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Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat? Vincent A Miller, MD Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center.

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Presentation on theme: "Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat? Vincent A Miller, MD Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center."— Presentation transcript:

1 Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat? Vincent A Miller, MD Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center

2 Consultant ArQule, Boehringer Ingelheim Pharmaceuticals Inc, Genentech BioOncology, Lilly USA LLC, OSI Pharmaceuticals Inc, Sanofi Grant/Research Boehringer Ingelheim Pharmaceuticals Inc, Lilly USA LLC, Sanofi Disclosure Slide

3 Background Patients with CML and GIST have a high rate of response to treatment with imatinib. These patients commonly acquire resistance after an initial response. There are a small number of conserved changes in the BCR-ABL tyrosine kinase domain which confer resistance in vivo. Other patients with acquired resistance have amplification of the BCR-ABL gene. Virtually all patients with response to gefitinib or erlotinib eventually have progression of disease.

4 21M 23M25M Pre-rx4M 19M bx Acquired Resistance to TKI

5 Clinical Definition of Acquired Resistance to EGFR TKIs in Lung Adenocarcinoma Prior treatment with single agent TKI Either: –EGFR ex 19 del, L858R, G719X, L861Q –PR or CR with TKI or SD lasting ≥6 months PD by RECIST or WHO in previous 30 days No therapy after TKI before start of new agent “Washout” after stopping TKI not >5 half-lives of the TKI (14 days for gefitinib or erlotinib) Obtain baseline scan on day 1 Jackman J Clin Oncol 2009

6 TreatmentRR (%)Reference EGFR TKI + everolimus0Riely et al CCR ‘07 Everolimus2Soria et al Ann Oncol ‘09 Neratinib3Sequist et al JCO ‘10 IPI-5044Sequist et al JCO ‘10 Erlotinib + cetuximab0Janjigian et al CCR ‘11 Dasatinib/erlotinib + dasatinib0/0Johnson et al JTO in press XL6474Miller et al PASCO ‘08 PF Campbell et al PASCO ‘10 PF * (only 2 pts w/ EGFR mt)Park et al PASCO ‘10 Erlotinib + XL1848 (only 1 pt w/ EGFR mt)Wakelee et al PASCO ‘10 Afatinib/placebo7/0.5Miller et al PESMO ‘10 * The number of patients enrolled into the trial with AR to EGFR TKIs was low. Trials to Overcome Acquired Resistance

7 T790M in Acquired Resistance Acquired exon 20 mutation found in >50% of pts with acquired resistance to TKI Increases relative affinity of mutant EGFR for ATP, may also cause steric hindrance Less commonly detected in CNS, thought to be due to poor CNS penetrance of TKI

8 Overall Survival from Start of TKI Survival of TKI_OS: Survival proportions HR 0.46, p = Median OS T790M-positive = 47 months Median OS T790M-negative = 26 months TKI_OS Percent survival OS_t790M OS_neg Courtesy of VA Miller.

9 Survival from Progressive Disease Survival of PPS: Survival proportions HR 0.59, p = Post-PD survival T790M-positive = 22 months Post-PD survival T790M-negative = 14 months PPS Percent survival PPS_t790M PPS_neg Courtesy of VA Miller. 40

10 T790M as a Biomarker T790M-type resistance –Longer survival –Later metastases –Indolent growth –Sensitivity to 2 nd -line EGFR inhibitors? Non-T790M-type resistance –Poorer survival –Earlier metastases –More aggressive? –Needs mechanisms better elucidated and alternate therapies?

11 EGFR - Cys 773 HER2 - Cys 805 Solca F et al. 17 th EORTC-NCI-AACR Symposium on “Molecular Targets and Cancer Therapeutics” Philadelphia, PA, USA, November 14 – 18, N N N F Cl O O N O N N S O N S O N N N F Cl O O N O N Afatinib (BIBW 2992) — Irreversible Dual EGFR/HER2 Inhibitor Anilino quinazoline derivative Activity versus T790M (100 nM) Binds covalently to Cys 773 of the EGFR and Cys 805 of HER2

12 LUX-Lung 1: Trial Design Randomization 2:1 (Double blind) Oral afatinib 50 mg once daily plus BSC Oral placebo once daily plus BSC Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL (LC13 & C30), safety Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter Exploratory biomarkers: Archival tissue testing for EGFR mutations (optional; central lab) Serum EGFR mutational analysis (all patients) Patients with: Adenocarcinoma of the lung Stage IIIB/IV Progressed after one or two lines of chemotherapy (incl one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib ECOG 0–2 N = 585

13 PFS by Independent Review Placebo, PFS events = 133, median = 1.1 months (95% CI: ) Afatinib, PFS events = 275, median = 3.3 months (95% CI: ) Hazard ratio (95% CI) = 0.38 (0.306, 0.475) Log-rank test p-value < PFS time since randomization (months) Estimated PFS probability Number at risk Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.

14 Primary Analysis: Overall Survival Placebo, deaths = 114 (58.5%), median = months (95% CI: ) Afatinib, deaths = 244 (62.6%), median = months (95% CI: ) Hazard ratio (afatinib vs placebo) = (0.862, 1.346) Log-rank test p-value (one-sided) = Time to death since randomization (months) Estimated survival probability Number at risk Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.

15 DrugL858RL858R + T790MT790M Remove doxResponse (6)Response (9)Response (5) PlaceboNo response (3)No response (6)No response (2) ErlotinibResponse (12)No response (6)No response (5) Pemetrexedn/aNo response (4)n/a Paclitaxeln/aNo response (5)n/a CetuximabResponse (6)No response (7)No response (2) Erloti/cetuxn/aNo response (4)n/a BIBW 2992Response (4)No response (6)n/a BIBW/cetuxn/aResponse! (8)n/a (number in parentheses = number of mice treated and assessed) Summary – HOPP Lab Animal Studies

16 Hypothesis We hypothesized that the combination of afatinib and cetuximab would overcome acquired resistance to erlotinib or gefitinib in patients with non-small cell lung cancer (NSCLC)

17 Methods: Study Design Phase Ib, open-label, multicenter trial in the US and the Netherlands Primary objective: Maximum tolerated dose (MTD) and recommended Phase II dose (RPIID) for afatinib and cetuximab in patients with acquired resistance to erlotinib and gefitinib Primary endpoint: –Occurrence of dose-limiting toxicity (DLT) Secondary endpoints include: –Safety as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading system –Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed at weeks 4, 8 and 12, and every 8 weeks thereafter

18 Methods Definitions of DLTs (CTCAE V3): Grade ≥2 decrease in cardiac left ventricular function Grade ≥2 diarrhea lasting for ≥7days, despite anti-diarrheal therapy Grade ≥3 rash or nausea/vomiting despite medical management Grade ≥3 fatigue lasting for ≥7 days Grade 3 or 4 hypomagnesemia with clinically significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia and allergic reaction) leading to an interruption of afatinib/cetuximab for ≥14 days until recovery

19 Expansion cohort part MTD cohort expanded up to 80 EGFR mutation- possible patients: 40 T790M-positive and 40 T790M-negative NSCLC with EGFR mutation AND Stable disease (SD) ≥6 months on erlotinib/gefitinib OR Partial or complete response to erlotinib/gefitinib Disease progression Stop erlotinib/ gefitinib for ≥72 hours Dose escalation schema 3-6 patients per cohort Afatinib PO daily + escalating doses of intravenous (IV) 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 Study Schema

20 1 EGFR G719X, exon 19 deletion, L858R, L861Q mandated in MTD expansion cohort Patient Eligibility Inclusion criteria: Pathologically confirmed NSCLC Presence of EGFR drug-sensitizing mutations 1 or RECIST response, or SD ≥6 months Systemic progression of disease on continuous treatment with erlotinib or gefitinib within 30 days No systemic therapy between cessation of gefitinib/erlotinib and initiation of the study treatment Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 Age ≥18 years Exclusion criteria: Prior treatment with EGFR targeting antibodies Prior severe infusion reaction to a monoclonal antibody Patients with disease progression only in the central nervous system Symptomatic brain metastases

21 Patient Characteristics Afatinib 40 mg Total Cetuximab 250 mg/m 2 Cetuximab 500 mg/m 2 n (%)4 (8)47 (92)51 Median age, years (range)63 (49–76)61 (41–82) Women, n (%)1 (25)36 (77)37 (73) Ethnicity: White/Black/Asian/American Indian, %75/0/25/083/4/13/082/4/14/0 Baseline ECOG 0/1/2, %25/75/021/75/422/75/4 Median time on erlotinib/gefitinib, months Prior chemotherapy, n (%)3 (75)36 (77)39 (77) T790M-positive*, n (%)—27 (57)27 (53) T790M-negative*, n (%)2 (50)15 (32)17 (33) EGFR deletion 19, n (%)2 (50)27 (58)29 (57) EGFR L858R, n (%)1 (25)17 (36)18 (35) Unknown/other, n (%)2 (50) 5 (11)7 (14) * Ongoing trial – T790M status not available in all patients

22 Dose cohorts tested in the dose escalation: –Afatinib 40 mg mg/m 2 cetuximab (n = 4) –Afatinib 40 mg mg/m 2 cetuximab (n = 6) –No DLT occurred in cycle 1 (28 days) Pre-defined MTD = RPIID: –Afatinib 40 mg daily + cetuximab 500 mg/m 2 47 patients have been enrolled in the MTD expansion cohort to date out of 80 planned –12 (26%) patients discontinued due to progression of disease –Six (13%) patients discontinued due to toxicity Results

23 Afatinib + Cetuximab at MTD: Responses by Mutation T790M+T790M-No mutationUninformative Patient index sorted by maximum % decrease Maximum percentage decrease from baseline (%) With permission from Janjigian Y et al. Proc ASCO 2011;Abstract 7525.

24 T790M positive T790M negative T790M unknown No EGFR mutationTotal Total treated Evaluable for efficacy* Best responsen (%) Any PR13 (50)8 (57)2 (67)—23 (51) Confirmed PR9 (35)7 (50)2 (67)—18 (40) SD11 (42)5 (36)1 (33)—19 (42) Clinical response (any PR + SD) 24 (92)13 (93)3 (100)2 (100)42 (93) Progression of disease2 (8)1 (7)——3 (7) * Two patients were not evaluable for efficacy Afatinib + Cetuximab at MTD Responses by Mutation

25 Jackman J Clin Oncol 2009 Case Presentation Middle-aged female diagnosed with Stage III-A lung adenocarcinoma in pack-yr smoker, no symptoms Treated with chemotherapy, lobectomy and adjuvant RT followed by adjuvant erlotinib May 2007 isolated bone met, treated with bisphosphonate, analgesics May 2008 XRT L hip June 2008 renal metastasis

26 Case Presentation Erlotinib continued February 2009 clinical trial with dasatinib – POD May 2009 pemetrexed added and then bevacizumab added – initial response then POD in October 2010 KPS 60-70% Left hip pain, nausea, malignant pleural effusion, nausea, hematuria Opiates, oxygen required

27 Case Presentation (cont’d) Commenced afatinib and cetuximab Nausea resolved; weight gain Opiates stopped, no need for wheelchair or cane Hematuria absent KPS 80% Tox – Grade 1 rash, xerosis, paronychia

28 9/14/1010/11/10

29 What Causes Non-T790M Resistance? 47 of 93 patients (51%) had tissue available for MET FISH –9 patient specimens failed testing 4 of 38 patients (11%) had MET:CEP7 ratio >2 –1 pt with high level amplification + T790M –2 of 3 pts with low level amplification had T790M Is FISH the optimal way to test for MET amplification?

30 ARQ : Study Design Randomized, placebo-controlled, double-blind clinical trial RANDOMIZERANDOMIZE Erlotinib 150 mg PO QD + placebo 28-day cycle Erlotinib 150 mg PO QD + placebo 28-day cycle Erlotinib 150 mg PO QD + ARQ mg PO BID 28-day cycle Erlotinib 150 mg PO QD + ARQ mg PO BID 28-day cycle Endpoints 1° PFS 2° ORR, OS Subset analyses Crossover: ORR NSCLC Inoperable locally adv/metastatic dz ≥1 prior chemo (no prior EGFR TKI) 33 sites in 6 countries Study accrual over 11 months (10/08-9/09) Randomization stratified by prognostic factors incl sex, age, smoking, histology, performance status, prior therapy and best response, and geography (US vs ex-US) PD With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.

31 ARQ : Progression-Free Survival (ITT Population) Proportion of patients progression-free Time from randomization (weeks) Erlotinib + ARQ wks (n = 84) Erlotinib + placebo 9.7 wks (n = 83) * Cox regression model PFS also measured by independent radiographic review: - median 15.6 vs 8.4 wks - unadjusted/adjusted HR = 0.74/0.51 HR = 0.81 (95% CI: 0.57, 1.15); p = 0.24 Adjusted HR = 0.68 (95% CI: 0.47, 0.98); p < 0.05* With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.

32 ARQ : Overall Survival (ITT Population) HR = 0.88 (95% CI: 0.60, 1.3); p = 0.50 Adjusted HR = 0.88 (95% CI: 0.6, 1.3); p = 0.52* Erlotinib + ARQ 197: 36.6 wks (n = 84) Erlotinib + placebo: 29.4 wks (n = 83) Survival time (weeks) Proportion of patients surviving *Cox regression model With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.

33 MetMAb Is an Anti-Met Monovalent Antibody That Inhibits HGF-Mediated Activation Rationale for targeting Met: –Met is amplified, mutated, overexpressed in many tumors –Met expression is associated with a worse prognosis in many cancers including NSCLC –Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations MetMAb: –One-armed format designed to prevent HGF-mediated stimulation of pathway –Preclinical activity across multiple tumor models HGF Met MetMAb Growth, migration, survival No activity With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.

34 OAM4558g Study Design: Global, Double- Blind, Placebo-Controlled, Phase II Study Arm A Erlotinib (150 qd-oral) + MetMAb (15 mg/kg IV q3w) Addition of MetMAb* PD * If eligible Co-primary objectives: PFS in “MET High” patients PFS in overall ITT population Other key objectives: OS in “MET High” patients OS in overall ITT patients Overall response rate Safety/tolerability Key eligibility: Stage IIIB/IV NSCLC 2 nd /3 rd -line NSCLC Tissue required PS 0-2 RANDOMIZATIONRANDOMIZATION 1:1 n = 128 n = 64 n = 23 - Enrollment from 3/2009 to 3/ Data cut-off: June 8, 2010 Arm B Erlotinib (150 qd-oral) + placebo (IV q3w) With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15. Stratification factors: Tobacco history Performance status Histology

35 PFS, HR = 0.56 OS, HR = 0.55 MetMAb + erlotinib improves both PFS and OS in MET high NSCLC patients With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15. Probability of Progression Free Time to Progression (weeks) Median PFS (wk) Hazard ratio p-value # Events Probability of Survival Overall Survival (months) Median OS (mo) Hazard ratio p-value # Events Erlotinib + Placebo (n = 30) Erlotinib + placebo Erlotinib + MetMAb (n = 35) Erlotinib + MetMAb Number at Risk: PFS and OS: MET High Population Erlotinib + Placebo (n = 30) Erlotinib + MetMAb (n = 35)

36 PFS and OS: MET Low Population PFS, HR = 2.01 OS, HR = 3.02 MET low NSCLC patients do worse with MetMAb + erlotinib With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15. Probability of Progression Free Time to Progression (weeks) Number at Risk: Probability of Survival Overall Survival (months) Number at Risk: Erlotinib + placebo Erlotinib + Placebo (n = 29) Erlotinib + placebo Erlotinib + MetMAb Erlotinib + MetMAb (n = 27) Erlotinib + MetMAb Median PFS (wk) Hazard ratio p-value # Events Median OS (mo) Hazard ratio p-value # Events Erlotinib + Placebo (n = 29) Erlotinib + MetMAb (n = 27)

37 Approach to Therapy of Acquired Resistance to EGFR TKIs Rebiopsy the patient –T790M prognostic and possibly predictive biomarker –Rare transformation to small cell phenotype Continue an EGFR TKI “Second generation” EGFR/ErbB2 TKIs Rational combination strategies –BIBW cetuximab –HSP-90 inhibitor + chemo or EGFR-TKI –Add MET inhibitor - best diagnostic unclear


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