Ulrich Keilholz

Results of a Phase III, Randomized, Placebo-Controlled Study of Sorafenib in Combination With Carboplatin and Paclitaxel As Second-Line Treatment in Patients With Unresectable Stage III or Stage IV Melanoma

PURPOSE This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen. PATIENTS AND METHODS A total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m2 plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively. RESULTS The median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with sorafenib. Dermatologic events, grade 3 thrombocytopenia, diarrhea, and fatigue were more common in patients treated with sorafenib plus CP versus placebo plus CP. CONCLUSION In this study, the addition of sorafenib to CP did not improve any of the end points over placebo plus CP and cannot be recommended in the second-line setting for patients with advanced melanoma. Both regimens had clinically acceptable toxicity profiles with no unexpected adverse events. A trial of similar design for the first-line treatment of patients with advanced melanoma (intergroup trial E2603) is currently ongoing.

Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial

BACKGROUND Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

Systematic review of medical treatment in melanoma: current status and future prospects.

The incidence of melanoma is increasing worldwide, and the prognosis for patients with high-risk or advanced metastatic melanoma remains poor despite advances in the field. A systematic literature review of treatments for advanced, metastatic disease was conducted to present the success of current treatments and the promise of those still in clinical development that may yield incremental improvements in the treatment of advanced, metastatic melanoma. Advances in the understanding of the mechanism of chemotherapy resistance offer the hope for improved results with chemotherapy, and the triumvirate of more effective chemotherapy, immunotherapy, and targeted therapy are likely to be combined with one another for significant advances in melanoma over the coming few years.

Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy.

The Society for Biological Therapy held a Workshop last fall devoted to immune monitoring for cancer immunotherapy trials. Participants included members of the academic and pharmaceutical communities as well as the National Cancer Institute and the Food and Drug Administration. Discussion focused on the relative merits and appropriate use of various immune monitoring tools. Six breakout groups dealt with assays of T-cell function, serologic and proliferation assays to assess B cell and T helper cell activity, and enzyme-linked immunospot assay, tetramer, cytokine flow cytometry, and reverse transcription polymerase chain reaction assays of T-cell immunity. General conclusions included: (1) future vaccine studies should be designed to determine whether T-cell dysfunction (tumor-specific and nonspecific) correlated with clinical outcome; (2) tetramer-based assays yield quantitative but not functional data (3) enzyme-linked immunospot assays have the lowest limit of detection (4) cytokine flow cytometry have a higher limit of detection than enzyme-linked immunospot assay, but offer the advantages of speed and the ability to identify subsets of reactive cells; (5) antibody tests are simple and accurate and should be incorporated to a greater extent in monitoring plans; (6) proliferation assays are imprecise and should not be emphasized in future studies; (7) the reverse transcription polymerase chain reaction assay is a promising research approach that is not ready for widespread application; and (8) there is a critical need to validate these assays as surrogates for vaccine potency and clinical effect. Current data and opinion support the use of a functional assay like the enzyme-linked immunospot assay or cytokine flow cytometry in combination with a quantitative assay like tetramers for immune monitoring. At present, assays appear to be most useful as measures of vaccine potency. Careful immune monitoring in association with larger scale clinical trials ultimately may enable the correlation of monitoring results with clinical benefit.

Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial

BACKGROUND Individuals affected by melanoma with thick primary tumours or regional node involvement have a poor outlook, with only 30-50% alive at 5 years. High-dose and low-dose interferon alfa have been assessed for the treatment of these patients, with the former having considerable toxicity and a consistent effect on disease free survival, but not on overall survival, and the latter no consistent effect on either. Our aim was, therefore, to assess the effect of two regimens of interferon of intermediate dose versus observation alone on distant metastasis-free interval (DMFI) and overall survival in such patients. METHODS We did a randomised controlled trial in 1388 patients who had had a thick primary tumour (thickness > or = 4 mm) resected (stage IIb) or regional lymph node metastases dissected (stage III) and had been assigned to 13-months (n=553) or 25 months (n=556) of treatment with subcutaneous interferon alfa 2b, or observation (n=279). Treatment comprised 4 weeks of 10 million units (MU) of interferon alfa (5 days per week) followed by either 10 MU three times a week for 1 year or 5 MU three times a week for 2 years, to a total dose of 1760 MU. Our primary endpoint was DMFI. Analyses were by intent to treat. FINDINGS After a median follow-up of 4.65 years, we had recorded 760 distant metastases and 681 deaths. At 4.5 years, the 25-month interferon group showed a 7.2% increase in rate of DMFI (hazard ratio 0.83, 97.5% CI 0.66-1.03) and a 5.4% improvement in overall survival. The 13-month interferon group showed a 3.2% increase in rate of DMFI at 4.5 years (0.93, 0.75-1.16) and no extension of overall survival. Toxicity was acceptable, with 18% (195 of 1076) of patients going off study because of toxicity or as a result of refusal of treatment because of side-effects. INTERPRETATION Interferon alfa as used in the regimens studied does not improve outcome for patients with stage IIb/III melanomas, and cannot be recommended. With respect to efficacy of the drug, duration of treatment seemed more important than dose, and should be assessed in future trials.

A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS

This study investigated the immunogenicity of Wilms tumor gene product 1 (WT1)-peptide vaccination in WT1-expressing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients without curative treatment option. Vaccination consisted of granulocyte-macrophage colony-stimulating factor subcutaneously days 1 to 4, and WT1.126-134 peptide and 1 mg keyhole limpet hemocyanin on day 3. The initial 9 patients received 4 vaccinations biweekly, then monthly, and the subsequent 10 patients received continual biweekly vaccination. Seventeen AML patients and 2 refractory anemia with excess blasts patients received a median of 11 vaccinations. Treatment was well tolerated. Objective responses in AML patients were 10 stable diseases (SDs) including 4 SDs with more than 50% blast reduction and 2 with hematologic improvement. An additional 4 patients had clinical benefit after initial progression, including 1 complete remission and 3 SDs. WT1 mRNA levels decreased at least 3-fold from baseline in 35% of patients. In 8 of 18 patients, WT1-tetramer(+) T cells increased in blood and in 8 of 17 patients in bone marrow, with a median frequency in bone marrow of 0.18% at baseline and 0.41% in week 18. This WT1 vaccination study provides immunologic, molecular, and preliminary evidence of potential clinical efficacy in AML patients, warranting further investigations.

Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

R. Dummer1, A. Hauschild2, N. Lindenblatt3, G. Pentheroudakis4 & U. Keilholz5, on behalf of the ESMO Guidelines Committee* Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany; Division of Plastic and Reconstructive Surgery, University Hospital Zurich, Zurich, Switzerland; Ioannina University Hospital, Ioannina, Greece; Charite Comprehensive Cancer Center, Charite-Universitatsmedizin, Berlin, Germany

Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients.

PURPOSE In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Coxs regression, respectively. RESULTS Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.

Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group.

PURPOSE The combination of interferon alfa-2a (IFN alpha) and high-dose interleukin-2 (IL-2) is active in metastatic melanoma. The addition of cisplatin (CDDP) has resulted in response rates greater than 50%. This study was performed to determine whether the addition of CDDP to a cytokine treatment regimen with IFN alpha and high-dose IL-2 influences survival of patients with metastatic melanoma. PATIENTS AND METHODS Patients with advanced metastatic melanoma were randomly assigned to receive treatment with IFN alpha 10 x 10(6) U/m2 subcutaneously on days 1 through 5 and a high-dose intravenous decrescendo regimen of IL-2 on days 3 through 8 (18 mIU/ m2/6 hours, 18 mIU/m2/12 hours, 18 mIU/m2/24 hours, and 4.5 mIU/m2/24 hours x 3) without (arm A) or with (arm B) CDDP 100 mg/m2 on day 1. Treatment cycles were repeated every 28 days to a maximum of four cycles. RESULTS One hundred thirty-eight patients with advanced metastatic melanoma, of whom 87% had visceral metastases, were accrued for the trial. Both regimens were feasible in a multicenter setting. The objective response rate was 18% without and 33% with CDDP (P = .04). The progression-free survival was 53 days without and 92 days with CDDP (P = .02, Wilcoxon; P = .09, log-rank). There was no statistically significant difference in survival between treatment arms, with a median overall survival duration for all patients of 9 months. CONCLUSION The addition of CDDP to cytokine treatment with IFN alpha and IL-2 does not influence survival of patients with advanced metastatic melanoma, despite a significant increase in response rate and progression-free survival.

Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity

Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity