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Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat?

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. Disclosure Slide. Background. Patients with CML and GIST have a high rate of response to treatment with imatinib.

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Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat?

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  1. Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat? Vincent A Miller, MDThoracic Oncology ServiceMemorial Sloan-Kettering Cancer Center

  2. 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. Acquired Resistance to TKI Pre-rx 4M 19M 23M 25M 21M bx

  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. Trials to Overcome Acquired Resistance * The number of patients enrolled into the trial with AR to EGFR TKIs was low.

  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 100 80 60 40 20 0 Survival of TKI_OS: Survival proportions OS_t790MOS_neg HR 0.46, p = 0.006 Percent survival Median OS T790M-positive = 47 months Median OS T790M-negative = 26 months 0 50 100 150 TKI_OS Courtesy of VA Miller.

  9. Survival from Progressive Disease 100 80 60 40 20 0 Survival of PPS: Survival proportions PPS_t790MPPS_neg HR 0.59, p = 0.057 Percent survival Post-PD survival T790M-positive = 22 months Post-PD survival T790M-negative = 14 months 0 20 40 60 80 PPS Courtesy of VA Miller.

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

  11. Afatinib (BIBW 2992) — Irreversible Dual EGFR/HER2 Inhibitor • Anilino quinazoline derivative • Activity versus T790M (100 nM) • Binds covalently to Cys773 of the EGFR and Cys805 of HER2 F F S N C l N C l N N N N N N N S O O O O N O N N O O O EGFR - Cys773 HER2 - Cys805 Solca F et al. 17th EORTC-NCI-AACR Symposium on “Molecular Targets and Cancer Therapeutics” Philadelphia, PA, USA, November 14 – 18, 2005.

  12. LUX-Lung 1: Trial Design • 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 (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)

  13. PFS by Independent Review 1.0 0.8 0.6 0.4 0.2 0.0 Placebo, PFS events = 133, median = 1.1 months (95% CI: 0.95-1.68) Afatinib, PFS events = 275, median = 3.3 months (95% CI: 2.79-4.40)Hazard ratio (95% CI) = 0.38 (0.306, 0.475)Log-rank test p-value <0.0001 Estimated PFS probability 0 3 6 9 12 15 18 PFS time since randomization (months) Number at risk 195 26 4 2 390 152 65 16 9 3 Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.

  14. Primary Analysis: Overall Survival Placebo, deaths = 114 (58.5%), median = 11.96 months (95% CI: 10.15-14.26)Afatinib, deaths = 244 (62.6%), median = 10.78 months (95% CI: 9.95-11.99)Hazard ratio (afatinib vs placebo) = 1.077 (0.862, 1.346)Log-rank test p-value (one-sided) = 0.7428 1.0 0.8 0.6 0.4 0.2 0.0 Estimated survival probability 0 3 6 9 12 15 18 21 24 Time to death since randomization (months) Number at risk 195 169 142 112 65 33 18 5 390 344 283 217 122 69 32 12 Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.

  15. Summary – HOPP Lab Animal Studies (number in parentheses = number of mice treated and assessed)

  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. Study Schema 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/m2 Predefined maximum dose: afatinib 40 mg +cetuximab 500 mg/m2 NSCLC withEGFR mutation AND Stable disease(SD) ≥6 months on erlotinib/gefitinib OR Partial orcomplete responseto erlotinib/gefitinib Stop erlotinib/gefitinib for≥72 hours Diseaseprogression Expansion cohort part MTD cohort expandedup to 80 EGFR mutation-possible patients:40 T790M-positive and 40 T790M-negative

  20. Inclusion criteria: Pathologically confirmed NSCLC Presence of EGFR drug-sensitizing mutations1 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 Patient Eligibility 1 EGFR G719X, exon 19 deletion, L858R, L861Q mandated in MTD expansion cohort

  21. Patient Characteristics *Ongoing trial – T790M status not available in all patients

  22. Dose cohorts tested in the dose escalation: Afatinib 40 mg + 250 mg/m2 cetuximab (n = 4) Afatinib 40 mg + 500 mg/m2 cetuximab (n = 6) No DLT occurred in cycle 1 (28 days) Pre-defined MTD = RPIID: Afatinib 40 mg daily + cetuximab 500 mg/m2 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 mutation Uninformative 70 60 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 Maximum percentage decrease from baseline (%) 0 4 8 12 16 20 24 28 32 36 40 44 48 Patient index sorted by maximum % decrease With permission from Janjigian Y et al. Proc ASCO 2011;Abstract 7525.

  24. Afatinib + Cetuximab at MTDResponses by Mutation *Two patients were not evaluable for efficacy

  25. Case Presentation • Middle-aged female diagnosed with Stage III-A lung adenocarcinoma in 2004 • 10 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 Jackman J Clin Oncol 2009

  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. 9/14/10 10/11/10

  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 197-209: Study DesignRandomized, placebo-controlled, double-blind clinical trial R A N D O M I Z E Erlotinib 150 mg PO QD + ARQ 197 360 mg PO BID 28-day cycle • NSCLC • Inoperable locally adv/metastatic dz • ≥1 prior chemo (no prior EGFR TKI) PD Erlotinib 150 mg PO QD + placebo 28-day cycle • Endpoints • 1° PFS • 2° ORR, OS • Subset analyses • Crossover: ORR • 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) With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.

  31. ARQ 197-209: Progression-Free Survival (ITT Population) 1.0 • 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* 0.9 0.8 0.7 Erlotinib + ARQ 197 16.1 wks(n = 84) 0.6 Proportion of patients progression-free 0.5 0.4 0.3 0.2 Erlotinib + placebo 9.7 wks(n = 83) 0.1 0 50 0 10 20 30 40 Time from randomization (weeks) • * Cox regression model • PFS also measured by independent radiographic review: • - median 15.6 vs 8.4 wks • - unadjusted/adjusted HR = 0.74/0.51 With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.

  32. ARQ 197-209: Overall Survival (ITT Population) 1.0 • 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* 0.9 0.8 Erlotinib + ARQ 197: 36.6 wks(n = 84) 0.7 0.6 Proportion of patients surviving 0.5 0.4 Erlotinib + placebo: 29.4 wks(n = 83) 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 70 Survival time (weeks) *Cox regression model With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.

  33. MetMAb Is an Anti-MetMonovalent 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 HGF MetMAb Met Met 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 n = 64 Arm AErlotinib (150 qd-oral) + MetMAb (15 mg/kg IV q3w) n = 128 1:1 RANDO M IZ A T I O N • Key eligibility: • Stage IIIB/IV NSCLC • 2nd/3rd-line NSCLC • Tissue required • PS 0-2 • Stratification factors: • Tobacco history • Performance status • Histology n = 64 Arm BErlotinib (150 qd-oral) +placebo (IV q3w) • 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 PD Addition of MetMAb* n = 23 • Enrollment from 3/2009 to 3/2010 • Data cut-off: June 8, 2010 * If eligible With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.

  35. PFS and OS: MET High Population Erlotinib +MetMAb(n = 35) Erlotinib +Placebo(n = 30) OS, HR = 0.55 PFS, HR = 0.56 Erlotinib +Placebo(n = 30) Erlotinib +MetMAb(n = 35) Median OS (mo)Hazard ratiop-value# Events 7.7 7.4 1.0 1.0 0.550.1113 0.8 0.8 20 13 Median PFS (wk)Hazard ratiop-value# Events 6.4 12.4 0.560.0547 0.6 0.6 Probability of Survival 25 Probability of Progression Free 19 0.4 0.4 0.2 0.2 0 0 0 3 6 9 12 15 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time to Progression (weeks) Overall Survival (months) Number at Risk: Number at Risk: Erlotinib + placebo Erlotinib + placebo 3035 1726 910 33 01 00 3035 1822 59 35 33 21 21 01 01 Erlotinib + MetMAb Erlotinib + MetMAb • MetMAb + erlotinib improves both PFS and OS in • MET high NSCLC patients With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.

  36. PFS and OS: MET Low Population Erlotinib +MetMAb(n = 27) Erlotinib +Placebo(n = 29) PFS, HR = 2.01 OS, HR = 3.02 Median OS (mo)Hazard ratiop-value# Events 9.2 5.5 Erlotinib +Placebo(n = 29) Erlotinib +MetMAb(n = 27) 3.020.0212 1.0 1.0 14 9 11.4 6.0 Median PFS (wk)Hazard ratiop-value# Events 0.8 0.8 2.010.0354 20 23 0.6 0.6 Probability of Survival Probability of Progression Free 0.4 0.4 0.2 0.2 0 0 0 3 6 9 12 15 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 51 Overall Survival (months) Time to Progression (weeks) Number at Risk: Number at Risk: Erlotinib + placebo Erlotinib + placebo 2927 2312 93 30 00 00 2927 2215 95 61 20 20 00 00 00 Erlotinib + MetMAb Erlotinib + MetMAb • MET low NSCLC patients do worse with • MetMAb + erlotinib With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.

  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 2992 + cetuximab • HSP-90 inhibitor + chemo or EGFR-TKI • Add MET inhibitor - best diagnostic unclear

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