Suresh S. Ramalingam, MD Associate Professor Director of Medical Oncology Emory University i Winship Cancer Institute EGFR inhibitors in NSCLC Role in 2nd/3 rd line setting Role in first-line and maintenance therapy Reasons why second line is preferred 1
FDA label: treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum- based first-line chemotherapy Null hypothesis: EGFR inhibitors are used for second and third line treatment of NSCLC Alternate hypothesis: EGFR TKIs are more effective in the first line or maintenance settings To reject null hypothesis, one must prove that the alternate hypothesis is acceptable 2
Stratified by Center Performance status (/1 vs 2/3) Response to prior Rx (CR/PR:SD:PD) Prior regimens (1 vs 2) Prior platinum (Yes vs no) R A N D O M I Z E 2 1 Erlotinib 15 mg daily Placebo 15 mg daily Shepherd et al, N Engl J Med, 25. 3
1. Erlotinib (n=488) Placebo (n=243) Surviva al distribution function n.75.5 25.25 Median survival (months) 67 6.7 47 4.7 1-year survival (%) 31 21 HR=.73, P<.1 31% Erlotinib Placebo 21% 5 1 15 2 25 3 Survival time (months) *HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status. Subset Tarceva: Placebo n 731 HR = hash mark on horizontal bar. 95% CI = length of horizontal bar. TARCEVA (erlotinib) PI. PS -1 486 PS 2-3 245 Male 475 Female 256 <65 y 452 65 y 279 Adenocarcinoma 365 Squamous cell carcinoma 222 Other histology 144 Prior weight loss <5% 486 Prior wt loss 5%-1% 132 Prior wt loss >1% 81 Never smoked 146 Current/exsmoker 545 1 prior regimen 364 2 prior regimens 367.5 1. 1.5 2. 2.5 Decreased risk of death Increased risk of death 4
Subset Tarceva: Placebo Prior platinum No prior platinum Prior taxane No prior taxane Best prior response: CR/PR Best prior response: SD Best prior response: PD <6 mo since diagnosis 6-12 mo since diagnosis >12 mo since diagnosis EGFR-positive EGFR-negative EGFR unmeasured Caucasian Asian Stage IV at diagnosis Stage <IV at diagnosis HR = hash mark on horizontal bar. 95% CI = length of horizontal bar. TARCEVA (erlotinib) PI. n 731 678 53 267 464 292 287 152 97 242 392 127 111 493 567 91 329 42.5 1. 1.5 2. 2.5 Decreased risk of death Increased risk of death Advanced d NSCLC 1 or 2 Prior Tx ECOG PS -2 Docetaxel 75 mg/m 2 Gefitinib 25 mg/day Kim et al, Lancet 28; 372: 189 18. 5
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Chemotherapy is standard of care for first line treatment of NSCLC In order to change standard practice, one must demonstrate Improved survival with a new agent High degree of PFS benefit Significant improvement in QOL Key Eligibility: Chemo-naïve, advanced NSCLC Stratified by: Stage ECOG PS Smoking history Region N=259 Mandatory tumor sampling Up to 4 cycles of first-line platinum-based doublet* PD during CT (n=424) Patients without PD were eligible for SATURN 1:1 open label Erlotinib 15 mg/day (n=23) Docetaxel or Pemetrexed* (n=221) *At investigator s discretion; standard regimens PD PD Primary endpoint: Overall survival (OS) Secondary endpoints: OS by EGFR IHC status, PFS in all patients and by EGFR IHC status, ORR, time to symptom progression, safety, PK/PD, biomarker analyses Stratification tifi ti factors: Stage of disease at start of chemotherapy (IIIB vs IV) ECOG PS ( or 1 vs 2) Smoking history (current vs former vs never) Region PD = progressive disease; CT = chemotherapy; IHC = immunohistochemistry; PFS = progression-free survival; ORR = overall response rate; PK/PD = pharmacokinetics/pharmacodynamics; ECOG = Eastern Cooperative Oncology Group; PS = performance status; *at investigator s discretion; standard regimens 14 7
Erlotinib (n=23) Chemotherapy (n=221) Median age, years (range) 59 (36 8) 59 (22 79) Gender, n (%) Male Female Ethnicity, n (%) Caucasian Asian ECOG PS, n (%) 1 2 Disease stage, n (%) IIIB IV 161 (79) 42 (21) 172 (85) 28 (14) 29 (14) 135 (67) 39 (19) 41 (2) 162 (8) 16 (72) 61 (28) 19 (86) 27 (12) 23 (1) 152 (69) 46 (21) 51 (23) 17 (77) Survival 1..9.8.7.6.5.4.3.2 1.1. mos (mos) Erlotinib 5.3 53 Comparator 5.5 HR=.96 (.78-1.19) Log-rank P=.7299 Patients at Risk: Comparator Erlotinib 3 6 9 12 15 18 21 24 27 3 33 36 39 42 45 48 51 5.5 Months Since Treatment 5.3 221 144 89 63 4 22 2 14 9 7 7 6 4 3 2 2 23 12 76 52 38 29 22 18 15 1 8 8 5 4 3 3 2 8
All Stage IIIB Stage IV PS /1 PS 2 White Asian Male Female Squamous Adenocarcinoma Other NSCLC Never smoker Former smoker Current smoker HR (95% CI) n.96 (.78 1.19) 424 1.2 (.74 1.93) 92.9 (.71 1.14) 332.93 (.73 1.19) 399 1.47 (.91 2.35) 85.94 (.75 1.19) 362.96 (.54 1.7) 55.86 (.67 1.1) 321 1.23 (.78 1.94) 13.86 (.61 1.23) 154.95 (.7 1.29) 21 1.43 (.81 2.5) 6.86 (.49 1.51) 74 1.1 (.73 1.66) 123.9 (.81 1.19) 227.4.6.8 1. 1.5 2. 3. Favors erlotinib HR Favors chemotherapy 9
Probability of survival 1..8.6.4.2 EGFR Mutation + Gefitinib (n=132) Carboplatin/paclitaxel (n=129) HR (95% CI) 1. (.76, 1.33); p=.99 No. events G 14 (79%) C / P 95 (74%) Median OS G 21.6 months C / P 21.9 months Probability of survival 1..8.6.4.2 EGFR Mutation Gefitinib - (n=91) Carboplatin/paclitaxel (n=85) HR (95% CI) 1.18 (.86, 1.63); p=.39 No. events G 82 (9%) C / P 74 (87%) Median OS G 11.2 months C / P 12.7 months. 4 8 12 16 2 24 28 32 36 4 44 48 52 Time from randomisation (months) Patients at risk: Gefitinib 132 126 121 C / P 129 123 112 13 95 88 8 7 68 58 55 46 48 38 4 24 26 11 15 6 7 3. 4 8 12 16 2 24 28 32 36 4 44 48 52 Time from randomisation (months) 91 85 69 52 76 57 4 44 29 26 33 25 Treatment by subgroup interaction test p=.48 19 19 16 11 16 11 8 3 5 1 1 1 1 Advanced/Recurrent NSCLC EGFR mutation positive ECOG PS /1 Age < 75 yrs Gefitinib N= 114 Carboplatin Paclitaxel N= 114 Primary endpoint: PFS Estimated sample size: 32 pts (closed early after N=23) Maemondo et al, N Engl J Med, 21 1
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Chemonaïve advanced d 4 cycles of 1tli 1st-line Non-PD NSCLC platinum-based n=889 n=1,949 doublet* Mandatory tumor sampling Erlotinib 15mg/day 1:1 Placebo PD PD Stratification factors: EGFR IHC (positive vs negative vs indeterminate) i t 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 Cappuzzo et al, Lancet Oncol, 21. Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumors Secondary endpoints: Overall survival (OS) in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC tumors; biomarker analyses; safety; time to symptom progression; quality of life (QoL) PFS probability 1..8 Erlotinib Placebo PFS at 12 wks (%) 53 4 PFS at 24 wks (%) 31 17.6.4.2 HR=.71 (.62.82) Log-rank p<.1 Erlotinib (n=437) Placebo (n=447) 8 16 24 32 4 48 56 64 72 8 88 96 Time (weeks) *PFS is measured from time of randomization into the maintenance phase; assessments were every 6 weeks; ITT = intent-to-treat population 12
PFS probability 1. Erlotinib (n=22).8.6 HR=.1 (.4.25) Log-rank p<.1 Placebo (n=27).4.2 8 16 24 32 4 48 56 64 72 8 88 96 Time (weeks) *6% censored 13
No improvement in OS with maintenance erlotinib This was attributed to the fact that 16 of 24 patients with EGFR mutation received post-study therapy with an EGFR TKI Second line therapy! The median improvement in OS is modest with erlotinib (12 m vs. 11 m) Pemetrexed resulted in improved OS over placebo in non-squamous histology (16 m vs. 11 m) In unselected patients,,pemetrexed has emerged as the preferred maintenance therapy 14
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OS? No Major PFS benefit? No Robust QOL gains? No 16
There is no compelling reason to use EGFR TKIs before second line therapy. 17