Management of EGFR TKI resistant NSCLC

Management of EGFR TKI resistant NSCLC
Anne S. Tsao, M.D. Associate Professor Director, Mesothelioma Program Director, Thoracic Chemo-XRT Program March 2015 The University of Texas Department of Thoracic/Head & Neck MD ANDERSON Medical Oncology CANCER CENTER

Outline: Management of EGFR TKI resistant NSCLC
EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Current EGFR TKI Resistance Management Oligo-metastatic disease resistance Global PD Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686, AD9291 EGFR TKI + Met EGFR TKI + immunotherapy Future combinations

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
12-00 12-02

Patient with L858 EGFR mutation
Newly diagnosed 3 months of erlotinib

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 Current EGFR TKI Resistance Management Oligo-metastatic disease resistance Global PD Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686, AZD9291 EGFR TKI + Met EGFR TKI + immunotherapy Future combinations

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

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

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

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 Chemotherapy + EGFR TKI combination

Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe
Chemo is safe Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe Chemotherapy Chemotherapy EGFR TKI SATURN IMPRESS INTACT I, II TRIBUTE, TALENT Chemotherapy + EGFR TKI combination

Continuing EGFR TKI +/- Chemo may have benefit
Trial Patients 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 TKI ORR 26%, DCR 78% Median PFS 7 months Median OS 11.4 months Delayed additional therapy Oxnard et al. 42 EGFR TKI 45% > 3 months 19% > 12 months ASPIRATION Phase II Asian multicenter trial for NSCLC EGFR mutation patients using continuation erlotinib beyond PD1 Enrollment: April 2011 – Dec Plan 207 patients Goldberg et al. ASCO 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

2 Trials to compare ongoing EGFR TKI for Acquired Resistance

IMPRESS Study Design (n=250)
Enrollment period: March 2012‒December 2013 Patients Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 (≤6 cycles) Gefitinib 250 mg Endpoints Age ≥18 years (≥20 years in Japan) WHO PS 0-1 Histologically confirmed stage IIIB / IV EGFR mutation-positive advanced NSCLC Chemotherapy-naïve Achieved CR / PR ≥4 months or SD >6 months with first-line gefitinib Disease PD (RECIST)a <4 weeks prior to study randomisation Primary Progression-free survival Secondary Overall survival Objective response rate Disease control rate Safety and tolerability Health-related quality of lifec Exploratory Biomarkersd Objectives N=133 1:1 randomisationb Reference Jackman et al. J Clin Oncol 2010; 28: Cisplatin 75 mg/m2 IV + Pemetrexed 500 mg/m2 IV (≤6 cycles) Placebo 250 mg N=132 aProgressive disease based on radiological evaluation (modified Jackman’s criteria1) and RECIST version 1.1. Tumour assessments were performed ≤4 weeks before the start of treatment (baseline), and every 6 weeks (±7 days) after randomisation until progressive disease; bRandomisation did not include stratification factors; analyses were adjusted for two covariates: age (<65 versus ≥65 years) and prior response to gefitinib (SD versus PR+CR) cWill be reported separately dAnalyses not yet completed and will be reported separately CR, complete response; PR, partial response; PS, performance status; SD, stable disease; WHO; World Health Organization 18 18 1Jackman et al 2010

71 centres across Europe and Asia-Pacific
Iressa Mutation Positive Multicentre Treatment Beyond ProgRESsion Study: IMPRESS 71 centres across Europe and Asia-Pacific IMPRESS was conducted in 71 centres across Europe and Asia-Pacific. Russia (n=2) Japan (n=23) China (n=118) South Korea (n=42) Taiwan (n=18) Hong Kong (n=5) Spain (n=22) Italy (n=16) Germany (n=6) France (n=9) Hungary (n=4)

Patient demographics (ITT)
Demographic characteristic Gefitinib (n=133) Placebo (n=132) ≥65 years 32% 26% Mean age, years (range) 59 (33-79) 57 (35-79) Female 65% 64% PS 0, 1 41%, 59% 40%, 60% Never-smoker 66% 69% Adenocarcinoma histology 95% 99% Metastatic (baseline) 93% 90% Brain metastases (baseline) 33% 23% CR or PR/SD to first-line gefitinib 68% / 32% 76% / 24% Time to progression after initial gefitinib treatment ≤10 months >10 months 39% 61% 44% 56% Exon 19 deletion, exon 21 L858R 64%, 30% 65%, 32%

No difference in ORR and DCR (ITT population)
Odds ratio (95% CI) = 0.92 (0.55, 1.55); p=0.760 Odds ratio (95% CI) = 1.39 (0.74, 2.62); p=0.308 There was no statistical difference in ORR or DCR between treatment arms. ORR (%) DCR (%) (n=133) (n=132) (n=133) (n=132) Odds ratio >1 favours gefitinib Odds ratio and p-value from logistic regression with covariates CI, confidence interval

PFS (primary endpoint; ITT)
Gefitinib (n=133) Placebo (n=132) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.2 0.3 0.1 0.0 2 4 6 8 10 12 14 Probability of PFS Time of randomisation (months) Patients at risk: Gefitinib Placebo 133 132 110 100 88 85 40 39 25 17 5 Gefitinib (n=133) Placebo (n=132) Median PFS, months 5.4 Number of events, n (%) 98 (73.7) 107 (81.1) HRa (95% CI) = 0.86 (0.65, 1.13); p=0.273 There was no statistically significant difference in PFS for the gefitinib treatment arm compared with the placebo arm. aPrimary cox analysis with covariates A HR <1 implies a lower risk of progression with gefitinib

Time of randomisation (months)
OS (ITT; 33% of events) Gefitinib (n=133) Placebo (n=132) Median OS, months 14.8 17.2 Number of events, n (%) 50 (37.6) 37 (28.0) HRa (95% CI) = 1.62 (1.05, 2.52); p=0.029 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.2 0.3 0.1 0.0 2 8 10 16 18 22 26 Probability of OS Time of randomisation (months) OS was immature (33% of patients had died), with a suggestion of better OS in the placebo arm versus the gefitinib arm. Gefitinib (n=133) Placebo (n=132) 4 6 12 14 20 24 Patients at risk: Gefitinib Placebo 133 132 111 119 64 76 43 55 19 27 8 10 2 4 7 125 129 88 94 27 39 12 16 aPrimary cox analysis with covariates A HR <1 implies a lower risk of death with gefitinib

Post-discontinuation therapy (ITT)
Anti-cancer therapy ITT population Gefitinib (n=133) Placebo (n=132) Any, n (%) 61 (45.9) 72 (54.5) Platinum alone,a n (%) 0 (0) 2 (1.5) Platinum-based regimen (doublet or triplet), n (%) 5 (3.8) 17 (12.9) Single-agent cytotoxic,b n (%) 27 (20.3) 27 (20.5) EGFR TKI,c n (%) 30 (22.6) 44 (33.3) Others, n (%) 16 (12.0) 14 (10.6) There was imbalance in post-discontinuation EGFR TKI therapy and platinum-based therapy between the treatment groups. aPlatinum: carboplatin, cisplatin, nedaplatin bSingle agent: docetaxel, paclitaxel, pemetrexed, gemcitabine, vinorelbine cEGFR TKI (gefitinib, erlotinib, AZD9291 [n=2 gefitinib arm; n=3 placebo arm])

IMPRESS Summary IMPRESS showed that in EGFR mutant NSCLC (resistant to first-line gefitinib) the combination of chemo+gefitinib does not improve ORR, DCR, nor PFS compared to chemo alone. The OS results are immature and not conclusive at this time. Chemo alone arm had improved OS There were imbalances in post study treatment in favour of the placebo plus cisplatin / pemetrexed arm IMPRESS results suggest that continuation gefitinib+chemo in gefitinib-resistant EGFR mutant NSCLC should not be done.

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

Chemo is safe Chemo then maintenance erlotinib is safe Chemo + EGFR TKIs are safe Chemotherapy Chemotherapy EGFR TKI SATURN IMPRESS INTACT I, II TRIBUTE, TALENT Chemotherapy + EGFR TKI combination

Tsao Summary on Acquired Resistance
For local oligo-PD, continue EGFR TKI and apply local therapy. For more global PD: 2 options until future trials elaborate on acquired resistance Chemo Chemo then EGFR TKI Ultimately – Re-biopsy and molecular profile will determine the optimal therapy

EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Current EGFR TKI Resistance Management Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686, AZD9291 EGFR TKI + Met EGFR TKI + immunotherapy Future combinations

Novel agents targeting EGFR TKI resistant disease
Inhibitor type Preclinical benefit against T790M Clinical Trial phase Dacomitinib (Pfizer) Irreversible TKI of EGFR, HER2, HER 4 yes II, III Afatinib (Boehringer Ingelheim) Irreversible TKI of EGFR, HER2, HER4 CO-1686 (Clovis) Selective covalent inhibitor EGFR mutations I/II (T790M selection) AZD9291 Irreversible TKI to mutant EGFR I Onartuzumab (Genentech) Monoclonal antibody that targets MET receptor n/a Tivantinib (ArQule) MET-R TKI Volitinib (AZ) cMET TKI Ariad 26113 EGFR, ALK, ROS1

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

Phase III Lung LUX-3 Trial
1269 screened, 452 EGFR mutation (+) => 345 randomized 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 Common Mutants (Del 19/L858R)
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

Summary Afatinib Afatinib (Gilotrif) 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.

Combination of Afatinib and Cetuximab is effective against EGFR T790M
Preclinical data demonstrates that the combination of afatinib plus cetuximab has anti-tumor activity in EGFR-TKI resistant T790M+ tumors. Regales et al. JCI 2009;

Phase Ib trial 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 126 patients available Lynch, T. IASLC Targeted Therapies Meeting Feb 2013; Janjigian, et al. ESMO 2012

Responses at MTD by T790M mutation
Outcome N EGFR mutation T790M+ T790M- Del 19 L858R Total treated 126 71 53 78 41 ORR 89 54 33 48 34 RR (CR/PR) 37 23 13 14 SD 52 31 20 25 Unconfirmed OR 5 4 1 3 All T790M+ T790M- DOR N=37 5.7 m 5.6m 9.5m PFS N=126 4.7m 4.8m 4.6m Lynch, T. IASLC Targeted Therapies Meeting Feb 2013; Janjigian, et al. ESMO 2012; Janjigian YY et al. Cancer Discov 4: ; 2014

Toxicity Profile Drug-related adverse events occurring in >20% of patients by grouped and preferred term and by highest CTCAE grade All Grades Grade 3 Grade 4 n (%) Total patients with related adverse events 125 (99) 56 (44) 2 (2) Rash 114 (90) 25 (20) 0 (0) Diarrhea 89 (71) 8 (6) Nail effects 72 (57) Stomatitis 71 (56) 1 (1) Fatigue 59 (47) Nausea 53 (42) 3 (2) Xerosis Pruritus 50 (39) Headache 46 (37) 4 (3) Ocular effects 38 (30) Dry skin 37 (29) Vomiting 33 (26) Hypomagnesemia 29 (33) Janjigian YY et al. Cancer Discov 4: ; 2014

Pre-ECOG Study Phase II/III Trial (Overcoming Resistance)
Upcoming Trials Pre-ECOG Study Phase II/III Trial (Overcoming Resistance) Afatinib+ Cetuximab Stage IIIB-IV NSCLC with EGFR mutation Erlotinib Failures Afatinib* R A N D O M I Z T O N SWOG (S1403) Phase II/III trial (Preventing resistance) Afatinib+ Cetuximab* Stage IIIB-IV NSCLC with EGFR mutation EGFR TKI naive Afatinib* R A N D O M I Z T O N * PDXs in post progression patients

Novel agents targeting EGFR TKI resistant disease
Inhibitor type Clinical benefit against T790M Clinical Trial phase Dacomitinib (Pfizer) Irreversible TKI of EGFR, HER2, HER 4 No III Afatinib (Boehringer Ingelheim) Irreversible TKI of EGFR, HER2, HER4 CO-1686 (Clovis) Selective covalent inhibitor EGFR mutations yes I/II, II (T790M selection) AZD9291 Irreversible TKI to mutant EGFR I, II (T790M selection) Onartuzumab (Genentech) Monoclonal antibody that targets MET receptor n/a Tivantinib (ArQule) MET-R TKI Volitinib (AZ) cMET TKI I Ariad 26113 EGFR, ALK, ROS1 I/II, II

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

Ongoing Phase 1/2 FIH study of CO-1686 (NCT01526928)
Key eligibility criteria Advanced or recurrent NSCLC with a documented activating EGFR mutation Prior treatment with EGFR-directed therapy Recent biopsy available or willing to undergo a new on-study biopsy Phase 2 only Disease progression while on treatment with EGFR-directed therapy T790M-positive biopsy at the time of entering study Phase 1 (Dose-escalation period) Phase 2 (RP2D evaluation) TIGER X Expansion Cohorts 500 mg BID 2nd-line patients PD upon 1 immediate prior TKI CO-1686 Treatment 625 mg BID 21-day cycles; escalate to MTD >2nd-line patients PD upon ≥2 TKI or chemotherapy 750 mg BID Primary outcome measures Phase 1: Safety; PK profile Phase 2: ORR; DoR per RECIST v1.1 DoR, duration of response; ORR, objective response rate; FIH, first in human; MTD, maximum tolerated dose PK, pharmacokinetic; RP2D, recommended Phase 2 dose Sequist ASCO 2014

CO-1686 Phase I Study: Dose Levels
BID dose (N) FB formulation BID dose (N) HBr formulation Exposure 1000 mg (6) 750 mg (12) 625 mg (17) 500 mg (28) 900 mg (19) 10 patients transitioned Efficacy threshold <900 mg (38) FB, free-base; HBr, hydrobromide salt Sequist ASCO 2014

Best response in Phase 1 and early Phase 2 expansion cohort patients
Centrally confirmed T790M+ patients within therapeutic dose range (N=40) 100 *Ongoing Change from Baseline (%) * * * * * * * * * * * * * * * * * * * ORR to date: 58% * * * * * * * * * * * * Sequist ASCO 2014

Sequist ASCO 2014

3 (4%) patients with any form of rash, all Grade 1
Adverse events Treatment-related adverse events* occurring in >10% of CO-1686 patients (N=72) treated at efficacious doses, n (%) Preferred term Grade 1 Grade 2 Grade 3 Grade 4 Nausea 14 (19) 10 (14) 1 (1) Hyperglycemia and IGT 8 (11) 16 (22) Diarrhea 3 (4) Vomiting 9 (13) 2 (3) Decreased appetite 7 (10) Myalgia QTc prolonged 5 (7) *excluding malignancy-related adverse events (eg, disease progression) 3 (4%) patients with any form of rash, all Grade 1 Sequist ASCO 2014

Promising clinical activity observed with CO-1686 – no evidence of WT inhibition
58% RECIST response rate in evaluable T790M+ with estimated median PFS >12 months CNS responses are seen CO-1686 is well tolerated with no acneiform rash, consistent with absence of WT-EGFR inhibition most common toxicity is elevated glucose TIGER Programs are ongoing

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 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)

AZD9291 Phase I study design
Phase I, open-label, multicenter study of AZD9291 administered once daily in Asian and Western patients with advanced NSCLC who have documented radiological progression while on prior therapy with an EGFR-TKI (AURA; NCT ) Objectives Primary: safety and tolerability in EGFR-TKI-refractory patients Secondary include: define maximum tolerated dose, pharmacokinetics, preliminary efficacy Escalation Not preselected by T790M status Rolling six design Cohort 1 20 mg Cohort 2 40 mg Cohort 3 80 mg Cohort mg Cohort mg Expansion Enrollment by local testing followed by central laboratory confirmation* of T790M status or by central laboratory testing alone T790M+ T790M+ T790M+ T790M+ T790M+ T790M- T790M- T790M- 1st-line EGFRm+ 1st-line EGFRm+ Biopsy Biopsy Tablet *cobas® EGFR Mutation Test (Roche Molecular Systems) Jänne ASCO 2014

Response rate* in overall population
40 Best percentage change from baseline in target lesion: all evaluable patients, escalation and expansion (N=205) 20 ####### -20 -40 Complete response Partial response* -60 Non-response -80 First patient dosed Mar 6, 2013 Longest response >9 months ongoing at time of data cutoff ORR* = 53% (109/205; 95% CI 46%, 60%); no difference in ORR by race Overall disease control rate (CR+PR+SD) = 83% (171/205; 95% CI 78%, 88%) -100 20 mg 40 mg 80 mg 160 mg 240 mg N (205) 20 57 61 55 12 ORR 55% 44% 54% 58% 67% *Includes confirmed responses and responses awaiting confirmation; #represents imputed values. Population: all dosed patients with a baseline RECIST assessment and an evaluable response (CR, PR, SD, or PD), N=205 (from 232 dosed patients, 27 patients with a current non-evaluable response are not included). CI, confidence interval; CR, confirmed complete response; ORR, overall response rate; PD, progressive disease; PR, confirmed partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease Jänne ASCO 2014

Response rate* in T790M+ (central test)
40 Best percentage change from baseline in target lesion: T790M+ evaluable patients, expansion cohorts only (N=107) Best percentage change from baseline in target lesion: all evaluable T790M+ patients, Part B # # D D 20 D D D D D D D -20 D D D D -40 D 20 mg QD D D D D 40 mg QD 80 mg QD D -60 D 160 mg QD D D 240 mg QD D -80 ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%) -100 20 mg 40 mg 80 mg 160 mg 240 mg N (107) 10 29 34 28 6 ORR 50% 62% 68% 64% 83% *Includes confirmed responses and responses awaiting confirmation; #represents imputed values Population: all dosed centrally confirmed T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD, or PD), N=107 (from 120 T790M+ patients; 13 patients with a current non-evaluable response are not included). D, discontinued; QD, once daily Jänne ASCO 2014

Maximum grade of AEs by dose
Safety summary* No dose-limiting toxicities have been seen at any dose evaluated MTD has not been defined and there are no observed differences in toxicity by race Patients with an AE, n (%) 20 mg (N=21) 40 mg (N=57) 80 mg (N=74) 160 mg (N=60) 240 mg (N=20) Total (N=232) Any AE 21 (100) 52 (91) 65 (88) 57 (95) 20 (100) 215 (93) Any AE Grade ≥3 4 (19) 16 (28) 16 (22) 15 (25) 5 (25) 56 (24) AE leading to dose reduction 1 (2) 2 (10) 4 (2) AE leading to discontinuation 1 (5) 3 (4) 4 (7) 10 (4) Serious AE# 3 (14) 10 (18) 45 (19) Maximum grade of AEs by dose *Data here and on following slides are preliminary from an ongoing study; do not include first-line or tablet cohorts; #total investigator drug-related serious AEs, n=12 (5.2%). Population: all dosed patients, N=232. AE, adverse event; MTD, maximum tolerated dose Jänne ASCO 2014

Mutant Selective EGFR Inhibitors
Data emerging on efficacy of three compounds (others in development) Some differences in toxicities CO-1686: drug induced diabetes Some need insulin AZD9291: ILD like events in some patients HM61713: some dyspnea NOS AZD9291 & CO-1686 have FDA breakthrough designation

EGFR mutations Common mutations Mechanisms of resistance to EGFR TKIs Current EGFR TKI Resistance Management Oligo-metastatic disease resistance Options: chemo chemo + EGFR TKI combination chemo then EGFR TKI Novel agents that target EGFR pathway Afatinib Afatinib-cetuximab for T790M CO-1686, AZD9291 EGFR TKI + Met EGFR TKI + immunotherapy Future combinations

MET has been an established mechanism of resistance to EGFR TKI
Yu H A et al. Clin Cancer Res 2013;19:

Immediate progression on EGFR TKI
Phase II trial of XL184 (cabozantinib) + erlotinib in EGFR mutant NSCLC that progressed on EGFR TKI Cabozantinib – TKI targets MET and VEGFR2, also RET, AXL, KIT, and TIE-2 EGFR mutant NSCLC Immediate progression on EGFR TKI ECOG PS 0-1 Cabozantinib 40 mg/day + Erlotinib 150 mg/day 3 PR 67% DCR Reckamp, KL, et al, ASCO 2014, Abstract #8014

Phase Ib/II trial of INC280 (cMet inhibitor) + gefitinib in EGFR mutant NSCLC that have PD post-EGFR TKI Molecular prescreen C-Met dysregulation in EGFR mutant NSCLC who developed resistance to gefitinib or erlotinib Phase IB dose escalation INC280 + gefitinib N> 18 Phase II Dose expansion INC280 + gefitinib N = 40 17% PR (n=8/46) All responders had high MET by IHC or FISH RP2D INC280 is 400 mg BID + gefitinib 250 mg Phase II began March 2014 Wu Y-L et al, ASCO 2014, Abstract #8017

A phase II trial EGF816 with Nivolumab in EGFR mutated NSCLC and INC280 in combination with Nivolumab in cMet positive NSCLC Dosing EGF mg daily INC mg BID Nivolumab 3mg/kg IV Q2wk

Phase Ib/II Study Design

Phase I trial of gefitinib + MEDI4736 (anti-PDL1)

Phase IIa trial of small molecules or tremelimumab with a sequential switch to 2nd line MEDI4736

Continue EGFR TKI + localized therapy
Tsao Conclusions on Clinical Management for EGFR mutation patients with Acquired Resistance March 2015 Continue EGFR TKI + localized therapy Oligo-PD Chemo Chemo then EGFR TKI Global PD Rebiopsy: Consider Clinical Trial If T790M+ then 3rd generation EGFR TKI

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

Tsao Algorithm: Histology and Molecular Profiling
NSCLC PATIENT Non-SCC SCC Neuroendocrine Avoid pemetrexed or bevacizumab Adenocarcinoma Platinum-etoposide; Switch Maintenance: pemetrexed, erlotinib EGFR mutation EGFR wild-type Consider 2nd line EGFR TKI or maintenance erlotinib (BR.21, SATURN) EML 4 ALK or ROS 1 EGFR TKI 1st or 2nd line Maintenance crizotinib ceritinib Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

Potential Future of NSCLC - Molecular Profiling
Adenocarcinoma EGFR mutation EGFR TKI Met + EML 4 ALK or ROS1 mutant PI3K mutant BRAF mutation KRAS mutant BRAF inhibitor PI3K inhibitor Resistance – rebiopsy T790M – irreversible EGFR TKI or 3rd generation EGFR TKI MET upregulation – Met inhibitor Resistance – rebiopsy Novel agent Met inhibition Resistance – rebiopsy Novel agent crizotinib Resistance – rebiopsy Novel agent MEK inhibitor combination Resistance – rebiopsy Ceritinib, alectinib Hsp90 inhibitor Novel ALK targeted agent Resistance – rebiopsy Novel Agent Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

Potential Future of NSCLC - Molecular Profiling
Adenocarcinoma EGFR mutation EGFR TKI – reversible or irreversible Global Resistance – rebiopsy T790M positive: 3rd generation EGFR TKI MET upregulation: Met inhibitor + EGFR TKI SCLC: chemo +/- EGFR TKI after Alternate upregulated pathway: combination targeted agent + EGFR TKI or EGFR TKI + immunotherapy Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Chemo monotherapy

Management of EGFR TKI resistant NSCLC

Similar presentations

Presentation on theme: "Management of EGFR TKI resistant NSCLC"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Management of EGFR TKI resistant NSCLC

Similar presentations

Presentation on theme: "Management of EGFR TKI resistant NSCLC"— Presentation transcript:

Similar presentations

About project

Feedback