Platinum (d1) Gemcitabine (d1, 8) + Placebo D15-28 Q4weeks x 6 cycles n=154 1o endpoint: 8-week non-PD rate 2nd: PFS, 16-week non-PD rate, ORR, TTP, OS Lee J et al. ASCO 2012 Abstract 8031

  24. FAST ACT 1 PFS favored GC-erlotinib Lee J et al. ASCO 2012 Abstract 8031

  25. FAST ACT-2 Mok T et al. ASCO 2012

  26. 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 Mok T et al. ASCO 2012

  27. 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

  28. Outline: Long-term management EGFR mutated NSCLC patients EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI Current EGFR TKI Resistance Management Met inhibition MetMAb (onartuzumab) Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686

  29. Novel agents targeting EGFR TKI resistant disease

  30. [TITLE] Yang et al. ASCO 2012 Abstract LBA7500

  31. Phase III Lung LUX-3 Trial 1269 screened, 452 EGFR mutation (+) => 345 randomized Yang et al. ASCO 2012 Abstract LBA7500

  32. [TITLE] Yang et al. ASCO 2012 Abstract LBA7500

  33. ORR favored afatinib Yang et al. ASCO 2012 Abstract LBA7500

  34. PFS favored afatinib Yang et al. ASCO 2012 Abstract LBA7500

  35. PFS Independent Review Subgroup Analysis Yang et al. ASCO 2012 Abstract LBA7500

  36. PFS Common Mutants (Del 19/L858R) Yang et al. ASCO 2012 Abstract LBA7500

  37. QOL: EORTC QLQ C-30 Yang et al. ASCO 2012 Abstract LBA7500

  38. Summary LUNG LUX-3 • Front-line afatinib improved QOL, RR, DCR, and median PFS over cisplatin-pemetrexed in both the overall EGFR mutation population and in the common EGFR mutation (del19/L858) patients. • Subgroup analysis showed benefit across most of the subgroups. • No new safety signals with diarrhea and rash as the most frequent AEs. Yang et al. ASCO 2012 Abstract LBA7500

  39. Summary Afatinib • Afatinib was approved July 12, 2013 by the FDA for first-line NSCLC patients with EGFR mutations (del exon 19 and exon 21 L858R) as detected by an FDA-approved assay. • It remains unknown which EGFR TKI (erlotinib, gefitinib, or afatinib) should be used first or whether these agents can be sequenced in the EGFR mutation population. • Additional studies are needed to clarify this issue. • Afatinib is currently under development in combination with cetuximab for resistant EGFR T790 mutant patients. • Future more broad application of afatinib is anticipated.

  40. Combination of Afatinib and Cetuximab is effective against EGFR T790M Regales et al. JCI 2009

  41. Afatanib/Cetuximab • No DLTs at afatinib 40mg po daily plus cetuximab 250 mg/m2 or 500mg/m2 IV q2 weeks • Expansion cohort dosing: afatinib 40mg po daily + cetuximab 500mg/m2 IV q2 weeks • Data on the first 100 patients available Lynch, T. IASLC Targeted Therapies Meeting Feb 2013; Janjigian, et al. ESMO 2012

  42. Responses at MTD by T790M mutation Lynch, T. IASLC Targeted Therapies Meeting Feb 2013; Janjigian, et al. ESMO 2012

  43. A randomized phase II/III trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced, EGFR mutation positive NSCLC Afatinib PO 40mg daily + Cetuximab IV 500mg/m2 Q2 weeks N=138 Repeat Biopsy at Progression Primary Endpoint: Progression-Free Survival Secondary Endpoints: ORR, OS, Safety, Tolerability, QOL Exploratory Biomarkers: Pre-and post-Rx T790M testing, whole exome sequencing, HER2 and MET FISH RANDOMIZE • Eligibility: • Recurrent or advanced NSCLC • Sensitizing EGFR mutation (i.e., exon 19 deletion, L858R) • Chemotherapy and TKI-naïve • PS 0-2 Afatinib PO 40mg daily N=138 Initial Evaluation: PET-CT Brain CT or MRI ECG, Echo/MUGA Tumor molecular analysis CT scans q8 wks Lynch, T. IASLC Targeted Therapies Meeting Feb 2013

  44. Novel, oral, selective covalent inhibitor of EGFR mutations in NSCLC Inhibits key activating and T790M resistance mutations Minimal activity against wild type EGFR First-in-human study ongoing in EGFR-mutation positive pts with recurrent advanced NSCLC, started with free base capsule formulation, hydrobromide salt form of CO-1686 with improved drug availability and reduced variability completed dose escalation. Early evidence of efficacy presented at ASCO 2013, WCLC 2013, free base dosed to 900 mg BID Roche Molecular Systems companion diagnostic collaboration Potential for use as first-line therapy CO-1686 is a novel TKI specifically targeting mutated EGFR Modified from Soria WCLC 2013

  45. Phase I Schema 92 patients will be enrolled into Phase 1 (57 on CO-1686 free base and approximately 35 on CO-1686 HBr). Dose 6 (n=6) Dose 5 (n=3-6); MTD Phase II Expansion Phase Target Exposure Dose 4 (n=3) 40 T790M pts Dose 3 (n=3) Phase 2 Cohort A-T790M : 1. Disease progression while on treatment with EGFR-directed therapy. Prior CT including intervening CT before planned initiation of CO-1686, is allowed (washout for EGFR TKI min 3 days, chemo 14 d) Phase 2 Cohort B-T790M 1. Disease progression while on treatment with the first single agent EGFR-directed therapy within the last 30 days, with no intervening treatment before planned initiation of CO-1686 . Dose 2 (n=3) Dose 1(n=3) 45

  46. CO-1686 freebase demonstrated limited and low-grade adverse events in patients GRADE 1 GRADE 2 GRADE 3 % patients with event Soria WCLC 2013

  47. 8 of 9 patients progressed on TKI immediately prior to CO-1686 67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID * * * * * * * * * 6 22 15 Weeks on treatment 11 8 21 24 18 30 * EGFRi immediately before CO-1686 Soria WCLC 2013

  48. 67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID (free base) A hydrobromide (HBr) formulation of CO-1686 with improved exposure has been introducedand a RP2D of 750mg BID has been identified CO-1686 is well tolerated with no acneiform rash, consistent with absence of WT-EGFR inhibition AEs all grades: nausea-25%, fatigue-21%, impaired glucose tolerance/hyperglycemia 21% The pivotal phase 2/3 TIGER program starts 1H14 Efficacy updates at ELCC2014 and ASCO2014 Promising clinical activity observed with CO-1686 – no evidence of WT inhibition Modified from Soria WCLC 2013

  49. TIGER: Third-generation Inhibitor of mutant EGFR in lung cancER All are global studies in mutant EGFR NSCLC: TIGER1: Phase 2/3 randomized registration study in newly-diagnosed patients (vs. erlotinib) TIGER2: Phase 2 registration study in 2nd line T790M+ patients directly progressing on first TKI TIGER3: Phase 2 registration study in later-line T790M+ patients, progressing on second or later TKI or subsequent chemotherapy TIGER4: Phase 2 study in 2nd or later-line patients with T790M detected with a blood/plasma assay TIGER5: Phase 3 randomized confirmatory study in 2nd or later-line patients (vs. chemo) CO-1686 phase 2/3 development: TIGER program

  50. Outline: Long-term management EGFR mutated NSCLC patients EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI chemo with intermittent EGFR TKI Current EGFR TKI Resistance Management Met inhibition MetMAb (onartuzumab) Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686

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