Maria Marples

Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): Preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study

BACKGROUND Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. METHODS We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7.5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. FINDINGS 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16-37) in the bevacizumab group and 25 months (17-37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0.97, 95% CI 0.78-1.22; p=0.76); this finding persisted after adjustment for stratification variables (HR 1.03; 95% CI 0.81-1.29; p=0.83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21-52) and dose intensity was 86% (41-96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70-0.98, p=0.03), but no significant difference between groups for distant-metastasis-free interval (HR 0.88, 95% CI 0.73-1.06, p=0.18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. INTERPRETATION Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0–1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

Ipilimumab-induced colitis: experience from a tertiary referral center

Background: Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody used for the treatment of malignant melanoma. It can cause immune-mediated inflammatory adverse events, including diarrhoea and even intestinal perforation or death in clinical trials but there is a dearth of data on postmarketing outcomes. Methods: A total of 546 patients attending for treatment of metastatic melanoma between 1 January 2009 and 31 August 2015 were identified by interrogation of the oncology database. A total of 83 of these patients received ipilimumab. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and prescription data. Results: A total of 83 patients received ipilimumab. Only 19.3% (n = 16) of patients developed a diarrhoeal illness not attributable to other causes. The median grade of diarrhoea among included patients was 2 (range 1–4). In two cases, diarrhoea settled spontaneously without any specific treatment. A total of 87.5% of patients received antidiarrhoeal agents such as loperamide or codeine. These resolved symptoms in all patients with grade 1 diarrhoea. For other treatment, 50% patients received systemic glucocorticosteroids and 31.3% required infliximab. Infliximab resolved symptoms in 100% of cases compared with 50% for systemic glucocorticosteroids. Conclusions: The rate of diarrhoea related to ipilimumab in real-world practice is substantial, but below the range observed in data from RCTs. Grade 1 colitis can usually be managed symptomatically, without recourse to stopping ipilimumab. When diarrhoea was grade 2 or above, results from glucocorticosteroids use proved disappointing; but infliximab has been shown to work well. Further research is required into the earlier use of infliximab as an effective treatment for ipilimumab-induced diarrhoea.

Treatment patterns, outcomes, and resource utilization of patients with metastatic melanoma in the U.K.: the MELODY study

Advanced melanoma is an aggressive disease with a poor prognosis. Approved therapy is limited in the U.K. and, until recently, no treatment had improved survival over best supportive care. A deeper understanding of current clinical practice will help new agents find a place in future treatment pathways.

Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Preplanned interim results for the AVAST-M trial.

LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. METHODS AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality of life (QoL). An associated translational study is ongoing. Results of the first pre-planned interim analysis (agreed by the IDSMC) are reported here. RESULTS Between July 2007 and March 2012, 1,343 pts were recruited. 56% were male; median age 56 years (range 18-88 years), 16% were stage IIB, 11% IIC, 15% IIIA, 36% IIIB, 20% IIIC, and 2% unknown stage. Ulceration status of the primary melanoma was: 38% present, 45% absent, 17% unknown. At the time of the interim analysis, 286 (21%) patients had died. Median follow-up for survival was 25 months. Median duration of Bev treatment in 671 treated pts was 51 weeks (dose intensity 86%). Main outcomes are shown in the table. Grade 3/4 adverse events were experienced in 101 (15%) Bev pts and 36 (5%) Obs pts. CONCLUSIONS Interim analysis of this large, multicenter trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev monotherapy is well tolerated and improved DFI. Longer follow-up is required to determine an impact on the primary endpoint of 5-year OS. CLINICAL TRIAL INFORMATION 81261306. [Table: see text].

Complications of bone metastases from malignant melanoma

Introduction Metastatic bone disease (MBD) carries significant morbidity for patients with cancer. MBD from malignant melanoma (MM) is understudied. We examined the characteristics, morbidity, management and outcome of MBD in patients with MM. Methods Patients with metastatic MM managed at two referral cancer centres in England were identified. Those with bone metastases (BMs) were selected. Patient and disease characteristics including skeletal related events (SREs) were extracted from medical records. The Kaplan Meier method was used to calculate median survival. Results Five hundred and eighteen patients with metastatic MM were managed between years 2000 and 2008. Eighty nine (17.2%) patients had BMs and are the subject of this study. Median age at diagnosis was 53 years and 55% were males. BMs were identified at the time of diagnosis of metastatic disease in 68.5% patients. Sixty-six (74.2%) had multiple bone lesions and 80.9% had axial skeleton involvement. One hundred and twenty nine skeletal related events occurred in 59 (66.3%) patients (50 radiotherapy, 28 hypercalcaemia, 20 bone fractures, 18 spinal cord compression and 13 orthopaedic surgery). The annual skeletal morbidity rate was 2.5. Median survival from diagnosis of BMs was 17.3 weeks and was 5.6 weeks from the first episode of hypercalcaemia. Conclusion MBD affects a clinically important proportion (17.2%) of patients with metastatic MM. It carries a substantial morbidity and mortality exceeding that caused by BMs from breast and prostate cancer. These patients should receive the currently licensed bone modifying agents and should be included in clinical trials addressing MBD.

1130TiPNEMO: A PHASE 3 TRIAL OF BINIMETINIB (MEK162) VERSUS DACARBAZINE IN PATIENTS WITH ADVANCED NRAS-MUTANT MELANOMA WHO ARE UNTREATED OR HAVE PROGRESSED AFTER ANY NUMBER OF IMMUNOTHERAPY REGIMENS

ABSTRACT Background: Melanoma tumors often harbor mutations in the mitogen-activated protein kinase-signaling pathway family members BRAF or NRAS. NRAS mutations, observed in about 20% of patients with melanoma, are associated with higher tumor proliferation and poorer prognosis. A large retrospective analysis (n = 677) demonstrated that NRAS mutations are independently predictive of poor survival in patients with cutaneous melanoma (Jakob et al., 2011). With no approved targeted therapies for melanoma patients with NRAS-mutant tumors, treatments are currently limited to chemotherapy and/or immunotherapy. Binimetinib (MEK162), a potent and selective inhibitor of MEK1/2, has demonstrated promising phase 2 clinical activity in this patient subset. Here we describe the “NRAS mElanoma and MEK inhibitOr” (NEMO) trial, an ongoing phase 3 study designed to compare the efficacy of binimetinib vs dacarbazine in patients with metastatic NRAS-mutant melanoma (NCT01763164). Trial design: NEMO is a 2-arm, open-label, 2:1 randomized trial of binimetinib vs dacarbazine. Eligible patients must have advanced unresectable or metastatic cutaneous melanoma or melanoma of unknown primary origin with a documented NRAS Q61 mutation (by central molecular screening) that was previously untreated or has progressed after any number of immunotherapy regimens. Patients are stratified by stage, performance status, and prior immunotherapy. The primary endpoint of the study is progression-free survival, and secondary endpoints include overall survival, overall response, disease control rate, safety, and quality of life. Binimetinib is administered orally at 45 mg twice daily and dacarbazine is dosed intravenously at 1000 mg/m2 once every 3 weeks. This phase 3 trial is designed to enroll 393 patients and is currently recruiting patients at more than 150 centers worldwide. This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting Chicago, June 2014 Abstract ID 7022. Disclosure: R. Dummer: Dr Dummer has received research funding and provided consultancy services for Novartis; P. Arenberger: Dr. Arenberger has received research funding from Novartis; P.A. Ascierto: Dr Ascierto received research funding from Novartis, Roche-Genentech, Ventana; been on a BOD or advisory committee for Novartis, Roche-Genentech, GSK, BMS; consulted for Roche-Genentech, MSD, GSK, Ventana, received honoraria from BMS, Roche-Genentech, GSK; S. Hallmeyer: Dr. Hallmeyer has received honoraria from Bristol Myers Squibb BMS, Novartis and Cardinal Health; G.V. Long: Dr. Long has been a member of an advisory committee for Novartis, GSK, BMS, Roche and Amgen; received honoraria from GSK and Roche; M. Marples: Dr. Marples has received sponsorship for attendance at scientific meetings from Novartis; D. Schadendorf: Dr Schadendorf has been on a board of directors and/or advisory board, consulted for, and received honoraria from Novartis, GSK, Roche, BMS, Merck, Amgen; received research funding from Merck; M. Taylor: Dr. Taylor has served as a consultant for Onyx; E. Wasserman: Dr. Wasserman is an employee of Novartis Pharmaceuticals Corporation; J. Ford: Mr. Ford is an employee of Novartis Pharmaceuticals Corporation; M. Weill: Ms. Weill is an employee of Novartis Pharmaceuticals Corporation; K.T. Flaherty: Dr. Flaherty has received research funding from Novartis; served as a consultant for Novartis. All other authors have declared no conflicts of interest.

Pneumocystis jirovecii pneumonia in a patient with melanoma treated with infliximab and corticosteroids for ipilimumab-associated colitis

Immunotherapy has been successfully used in the management of malignancies including metastatic melanoma but is associated with autoimmune complications that may require corticosteroids and other immunosuppressive therapies to manage. We describe a case of a woman with metastatic melanoma treated with ipilimumab who developed severe Pneumocystis jirovecci pneumonia (PCP) following treatment for ipilimumab-associated colitis with corticosteroids and infliximab. We outline the approach to diagnosis and management of this opportunistic infection. PCP is an important infection to consider in the differential diagnosis for patients who are immunosuppressed and have an acute respiratory presentation. Early diagnosis and treatment is important especially since mortality is high in patients with cancer. Bronchoalveolar lavage and polymerase chain reaction is a useful diagnostic tool. First line therapy for PCP is trimethoprim/sulfamethoxazole. Patients with melanoma treated with immunomodulating therapies are at risk of autoimmune-related adverse events that may require powerful immunosuppressive treatments with the threat of subsequent opportunistic infection. Consideration should be given to PCP prophylaxis in these patients. Correspondence to: Dr. Finbar Slevin, Specialty Registrar in Clinical Oncology, St James’s Institute of Oncology, Leeds, United Kingdom, E-mail: finbarslevin@nhs.net