West egfr mutation acquired resistance

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Review by Dr. H. Jack West of current understanding of mechanisms behind and emerging treatment options for patients with advanced NSCLC with acquired resistance to EGFR tyrosine kinase inhibitors after a good initial response.

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West egfr mutation acquired resistance

  1. 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 San Francisco, CA October 22, 2011
  2. 2. Why Do We SeeAcquired Resistance?
  3. 3. Overcoming T790M: Irreversible TKIs
  4. 4. 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 Oxnard, Clin Cancer Res 2010
  5. 5. 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
  6. 6. Such Patients Often Show Slow, Modest ProgressionBrakes may not be as good, but better than no brakes
  7. 7. 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
  8. 8. LUX-Lung 1: Trial designPatients 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 (Double Blind) Oral afatinib (BIBW2992) 50 mg once daily Oral placebo once daily plus BSC 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) Miller, ESMO 2010
  9. 9. Maximum decrease in tumor size from baseline (independent review) Miller, ESMO 2010
  10. 10. Afatinib vs. Placebo:Disease control rate and objective responses Independent Review Afatinib (%) Placebo (%)PR, (regardless of confirmation) 13* 0.5PR, (confirmed) 7* 0.5SD ≥ 8 wks 51 18DCR (PR+SD) ≥ 8 wks 58** 19Median duration of confirmed response: 24 weeks* P < 0.01 compared to placebo** P < 0.0001 compard to placebo Miller, ESMO 2010
  11. 11. Afatinib vs. Placebo:PFS by independent review Miller, ESMO 2010
  12. 12. Afatinib vs. Placebo: Patient Reported Outcomes*All scores were estimated from the EORTC QLQ-LC13 except for “Short of Breath” and “Pain” which used EORTC QLQ-C30; improvedmeans that EORTC symptom scores were ≥10 points lower than baseline at any time during the study**EORTC cough, dyspnea and pain endpoints as pre-specified in the trial protocol Miller, ESMO 2010
  13. 13. Afatinib vs. Placebo:Primary analysis of Overall Survival Miller, ESMO 2010
  14. 14. 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, L861Q2Progression of disease (RECIST v1.1) on continuous treatment with erlotinib or gefitinib within the last 30 Expansion cohort part4 days. MTD cohort expanded3Amended from original 14 days interval up to 80 EGFR mutation-positive patients:4Acquisition of tumor tissue after the emergence of 40 T790M-positive and 40 T790M-negative acquired resistance was mandated Jangigian & Pao, ASCO 2011, #7525
  15. 15. Afatinib + Cetuximab at MTD: Responses by EGFR Mutation40% confirmed response rate and a clinical benefit rate of 90%Jangigian & Pao, ASCO 2011, #7525
  16. 16. 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
  17. 17. MET Overexpression
  18. 18. 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
  19. 19. 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
  20. 20. 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/tolerabilitySpigel, ASCO 2011, #7505
  21. 21. 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 1000 Negative Positive MET mRNA (2-Δct) 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’ Spigel, ASCO 2011, #7505
  22. 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) Probability of survival Log-rank p-value 0.69 Log-rank p-value 0.34 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. 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 0.37Probability of progression free (95% CI) (0.28–0.99) (95% CI) (0.19–0.72) 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. 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. 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. 26. Erlotinib + Tivantinib or Placebo: Efficacy (ITT Population)Sequist, J Clin Oncol 2011
  27. 27. Erlotinib + Tivantinib or Placebo: PFS & OS in Non-Squamous NSCLC PatientsSequist, J Clin Oncol 2011
  28. 28. Erlotinib + Tivantinib or Placebo: Time to New Metastatic Lesions (ITT & Non-Squamous)Sequist, J Clin Oncol 2011
  29. 29. Erlotinib + Tivantinib or Placebo: PFS in Histologic and Molecular Subgroups ARQ197/ Placebo/ 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. 30. Erlotinib + Tivantinib or Placebo: Crossover Patients 2 PR2 2 Pt # 24: EGFR IND 34 Crossover 23 Evaluable KRAS WT Patients for Response1 9 SD3 c-MET > 4 Pt # 58: EGFR MUT 1 Baseline + ≥1 post-baseline scan. 12 PD KRAS WT Reasons for non-evaluable incl: c-MET > 5 - Clinical progression (n=4) - Active but haven’t received 1st post- progression scan (n=2) 3 3‒18+ weeks - Death (n=1) - Dosing delay (n=1) - Withdrew consent (n=1) - Investigator decision (n=1)Schiller, ASCO 2010
  31. 31. Research Efforts for Acquired Resistance to EGFR TKIs•  Afatinib/cetuximab 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
  32. 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”•  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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