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

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

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 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: ; Wu et al. J Thorac Oncol. 2007;2:

Patient with EGFR mutation deletion exon 19

Newly diagnosed months of erlotinib Patient with L858 EGFR mutation

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

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:

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

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

EGFR mutant on TKI develops oligometastatic PD Continue EGFR TKI Utilize radiation therapy or surgical resection Close monitoring Several studies demonstrate additional PFS benefit ( months) and possibly OS (41 months) benefit with this strategy. Weickhardt et al. JTO 7: , 2012; Yu et al. ASCO 2012 abstract 7527, JCO 30, 2012

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

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

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): , 2011

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

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

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel. 1:1 Chemotherapy- naïve 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 (abstr 8001).

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 ( ) P= HR=0.10 ( ) P< Erlotinib (N=22) Placebo (N=27) Erlotinib (N=199) Placebo (N=189) Cappuzzo. ASCO (abstr 8001). Time (Weeks)

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

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

2 Trials to compare ongoing EGFR TKI for Acquired Resistance

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

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): , 2006; Encyclopedia of Science Cell Biology

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

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

FAST ACT-2 Mok T et al. ASCO 2012

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

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

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

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

[TITLE] Yang et al. ASCO 2012 Abstract LBA7500

Phase III Lung LUX-3 Trial 1269 screened, 452 EGFR mutation (+) => 345 randomized

[TITLE] Yang et al. ASCO 2012 Abstract LBA7500

ORR favored afatinib Yang et al. ASCO 2012 Abstract LBA7500

PFS favored afatinib Yang et al. ASCO 2012 Abstract LBA7500

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

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

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

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

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. Summary Afatinib

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

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

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

Eligibility: Recurrent or advanced NSCLC Sensitizing EGFR mutation (i.e., exon 19 deletion, L858R) Chemotherapy and TKI-naïve PS 0-2 RANDOMIZE Afatinib PO 40mg daily + Cetuximab IV 500mg/m2 Q2 weeks N=138 Afatinib PO 40mg daily 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 Initial Evaluation: PET-CT Brain CT or MRI ECG, Echo/MUGA Tumor molecular analysis CT scans q8 wks A randomized phase II/III trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced, EGFR mutation positive NSCLC Lynch, T. IASLC Targeted Therapies Meeting Feb 2013

CO-1686 is a novel TKI specifically targeting mutated EGFR 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 Modified from Soria WCLC 2013

Phase I Schema Dose 1 (n=3) Phase II Expansion Phase Dose 2 (n=3) Dose 4 (n=3) Dose 6 (n=6) Dose 5 (n=3-6); MTD Dose 3 (n=3) 40 T790M pts Target Exposure 45 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 patients will be enrolled into Phase 1 (57 on CO-1686 free base and approximately 35 on CO HBr).

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

* 67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID EGFRi immediately before CO-1686 * Weeks on treatment ** * * * * * Number of Previous EGFR TKI lines of 9 patients progressed on TKI immediately prior to CO-1686 * Soria WCLC 2013

Promising clinical activity observed with CO-1686 – no evidence of WT inhibition 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 introduced and 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 Modified from Soria WCLC 2013

CO-1686 phase 2/3 development: TIGER program 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 2 nd 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 2 nd or later-line patients with T790M detected with a blood/plasma assay −TIGER5: Phase 3 randomized confirmatory study in 2 nd or later- line patients (vs. chemo)

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

ASCO 2011 Abstract #7505 MetMab Onartuzumab Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations. Met expression is associated with a worse prognosis in NSCLC MetMab is an anti-Met one-armed antibody that inhibits hepatocyte growth factor (HGF)-mediated activation Spigel et al. ASCO 2011 Abstract 7505 MetMAb Met HGF Met Growth Migration Survival No activity

Spigel et al. ASCO 2011 Abstract 7505 Abstract #7505 Phase II Onartuzumab

Met IHC Biomarker Spigel et al. ASCO 2011 Abstract 7505 “Met Diagnostic Positive” = >50% tumor cells with moderate or strong staining intensity 93% had adequate tissue for analysis and 52% were “Met Diagnostic Positive”

Spigel et al. ASCO 2011 Abstract 7505 MetMAb + erlotinib in ITT PFS HR 1.09 OS HR 0.8

Spigel et al. ASCO 2011 Abstract 7505 MetMAb + erlotinib in Met Dx+ pts PFS HR 0.53 OS HR 0.37

Spigel et al. ASCO 2011 Abstract 7505 MetMAb + erlotinib in Met Dx- pts PFS HR 1.82 OS HR 1.78

Spigel et al. ASCO 2011 Abstract 7505 MetMAb benefit is not driven by EGFR mutation nor FISH status

Spigel et al. ASCO 2011 Abstract 7505 PFS HR 1.71 OS HR 2.61 Met expression correlates to worse outcome in erlotinib + placebo treated pts.

Spigel et al. ASCO 2011 Abstract 7505 Most commonly reported AE frequency > 10%

Phase II Met IHC expression inversely correlates with prognosis. MetMAb + erlotinib was well-tolerated with no new safety signals. MetMAb + erlotinib improved PFS and OS in Met Diagnostic Positive patients. A phase III study of MetMAb + erlotinib in Met Diagnostic positive patients started enrollment January 2012 and has completed accrual.

Tsao Conclusions on Clinical Management for EGFR mutation patients with Acquired Resistance Feb 2013 Oligo-PD Continue EGFR TKI + localized therapy Global PD Chemo Chemo then EGFR TKI Chemo + EGFR TKI Chemo intercalated with EGFR TKI

Tsao Conclusions: Molecular Age Will Come Molecular Rebiopsy: -Unknown (other pathways) -MET -PIK3CA -SCLC -HER2 Sequist L et al. Sci Transl Med 2011;3:75ra26-75ra26

Future Clinical Options for T790M or Met pathway acquired resistance 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