Jean-Baptiste Meric

Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma

Purpose: This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)–1, 2, and 3, in patients with metastatic melanoma. Experimental Design: Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate. Results: Objective response rate was 18.8% [95% confidence interval (CI), 7.2–36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0–17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2–9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels. Conclusions: Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing. Clin Cancer Res; 17(23); 7462–9. ©2011 AACR.

Pretreatment serum interleukin-6 concentration as a prognostic factor of overall survival in metastatic malignant melanoma patients treated with biochemotherapy: a retrospective study.

Biological response parameters during biochemotherapy, including chemotherapy with immune modulating agents, have been studied extensively. Of these parameters, interleukin-6 (IL-6) has been implicated in advanced stage disease and tumour recurrence. However, there is limited information available about the significance of IL-6 in metastatic malignant melanoma (MMM). In this study, we evaluated the possible relationship between serum IL-6 level and overall survival. This retrospective study included 125 patients with MMM. Pretreatment serum IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay (ELISA) test. Kaplan–Meier survival curves were constructed and compared using the log-rank test. Cox proportional analysis was performed to assess the predictors of overall survival, which was calculated from the beginning of biochemotherapy until death. In order to establish the possible relationship between IL-6 level and overall survival, patients were divided into two groups according to a cut-off of 5 pg/ml, corresponding to the first quartile obtained by descriptive statistics of the pretreatment IL-6 level in all patients. Thirty-five patients were in the low IL-6 group and 76 patients were in the high IL-6 group. Based on this stratification, overall survival was shown to be affected by IL-6 serum level: it was higher (24.6 months) in the low IL-6 group when compared with the high IL-6 group (9.7 months) (P=0.0006). Furthermore, Cox multivariate analysis including standard melanoma prognostic factors showed that IL-6, as a variable, lactate dehydrogenase (LDH) and tumour burden were significant prognostic factors for overall survival. On the basis of this evidence, the pretreatment serum IL-6 level is a predictive factor of overall survival in MMM.

Serum interleukin-6 concentrations as predictive factor of time to progression in metastatic malignant melanoma patients treated by biochemotherapy: a retrospective study

This retrospective study sought to evaluate the impact of IL-6 concentration on time to progression in advanced melanoma. One hundred and thirty-five patients were included, serum IL-6 levels were determined before (Day 0), at the end of the treatment (Day 49) and at recurrence: the relationship between IL-6 concentration and time to progression (TTP) was also evaluated. The baseline median serum IL-6 level was 16.5 pg/ml. When disease progression was observed, an increase in serum IL-6 level was noted. In order to establish the possible relationship between IL-6 level and TTP, patients were divided into two groups (low and high) using the median IL-6 level (16.5 pg/ml) detected in the pretreatment serum of overall patients as a cut-off. Sixty patients were in the low IL-6 group and 56 patients in the high IL-6 group. Time to progression was calculated from the beginning of treatment to recurrence, and analyzed using the Kaplan-Meier method. Patients with low IL-6 serum concentration showed a significantly (p<0.00001) higher median TTP than patients with high IL-6 level. Patients maintaining a low IL-6 level during the treatment showed the longest median TTP compared with those supporting high levels (24.4 versus 5.5 months). Taken together, our results showed that serum IL-6 level could be considered a predictive marker of recurrent disease in metastatic malignant melanoma.

Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours

BACKGROUND To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. RESULTS Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. CONCLUSION Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.

Somatic von Hippel-Lindau (VHL) gene analysis and clinical outcome under antiangiogenic treatment in metastatic renal cell carcinoma: preliminary results

Researchers have recently demonstrated a significant activity in the use of antiangiogenic compounds for the treatment of clear-cell metastatic renal cell carcinoma (RCC). The pVHL protein plays an important role in angiogenesis. Germline or somatic alterations of the VHL gene result in an abnormal accumulation of hypoxia inducible factor (HIF) inducing the upregulation of proangiogenic downstream genes. From a cohort of 13 patients with RCC included in a phase II study testing the activity of AG-013736 (axitinib), a multi-target receptor tyrosine kinase inhibitor (including VEGFR-1 and -2, PDGFR-β), we investigated the correlation between the presence of VHL somatic mutations and the activity of axitinib. Tumor samples collected were formalin-fixed paraffin-embedded tissues. DNA extracted from these samples were PCR-amplified and directly sequenced for the VHL gene. Among the 13 tumor DNA samples studied, 12 were successfully sequenced. There was an objective response in six patients. Two patients who experienced an objective response had evidence of VHL sequence variants. No VHL mutation was detected among the other patients. In conclusion, no correlation was observed between the somatic mutational status of the VHL gene and the objective response to axitinib in our series.