Who is the Ideal Candidate for PEG Intron? Sanjiv S. Agarwala, MD Chief, Oncology & Hematology St. Luke s Cancer Center Professor, Temple University School of Medicine Philadelphia, PA, USA
Overview Introduction and Review of EORTC 18991 Is there an impact of stage on benefit? Is there an impact of ulceration on benefit? Who is the best candidate?
Pegylated IFN-α EORTC Regimen Schedule Dose Frequency Duration Induction 6 μg/kg SC Q weekly 8 weeks Maintenance 3 μg/kg SC Q weekly up to 5 years PEG IFN is an intermediate dose regimen
EORTC 18991 (peginterferon alfa-2b): Study Design 1 N=1,256 Stage III, Enrolled 2000 2003 Stratification Microscopic, palpable nodes Number of nodes (1, 2 4, 5+) Ulceration Breslow thickness Sex Institution R A N D O M I Z E Weekly PEG-IFN Observation Weekly PEG-IFN First 8 doses: 6 mcg/kg SC weekly x 8 Doses 9 260: 3 mcg/kg SC weekly for up to 5 years Dose adjustments: 3, 2, 1 mcg/kg for safety and maintenance of ECOG Performance Status at 0 or 1 SC=subcutaneous; ECOG=Eastern Cooperative Oncology Group. 1. Eggermont AMM et al. Lancet. 2008;372:117 126.
Baseline Characteristics 1 Sex, % Female Male PEG-IFN (n=627) 42 58 Observation (n=629) 42 58 Age, y Median, range 50, 19 70 50, 18 70 Age, % 18 to <50 yrs 50 to <65 yrs 65 yrs 50 40 10 49 38 13 1. Eggermont AMM et al. Lancet. 2008;372:117 126.
Disease Characteristics 1,a PEG-IFN n=627 Patients, % Observation n=629 Nodal involvement Microscopic 43 43 Palpable 57 57 Node, n 1 Node 54 54 2 4 Nodes 33 32 5 Nodes 12 13 Not Evaluable 1 1 Ulceration No 48 48 Yes 25 25 Unknown 27 27 Breslow <1.5 mm 23 23 1.5 3.99 mm 43 43 4.0 mm 22 23 Unknown 12 12 a At baseline, used for stratification of randomization. 1. Eggermont AMM et al. Lancet. 2008;372:117 126.
Primary Analysis Relapse-Free Survival: Intent-to-Treat, Independent Review 1 PEG-IFN Observation Patients 627 629 RFS events 328 368 Hazard ratio 0.82 95% CI 0.71, 0.96 P value 0.01 Median RFS, mo 34.8 25.6 RFS=relapse-free survival; CI=confidence interval. 1. Eggermont AMM et al. Lancet. 2008;372:117 126.
Relapse-Free Survival (ITT) 2007 evaluation 2011 evaluation Trial 18991 100 90 80 70 60 50 40 30 20 10 0 (years) 0 2 4 6 8 10 O N Number of patients at risk : 368629 311 76 0 0 Observation 328627 346 85 0 0 Peg-IFN alfa 100 90 80 70 60 50 40 30 20 10 0 (years) 0 2 4 6 8 10 O N Number of patients at risk : 406629 317 238 205 63 Observation 384627 349 283 233 94 Peg-IFN alfa P=0.01 HR = 0.82 (95% CI 0.71, 0.96) P=0.05 HR = 0.87 (95% CI 0.76, 1.00)
Overview Introduction and Review of EORTC 18991 Is there an impact of stage on benefit? Is there an impact of ulceration on benefit?
Design EORTC 18952 Intermediate dose IFN Patients (n=1,388): Resected IIB or TxN1-2M0 melanoma, Randomization Stratified by: IIB, III-N1 vs. III-N2 1 vs. 2-4 vs. 5+ nodes Breslow Ulceration Gender Site Observation IFN alfa-2b 10 MIU, qd, 4wks, 10 MIU, tiw 12 Mts IFN alfa-2b 10 MIU, qd, 4 wks, 5 MIU, tiw 24 Mts Primary Endpoint: Distant Metastasis-Free Interval (DMFI) Eggermont
Intermediate dose IFN Trial EORTC 18952 NORDIC Stage Treatment DFS OS IIB-III 1388 pts IIB,III 855 pts IFNα2b, 10 MIU/qd1-5/sc, 4wk +3x10MIU/wk,sc,12mts or + 3x5MIU/wk,sc,24mts IFNα2b, 10MIU/qd1-5, sc,4 wk +3x10MIU/wk,sc,12mts or3x10miu/wk,sc,24mts 4.65-yr; HR=0.81; p=0.12 6 yr; HR=0.83 p=0.05 4.65-yr; HR=0.88; p=0.40 6 yr; HR =0.88 p = 0.47 HR=0.82 PEG-IFN EORTC 18991 III 1256 pts PEG-IFNα2b, 180 MIU/wk, sc, 8 wks + 30-90MIU//wk,sc,5yr 3.65 yr; HR=0.82; p=0.012 3.65 yr; HR = 0.98; p= 0.98 BIOAVAILIBILITY 50% HR=0.82
INTERFERON SENSITIVITY LIMITED TO STAGES IIB AND III-N1 EORTC 18952 (1388 pts): Efficacy EORTC 18991 (1256 pts): Efficacy IIB > N1 > N2 at 4.9 yrs N1 > N2 at 7.6 yrs RFS/DMFI DMFS OS: HR estimate EORTC 18952 13-month interferon alfa-2b (4 wk 10MU + 12 mts 10MU) OR 25-month interferon alfa-2b (4wk 10MU 24 mts 5 MU) EORTC 18991 8 wks Peg-IFN alfa-2b at 6 µg/kg + up to 5 years Peg-IFN alfa-2b At 3 µg/kg Stage IIb III N1 III N2 IIb III N1 III N2 n subjects 356 353 679-543 713 RFS or DMFI 0.66 0.78 0.95-0.82 0.89 DMFS 0.67 0.83 0.97-0.86 0.96 OS 0.63 0.88 1.03-0.86 1.00
Overview Introduction and Review of EORTC 18991 Is there an impact of stage on benefit? Is there an impact of ulceration on benefit?
ULCERATED MELANOMA : A DISTINCT BIOLOGIC ENTITY Survival much lower for same Breslow Stromal Response Ulcerated Melanoma EJC 2004 Geneprofile Signature JNCI 2006 PlosOne 2013 Sentinel Node Suppression Clin Cancer Res 2009 Balch CM et al. AJCC staging and Prognostic factors analysis JCO. 2001; 19:3622-34
EORTC 18991 RFS in the SLN+ Ulcerated Primary Population Hazard Ratio 0.72 (99% CI 0.46, 1.13) Median RFS 2.7 years vs 1.7 years Eggermont et al, J Clin Oncol 2012;30:3810
EORTC 18991 OS in the SLN+ Ulcerated Primary Population Hazard Ratio 0.59 (99% CI 0.35, 0.97) Median OS not reached vs 3.6 years Eggermont et al, J Clin Oncol 2012;30:3810
Summary from EORTC 18991 trial III- N1 (Sentinel Node +) pts experienced greater benefit in terms of RFS and trend for DMFS and OS (HRs 0.82; 0.86; 0.86) ULCERATED primary - SN-positive III-N1 pts significantly benefited on all endpoints (HRs: RFS 0.72; DMFS 0.65; OS 0.59; median OS difference of 3.7 yrs vs > 8 years)
Stage IIb & III-N1 & Ulceration: OVERALL SURVIVAL by trt by study Consistency between 18952 and 18991 (ASCO2009) 100 18952 100 18991 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 10 HR = 0.56 95% CI (0.38, 0.83) P = 0.003 20 10 HR = 0.61 95% CI (0.39, 0.96) P = 0.03 0 0 1 2 3 4 5 6 O N 95 237 13- or 25-month IFN 36 61 Obs 0 (yrs) 0 1 2 3 4 5 6 O N 33 96 44 90 5-yr PEG-IFN Obs
Who is the best candidate? Appears to be. The surgically staged patient who has had a sentinel LN biopsy and has only microscopically positive lymph nodes in the presence of an ulcerated primary melanoma
But..
Is Effectiveness of HDI Stage Dependent? Not in US Trials of HDI Trial/Yr Eligibility N Total # of Patients w/ micromet LN IFN Obs only E1684* 1996 IIB, III 280 34 2 14 E1690 2000 IIB, III 608 68 18 29 E1694 2001 IIB, III 774 316 149 166 MD Anderson 2007 III 486 110 42 68 Subgroup findings Major impact on patients with clinically evident lymph node positive disease Major impact on patients with lymph node + disease, particularly those with 2 3+ lymph nodes High-dose IFN was of the most benefit for patients with no lymph node involvement (IIB) (P=.01). Stage IIIA absolute increase in RFS of 9% (P=.09); P=.02 after adjustment for multiple variables Anaya DA, et al. Cancer. 2008;112:2030.
EORTC 18991: RFS in Stratified Subsets The result is internally consistent across relevant subgroups defined by baseline demographics and prognostic variables Herndon et al. Oncologist 2012;17:1323 Unpublished data presented to FDA ODAC, October 5, 2009
Conclusions Maximal benefit of PEG-IFN seen in patients with ulcerated N1 disease Pre-specified subset but not a prospective trial in that subset Needs to be validated in a prospective trial In the US it is approved for all stage III patients