EGFR MUTATIONS: EGFR PATHWAY AND SELECTION OF FIRST-LINE THERAPY WITH TYROSINE KINASE INHIBITORS Federico Cappuzzo Istituto Clinico Humanitas IRCCS Rozzano-Italy
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
EGFR Tyrosine Kinase Inhibitors Reversible Irreversible Gefitinib EKB-586 Erlotinib CI 1033 Lapatinib HKI-272 PF 299804 BIBW 2992 CL 367-785
EGFR-TKIs efficacy in unselected NSCLC Reference # Line Drug RR (%) PFS (months) OS (months) Akerley 40 I Erlotinib 15 1.9 11.5 Hesketh 81 I Erlotinib 8 2.1 5 Jackman 80 I Erlotinib 10 3.5 10.9 Giaccone 53 I Erlotinib 22.7 2.7 12.8 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 28.3 2.5 14.7 Perng 299 II/III Erlotinib 29 5.6 NR Perez-Soler 57 II/III Erlotinib 12.3 2.1 8.4 Fukuoka 210 II/III Gefitinib 18.4 2.7 7.6 Cappuzzo 106 II/III Gefitinib 14 3.4 9.4 Kris 216 III Gefitinib 12 NR 7 Simon 183 I/II/III+ Gefitinib 3.8 3.6 8.8 Chen 36 II/III/IV Gefitinib 33.3 4.7 9.5 Felip 83 II/III/IV Erlotinib 10 1.4 3.9
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
EGFR-TKIs in unselected NSCLC: better than nothing but worse than chemotherapy Study N Drug RR (%) PFS (months) HR OS (months) HR INVITE 97 99 Gefitinib Vinorelbine 3.1 5.1 2.7 2.9 1.19 5.9 8.0 0.98 INSTEP 100 101 Gefitinib Placebo 6.0 1.43 1.36 0.82 3.7 2.8 0.84 Lilenbaum 52 51 Erlotinib Carbo/taxol 2.0 12.0 1.9 3.5 1.45 6.5 9.7 1.73
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
Response to TKIs According to EGFR Status in Retrospective and Prospective Studies Reference # Method Study RR (%) p value EGFR+ EGFR- Cappuzzo 102 FISH Retrosp 36.4 2.9 <0.001 Cappuzzo 36 FISH Prospec 68.0 9.1 <0.001 FISH: Response rate up to 68% Hirsch 81 FISH Retrosp 26.0 1 0.14 Hirsch 370 FISH Retrosp 16.4 3.2 <0.001 Tsao 221 FISH Retrosp 21.4 4.8 0.02 Mitsudomi 59 MUT Retrosp 82.7 9.5 <0.0001 Takano 66 MUT Retrosp 82.0 1 <0.0001 Mutation: Response rate up to 82% Cappuzzo 37 MUT Prospec 62.5 23.1 0.001 Paz-Ares 127 MUT Prospec 82.0 - - Sequist 31 MUT Prospec 55.0 - -
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 75 8.9 Not reached Inoue 30 EGFR mutation I Gefitinib 66 6.5 17.8 Inoue 16 EGFR mutation I Gefitinib 75 9.7 Not reported Kimura 13 EGFR mutation I Gefitinib 53.8 3.2 10.1 Rosell 217 EGFR mutation I/II Erlotinib 70.6 14 27 Rosell 12 EGFR mutation I Erlotinib 90 13 >28.0 Sequist 34 EGFR mutation I Gefitinib 55 9.2 17.5 Yang 55 EGFR mutation I Gefitinib 69 8 24 Sugio 20 EGFR mutation I/II Gefitinib 63.2 7.1 20 Sunaga 21 EGFR mutation I/II Gefitinib 76 12.9 Not reached Sutani 38 EGFR mutation I/II Gefitinib 78 9.4 15.4 Yoshida 27 EGFR mutation I/II Gefitinib 90.5 7.7 Not reached Han 17 EGFR mutation I/II+ Gefitinib 64.7 21.7 30.5 Tamura 28 EGFR mutation I/II/III Gefitinib 75 11.5 Not reached
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 18-75 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
IPASS:PFS in ITT population Probability of PFS 0.8 N Events Gefitinib 609 453 (74.4%) Carboplatin / paclitaxel 608 497 (81.7%) HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001 0.6 0.4 0.2 Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free 5.7 61% 48% 25% 5.8 74% 48% 7% 12 months progression-free 25% 7% Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS At risk : Gefitinib Carboplatin / paclitaxel 0.0 0 4 8 12 16 20 24 Months 609 363 212 76 24 5 0 608 412 118 22 3 1 0 Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib
IPASS: Overall Survival in ITT Population Probability of survival N Events Gefitinib Carboplatin / paclitaxel 609 223 (36.6%) 608 227 (37.3%) 0.8 0.6 HR (95% CI) = 0.91 (0.76, 1.10) Median OS (months) 6 month OS 12 month OS 18.6 84% 68% 17.3 86% 64% 0.4 0.2 0.0 0 4 8 12 16 20 28 Months At risk : 24 Gefitinib 609 514 423 239 118 38 0 0 Carboplatin / 608 524 401 212 104 32 1 0 paclitaxel Cox analysis with covariates HR <1 implies a lower risk of death on gefitinib OS, overall survival
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 0.8 0.6 0.4 0.2 0.0 At risk : Gefitinib C / P HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) 0 4 8 12 16 20 24 Months 132 108 71 31 11 3 0 129 103 37 7 2 1 0 Probability of progressio on-free survival EGFR mutation negative We need biological selection Treatment by subgroup interaction test, p<0.0001 ITT population Cox analysis with covariates 0.8 0.6 0.4 0.2 0.0 Gefitinib (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib, 88 (96.7%) No. events C / P, 70 (82.4%) 0 4 8 12 16 20 24 Months 91 21 4 2 1 0 0 85 58 14 1 0 0 0
IPASS: overlap of biomarkers High EGFRgene-copy number N=198 13 25 51 EGFR expression positive N=242 28 Positive for all 3 biomarkers N=132 EGFR mutation positive N=209 15 34 N=329 with known biomarker status for all 3 biomarkers Negative for all 3 biomarkers N=31
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 0.8 0.6 0.4 0.2 0.0 At risk : Gefitinib C/P Gefitinib (n=124) Carboplatin/paclitaxel (n=125) HR (95% CI) = 0.66 (0.50, 0.88) p=0.0050 No. events gefitinib, 98 (79.0%) No. events C/P, 104 (83.2%) 0 4 8 12 16 20 24 Months 124 87 53 20 5 1 0 125 95 32 5 1 1 0 Probability of pro ogression-free survival 0.8 0.6 Gefitinib (n=81) Carboplatin/paclitaxel (n=76) HR (95% CI) = 1.24 (0.87, 1.76) p=0.2368 No. events gefitinib, 69 (85.2%) No. events C/P, 68 (89.5%) 0 4 8 12 16 20 24 Treatment by EGFR-gene-copy number interaction test, p=0.0437 Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population 0.4 0.2 0.0 Months 81 34 17 10 6 2 0 76 58 18 3 1 0 0
EGFR-TKIs versus chemotherapy in firstline: Phase III trials in biologically selected patients NEJ002 Chemonaive Age 20-75 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
Gefitinib more effective than chemotherapy in EGFR Mutation+ NSCLC NEJ002: PFS WJTOG3405 0.9 0.8 HR 0.36 95% CI 0.25, 0.51 p<0.001 Median 10.4 vs 5.5 months Gef CT p HR 0.7 0.6 0.5 0.4 Gefitinib RR (%) 56.3 25.3 0.3 0.2 0.1 Carb / pac PFS (months) 9.2 6.3 <0.001 0.48 0 0 100 200 300 400 500
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
PFS*: all patients (ITT) PFS probability 0.8 Erlotinib Placebo PFS at 12 wks (%) 53 40 PFS at 24 wks (%) 31 17 0.6 0.4 0.2 HR=0.71 (0.62 0.82) Log-rank p<0.0001 Erlotinib (n=437) Placebo (n=447) 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) *PFS is measured from time of randomization into the maintenance phase; assessments were every 6 weeks
Largest PFS benefit with erlotinib in patients with EGFR mutated tumours EGFR mutation+ EGFR wild-type PFS probab bility 0.8 0.6 0.4 0.2 HR=0.10 (0.04 0.25) Log-rank p<0.0001 Erlotinib (n=22) Placebo (n=27) 0.8 0.6 0.4 0.2 HR=0.78 (0.63 0.96) Log-rank p=0.0185 Erlotinib (n=199) Placebo (n=189) 0 0 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) Time (weeks) Interaction p<0.001
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)
ATLAS: Progression-Free Survival (ITT population, investigator assessment) Without Event Proportion 0.8 0.6 0.4 0.2 0.0 Bev + Placebo (n=373) Bev + Erlotinib (n=370) HR=0.722 (0.592-0.881) Log-rank P=0.0012 0 3 6 9 12 15 Progression-Free Survival (months) 18 21 No. of patients at risk: Bev + Placebo Bev + Erlotinib 373 142 58 27 15 6 3 0 370 178 81 43 20 6 3 1
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 = 0.850 (95% CI: 0.638-1.131) Log-rank P=0.2620 HR = 0.439 (95% CI: 0.223-0.864) Log-rank P=0.0137
IS EGFR MUTATION TESTING THE BEST PREDICTOR FOR PATIENT SURVIVAL?
EGFR Mutations: A Positive Prognostic Factor? TRIBUTE INTACT 1&2
No trial demonstrated survival benefit for EGFR mutated patients treated with TKIs IPASS SATURN Gefitinib (n=132) Carboplatin / paclitaxel (n=129) 0.8 0.6 Probability of overall survival 0.8 0.6 0.4 0.2 0.0 0 HR (95% CI) = 0.776 (0.500, 1.202) No. events gefitinib, 38 (28.8%) No. events C / P, 43 (33.3%) 4 8 12 16 20 24 28 0.4 0.2 0 HR=0.83 (0.34 2.02) Log-rank p=0.6810 Erlotinib Placebo 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) First-SIGNAL Time from randomisation (months)
BR21: Survival According to Updated EGFR Mutation Status P=0.12 Hazard ratio, 0.55 (95% CI, 0.25-1.19) P=0.09 Hazard ratio, 0.74 (95% CI, 0.52-5) Interaction P value = 0.47 Shepherd et al, ASCO 2007
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),0 0 20 40 60 80 100 120,0 0 20 40 60 80 100 120 MONTHS MONTHS At risk 376 191 4 Negative 215 111 1 HP 122 61 2 GA 39 19 1 At risk 376 191 4 FISH+ 161 80 3 FISH- 215 111 1 Cappuzzo et al. JCO 2009
FISH Predicts Benefit of EGFR-TKIs Proportion surviving 0.8 0.6 0.4 ISEL FISH + BR21 FISH + Gefitinib Placebo 0.8 0.6 0.4 Erlotinib Placebo Proportion surviving 0.2 0.0 0.8 0.6 0 4 8 12 16 Time (months) ISEL FISH - Cox: p=0.07 HR=0.61 (0.36, 4) Gefitinib Placebo 0.2 0.0 0.8 0.6 0 6 12 18 24 30 Time (months) BR21 FISH - Erlotinib Placebo Log-rank: p=0.008 HR=0.44 (0.23, 0.82) 0.4 0.2 Cox: p=0.42 HR=1.16 (0.81, 1.64) 0.4 0.2 Log-rank: p=0.59 HR=0.85 (0.48, 1.51) 0.0 0.0 0 4 8 12 16 0 6 12 18 24 30 Hirsch 2005 Time (months) Time (months) Tsao 2005
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
EGFR Mutations and Cetuximab Sensitivity in NSCLC: BMS 099 Data
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