Tabea Wilhelm

Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial

BACKGROUND Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17-22 weeks. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. METHODS We undertook a multicentre, open-label, phase 2 trial in 24 centres in six countries. We enrolled patients with histologically confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (≥5 mm and ≤40 mm in diameter). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01266967. FINDINGS Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39·2%, 95% CI 28·0-51·2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30·8%, 19·9-43·4) of 65 in cohort B. One (6·7%, 0·2-31·9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22·2%, 6·4-47·6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial haemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%]). INTERPRETATION Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irrespective of whether they are untreated or have been previously treated but have progressed. FUNDING GlaxoSmithKline.

Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma

PURPOSE Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM). PATIENTS AND METHODS Histologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF(V600E) mut(+) MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. RESULTS Seventy-six patients with BRAF(V600E) and 16 patients with BRAF(V600K) mut(+) MM were enrolled onto the study. In the BRAF(V600E) group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF(V600K) mut(+) MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF(V600E) and BRAF(V600K) groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF(V600E) mut(+) MM patients. CONCLUSION Dabrafenib was well tolerated and clinically active in patients with BRAF(V600E/K) mut(+) MM. cfDNA may be a useful prognostic and response marker in future studies.

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

GABAB receptor antibodies in paraneoplastic cerebellar ataxia.

Autoantibodies to the gamma-aminobutyric acid-B (GABAB) receptor were recently described in patients with limbic encephalitis presenting with early or prominent seizures. We report on a 64-year-old man with malignant melanoma who during adjuvant therapy with interferon (IFN)-alpha developed cerebellar ataxia. Indirect immunofluorescence on brain tissue sections revealed high-titer (1:20,000) IgG1 serum autoantibodies to the cerebellar molecular and granular layer, which were confirmed to be directed against GABAB receptor in a cell-based assay. This case highlights cerebellar ataxia in the absence of seizures as a clinical manifestation of GABAB receptor autoimmunity and extends the spectrum of tumors underlying this condition to malignant melanoma. IFN-alpha therapy may have contributed to the development of autoimmunity in this patient.

Aviscumine (ME-503)-Skin Reaction as significant Factor for its EfficacyExpanded Evaluation of the Results from the Phase II Trial NCT00658437 inPatients with Unresectable stage IV Metastatic Melanoma

Aviscumine (ME-503), a recombinant lectin, enhances inflammatory cytokine (esp. IL-1β) release, activation of Langerhans cells, and T-cell responses. An extended evaluation of phase II data of the patient cohorts with/without skin reactions within the first treatment cycle after SC injection regarding the efficacy of aviscumine are presented. 31 patients (ITT total population) (ECOG: 0 or 1) with progressive stage IV malignant melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial (NCT00658437). Patients received 350 ng aviscumine twice weekly by SC injection until progression. Tumor response was assessed every eight weeks, survival of patients was followed up to one year after the end of therapy. 21 patients with skin reactions vs. 9 patients without skin reactions as adverse events were assessed for efficacy in an expanded evaluation. Comparing the median overall survival data (mOS) in patients (n=9) without injection site reactions (mOS: 5.1 months; 95% CI 2.1-6.9; 1-year survival rate: 0%) with survival data in patients (n=21) showing injection site reactions (mOS: 14.6 months; 95% CI 11.0-19.8; 1-year survival rate: 62%) a clear difference in favor of the patients with skin reactions is seen. The difference in overall survival between these two groups of patients was high significant (p<0.0001). In the total ITT population (n=31) the mOS was 11.0 months (95% CI 6.9-19.8) and the 1- year survival rate was 45%. Preliminary conclusions from our small cohorts suggest a strong clinical impact of aviscumine in patients with previously treated metastatic melanoma if those patients show injection site reactions as adverse events after SC injection within the first treatment cycle. Patients without any injection site reactions apparently failed to prove clinical benefit.

Abstract CT123: Aviscumine (ME-503), a plant protein with a novel mode of action, shows clinical activity in unresectable stage IV metastatic melanoma: data from a phase II trial

Background: Aviscumine, a recombinant protein, inactivates the 28S rRNA (“ribotoxic stress”) after endocytosis and enhances inflammatory cytokine (esp. IL-1s) release, activation of Langerhans cells and T-cell responses. Phase II data of the total patient population vs. a small patient cohort with/without skin reactions after SC injection are reported regarding the efficacy of aviscumine in patients with progressive metastatic melanoma stage IV. Methods: 32 pts. (ECOG: 0 or 1) were enrolled onto a single-arm, multi-centre, open-label, phase II trial (NCT00658437). Patients received 350 ng aviscumine twice weekly by SC injection until progression. Tumor response was assessed every eight weeks, survival of patients was followed up to one year after the end of therapy. 30 patients were assessed for overall survival (OS) and skin reactions were monitored as adverse events. Results: The median OS of the 30 patients was 10.7 months; (95% CI 6.4-14.3). The patients had a 1-year survival rate of 43.3%. The patients with an injection side reaction (n = 21) during the first cycle of treatment showed a mOS of 14.6 months (95% CI 11.0 - 19.8) whereas the survival data in patients (n = 9) without injection site reactions were 5.1 months (95% CI 2.1-6.9). No patient in this group without skin reactions survived 1-year. Comparing the 2 groups with / without skin reactions a clear difference in favor of the patients with injection site reactions is seen. High significance (p Conclusion: These results suggest a strong clinical impact of aviscumine in patients with previously treated metastatic melanoma if those patients show injection site reactions as a sign of an immune reaction after SC injection within the first treatment cycle. Patients without any injection site reactions apparently failed to prove clinical benefit. Due to relatively small sample size in this study, these findings require validation in a larger patient cohort. Citation Format: Peter Mohr, Uwe Trefzer, Ralf Gutzmer, Tabea Wilhelm, Florian Schenck, Katharina C. Kahler, Volkmar Jacobi, Klaus Witthohn, Hans Lentzen. Aviscumine (ME-503), a plant protein with a novel mode of action, shows clinical activity in unresectable stage IV metastatic melanoma: data from a phase II trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT123.

A phase II multicenter study on CY-503 in the treatment of patients with unresectable stage IV metastatic melanoma after failure of previous chemotherapy.

e19015 Background: CY-503 is a recombinant mistletoe lectin ( INN: aviscumine) leading to catalytical inactivation of ribosomes, thereby inhibiting protein synthesis. Dependent on dosage immunomodu...