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Adjuvant Therapy for Melanoma What is the role of PegIFN in relation to HDIFN?

Adjuvant Therapy for Melanoma What is the role of PegIFN in relation to HDIFN?. John M. Kirkwood, MD Professor of Medicine, Dermatology and Translational Science University of Pittsburgh School of Medicine &Cancer Institute Melanoma Committee, Eastern Cooperative Oncology Group

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Adjuvant Therapy for Melanoma What is the role of PegIFN in relation to HDIFN?

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  1. Adjuvant Therapy for MelanomaWhat is the role of PegIFN in relation to HDIFN? John M. Kirkwood, MD Professor of Medicine, Dermatology and Translational Science University of Pittsburgh School of Medicine &Cancer Institute Melanoma Committee, Eastern Cooperative Oncology Group International Melanoma Working Group kirkwood@pitt.edu

  2. Relapse and Mortality Risk of Operable Melanoma Guides Adjuvant Therapy Local stage I disease: IA-B/IIA Lower risk • Primary risk guided by Breslow thickness & ulceration • Primary >2mm thick, ulcerated (T3b) or >4 mm (T4) IIB Intermediate risk Regional Stage III Lymph Node Disease: IIIAHigh risk • Sentinel lymph node status: key prognostic assessment for >1 mm thick primaries • Risk varies by numbers of nodes involved 1, 2-3, >3 (N1, 2, 3) • Microscopic: Stage IIIA 35% relapse risk • Macroscopic: Stage IIIB >60% relapse risk IIIB Higher risk Distant Resectable Stage IV Disease: IV Highest risk

  3. Questions Regarding IFN Adjuvant Therapy • Relapse free survival benefit (RFS) correlation with overall survival (OS) benefit? • Difference by disease/stage burden? • Durability of benefit in advanced disease that assures RFS, OS adjuvant impact? • Optimal duration of therapy? • Dose-response relationship? • Role of intravenous IFN induction?

  4. E1684, E1690, and E1694: Durable and Significant Impact upon Relapse-free * and Overall Survival** E1690: IFN vs Observation* E1684: IFN vs Observation** HR=1.24 P2=0.09 HR=1.38P2=0.02 1.0 1.0 0.8 0.8 Proportion Alive and Relapse Free 0.6 0.6 Proportion Alive and Relapse Free 0.4 0.4 0.2 0.2 0.0 0.0 0 1 2 3 4 5 6 7 8 9 10 0 2 4 6 8 10 12 14 16 Time (Years) Time (Years) Time Interval (Years) Time Interval (Years) 8-10 0-2 2-4 4-6 6-8 0-2 2-4 4-6 6-8 8-10 10-12 12-14 14-16 0/13 Observ. 105/212 16/94 5/72 2/44 Observ. 89/140 12/51 3/39 0/35 1/32 1/29 0/15 0/3 0/20 IFN 98/215 15/108 5/85 2/53 IFN 73/146 14/68 3/53 1/50 2/48 2/44 0/31 0/10 (No. events/No. at risk) (No. events/No. at risk) E1694: IFN vs GMK** 1.0 HR=1.33 P2=0.006 0.8 Proportion Alive and Relapse Free 0.6 0.4 0.2 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Time (Years) Time Interval (Years) 0-1 1-2 2-3 3-4 4-5 IFN 118/436 28/257 8/123 3/47 0/3 GMK 153/439 40/240 6/113 3/40 0/0 (No. events/No. at risk) Kirkwood et al., J Clin Onc. 1996, 2000, 2001; Clin Cancer Res. 2004;10:1670; Tarhini and Kirkwood J Clin Onc. 2012

  5. Rationale for Adjuvant Therapy: Improved Responsiveness of Micro-metastatic Disease • IFNα therapy of advanced melanoma: 16% response rate, survival benefit unknown • Response inversely correlated with disease burden, durable in one-third • Mechanisms unclear; agent pleiotropic • IFNα adjuvant therapy: greater impact, relapse/mortality reduced up to 33%

  6. Do Benefits of IFNα Differ by Stage? TrialBenefit Greatest • E1684 high tumor burden (N1-2b) • E1690 intermediate tumor (N1-2a) • E1694 lower tumor burden (T4, N-) benefit across stages with high-dose IFNα • 18952 lower burden N1 • 18991 lower burden N1 • 18071 lower burden N1 benefit confined to microscopic disease with PegIFN

  7. Meta-analyses of IFN trials demonstrate an impact of IFN on RFS and OS

  8. IFNα as Paradigm for Adjuvant Therapy • Relapse-free benefit in all regimens • intermediate dose impact is transient • HDI impact is durable to >10+ years • Survival improved in 2 of 14 trials • HDI only demonstrates OS benefit • Mechanisms evaluated for HDI, IDI: • anti-angiogenic(-/?), • pro-apototic(-/?), • immunological (+/?)

  9. Recent Trials Address Duration of Therapy Required and Role of Induction • E1697 Intergroup Trial of 1 month IFNα2b • No benefit of 1 month IFN compared to Observation in 1150 patients with Stage II-III melanoma (Agarwala et al., Proc ASCO 2011) • EORTC 18991 Trial of 5 years PegIFNα2b • Relapse reduction without improved survival at 7.6 years follow-up (Eggermont JCO 2012) • Benefit among N1 (microscopic~IIIA), not N2 (IIIB) • Treatment tolerated a median of ~14 months

  10. Is there evidence for benefit of prolonged therapyEORTC 18991: Pegylated IFN-a2b x 5 years vs. Observation in Resected Stage III (TxN1-2M0) Melanoma Patients (n=1,256):Resected TxN1-2M0 melanoma, within 7 weeks of lymphadenectomy Observation Randomization Stratified by: • Microscopic (N1) vs. palpable (N2) • 1 vs. 2-4 vs. 5+ nodes • Breslow • Ulceration • Gender and site Peg-IFN alfa-2b for up to 5 years • Induction (8 weeks) 6 µg/kg/week • Maintenance (5 years or distant metastasis) 3 µg/kg/week • Dose reduction to 3, 2, 1 to maintain performance status Primary Endpoints: • Relapse-free survival (RFS) • Distant metastasis-free survival (DMFS) Eggermont AM, et al. Lancet 2008; 372: 117–26 J Clinical Oncology 2012

  11. RFS benefit of adjuvant peginterferon maintenance sustained at 7.6 years follow-up • No change in DMFS or OS observed from 2007 to 2011 EORTC 18991: Outcome at 7.6 yrs. Is diminished compared with 3.8 yrs. maturity • RFS benefit diminished at 7.6 years • No significant impact upon DMFS or OS early or at maturity

  12. EORTC 18991: Outcome in N1 population in 2007, 2012 • Stage III N1 disease showed significant RFS and DMFS in 2007 • Improvements at 7.6 years are no longer statistically significant

  13. EORTC 18991: N2 population lacks benefit at either 3.8 or 7.6 yrs. evaluation • Patients with stage III N2 show no significant benefit in any endpoint

  14. EORTC 18991: Stage III N1, Ulcerated Disease • Greatest benefit of Peg IFN in Stage III N1 subset, ulcerated primary • Median OS peg IFN vs. observation: > 9 vs. 3.7 years • EORTC 18081 trial compares Peg IFN x 2 yrs vs. observation in patients with ulcerated primary tumors

  15. EORTC 18991: Primary Tumor Ulceration** • Primary tumor ulceration is associated with trend to IFN benefit:* *not significant at maturity in 2012; **US Intergroup trials have never shown this correlation

  16. Summary of IFNαtrials leading to regulatory approval Tarhini and Kirkwood J Clin Oncol 2012

  17. Biomarkers of Risk & Benefit are Needed to Tailor and Improve Adjuvant Therapy Risk/Prognosis • S100B may add to risk assessment (Tarhini et al., J. Clin Onc 2008) Benefit: Predictors of IFN clinical benefits • Autoimmunity (Gogas, et al., NEJM 2006) • Cytokine profile in serum(Yurkovetsky, 2007) • Ulceration of primary tumor (Ives, 2007) • Inflammatory profile in tumor (Gajewski, 2011)

  18. Conclusions: IFNα Adjuvant Therapy • Relapse-free survival benefit HR ~.70 correlates with overall survival benefit • Disease/stage burden predicts PegIFN benefit, but not HDI benefit • Duration of therapy feasible with HDI & PegIFN are both ~1 year • Dose-response relationship still unclear • Adjuvant recommendation should be HDI • If HDI not tolerated, and disease is of stage <IIIA, PegIFN is a fallback option

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