scholarly journals Contemporary Neoadjuvant Therapies for High-Risk Melanoma: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1905
Author(s):  
Kerianne Boulva ◽  
Sameer Apte ◽  
Ashley Yu ◽  
Alexandre Tran ◽  
Risa Shorr ◽  
...  
Keyword(s):  
Systematic Review ◽  
High Risk ◽  
Phase Iii ◽  
Stage Iii ◽  
Cochrane Central Register ◽  
Phase Ii Trials ◽  
Term Survival ◽  
Intralesional Therapy ◽  
High Risk Melanoma ◽  
Risk Melanoma

Despite advances in adjuvant immuno- and targeted therapies, the risk of relapse for stage III melanoma remains high. With 43 active entries on clinicaltrials.gov (8 July 2020), there is a surge of interest in the role of contemporary therapies in the neoadjuvant setting. We conducted a systematic review of trials performed in the last decade evaluating neoadjuvant targeted, immuno- or intralesional therapy for resectable stage III or IV melanoma. Database searches of Medline, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception to 13 February 2020. Two reviewers assessed titles, abstracts, and full texts. Trials investigating contemporary neoadjuvant therapies in high-risk melanoma were included. Eight phase II trials (4 randomized and 4 single-arm) involving 450 patients reported on neoadjuvant anti-BRAF/MEK targeted therapy (3), anti-PD-1/CTLA-4 immunotherapy (3), and intralesional therapy (2). The safest and most efficacious regimens were dabrafenib/trametinib and combination ipilimumab (1 mg/kg) + nivolumab (3 mg/kg). Pathologic complete response (pCR) and adverse events were comparable. Ipilimumab + nivolumab exhibited longer RFS. Contemporary neoadjuvant therapies are not only safe, but also demonstrate remarkable pCR and RFS—outcomes which are regarded as meaningful surrogates for long-term survival. Studies defining predictors of pCR, its correlation with oncologic outcomes, and phase III trials comparing neoadjuvant therapy to standard of care will be crucial.

Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8504-8504 ◽  
Author(s):  
Lawrence E. Flaherty ◽  
James Moon ◽  
Michael B. Atkins ◽  
Ralph Tuthill ◽  
John A. Thompson ◽  
...  
Keyword(s):  
High Risk ◽  
Stage Iv ◽  
Phase Iii ◽  
Stage Iii ◽  
Rank Test ◽  
High Dose ◽  
Phase Iii Trial ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
High Dose Interferon

8504 Background: High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts to modify IFN dose or schedule have not improved efficacy. A meta-analysis demonstrated that biochemotherapy (BCT) produced superior response rates compared with chemotherapy in pts with stage IV melanoma (Wheatley et al J Clin Oncol 25:5426, 2007). We sought to determine whether a short course of BCT would be more effective than HDI as adjuvant treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial) enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and randomized them to receive either HDI or BCT consisting of dacarbazine 800 mg/m2 day 1, cisplatin 20 mg/m2/ days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2/day continuous IV days 1-4, IFN 5 MU/m2/day sc days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were given every 21 days x 3 cycles (9 weeks total). Pts were stratified for number of involved nodes (1-3 v ≥4), micro v macro metastasis, and ulceration of the primary. Co-primary endpoints were relapse free survival (RFS) and overall survival (OS) using a one-sided log rank test at p= 0.05. Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in 57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a median f/up of 6 yrs, BCT improved RFS (p = 0.02, HR 0.77 [90% CI: 0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9 yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not different between the two arms (p = 0.49 HR 1.0 [90% CI: 0.78 – 1.27]) with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT provides a statistically significant improvement in RFS compared to HDI, but no discernable difference in OS and more grade IV toxicity. BCT represents a shorter, alternative treatment for pts with HRM, and a potential control arm and basis for future combinations in the adjuvant setting.

High-Dose Interferon Alfa-2b Does Not Diminish Antibody Response to GM2 Vaccination in Patients With Resected Melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696

2001 ◽  
Vol 19 (5) ◽  
pp. 1430-1436 ◽  
Author(s):  
John M. Kirkwood ◽  
Joseph Ibrahim ◽  
David H. Lawson ◽  
Michael B. Atkins ◽  
Sanjiv S. Agarwala ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Interferon Alfa ◽  
Immunoglobulin M ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
High Dose Interferon ◽  
Very High

PURPOSE: High-dose interferon alfa-2b (IFNα2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNα2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNα2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNα2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies. PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high–risk melanoma (AJCC stages IIB, III, and IV). RESULTS: The results demonstrate that IFNα2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNα2b and GMK is well tolerated in this patient population. CONCLUSION: Cox analysis of the results of the combination with IFNα2b show improvement in the relapse-free survival of patients with very high–risk melanoma (including those with resectable M1 disease).

Multi-institutional, prospective, randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine to prevent recurrence in high-risk melanoma patients: A subgroup analysis.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 63-63
Author(s):  
Robert Connor Chick ◽  
Mark B. Faries ◽  
Diane F. Hale ◽  
Phillip M. Kemp Bohan ◽  
Annelies Hickerson ◽  
...  
Keyword(s):  
High Risk ◽  
Subgroup Analysis ◽  
Stage Iv ◽  
Stage Iii ◽  
Tumor Lysate ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
Melanoma Patients ◽  
Resected Stage ◽  
Disease Free

63 Background: A novel vaccine strategy may prevent recurrence in high-risk melanoma patients (pts). The TLPLDC vaccine uses yeast cell wall particles (YCWP) to load tumor lysate into autologous dendritic cells (DC). In this phase IIb trial of TLPLDC vs. placebo in resected stage III/IV pts, TLPLDC increased 24 month (mo) disease free survival (DFS) in the per treatment (PT) population. Here, we present a 24mo DFS subgroup analysis and estimated overall 36mo DFS. Methods: Disease-free pts were randomized 2:1 to the TLPLDC vaccine vs. unloaded YCWP+DC at 0, 1, 2, 6, 12, and 18mo. The protocol was amended to allow concurrent adjuvant checkpoint inhibitor (CPI) therapy once approved. The pre-specified PT population included only pts completing the primary vaccine/placebo series (PVS) at 6 mo. Kaplan-Meier estimates of DFS were used to compare treatment arms by stage (III or IV) and CPI therapy (yes/no) in the ITT and PT populations. Results: 144 pts were randomized (103 TLPLDC, 41 placebo); 98 pts (66 TLPLDC, 32 placebo) completed the PVS. There were no clinicopathologic differences between treatment groups. There was no difference in 24mo DFS in stage III pts (n = 112), but in stage IV pts (n = 32), the 24mo DFS was 44% vs 0% (TLPLDC vs placebo) (p = 0.41) in ITT and 73.3% vs. 0% (HR 0.14, p = 0.002) in PT. Stage IV pts were more likely to receive CPI than stage III pts (50% vs. 30%, p = 0.003). There was no difference in 24mo DFS for pts who did not receive CPI (n = 102), but in pts who received CPI (n = 42), the 24mo DFS was 49.3% vs. 31.3% (p = 0.71) in ITT and 68.8% vs. 41.7% (HR 0.46, p = 0.28) in PT, showing a trend toward improved DFS in pts who completed the PVS and received CPI (n = 31). Overall, the 36mo estimated DFS was 34.2% vs. 21.6% (p = 0.89) for ITT and 56.9% vs. 27.9% (p = 0.021) for PT. Conclusions: The TLPLDC vaccine improved DFS in patients completing the PVS at 24 and 36 mos, particularly in the resected stage IV subset. The apparent synergistic effect with TLPLDC + CPI will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI vs. CPI alone in resected stage IV melanoma pts. Clinical trial information: NCT02301611.

Interferon alfa-induced autoimmunity and serum S100 levels as predictive and prognostic biomarkers in high-risk melanoma in the ECOG-intergroup phase II trial E2696

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8506-8506 ◽  
Author(s):  
J. J. Stuckert ◽  
A. A. Tarhini ◽  
S. Lee ◽  
C. Sander ◽  
J. M. Kirkwood
Keyword(s):  
High Risk ◽  
Serum Protein ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Interferon Alfa ◽  
Phase Iii ◽  
Time Points ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
S 100

8506 Background: Uncontrolled evidence demonstrates that adjuvant high-dose interferon alfa-2b (HDI) benefit in high-risk melanoma patients is predicted by autoimmunity induction, and the prognosis of melanoma has been correlated with levels of S-100 protein. We have evaluated these two serological markers in the context of a completed phase II study E2696. Methods: Patients with resectable AJCC stage IIB, III, and IV melanoma were randomly assigned to receive GM2-KLH/QS-1 (GMK vaccine) plus concurrent HDI (Arm A) or GMK plus sequential HDI (Arm B), or GMK without HDI (Arm C). Sera from 103 patients were banked at baseline and 3 additional time points, and have been tested for serum protein S100, and anti-nuclear, anti-thyroid peroxidase, anti-thyroglobulin, anti-mitochondrial, and total anti-cardiolipin autoantibodies (AA) using ELISA. Results: At a median follow-up of 96.5 mo (range: 17–109), the median relapse-free survival (RFS) was 28.3 mo, 95% CI (18.4, 43.6) (64 /103 patients relapsed). Median survival has not been reached (54/103 alive). AA were induced in 17 subjects (25%; n=69) receiving HDI and GMK versus 2 (6%; n=34) receiving GMK alone (2p-value=0.031). In HDI arms induced AA were detected = 12 weeks after therapy initiation. RFS was improved among HDI recipients with AA, but with the limited numbers in this phase II trial this trend does not achieve significance. In the multivariate (Cox regression model) analysis, adjusting for treatment (HDI vs. no HDI) and baseline S-100 value for later time points, S-100 level ≥0.08 microg/l was an independent prognostic factor for RFS at baseline (HR=1.96; p=0.0273), week 4–6 (HR=1.72; p=0.073), wk 12–14 (HR=1.81; p=0.048) and wk 52 (HR=4.3; p<0.001). The hazard ratio (HR) for OS was 1.86 at wk 12–14 (p=0.061), and 5.7 at wk 52 (p<.001). In the model using wk 52 S-100 value (at completion of HDI), the HR adjusted for treatment was 7.1 p=0.009. Conclusions: Autoimmunity is a predictive biomarker of RFS with HDI in the E2696 trial compared to GMK. Serum protein S-100 level ≥0.08 microg/l is an independent prognostic marker for RFS and OS most significant at baseline and 1 year of followup. Current studies will evaluate these markers in the larger phase III trial E1694 with 880 subjects. [Table: see text]

Quality-of-Life–Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data

2002 ◽  
Vol 20 (5) ◽  
pp. 1311-1318 ◽  
Author(s):  
Kerry L. Kilbridge ◽  
Bernard F. Cole ◽  
John M. Kirkwood ◽  
Frank G. Haluska ◽  
Michael A. Atkins ◽  
...  
Keyword(s):  
Quality Of Life ◽  
High Risk ◽  
Interferon Alfa ◽  
Trial Data ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
Adjuvant Interferon

PURPOSE: High-dose adjuvant interferon alfa-2b (IFNα2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life–adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFNα2b treatment and melanoma recurrence. PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFNα2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS. RESULTS: Using E1684 data, IFNα2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P < .05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of patients would experience a benefit in QAS from IFNα2b and 23% would experience a decrease in QAS; neither of these effects was statistically significant. Using utility predictors and the E1690/S9111/C9190 analysis, a decision rule was formulated that helps identify patients in whom IFNα2b may detract from QAS. CONCLUSION: Most patients experienced improvement in QAS in both trials, but this benefit was statistically significant in only 16% of patients in E1684. Change in QAS depends more on the utility for IFNα2b toxicity than on the utility for melanoma recurrence. Cancer patients probably have higher utilities for IFNα2b toxicity than members of the general population and will tend to favor IFNα2b treatment as a result.

scholarly journals Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial

2016 ◽  
Vol 27 (8) ◽  
pp. 1625-1632 ◽  
Author(s):  
T.K. Eigentler ◽  
R. Gutzmer ◽  
A. Hauschild ◽  
L. Heinzerling ◽  
D. Schadendorf ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Treatment ◽  
Low Dose ◽  
Pegylated Interferon ◽  
Phase Iii ◽  
Interferon Α ◽  
High Risk Melanoma ◽  
Risk Melanoma

Long-term survival of high-risk melanoma patients immunized with a Hyper-IL-6-modified allogeneic whole-cell vaccine after complete resection

2012 ◽  
Vol 21 (6) ◽  
pp. 773-783 ◽  
Author(s):  
Andrzej Mackiewicz ◽  
Jacek Mackiewicz ◽  
Piotr J. Wysocki ◽  
Maciej Wiznerowicz ◽  
Malgorzata Kapcinska ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Resection ◽  
Cell Vaccine ◽  
Term Survival ◽  
Whole Cell ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
Whole Cell Vaccine ◽  
Melanoma Patients

United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9504-9504 ◽  
Author(s):  
Ahmad A. Tarhini ◽  
Sandra J. Lee ◽  
F. Stephen Hodi ◽  
Uma N. M. Rao ◽  
Gary Irvin Cohen ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Primary Endpoint ◽  
Randomized Study ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Relative Safety ◽  
Risk Melanoma ◽  
Systemic Adjuvant Therapy

9504 Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.

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