Advances in Understanding EGFR Resistance Pathways

Transcription

1 Advances in Understanding EGFR Resistance Pathways Philip C. Mack, PhD Assistant Adjunct Professor UC Davis Cancer Center Resistance to EGFR Inhibitors Primary vs Secondary Primary: best response = progressive disease (PD) Secondary: initial response relapse Potential Mechanisms of Resistance Pharmacodynamic Dose response Altered pharmacokinetics (active smoking) Molecular Mechanisms EGFR signaling not critical to cell survival or proliferation Downstream or alternative signaling factors engaged Theoretical Algorithm for Treatment of Advanced NSCLC EGFR mutation+ No Resistance markers (KRAS, cmet, T790M, etc) Consenting Patients With Advanced NSCLC, with plasma, archival material Molecular Analysis EGFR FISH+ High EGFR ligands? KRAS wt? Unfavorable EGFR markers Favorable expression of: ERCC1 RRM1 BRCA1 Yes No Front line erlotinib or doc erlot carbo/pac + cetuximab (+/-Bev) Platinum doublet Non-Plat Doublet (+/- Bev) T790M Mut No T790M CTCs pos for cmet/igf-1r? No EGFR Resistance low TS, etc all others low TS, etc all others Yes No Second line XL-647 or HKI-272 erlotinib with targeted agent Appropriate Chemo erlotinib pemetrexed docetaxel pemetrexed docetaxel Relative Sensitivity and Resistance to EGFR TKIs Sensitivity Resistance Activating EGFR mutations In-frame deletions in exon 19 (del ) Point mutations in exon 21 (L858R) EGFR high copy number Gene amplification High polyploidy EGFR-epiregulin loops Absence of EGFR Protein Expression Exon 20 mutations (T790M) Alternative signal transduction c-met amplification Her3 activation Downstream signaling events KRAS PTEN, pakt 1

2 Relative Sensitivity and Resistance to Cetuximab EGFR Inhibitors: Sensitivity and Resistance Sensitivity Resistance Activating EGFR mutations In-frame deletions in exon 19 (del ) Point mutations in exon 21 (L858R) EGFR high copy number Gene amplification High polyploidy EGFR-epiregulin loops Absence of EGFR Protein Expression Exon 20 mutations (T790M) Alternative signal transduction c-met amplification Her3 activation Downstream signaling events KRAS PTEN, pakt Oncogenic Abnormalities indicative of sensitivity to EGFR inhibitors Oncogenic Abnormalities indicative of Resistance to EGFR inhibitors KRAS mutations in NSCLC 15-25% Addition of Cetuximab Shows Benefit in Patients with Wild-type KRAS in Phase III Trials CRYSTAL Trial: Cetuximab plus FOLFIRI versus FOLFIRI in Patients with mcrc (Van Cutsem ASCO 2008) OPUS Trial: Cetuximab plus FOLFOX4 versus FOLFOX4 in Patients with mcrc (Bokemeyer ASCO 2008) CRYSTAL Trial Impact of KRAS Mutations on PFS Tissue available from 45% of patients (540 of 1198 pts) 36% KRAS Van Cutsem, ASCO

3 CRYSTAL Trial: Relationship between KRAS status and PFS Cetuximab + FOLFIRI KRAS WT KRAS HR=0.63; p=0.007 mpfs wt KRAS: 9.9 mo. mpfs KRAS 7.6 mo. FOLFIRI only KRAS WT KRAS HR=0.97; p=0.87 mpfs wt KRAS: 8.1 mo. mpfs KRAS 8.7 mo. S0342: Response to Therapy by KRAS status S0342: a phase II study of sequential versus concurrent paclitaxel, carboplatin, and cetuximab Tissue Specimens 216 Patients enrolled 76 Available for FISH 45 Available for KRAS 110 Plasma samples available S0342: KRAS status and PFS S0342: KRAS status and Overall Survival 100% 80% Progression-free survival by KRAS in plasma or tissue Wild-Type Other N Events P =.65 Median in Months % 80% Overall survival by KRAS in tissue or plasma Wild type N P =.17 Events Median in Months % 60% 40% Wild-Type 40% Wild-Type 20% 20% 0% Months After Registration 0% Months After Registration 3

4 Role of KRAS in Cetuximab Efficacy In Metastatic Colorectal Cancer: KRAS Mutations are predictive of a lack of response to cetuximab In Metastatic NSCLC: Analysis of S0342 showed a nonsignificant trend towards a worse overall survival for patients with KRAS mutations Not controlled: all patients received CT and cetuximab May be responding only to chemotherapy component May be purely prognostic for poor outcome KRAS may not play as definitive a role in NSCLC as it does in CRC. Future NSCLC Research Analysis of KRAS in large randomized trials (FLEX, BMS-099) Relationship between EGFR Mutations and Clinical Response to Docetaxel Erlotinib /2 4/10 0/20 0/13 CR PR SD PD T790M resistance mutation identified de novo EGFR E19/21 EGFR E20 wt EGFR mt KRAS Association between activating mutation and response: p = (Fisher s Exact Test) Progression-free Survival by Mutation Type Probability WT KRAS E20 E19/ Months EGFR WT: 4.0 months (n = 37) KRAS : 1.4 months (n = 2) E20 : 3.9 months (n = 4) EGFR E19/21: 18.3 months (n = 6) Significant difference in PFS between E19/E21 mutations and: 1) EGFR WT: p = ) All others: p = EGFR Inhibitors: Active in EGFR Resistance (T790M) TKI (reversible) TKI (irreversible) Antibody Gefitinib XL-647 Cetuximab Erlotinib CI-1033 Panitumumab Lapatinib HKI-272 EMD 7200 ZD6474 HKI-357 CL BIBW 2992 Regimen: Intermittent Docetaxel and Erlotinib 4

5 Reversal of Resistance to T790M mutation by 2 nd Generation EGFR TKIs (HKI-272, HKI-357, EKB-569) Role of Her3 and c-met Amplification in Resistance to EGFR TKIs Kwak: PNAS, 2005 H1975 cells (L858R + T790M mutation) Arteaga: Nat Med, 2007 (reviewing Engelman et al: Science 2007) Role of Her3 and c-met Amplification in Resistance to Gefitinib Role of Her3 and c-met Amplification in Resistance to Gefitinib Arteaga: Nat Med, 2007 Arteaga: Nat Med,

6 Algorithm for Management of Resistance to 1 st Generation EGFR TKI (Gefitinib or Erlotinib) Patient with Clinical Resistance Algorithm for Management of Resistance to 1 st Generation EGFR TKI (Gefitinib or Erlotinib) Patient with Clinical Resistance EGFR Dependent EGFR Independent EGFR Dependent EGFR Independent T790M Mutation Activation of alternative pathway T790M Mutation Activation of C-Met Pharmacodynamic Pharmacodynamic 2 nd Gen EGFR TKI EGFR TKI plus targeted Inhibitor Increase Dose?? Alternative Therapy 2 nd Gen EGFR TKI EGFR TKI plus C-Met Inhibitor Increase Dose?? Alternative Therapy Theoretical Algorithm for Treatment of Advanced NSCLC EGFR mutation+ No Resistance markers (KRAS, cmet, T790M, etc) Front line erlotinib or doc erlot T790M Mut No T790M CTCs pos for cmet/igf-1r? Yes No Second line XL-647 or HKI-272 erlotinib with targeted agent Appropriate Chemo Consenting Patients With Advanced NSCLC, with plasma, archival material Molecular Analysis EGFR FISH+ High EGFR ligands? KRAS wt? Unfavorable EGFR markers Favorable expression of: ERCC1 RRM1 BRCA1 Yes No carbo/pac + cetuximab (+/-Bev) Platinum doublet Non-Plat Doublet (+/- Bev) No EGFR Resistance low TS, etc all others low TS, etc all others erlotinib pemetrexed docetaxel pemetrexed docetaxel 6

7 8 Predictive Versus Prognostic Markers EGFR kinase domain mutation likely both a favorable prognostic factor and predictive of response to EGFR TKIs KRAS mutation trend towards being an unfavorable prognostic factor and a strong predictor of resistance to EGFR TKIs and monoclonal antibodies (i.e., cetuximab) Not usually possible to distinguish between prognostic and predictive in non-randomized study PFS Stratified by Mutation Type PFS (Months) 45 PFS Coded by Mutation Type Patients wt EGFR/KRAS EGFR mutant exon 20 (T790M) mutant KRAS EGFR mutant exon 19 or 21 Regimen: Intermittent Docetaxel and Erlotinib Retrospective Studies of KRAS Mutations and Clinical Response to EGFR-targeted Monoclonal Abs in mcrc Reference Treatment N Lievre JCO 2008 Benvenuti CR 2007 DeRoock Ann Oncol 2008 Finocchiaro ASCO 2007 Di Fiore BJC 2007 Khambata-Ford JCO 2007 Amado JCO 2008 % KRAS Objective Response Wild-type Cetuximab + CT (44%) 0 Panitumumab or cetux or cetuximab + CT Cetuximab or Cetuximab + irinotecan Cetuximab + CT Cetuximab + CT Cetuximab (31%) 1 (6) (41%) (26%) 2 (6) (28%) (10%) 0 Panitumumab (17%) 0 Compiled by Carsten Bokemeyer, ASCO 2008 Total: 703 (36.8%) Erlotinib Pharmacokinetics Smokers vs. Nonsmokers Single 150 mg Dose in Healthy Male Subjects Mean ± SEM Erlotinib in Plasma, ng/ml Nonsmokers (n=16) Smokers (n=16) Time (Hrs) AUC 0- (ng h/ml) Nonsmoker: Smoker: 6718 S/NS: 35.9% C max (ng/ml) Nonsmoker: 1056 Smoker: 689 p< p= S/NS: 65.2% 7

8 Ability of 2 nd Generation TKIs to inhibit Downstream Signaling Anti-EGFR Agents with T790M Mutation: Activity of CL387,785, Lack of Activity of Cetuximab H1975 cells (L858R + T790M mutation) Kobayashi: Cancer Res,