Acquired resistance to EGFR TKIs in Lung Cancer (NSCLC)

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Discussion of mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibitors in lung cancer after an initial good response.

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  • -Met is a Receptor tyrosine kinase. -Following binding to its only known ligand, hepatic growth factor, Met receptors dimerize, leading to growth, migration and survival signals -Met is amplified, mutated, over-expressed or uniquely activated in many tumors -Expression of Met is associated with worse prognosis in NSCLC; additionally aberrant Met activation results in resistance to EGFR inhibitors -MetMAb is a unique one-armed antibody, designed to prevent HGF-mediated signaling
  • Methodology CONFIRM anti-total Met, as per manufacturer’s instructions Run on Ventana Benchmark instrument at GNE Negative controls (isotype control) performed on each specimen Positive controls (cell pellets) included on every run
  • Acquired resistance to EGFR TKIs in Lung Cancer (NSCLC)

    1. How Do We Manage Acquired Resistance to EGFR TKI Therapy? Howard (Jack) West, MD Swedish Cancer Institute Seattle, WA Challenging Cases in Breast & Lung Cancer Las Vegas, NV April 21, 2012
    2. Why Do We SeeAcquired Resistance?
    3. T790M Mutation • Most common mechanism of resistance to EGFR TKIs (50-68%) • May have a better prognosis than non-T790M mechanisms: 19 vs. 12 mo post-progression, Oxnard, CCR 2010N = 93 • T790M more likely to show progression in lungs/pleura • Non-T790M more likely to progress distantly, & worse PS
    4. Rapid Progression with Discontinuation of EGFR TKI after Prolonged PFS Rapid acceleration of disease progression resulting in hospitalization and/or death after discontinuation of gefitinib or erlotinib and before initiation of study drug (up to ~1/4 of pts in MSKCC series (Chaft, CCR, 2011) Last day of TKI Off EGFR TKI Resumed TKI Day 0 Day 21 Day 42From Riely, CCR 2007
    5. For Cancers with a Known Driver Mutation, ContinuingInhibition of that Target is Beneficial after Progression • Progression of CML on imatinib  increase dose, or dasatinib, or nilotinib lead to consistent response • Solid tumor example: HER2+ breast cancerMinckwitz, JCO 2009
    6. Such Patients Often Show Slow, Modest ProgressionBrakes may not be as good, but better than no brakes No change in therapy may be needed initially
    7. Combining Systemic and Local Targeted Therapies:Radiation (or Surgery) to Isolated Area of Progression Survival after RT to 1-2 sites of Freedom from Locoregional metastatic disease (Lung Ca) Recurrence after Chest RT 1.0 0.9 Freedom from Locoregional Recurrence EGFR mutation 0.8 0.7 0.6 0.5 0.4 EGFR wild type 0.3 0.2 0.1 0.0 0 12 24 36 48 60 72 84 96 108 Time (months)Kahn, Radiotherapy & Oncology, 2006 Mak, ASCO 2010, A#7016 Perhaps extend the idea of the “precocious metastasis” to “precocious recurrence”
    8. Overcoming T790M: Irreversible TKIs
    9. Irreversible TKIs in Clinical Trials• HKI-272 (EGFR + Her2) • RR 2% in TKI-resistant patients • Intriguing responses in G719X patients (Sequist, JCO 2010)• XL-647 (EGFR, Her2, VEGF) • RR 2% in TKI-resistant patients (Pennell, Chicago Lung ’08)• PF-299804 (EGFR + Her2) • RR 7% in TKI-resistant patients (Janne, ASCO ’09)• BIBW-2992 (EGFR + Her2) • RR 7% in TKI-resistant pts, 2 mo PFS increase (Miller, ESMO’10) • Interesting ongoing study combining afatinib and cetuximab based on a mouse model that was successfully treated w/ this combo
    10. LUX Lung 1• Does Afatinib work in patients with acquired resistance to first generation EGFR TKI?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 Randomization 2:1 Oral BIBW 2992 50 mg once daily Oral placebo once daily plus best supportive care plus best supportive care Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL, safety
    11. LUX Lung 1: Efficacy Progression-Free Survival Overall SurvivalMiller, ESMO 2010
    12. Implication of LUX Lung1• Lack of OS – OS of 11.9 months in Placebo group• Suggestive evidence of efficacy: – RR at 13.3% and PFS (HR 0.38)• Relationship to T790M not known• Future implication – Biomarker selection – Combination with cetuximab
    13. Afatinib/Cetuximab in EGFR TKI-Resistant NSCLC Dose escalation schema NSCLC w/ 3-6 patients per cohort EGFR mut’n1 and PD2 afatinib p.o. daily + escalating doses of SD ≥ 6 mo on Stop EGFR TKI cetuximab IV q 2 weeks erlotinib/gefitinib For ≥ 72 hours3 or Dose levels starting at: CR or PR afatinib 40 mg + to erlotinib/gefitinib cetuximab 250 mg/m2 Predefined maximum dose: afatinib 40mg + cetuximab 500 mg/m21 EGFR G719X, exon 19 deletion, L858R, L861Q2 Progression of disease (RECIST v1.1) on continuous treatment with erlotinib or gefitinib within the last 30 Expansion cohort part4 days. MTD cohort expanded3 Amended from original 14 days interval up to 80 EGFR mutation-positive patients:4 Acquisition of tumor tissue after the emergence of 40 T790M-positive and 40 T790M-negative acquired resistance was mandated Jangigian & Pao, ASCO 2011, #7525
    14. Afatinib + Cetuximab at MTD: Responses by EGFR Mutation40% confirmed response rate and a clinical benefit rate of 90%Jangigian & Pao, ASCO 2011, #7525
    15. Afatinib + Cetuximab: Insights & Future Directions• Remarkable efficacy seen in EGFR TKI- resistant tumors – Requires further validation• Activity not specific to common T790M mutant• Need to further define biology and refine patient population for phase III trial
    16. MET Overexpression
    17. Met Inhibitors in Clinical Trials• ARQ-197, specific MET inhibitor – Randomized phase II of erlotinib +/- ARQ-197 in TKI-naïve patients showed some benefit of combo but wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Schiller, ASCO 2010)• Met-Mab – Randomized phase II of erlotinib +/- MET-Mab in TKI-naïve pts showed benefit of combo, but again wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Spigel , ASCO 2011• XL-184, MET + RET + VEGF – Randomized phase II of erlotinib +/- XL-184 in TKI-resistant patients, completed but not reported yet• PF-02341066: – Still in early phase studies
    18. MetMAb is an anti-Met Monovalent Antibody that Inhibits HGF-MediatedActivation Rationale for targeting Met: HGF HGF • Met is amplified, mutated, overexpressed or uniquely activated in many tumors MetMAb • Met expression is associated with worse prognosis in many cancers including NSCLC Met Met • Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations MetMAb: Growth No Migration activity • One-armed format designed to Survival prevent HGF-mediated stimulation of pathwayHGF: Hepatocyte growth factor • Preclinical activity across multipleSpigel, ASCO 2011, #75051 tumor models
    19. Randomized Phase II: Erlotinib + MetMAb or Placebo in 2nd/3rd line NSCLCStage IIIB/IV NSCLC N = 692nd/3rd line Erlotinib 150 mg PO dailyTissue required R MetMAb 150 mg/kg IV Q3wkPS 0–2 AStratification factors: N•Tobacco history•Performance status D Erlotinib 150 mg PO daily•Histology Placebo IV Q3wk N = 68 N = 137 PD N = 27Co-primary objectives: Other key objectives:• PFS in ‘Met Diagnostic • OS in ‘Met Diagnostic positive’ add MetMAb positive’ patients (est. 50%) patients Must be eligible to be• PFS in overall ITT population • OS in overall ITT patients treated with MetMAb • Overall response rate • Safety/tolerabilitySpiegel, ASCO 2011, #7505
    20. Development of Met IHC for Use as a Companion Diagnostic• Technical metrics – Tissue was obtained from 100% of patients. – 93% of patients had adequate tissue for evaluation of Met by IHC• Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories Met Dx Met Dx Positive 1000 Negative MET mRNA (2-∆ct) Negative (0) Weak (1+) 100 Met Dx Negative 10 1 Moderate (2+) Strong (3+) Met Dx 0 Positive 0 1 2 3 MET IHC score• Met diagnostic status was assessed after randomization and prior to unblinding – ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining intensity 52% patients enrolled were ‘Met Diagnostic Positive’ Spiegel, ASCO 2011, #7505
    21. Erlotinib + MetMAb or Placebo in 2nd/3rd line NSCLC: Safety Met Diagnostic Positive Met Diagnostic Negative No.of patients (%) MetMAb + Placebo + erlotinib MetMAb + erlotinib Placebo + erlotinib erlotinib (n=31) (n=35) (n=31) (n=31) Any adverse event 31 (100) 35 (100) 31 (100) 31 (100) Grade ≥3 adverse 17 (54.8) 20 (57.1) 13 (41.9) 17 (54.8) event Serious adverse 11 (35.5) 15 (42.9) 9 (29.0) 13 (41.9) event Adverse events leading to treatment 2 (6.5) 8 (22.9) 0 (0) 2 (6.5) discontinuation Adverse events 4 (12.9) 1 (2.9) 0 (0) 3 (9.7) leading to deathSpiegel, ASCO 2011, #75051
    22. Erlotinib + MetMAb or Placebo: Efficacy in ITT Population PFS: HR=1.09 OS: HR=0.8 Placebo + MetMAb + Placebo + MetMAb + erlotinib erlotinib erlotinib erlotinib Median (mo) 2.6 2.2 Median (mo) 7.4 8.9 1.0 HR 1.09 1.0 HR 0.80Probability of progression free (95% CI) (0.73–1.62) (95% CI) (0.50–1.3) Log-rank p-value 0.69 Log-rank p-value 0.34 Probability of survival 0.8 No. of events 56 48 0.8 No. of events 41 34 0.6 0.6 0.4 0.4 0.2 0.2 Note: + = censored value. Note: + = censored value. 0.0 0.0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 Time to progression (months) Overall survival (months) Control arm was consistent with previous studies in a similar population (Br21 PFS 2.2 mo, OS 6.7 mo, ORR 8.9%) Spigel, ASCO 2011, #75051
    23. Erlotinib + MetMAb or Placebo: Efficacy in Met Diagnostic Positive NSCLC Patients PFS: HR=0.53 OS: HR=0.37 Placebo + MetMAb + Placebo + MetMAb + erlotinib erlotinib erlotinib erlotinib Median (mo) 1.5 2.9 Median (mo) 3.8 12.6 1.0 HR 0.53 1.0 HR 0.37 (95% CI) (0.28–0.99) (95% CI) (0.19–0.72)Probability of progression free Log-rank p-value 0.042 Log-rank p-value 0.002 0.8 No. of events 27 20 0.8 No. of events 26 16 Probability of survival 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 Time to progression (months) Overall survival (months) The addition of MetMAb to erlotinib doubled the progression free survival and nearly tripled the overall survival in this population Spigel, ASCO 2011, #75051
    24. ARQ-197: c-MET Receptor Tyrosine Kinase• Implicated in tumor cell migration, invasion, proliferation, and angio- genesis1• Only known high-affinity receptor for hepatocyte growth factor (HGF)1• c-MET amplification associated with: • Poor prognosis in NSCLC2 • Resistance to EGFR TKIs3,4 1. Birchmeier C and Gherardi E. Trends Cell Biol 1998;8:404–10 2. Cappuzzo F et al. JCO 2009;27:1667–74 3. Engelman JA et al. Science 2007;316:1039–43 4. Bean J et al. PNAS 2007;104:20932–7
    25. Rand Phase II: Erlotinib + Tivantinib (ARQ-197) or Placebo in Prev Treated Adv NSCLCInop Loc Adv/Met NSCLC>1 prior line of Rx N = 84 Erlotinib 150 mg PO dailyNo prior EGFR TKI R ARQ-197 360 mg PO BIDPS 0–2 AStratification factors:sex, age, ECOG PS, Nsmoking status, histology, D Erlotinib 150 mg PO daily prior Rx, best response, & Placebo PO BID geography (U.S. vs. ex- N = 83 U.S.) PD N = 167 N = 21 Endpoints add ARQ-197 • 1° PFS • 2° ORR, OS • Subset analysesSequist, JCO 2011 • Crossover: ORR
    26. Erlotinib + Tivantinib or Placebo: Efficacy (ITT Population)Sequist, JCO 2011
    27. Erlotinib + Tivantinib or Placebo: PFS & OS in Non-Squamous NSCLC PatientsSequist, JCO 2011
    28. Erlotinib + Tivantinib or Placebo: Time to New Metastatic Lesions (ITT & Non-Squamous)Sequist, JCO 2011
    29. Erlotinib + Tivantinib or Placebo: PFS in Histologic and Molecular Subgroups Placebo/ ARQ197/erlotinib erlotinib N Median PFS (95% CI, weeks) Unadjusted HR (95% CI) HR=1.05 Squamous Cell 26 / 24 13.7 (8.0‒18.1) 8.4 (7.9‒21.0) Non-Squamous Cell 58 / 59 18.9 (15.0‒31.1) 9.7 (8.0‒16.0) HR=0.71 HR=0.71 c-MET FISH >4 19 / 18 15.4 (8.1‒24.4) 15.3 (7.1‒16.3) HR=0.45 c-MET FISH >5 8 / 11 24.1 (16.3‒NE) 15.6 (7.9‒31.4) HR=1.23 EGFR mutant 6 / 11 24.1 (8.0‒32.1) 21.0 (8.1‒36.0) EGFR wt 51 / 48 13.7 (8.1‒18.1) 8.1 (7.9‒9.9) HR=0.70 KRAS mutant 10 / 5 9.7 (7.9‒NE) 4.3 (1.1‒8.0) HR=0.18 HR=1.01 KRAS wt 49 / 45 15.4 (8.1‒18.1) 9.9 (8.0‒16.0) 0 0.5 1.0 1.5 2.0 5.0Schiller, ASCO 2010 Favors Favors ARQ 197/Erlotinib Erlotinib/placebo
    30. Erlotinib + Tivantinib or Placebo: Crossover Patients 2 PR2 34 Crossover 23 Evaluable Patients for Response1 9 SD3 2 Pt # 24: EGFR IND 1 Baseline + ≥1 post-baseline scan. 12 PD KRAS WT Reasons for non-evaluable incl: c-MET > 4 - Clinical progression (n=4) - Active but haven’t received 1st post- Pt # 58: progression scan (n=2) EGFR MUT - Death (n=1) KRAS WT - Dosing delay (n=1) c-MET > 5 - Withdrew consent (n=1) - Investigator decision (n=1) 3 3‒18+ weeksSchiller, ASCO 2010
    31. Research Efforts for Acquired Resistance to EGFR TKIs• Afatinib/cetuximab looks very promising • Unexpectedly, not correlated with T790M • Phase III trial in development• MetMAb phase II trial encouraging in subset • Benefit appears limited to high Met expression (detrimental in low Met expression) • Phase III trial in development• Tivantinib phase II trial favorable, esp in non-squamous • Phase III trial now ongoing • Possibly particularly helpful for KRAS mut’n positive• Increasing interest in post-PD biopsies, though not yet useful outside of trial setting
    32. Acquired Resistance to EGFR TKIs: Practical Principles for the Clinic• Patients can respond to EGFR TKI with rechallenge, especially after long interval off of EGFR TKI (breaks onc rule of “you can never go back”• ?Consider local therapy to solitary area of PD• Some patients will have a rebound rapid progression after being taken off of an EGFR TKI • Heterogeneous populations of cancer cells • Is it better to continue the EGFR TKI and add an agent/regimen, or to stop it and potentially restart it later?? • I favor continuing EGFR TKI when PD < PR, but not when PD is very clear • No comparison and no good data to address this

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