PROGNOSTIC AND PREDICTIVE BIOMARKERS IN NSCLC. Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile-Livorno Italy

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1 PROGNOSTIC AND PREDICTIVE BIOMARKERS IN NSCLC Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile-Livorno Italy

2 Prognostic versus predictive Prognostic: In presence of the biomarker patient outcome independent of the treatment Predictive: In presence of the biomarker patient outcome is different according to the treatment

3 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 2 insertion HER2 exon 2 mutation Acquired Resistance EGFR T79M-D761Y MET Amplification

4 EGFR mutations in prospective studies: the strongest predictor for response Reference # Selection criterion Line Drug RR (%) PFS (months) OS (months) Asahina 16 EGFR mutation I Gefitinib Not reached Inoue 3 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 9 13 >28. Sequist 34 EGFR mutation I Gefitinib Yang 55 EGFR mutation I Gefitinib Sugio 2 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

5 EGFR-TKIs versus chemotherapy in firstline: Phase III trials in clinically selected patients IPASS Chemonaive Age> 18 Adenocarcinoma Never/light smokers ECOG PS:-2 Stage IIIB-IV 1 R 1 Gefitinib (25 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (2 mg / m 2 ) 3 weekly # FIRST SIGNAL Primary end-point: PFS Chemonaive Age years Adenocarcinoma Never smokers ECOG PS:-2 Stage IIIB-IV 1 R Gefitinib (25 mg / day) 1 Gemcitabine 125 mg/mq 1,8 Cisplatin 8 mg/mq 1 Q 21 days, up to 9 cycles

6 IPASS:PFS in ITT population Probability of PFS 1..8 N Events Gefitinib (74.4%) Carboplatin / paclitaxel (81.7%) HR (95% CI) =.741 (.651,.845) p< Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free % 48% 25% % 48% 7% Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS. At risk : Months Gefitinib Carboplatin / paclitaxel Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib

7 Progression-free Survival in EGFR Mutation Positive and Negative Patients EGFR mutation positive EGFR mutation negative Probability of progression-free survival At risk : Gefitinib C / P Gefitinib (n=132) Carboplatin / paclitaxel (n=129) HR (95% CI) =.48 (.36,.64) p<.1 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.%) Months Probability of progression-free survival Gefitinib (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.5, 3.98) p<.1 No. events gefitinib, 88 (96.7%) No. events C / P, 7 (82.4%) Months ITT population Cox analysis with covariates Treatment by subgroup interaction test, p<.1

8 EGFR-TKIs versus chemotherapy in firstline: Phase III trials in biologically selected patients NEJ2 Chemonaive Age 2-75 years EGFR mutation+ ECOG PS:-1 Stage IIIB-IV 1 R 1 Gefitinib (25 mg / day) Carboplatin/ paclitaxel q 3 weeks WJTOG345 Primary end-point: PFS Chemonaive Age >2 years EGFR Mutation+ ECOG PS:-1 Stage IIIB-IV 1 R Gefitinib (25 mg / day) 1 docetaxel 6 mg/mq Cisplatin 8 mg/mq Q 21 days, up to 6 cycles

9 Gefitinib more effective than chemotherapy in EGFR Mutation+ NSCLC NEJ2: PFS WJTOG HR.36 95% CI.25,.51 p<.1 Median 1.4 vs 5.5 months Gef CT p HR Gefitinib RR (%) Carb / pac PFS (months) <

10 SATURN study design Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinumbased doublet* Non-PD n=889 Erlotinib 15mg/day 1:1 PD Mandatory tumor sampling Placebo PD Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS ( 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

11 Largest PFS benefit with erlotinib in patients with EGFR mutated tumours EGFR mutation+ EGFR wild-type PFS probability HR=.1 (.4.25) Log-rank p<.1 Erlotinib (n=22) Placebo (n=27) HR=.78 (.63.96) Log-rank p=.185 Erlotinib (n=199) Placebo (n=189) Time (weeks) Time (weeks) Interaction p<.1

12 ATLAS Study Design Chemo-naïve Advanced NSCLC N=1,16 4 cycles of 1st-line chemotherapy* + bevacizumab Non-PD n=768 (66%) Bevacizumab + Erlotinib to PD 1:1 Bevacizumab + Placebo to PD Unblind at PD Post progression therapy Eligibility Stage III/IV NSCLC ECOG performance status -1 Stratification factors Gender Smoking history (never vs former/current) ECOG performance status ( v >1) Chemotherapy regimen Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel. Primary endpoint PFS in all randomized pts Secondary endpoints Overall survival Safety Exploratory endpoints Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation)

13 PFS K-M Curves by EGFR Mutation Status EGFR Wild-Type EGFR Mutant B+E (n=15) B+P (n=145) Censored value B+E (n=27) B+P (n=25) Censored value HR =.85 (95% CI: ) Log-rank P=.262 HR =.439 (95% CI: ) Log-rank P=.137

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

15 EGFR Mutations: A Positive Prognostic Factor? Survival Rate Chemo, Wild Type (n=99) Chemo, Mutant (n=14) Erlotinib+Chemo, Wild Type (n=99) Erlotinib+Chemo, Mutant (n=15) Months TRIBUTE INTACT 1&2

16 No trial demonstrated survival benefit for EGFR mutated patients treated with TKIs IPASS 1. SATURN 1. Gefitinib (n=132) Carboplatin / paclitaxel (n=129).8.6 Probability of overall survival HR (95% CI) =.776 (.5, 1.22) No. events gefitinib, 38 (28.8%) No. events C / P, 43 (33.3%) HR=.83 ( ) Log-rank p=.681 Erlotinib Placebo Time (months) First-SIGNAL Time from randomisation (months)

17 BR21: Survival According to Updated EGFR Mutation Status P=.12 Hazard ratio,.55 (95% CI, ) P=.9 Hazard ratio,.74 (95% CI, ) Interaction P value =.47 Shepherd et al, ASCO 27

18 EGFR Gene Gain: A Prognostic Factor? Reference Method Total Number Survival (months) EGFR+ EGFR- P value Hirsch FISH Jeon FISH NR.12 Suzuki FISH 71 NA NA.9 NR: Not Reached; NA: Not available

19 EGFR Gene Copy Number and Survival in the NSCLC Cohort 1, 1,,9,9 p=.4 CUMULATIVE SURVIVAL,8,7,6,5,4,3,2,1 EGFR FISH-: (N=215) EGFR FISH+: High Polysomy (HP, N=122) Median survival: EGFR FISH-:48.3 months EGFR FISH HP:4.7 months EGFR FISH GA: 3.7 months EGFR FISH+ : Gene Amplification (GA, N=39) CUMULATIVE SURVIVAL,8,7,6,5,4,3,2,1 EGFR FISH-(N=215) Median survival: EGFR FISH-:48.3 months EGFR FISH+: 4.7 months EGFR FISH+ (N=161), , MONTHS MONTHS At risk Negative HP GA At risk FISH FISH Cappuzzo et al. JCO 29

20 FISH Predicts Benefit of EGFR-TKIs Proportion surviving ISEL FISH + BR21 FISH + Gefitinib Placebo Erlotinib Placebo Proportion surviving Time (months) ISEL FISH - Cox: p=.7 HR=.61 (.36, 1.4) Gefitinib Placebo Time (months) BR21 FISH - Erlotinib Placebo Log-rank: p=.8 HR=.44 (.23,.82).4.2 Cox: p=.42 HR=1.16 (.81, 1.64).4.2 Log-rank: p=.59 HR=.85 (.48, 1.51) Hirsch 25 Time (months) Time (months) Tsao 25

21 EGFR EXPRESSION: THE WEAKEST PREDICTOR

22 EGFR IHC: No Prognostic Effect in Resected NSCLC in Large Meta-Analysis Nakamura et al., Thorax 25

23 RESPONSE ACCORDING TO EGFR IHC - ISEL, IDEAL & BR.21 EGFR Status ISEL IDEAL BR.21 TOTAL ORR (%) ORR (%) ORR (%) ORR (%) EGFR +ve N= (8.2%) N=84 13 (13.4%) N=16 12 (11.3%) N= (1.9%) EGFR -ve N=69 1 (1.5%) N=17 1 (5.6%) N=8 3 (3.8%) N=166 5 (3.%) *P=.3

24 BR.21 Survival According to EGFR Protein Expression HER1/EGFR+ HER1/EGFR Percentage Erlotinib Placebo Log-rank: p=.2 HR=.68 (.49,.95) Percentage Erlotinib Placebo Log-rank: p=.7 HR=.93 (.63, 1.36) At risk Months Erlotinib Placebo p value for interaction = At risk Months Erlotinib Placebo Shepherd et al. N Engl J Med, 25

25 SATURN: PFS in EGFR IHC+ tumors PFS probability Erlotinib Placebo PFS at 12 wks (%) 54 4 PFS at 24 wks (%) HR=.69 (.58.82) HR:.71 in the whole population Log-rank p<.1 Erlotinib (n=37) Placebo (n=311) Time (weeks) *PFS is measured from time of randomization into the maintenance phase; assessments were every 6 weeks

26 OTHER BIOMARKERS: KRAS AND MET

27 KRAS Mutations and Survival: Prognostic or Predictive? Over 5 studies published Different methods for detection (IHC versus PCR) Conflicting results Reference N % Mutated p value Tsao Schiller Graziano Siegfried Fukuyama <.5 Huang Miyake

28 BR.21: prognostic analysis for KRAS mutation (PFS) in placebo arm PFS probability.5.25 Log-rank p=.917 Placebo (KRAS MUT+) n=8 Placebo (KRAS WT) n= Time (months) Conclusion: not prognostic

29 SATURN: prognostic analysis for KRAS mutation (PFS) in placebo arm 1..8 PFS probability.6.4 Log-rank p=.169 Placebo (KRAS MUT+) n=41.2 Placebo (KRAS WT) n= Time (weeks) Conclusion: prognostic

30 ATLAS: prognostic analysis for KRAS mutation (PFS) in placebo arm 1..8 Avastin + Placebo PFS probability.6.4 Log rank p=.3564 Placebo (KRAS MUT+) n=46.2 Placebo (KRAS WT) n= Time (months) Conclusion: prognostic

31 KRAS Mutations: predictive for worst survival? BR21 TRIBUTE 1 8 KRAS Wild Type Erlotinib Placebo Median:7.5 (5.4,1.7) 3.4 (3.,7.1) HR=.69 (.49,.97) p=.311 Pe r cen t age # at Risk Placebo Erlotinib Time(Months) KRAS Mutation Erlotinib Placebo Median:3.7 (1.9,7.9) 7. (1.7,19.5) HR=1.67 (.62,4.5) p=.396 Per cen t age 6 4 # at Risk Placebo Erlotinib Time(Months) Few data in low patient number ~5% of KRAS mutated are EGFR FISH+

32 SATURN: PFS according to KRAS status KRAS MUT+ KRAS WT PFS probability HR=.75 ( ) Log-rank p=.2246 Tarceva (n=49) Placebo (n=41) HR=.73 (.6.9) Log-rank p=.9 Tarceva (n=25) Placebo (n=198) Time (weeks) Time (weeks) Interaction p=.95

33 OS in SATURN: biomarker subgroup analyses All HR (95% CI) n.81 (.7.95) 889 EGFR IHC+ EGFR IHC-.77 (.64.93) ( ) 121 EGFR FISH+ EGFR FISH-.96 ( ) ( ) 256 KRAS mutation+ KRAS wild-type.79 ( ) 9.86 ( ) 43 EGFR mutation+ EGFR wild-type.83 ( ) (.61.97) Favours erlotinib HR Favours placebo

34 MET FISH Results Total evaluated: 435 Low copy number: 383 (88.9%) High polysomy: 3 (7.%) Gene amplification: 18 (4.1%)

35 Survival of Resected NSCLC According to MET Copy Number 1, 1, CUMULATIVE SURVIVAL,8,6,4,2, <5 copies/cell <2 copies/cell 6 copies/cell 5 - <6 copies/cell 6 MONTHS At risk < < < < <4 copies/cell 2 - <3 copies/cell 8 1 CUMULATIVE SURVIVAL,8,6,4,2, Median survival: MET FISH-:47.5 months MET FISH+: 25.8 months 2 4 MET <5 copies/cell(n=383) MET 5 copies/cell (N=48) 6 MONTHS At risk MET MET p= < Cappuzzo et al., JCO 29

36 Conclusions EGFR expression is the weakest predictor with no prognostic role At the gene level EGFR testing identifies patients with the highest benefit in response (mutation) or survival (FISH) KRAS testing is not recommended in clinical practice for patient selection MET gene copy number is a negative prognostic factor