Adjuvant Therapy of High Risk Melanoma William Sharfman, MD, FACP Associate Professor of Oncology and Dermatology Johns Hopkins University School of Medicine July 5, 2012
Adjuvant options for Stage IIB/C or III Close Observation Every 3-6mo x 2 yrs -> every 3-12 mo x 3 yrs -> annually, as clinically indicated (NCCN, 2012). Imaging studies? High dose Interferon alfa-2b (HDI)(Intron) FDA approved in 1996; Stage IIB/C, III Pegylated Interferon alfa (Peg-IFN)(Sylatron) FDA approved in 3/2011; Stage III nodal GM-CSF(Leukine)? Biochemotherapy? SWOG S0008 ASCO Abst 8504 Clinical Trials - the preferred option Vaccines Ipilimumab BRAF inhibitors Hu et al: ASCO Abst 8595: ~30% of stage III pts receive adjuvant systemic tx Leslie Fecher, MD, ASCO 2012
E1684: Study Design Resected T4N0 or TanyN+ or nodal recurrence (n = 287) R A N D O M I Z E Observation 52 Weeks IFN-α2b Induction Maintenance 4 Weeks 48 Weeks Endpoint: RFS Induction: 20 MIU/m 2 IV 5x weekly x 4 weeks Maintenance: 10 MIU/m 2 SC TIW x 48 weeks Accrual: 1984-1990 Kirkwood. J Clin Oncol. 1996;14:7-17.
E1684: Relapse-Free Survival Probability of relapse-free survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Arm IFNα2b Obs Median RFS 1.72 yr 0.98 yr P=0.0023 IFN-α2b (n=143) Observation (n=137) 0 1 2 3 4 5 6 7 8 Years Median f/u 6.9yr Kirkwood. J Clin Oncol. 1996;14:7-17.
E1684: Overall Survival Probability of survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Arm IFNα2b Obs Median OS 3.82 yr 2.78 yr P=0.0237 IFN-α2b (n=143) Observation (n=137) 0.2 0.1 0 1 2 3 4 5 6 7 8 Median f/u 6.9yr KirkwoodJ Clin Oncol. 1996;14:7-17.
Risk of Death: High-Dose IFN High Dose Trials ECOG 1684 Intergroup E1690 (H) Intergroup E1694 Total Deaths/Patients Statistics HR & 95% CI Odds Redn. IFN Control (O-E) VAR. (IFN : Control) (SD) 93/146 98/215 65/440 256/801 95/140 93/212 90/440 278/792-9.2 0.0-12.5-21.6 47.0 46.8 38.7 132.6 18% (13): 2P = 0.2 0% (15): 2P = 1.0 27% (14): 2P = 0.05 (32%) (35.1%) 0.0 0.5 1.0 1.5 2.0 IFN Better Control Better HDI reduced risk of death by 15%, P 2 = 0.06 P 2 =2-sided P Test for heterogeneity (3 trials) χ 2 2 = 2.3; P=0.3 Cancer Treat Rev. 2003;29:241-252.
Meta-analysis of High Dose Interferon Wheatley 2007, meta-analysis 13 RCT studies; n=6067 Stage II/III EFS: OR=0.87 (CI 0.81-0.93) p=0.00006 OS: OR=0.9 (CI 0.84-0.97) p=0.008 3% OS absolute benefit at 5 yrs No difference re: dose or duration Wheatley. ASCO 2007, abst 8526; Mocellin. JNCI 2010; 102:493-501
HDI Toxicity Hauschild. Cancer 2008; 112:982-994
EORTC 18991: Study Design Resected stage III: any T N1-2 M0 No in transit (n = 1256) R A N D O M I Z E Observation PEG-IFN Induction Maintenance 8 Weeks Up to 5 years 1 endpoint: DMFS, changed to RFS PEG-IFN Induction: 6 mcg/kg/wk SC x 8 weeks Maintenance: 3 mcg/kg/wk SC up to 5 years Eggermont A, et al. Lancet 2008;372:117-26; ASCO 2011; abst 8506b
EORTC 18991: PEG-IFN median f/u: 7.6 yr yr 4-5, 23 % still on therapy median RFS was 34.8 months (95% CI: 26.1,47.4) for PEG vs 25.5 months (95% CI: 19.6, 30.8) for placebo. No overall survival benefit More convenient schedule and less toxic ASCO 2011; abst 8506b
S0008: Study Design Resected Stage IIIA-N2a through Stage IIIC-N3 (n = 432) R A N D O M I Z E Induction 4 Weeks Biochemotherapy every 3 weeks x 3 IFN-α2b Maintenance 48 Weeks 1 endpoint: RFS and OS HDI: Induction: 20 MIU/m 2 IV 5x weekly x 4 weeks Maintenance: 10 MIU/m 2 SC TIW x 48 weeks BCT: DTIC 800mg/m2 D1 Cisplatin 20mg/m2 D1-4 Vinblastine 1.2mg/kg D1-4 IL-2, continuous infusion -9 MIU/m2/d D1-4 IFN 5 MU/m2 SC D1-4, 8, 10, 12 ASCO 2012 Abst 8504
SWOG S0008: Accrual: 8/00-11/07 Biochemotherapy? RFS: HR 0.77 [90% CI: 0.62-0.96], p=0.02; median RFS BCT = 4 years [90% CI: 1.9-5.9] vs 1.9yrs [90%CI 1.4-2.5] 5yr RFS 47% (BCT) vs 39% (HDI) Median OS: HR 1.0 [90% CI:0.78-1.27] p=0.49; Median OS NR (BCT) vs 8.4 yrs (HDI) 5yr OS = 56% for both arms Is this a new standard of care? Is this a new comparator arm? Quality of life?
Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node fi eld relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Bryan H Burmeister*, Michael A Henderson*, Jill Ainslie, Richard Fisher, Juliana Di Iulio, B Mark Smithers, Angela Hong, Kerwin Shannon, Richard A Scolyer, Scott Carruthers, Brendon J Coventry, Scott Babington, Joao Duprat, Harald J Hoekstra, John F Thompson.Lancet Oncol 2012; 13: 589 97
Figure 2 Kaplan-Meier curves of time to lymph-node field relapse by treatment group In the eligible population (A) and the intention-to-treat population (B). Hazard ratios are for adjuvant radiotherapy versus observation. The Lancet Oncology Volume 13, Issue 6 2012 589-597
Figure 4 Survival by group in the eligible population Relapse-free survival (A) and overall survival (B). Hazard ratios are for adjuvant radiotherapy versus observation. Bryan H Burmeister, Michael A Henderson, Jill Ainslie, Richard Fisher, Juliana Di Iulio, B Mark Smithers, An... Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial The Lancet Oncology Volume 13, Issue 6 2012 589-597 http://dx.doi.org/10.1016/s1470-2045(12)70138-9
Newer Approaches to Adjuvant Therapy of High Risk Melanoma
MSLT-2 Completion lymph node dissection vs observation with high resolution ultrasound. Patients with stage IIIA of IIIB microscopic lymph node involvement on sentinel biopsy.
Newer Approaches to Adjuvant Therapy of High Risk Melanoma Vaccines-no proven benefit Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Preplanned interim results for the AVAST-M trial-asco 2013, LBA9000- no survival benefit Immunotherapy Targeted Therapy
Key Autoimmune Adverse Events with Ipilimumab Colitis Skin rash Hepatitis Hypopituitarism Hypothyroidism
Ipilimumab Adjuvant Therapy Clinical Trials EORTC 18071: Phase 3 RCT of Ipilimumab v. placebo in resected stage III melanoma ECOG 1609: Phase III RCT HDI vs. Ipilimumab 3mg/kg vs. Ipilimumab 10mg/kg
Components of the MAPK pathway. Alcalá A M, Flaherty K T Clin Cancer Res 2012;18:33-39 2012 by American Association for Cancer Research
Pt #69 (MDACC): PET Scans at Baseline and Day 15 #59 Peter MacCallum Courtesy of P. Chapman Pre-treatment Pt #69 (MDACC) Cycle 2 Cycle 4
Adjuvant Targeted Therapy Trials About to Open Vemurafenib vs. Placebo Dabrafenib plustrametinib vs. Placebo How long do you give them? Neoadjuvant therapy?
Gene Expression Profile Signature(DecisionDx- Melanoma) to Predict Visceral Metastatic Risk in Patients with Stage I and II Cutaneous Melanoma. Dhillon et al. ASCO 2013