Presentation is loading. Please wait.

Presentation is loading. Please wait.

Adjuvant Therapy for Melanoma What is the role of PegIFN in relation to HDIFN? John M. Kirkwood, MD Professor of Medicine, Dermatology and Translational.

Similar presentations


Presentation on theme: "Adjuvant Therapy for Melanoma What is the role of PegIFN in relation to HDIFN? John M. Kirkwood, MD Professor of Medicine, Dermatology and Translational."— Presentation transcript:

1 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 International Melanoma Working Group 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

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: IIIA High 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 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: IIIA High 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 Cooperative group/PI Eligibility n Treatment agent/dosage/duration Impact on DFSOS NCCTG CreaganT3-4, N1262 IFNα2a 20 MU/m2/D IM TIW x3 mos+- ECOG 1684 Kirkwood T4, N1 287 IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIW for 11 mos ++ at 6.9 –12.6 yrs E1690 Intergroup Kirkwood T4, N1 642 IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIWx11 mos vs 3 MU/D SC TIWx2 yrs +- at 4.3 – 6.6 yrs WHO #16 Cascinelli N IFNα2a 3 MU/D SC TIWx3 yrs +/-- EORTC Kleeberg T3-4, N1 830 IFNα2b 1 MU/D SC QODx1 yr vs IFNg 0.2 mg/D SC QODx1yr-- E1694 Intergroup Kirkwood T4, N1 880 IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIWx11 mos vs GMK vaccine x 96 wks ++ at 1.3 –2.1 yrs ECOG 2696 Kirkwood T4, N1, M1 107 GMK + IFN or -->IFN vs GMK +- at 1.4 – 2.6 yrs UKCCR Aim-High Hancock T4, N1 674 IFNα2a 3 MU/D SC QODx2 yrs -- EORTC Eggermont T4, N IFNα2b 10MU/d then10 MU TIW x1 or 5 MU TIW x 2 years EORTC Eggermont TxN Peg-IFN alfa-2b SC 6 µg/kg/week (8 weeks) then 3 µg/kg/week (5 years) vs Observation +, +/- at yrs- French Grob T2-T4 (≥1.5mm), N0489 IFNα2a 3 MU SC TIW x 18 mo vs Obs+- Austrian Pehamberger T2-T4 (≥1.5mm), N0311 IFNα2a 3 MU SC QD x 3 wks then TIW x 1 yr vs Obs+-

4 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? 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?

5 Time (Years) Proportion Alive and Relapse Free E1684: IFN vs Observation** Time (Years) Proportion Alive and Relapse Free Observ.105/21216/945/722/44 0/13 IFN98/21515/1085/852/53 0/20 E1690: IFN vs Observation* Time (Years) Proportion Alive and Relapse Free IFN118/43628/2578/1233/470/3 GMK 153/43940/2406/1133/400/0 E1694: IFN vs GMK** E1684, E1690, and E1694: Durable and Significant Impact upon Relapse-free * and Overall Survival** Time Interval (Years) Observ. 89/14012/513/390/351/321/290/150/3 IFN 73/14614/683/531/502/482/440/310/10 (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 Time Interval (Years) (No. events/No. at risk) Time Interval (Years) (No. events/No. at risk) HR=1.38 P 2 =0.02 HR=1.24 P 2 =0.09 HR=1.33 P 2 =0.006

6 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% 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%

7 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 lower burden N lower burden N lower burden N1  benefit confined to microscopic disease with PegIFN 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 lower burden N lower burden N lower burden N1  benefit confined to microscopic disease with PegIFN

8 Meta-analysis#RCTRFSOSComment Ives, JCO /+↑ benefit with ↑IFN dose Wheatley, ASCO OR=0.87, 95% CI= , p= OR=0.9, 95% CI= , p=0.008 OS benefit of 3% (CI 1%-5%) at 5 yrs Mocellin, JNCI HR = 0.82, 95% CI = ; P < HR = 0.89, 95% CI= ; P = % DFS benefit 11% OS benefit Meta-analyses of IFN  trials demonstrate an impact of IFN on RFS and OS

9 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 (+/?) 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 (+/?)

10 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 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 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 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

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

12 EORTC 18991: Outcome at 7.6 yrs. Is diminished compared with 3.8 yrs. maturity Outcome (ITT) HR (95% CI)P ValueHR (95% CI)*P Value RFS0.82 ( ) ( ).05 DMFS0.88 ( ) ( ).33 OS0.98 ( ) ( ).57 RFS benefit of adjuvant peginterferon maintenance sustained at 7.6 years follow-up No change in DMFS or OS observed from 2007 to 2011 RFS benefit diminished at 7.6 years No significant impact upon DMFS or OS early or at maturity RFS benefit diminished at 7.6 years No significant impact upon DMFS or OS early or at maturity

13 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 Stage III N1 disease showed significant RFS and DMFS in 2007 Improvements at 7.6 years are no longer statistically significant Outcome in N1 Population HRP Value HR (99% CI)* P Value RFS ( ).08 DMFS ( ).22 OS ( ).26

14 Patients with stage III N2 show no significant benefit in any endpoint EORTC 18991: N2 population lacks benefit at either 3.8 or 7.6 yrs. evaluation Outcome in N Evaluation2012 Evaluation HRP Value HR (99% CI)* P Value RFS ( ).21 DMFS ( ).66 OS ( ).97

15 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 trial compares Peg IFN x 2 yrs vs. observation in patients with ulcerated primary tumors Greatest benefit of Peg IFN in Stage III N1 subset, ulcerated primary –Median OS peg IFN vs. observation: > 9 vs. 3.7 years EORTC trial compares Peg IFN x 2 yrs vs. observation in patients with ulcerated primary tumors Outcome in 2007 in Patients With Stage III N1, Ulcerated Primary HR (99% CI) P Value RFS 0.72 ( ).06 DMFS 0.65 ( ).02 OS 0.59 ( ).006

16 EORTC 18991: Primary Tumor Ulceration** Primary tumor ulceration is associated with trend to IFN benefit:* OS Outcome in 2011 Based on Primary Tumor Ulceration HR (99% CI) P Value Ulcerated 0.81 ( ).11* Not ulcerated 1.05 ( ).64 * not significant at maturity in 2012; **US Intergroup trials have never shown this correlation

17 Study/PIStageNTreatment agent/ dosage/duration Median Follow up (year) Impact on (%) Toxicity Attrition Rate Comment PFS OS E1684 Kirkwood T4, N+ 287 IFNα2b 20 MU/m2/D IV for 1 month. Then, 10 MU/m2 SC TIW for 11 months vs. Observation ; p= ; p= At 12.6 yr, the impact of competing causes of death on OS cannot be ignored ; p= ; p=.18 E1690 Kirkwood T4, N+ 642 IFNα2b 20 MU/m2/D IV for 1 month. Then, 10 MU/m2 SC TIW for 11 months vs. 3 MU/D given SC TIW for 2 years vs. Observation ; p= Cross over of observation pts to HDI at nodal relapse (n=38 pts) is expected to affect OS analysis ; p= E1694 Kirkwood T4, N+ 880 IFNα2b 20 MU/m2/D IV for 1 month. Then 10 MU/m2 SC TIW for 11 months vs. GMK vaccine for 96 wks ; p= ; p= Symmetrical impact upon RFS, OS for IFN over GMK led to early closure for vaccine futility at 2 yr ; p= ; p=.04 EORTC Eggermont N PegIFNα2b given SC at 6 µg/kg/week (8 weeks) then 3 µg/kg/week (5 years) vs. Observation ; P= No impact upon OS, or DMFS at initial reporting or mature publication ; P= Summary of IFNα trials leading to regulatory approval Tarhini and Kirkwood J Clin Oncol 2012

18 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) 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)

19 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 { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/3351390/12/slides/slide_18.jpg", "name": "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


Download ppt "Adjuvant Therapy for Melanoma What is the role of PegIFN in relation to HDIFN? John M. Kirkwood, MD Professor of Medicine, Dermatology and Translational."

Similar presentations


Ads by Google