EGFR MUTATIONS: EGFR PATHWAY AND SELECTION OF FIRST-LINE THERAPY WITH TYROSINE KINASE INHIBITORS

Transcription

1 EGFR MUTATIONS: EGFR PATHWAY AND SELECTION OF FIRST-LINE THERAPY WITH TYROSINE KINASE INHIBITORS Federico Cappuzzo Istituto Clinico Humanitas IRCCS Rozzano-Italy

2 The EGFR/HER Family Ligand binding domain Transmembrane erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 = Tyrosine Kinase Domain

3 EGFR Tyrosine Kinase Inhibitors Reversible Irreversible Gefitinib EKB-586 Erlotinib CI 1033 Lapatinib HKI-272 PF BIBW 2992 CL

4 EGFR-TKIs efficacy in unselected NSCLC Reference # Line Drug RR (%) PFS (months) OS (months) Akerley 40 I Erlotinib Hesketh 81 I Erlotinib Jackman 80 I Erlotinib Giaccone 53 I Erlotinib Govindan 198 I Gefitinib 6.3 NR 6 Niho 42 I Gefitinib 30 NR 13.9 West 136 I/II Gefitinib 17 NR 13 Janne 200 I/II+ Gefitinib 4.1 NR 4.5 Kubota 62 II/III Erlotinib Perng 299 II/III Erlotinib NR Perez-Soler 57 II/III Erlotinib Fukuoka 210 II/III Gefitinib Cappuzzo 106 II/III Gefitinib Kris 216 III Gefitinib 12 NR 7 Simon 183 I/II/III+ Gefitinib Chen 36 II/III/IV Gefitinib Felip 83 II/III/IV Erlotinib

5 EGFR-TKI single agent versus CT or placebo in first-line unselected NSCLC: phase II randomized studies PS 2: Lilenbaum UNFIT FOR CHEMO: INSTEP Stratified by: Center Age (< 70 vs > 70) Extent of Disease (Stage IIIB vs IV) R A N D O M I Z E Erlotinib 150 mg daily Carboplatin AUC 6 + Paclitaxel 200 mg/m 2 Randomize d Phase II study NSCLC wet IIIB/IV PS 2-3 unfit for CT Gefitinib 250 mg/day + BSC BSC 1: 1 Day 1 q 21 days x 4 cycles ELDERLY: INVITE Phase II (open-label) Stage IIIB/IV NSCLC Chemonaïve >70 years WHO PS 0-2 1:1 randomization Gefitinib 250 mg/day (n=97) Vinorelbine 30 mg/m 2 on Days 1 & 8 of 21-day cycle (n=99) Primary endpoint: Progression-free survival (PFS) Secondary endpoints: Overall survival Response rate Quality of life Pulmonary symptom improvement Tolerability Exploratory endpoints: EGFR biomarkers

6 EGFR-TKIs in unselected NSCLC: better than nothing but worse than chemotherapy Study N Drug RR (%) PFS (months) HR OS (months) HR INVITE Gefitinib Vinorelbine INSTEP Gefitinib Placebo Lilenbaum Erlotinib Carbo/taxol

7 Predictive Factors for EGFR-TKI Sensitivity Clinical Biological Predictive for Response Gender Histology Smoking history Ethnicity EGFR Gene mutation EGFR high copy number HER2 high copy number Akt activation Predictive for Survival Smoking history Response to prior therapy PS Histology Previous Platinum Skin rash Ethnicity EGFR gene mutation EGFR high copy number Primary Resistance Predictive for Resistance K-Ras Mutation EGFR exon 20 insertion HER2 exon 20 mutation Acquired Resistance EGFR T790M-D761Y MET Amplification

8 Response to TKIs According to EGFR Status in Retrospective and Prospective Studies Reference # Method Study RR (%) p value EGFR+ EGFR- Cappuzzo 102 FISH Retrosp <0.001 Cappuzzo 36 FISH Prospec <0.001 FISH: Response rate up to 68% Hirsch 81 FISH Retrosp Hirsch 370 FISH Retrosp <0.001 Tsao 221 FISH Retrosp Mitsudomi 59 MUT Retrosp < Takano 66 MUT Retrosp < Mutation: Response rate up to 82% Cappuzzo 37 MUT Prospec Paz-Ares 127 MUT Prospec Sequist 31 MUT Prospec

9 Prospective studies of EGFR-TKI in EGFR Mutated NSCLC Reference # Selection criterion Line Drug RR (%) PFS (months) OS (months) Asahina 16 EGFR mutation I Gefitinib Not reached Inoue 30 EGFR mutation I Gefitinib Inoue 16 EGFR mutation I Gefitinib Not reported Kimura 13 EGFR mutation I Gefitinib Rosell 217 EGFR mutation I/II Erlotinib Rosell 12 EGFR mutation I Erlotinib >28.0 Sequist 34 EGFR mutation I Gefitinib Yang 55 EGFR mutation I Gefitinib Sugio 20 EGFR mutation I/II Gefitinib Sunaga 21 EGFR mutation I/II Gefitinib Not reached Sutani 38 EGFR mutation I/II Gefitinib Yoshida 27 EGFR mutation I/II Gefitinib Not reached Han 17 EGFR mutation I/II+ Gefitinib Tamura 28 EGFR mutation I/II/III Gefitinib Not reached

10 EGFR-TKIs versus chemotherapy in firstline: Phase III trials in clinically selected patients IPASS Chemonaive Age> 18 Adenocarcinoma Never/light smokers ECOG PS:0-2 Stage IIIB-IV 1 R 1 Gefitinib (250 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # FIRST SIGNAL Primary end-point: PFS Chemonaive Age years Adenocarcinoma Never smokers ECOG PS:0-2 Stage IIIB-IV 1 R Gefitinib (250 mg / day) 1 Gemcitabine 1250 mg/mq 1,8 Cisplatin 80 mg/mq 1 Q 21 days, up to 9 cycles

11 IPASS:PFS in ITT population Probability of PFS 0.8 N Events Gefitinib (74.4%) Carboplatin / paclitaxel (81.7%) HR (95% CI) = (0.651, 0.845) p< Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free % 48% 25% % 48% 7% 12 months progression-free 25% 7% Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS At risk : Gefitinib Carboplatin / paclitaxel Months Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib

12 IPASS: Overall Survival in ITT Population Probability of survival N Events Gefitinib Carboplatin / paclitaxel (36.6%) (37.3%) HR (95% CI) = 0.91 (0.76, 1.10) Median OS (months) 6 month OS 12 month OS % 68% % 64% Months At risk : 24 Gefitinib Carboplatin / paclitaxel Cox analysis with covariates HR <1 implies a lower risk of death on gefitinib OS, overall survival

13 Progression-free Survival in EGFR Mutation Positive and Negative Patients: Two Important Findings EGFR mutation positive 1. Maintenance effect 2. EGFR mutant Gefitinib more (n=132) sensitive Carboplatin / paclitaxel (n=129) to chemotherapy Probability of progressio on-free survival At risk : Gefitinib C / P HR (95% CI) = 0.48 (0.36, 0.64) p< No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) Months Probability of progressio on-free survival EGFR mutation negative We need biological selection Treatment by subgroup interaction test, p< ITT population Cox analysis with covariates Gefitinib (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.05, 3.98) p< No. events gefitinib, 88 (96.7%) No. events C / P, 70 (82.4%) Months

14 IPASS: overlap of biomarkers High EGFRgene-copy number N= EGFR expression positive N= Positive for all 3 biomarkers N=132 EGFR mutation positive N= N=329 with known biomarker status for all 3 biomarkers Negative for all 3 biomarkers N=31

15 Progression-free survival in high and low EGFR-gene-copy number patients High EGFR-gene-copy number Low EGFR-gene-copy number Probability of pro ogression-free survival At risk : Gefitinib C/P Gefitinib (n=124) Carboplatin/paclitaxel (n=125) HR (95% CI) = 0.66 (0.50, 0.88) p= No. events gefitinib, 98 (79.0%) No. events C/P, 104 (83.2%) Months Probability of pro ogression-free survival Gefitinib (n=81) Carboplatin/paclitaxel (n=76) HR (95% CI) = 1.24 (0.87, 1.76) p= No. events gefitinib, 69 (85.2%) No. events C/P, 68 (89.5%) Treatment by EGFR-gene-copy number interaction test, p= Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population Months

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18 EGFR-TKIs versus chemotherapy in firstline: Phase III trials in biologically selected patients NEJ002 Chemonaive Age years EGFR mutation+ ECOG PS:0-1 Stage IIIB-IV 1 R 1 Gefitinib (250 mg / day) Carboplatin/ paclitaxel q 3 weeks WJTOG3405 Primary end-point: PFS Chemonaive Age >20 years EGFR Mutation+ ECOG PS:0-1 Stage IIIB-IV 1 R Gefitinib (250 mg / day) 1 docetaxel 60 mg/mq Cisplatin 80 mg/mq Q 21 days, up to 6 cycles

19 Gefitinib more effective than chemotherapy in EGFR Mutation+ NSCLC NEJ002: PFS WJTOG HR % CI 0.25, 0.51 p<0.001 Median 10.4 vs 5.5 months Gef CT p HR Gefitinib RR (%) Carb / pac PFS (months) <

20 SATURN study design Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinumbased doublet* Non-PD n=889 Erlotinib 150mg/day 1:1 PD Mandatory tumor sampling Placebo PD Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumors Secondary endpoints: OS in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC tumors; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

21 PFS*: all patients (ITT) PFS probability 0.8 Erlotinib Placebo PFS at 12 wks (%) PFS at 24 wks (%) HR=0.71 ( ) Log-rank p< Erlotinib (n=437) Placebo (n=447) Time (weeks) *PFS is measured from time of randomization into the maintenance phase; assessments were every 6 weeks

22 Largest PFS benefit with erlotinib in patients with EGFR mutated tumours EGFR mutation+ EGFR wild-type PFS probab bility HR=0.10 ( ) Log-rank p< Erlotinib (n=22) Placebo (n=27) HR=0.78 ( ) Log-rank p= Erlotinib (n=199) Placebo (n=189) Time (weeks) Time (weeks) Interaction p<0.001

23 ATLAS Study Design Chemo-naïve Advanced NSCLC N=1,160 Eligibility Stage III/IV NSCLC 4 cycles of 1st-line chemotherapy* + bevacizumab ECOG performance status 0-1 Stratification factors Gender Smoking history (never vs former/current) ECOG performance status (0 v >1) Chemotherapy regimen Non-PD n=768 (66%) Bevacizumab + Erlotinib to PD 1:1 Bevacizumab + Placebo to PD Primary endpoint Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel. Unblind at PD PFS in all randomized pts Secondary endpoints Overall survival Safety Exploratory endpoints Post progression therapy Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation)

24 ATLAS: Progression-Free Survival (ITT population, investigator assessment) Without Event Proportion Bev + Placebo (n=373) Bev + Erlotinib (n=370) HR=0.722 ( ) Log-rank P= Progression-Free Survival (months) No. of patients at risk: Bev + Placebo Bev + Erlotinib

25 PFS K-M Curves by EGFR Mutation Status EGFR Wild-Type B+E (n=150) B+P (n=145) Censored value EGFR Mutant B+E (n=27) B+P (n=25) Censored value HR = (95% CI: ) Log-rank P= HR = (95% CI: ) Log-rank P=0.0137

26 IS EGFR MUTATION TESTING THE BEST PREDICTOR FOR PATIENT SURVIVAL?

27 EGFR Mutations: A Positive Prognostic Factor? TRIBUTE INTACT 1&2

28 No trial demonstrated survival benefit for EGFR mutated patients treated with TKIs IPASS SATURN Gefitinib (n=132) Carboplatin / paclitaxel (n=129) Probability of overall survival HR (95% CI) = (0.500, 1.202) No. events gefitinib, 38 (28.8%) No. events C / P, 43 (33.3%) HR=0.83 ( ) Log-rank p= Erlotinib Placebo Time (months) First-SIGNAL Time from randomisation (months)

29 BR21: Survival According to Updated EGFR Mutation Status P=0.12 Hazard ratio, 0.55 (95% CI, ) P=0.09 Hazard ratio, 0.74 (95% CI, ) Interaction P value = 0.47 Shepherd et al, ASCO 2007

30 EGFR Gene Copy Number and Survival in the NSCLC Cohort 1,0,9 1,0,9 p=0.4 CUMULAT TIVE SURVIVAL,8,7,6,5,4,3,2,1 EGFR FISH-: (N=215) EGFR FISH+ : Gene Amplification (GA, N=39) EGFR FISH+: High Polysomy (HP, N=122) Median survival: EGFR FISH-:48.3 months EGFR FISH HP:40.7 months EGFR FISH GA: 30.7 months CUMULAT TIVE SURVIVAL,8,7,6,5,4,3,2,1 EGFR FISH-(N=215) Median survival: EGFR FISH-:48.3 months EGFR FISH+: 40.7 months EGFR FISH+ (N=161), , MONTHS MONTHS At risk Negative HP GA At risk FISH FISH Cappuzzo et al. JCO 2009

31 FISH Predicts Benefit of EGFR-TKIs Proportion surviving ISEL FISH + BR21 FISH + Gefitinib Placebo Erlotinib Placebo Proportion surviving Time (months) ISEL FISH - Cox: p=0.07 HR=0.61 (0.36, 4) Gefitinib Placebo Time (months) BR21 FISH - Erlotinib Placebo Log-rank: p=0.008 HR=0.44 (0.23, 0.82) Cox: p=0.42 HR=1.16 (0.81, 1.64) Log-rank: p=0.59 HR=0.85 (0.48, 1.51) Hirsch 2005 Time (months) Time (months) Tsao 2005

32 Different Effect of Cetuximab and Gefitinib in NSCLC Cell-lines with or without EGFR Mutations EGFR WT EGFR MT Mukohara, T. et al. J. Natl. Cancer Inst. 2005

33 EGFR Mutations and Cetuximab Sensitivity in NSCLC: BMS 099 Data

34 Conclusions EGFR-TKIs should be considered in EGFR mut+ patients as first-line therapy Higher RR Longer PFS At least equal surviva Lower toxicity EGFR mutation is not the best predictor for survival EGFR mutation test is not useful for selection of patients candidate for cetuximab therapy