Randomized phase III trial of consolidation therapy with bortezomib–lenalidomide–Dexamethasone (VRd) vs bortezomib–dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen

Long-awaited results from the the Southwest Oncology Group (SWOG) trial comparing bortezomib–lenalidomide-dexamethasone (VRd) versus lenalidomide-dexamethasone (Rd) as induction treatment for previously untreated multiple myeloma (MM) patients were recently presented (S0777).1 Results justified the early adoption of VRd in the frontline setting over 5 years ago by the NCCN based on Level 2A evidence according to their guidelines.2 The randomized study E1A05 also sought to evaluate VRd superiority over a doublet (Vd), but in the consolidation setting. The trial was closed to enrollment prematurely due to slow accrual. Results reported here include 48 enrolled patients.This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L Comis, MD, and Mitchell D Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: CA180820, CA180794, CA21115, CA23318, CA66636, CA180790, CA13650, CA189956, CA35412, CA15488, CA180799 and CA21076.http://www.sherpa.ac.uk/romeo/issn/2044-5385/am2016Medical Oncolog

Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1) : a phase 3, randomised, double-blind, multicentre trial

BACKGROUND : mTOR inhibition has been shown to reverse trastuzumab resistance from hyperactivated the PIK/AKT/mTOR pathway due to PTEN loss, by sensitizing PTEN-deficient tumors towards trastuzumab. The BOLERO-1 study evaluated the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line therapy for HER2+ advanced breast cancer (ABC). METHODS : In this phase III, randomized, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were ≥18 years of age, with locally assessed HER2+ advanced breast cancer (ABC), with Eastern Cooperative Oncology Group performance status of 0-1, who had not received prior trastuzumab or chemotherapy for ABC, had measurable disease as per Response Evaluation Criteria in Solid Tumors or bone lesions in the absence of measurable disease, without prior systemic therapy for advanced disease except endocrine therapy. The patients were randomized 2:1 (with an interactive voice and web response system) to receive either daily everolimus (10 mg/day) orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on Day-1 with subsequent weekly doses of 2 mg/kg of each 4-week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4- week cycle. Randomization was stratified according to prior use of trastuzumab and visceral metastasis. Patients and investigators were blinded to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival (PFS) in the full study population and in the subset of patients with hormone receptor-negative (HR) breast cancer at baseline; the latter was added during the course of the study, prior to unblinding based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final PFS analyses are presented here. Clinicaltrials.gov identifier: NCT00876395. FINDINGS : Between 10-Sep-2009 and 16-Dec-2012, 719 patients were randomized to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41.3 months (IQR: 35.4 – 46.6 months). INTERPRETATION : The primary objective in the full population was not met; median PFS was 15.0 months with everolimus vs 14.5 months with placebo (hazard ratio, 0.89; 95% CI, 0.73-1.08; p=0.1166). In the HR subpopulation (n=311), median PFS with everolimus was 20.3 months vs 13.1 months with placebo (hazard ratio, 0.66; 95% CI, 0.48-0.91; p=0.0049), however, the protocol-specified statistical significance threshold (p=0.0044) was not crossed. The most common adverse events (AEs) with everolimus vs placebo were stomatitis (314 [66.5%] vs 77 [32.4%] patients), diarrhea (267 [56.6%] vs 111 [46.6%] patients), and alopecia (221 [46.8%] vs 125 [52.5%]). The most frequently reported grade 3/4 AEs in the EVE arm vs PBO arm were neutropenia (117 [24.8%] of 472 patients vs 35 [14.7%] of 238 patients), stomatitis (59 [12.5%] of 472 patients vs 3 [1.3%] of 238 patients), anemia (46 [9.7%] of 472 patients vs 6 [2.5%] of 238 patients) and diarrhea (43 [9.1%] of 472 patients vs 10 [4.2%] of 238 patients) On-treatment AE-related deaths were reported in 17 [3.6%] vs 0% of patients respectively.Interpretation: The primary objective of PFS was not met. However, consistent with the preliminary observations from BOLERO-3, everolimus prolonged median PFS by 7.2 months in patients with HR, HER2+ ABC, which warrants further investigation. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of AEs in patients treated with everolimus and chemotherapy is critical..Novartis Pharmaceuticals Corporation.http://www.journals.elsevier.com/the-lancet-oncology2016-07-31hb201

Recommendations for the management of adult chronic myeloid leukaemia in South Africa

INTRODUCTION: Chronic myeloid leukaemia (CML) is a chronic myeloproliferative disorder characterised by a chromosomal translocation between the long arms of chromosomes 9 and 12 resulting in the formation of the BCR-ABL fusion gene. The management of CML has undergone major changes over the past decade. Novel treatment approaches have had a dramatic impact on patient outcomes and survival. Nevertheless, these outcomes can only be achieved in the context of expert management, careful monitoring of disease response, appropriate management of adverse events and timeous adjustments to therapy when responses are not achieved within stated time frames. AIM: With the advent of novel treatments providing molecular responses, both the monitoring and management of CML have become more complicated. The aim of these recommendations was to provide a pragmatic yet comprehensive roadmap to negotiate these complexities. METHODS: Recommendations were developed based on local expert opinion from both the academic and private medical care arenas after careful review of the relevant literature and taking into account the most widely used international guidelines. About five meetings were held at which these recommendations were discussed and debated in detail. RESULTS: A comprehensive set of recommendations was compiled with an emphasis on diagnosis, investigation, treatment and monitoring of disease. Careful attention was given to circumstances unique to South Africa, funding constraints, availability and access to laboratory resources, as well as the effects of concurrent HIV infection. CONCLUSION: Most patients with CML can live a reasonably normal life if their disease is appropriately managed. These recommendations should be of value to all specialists involved in the treatment of haematological disorders.http://www.samj.org.z

Ipilimumab in Pretreated Patients With Advanced Malignant Melanoma: Results of the South African Expanded-Access Program

Purpose: The primary objective of this study was to evaluate 1- and 2-year survival rates and durable remissions in pretreated patients with advanced (unresectable or metastatic) malignant melanoma treated with ipilimumab in a South African expanded-access program (SA-EAP). Patients and Methods: This multicenter, retrospective study obtained data from pretreated patients with advanced malignant melanoma who were eligible for the ipilimumab SA-EAP. Ipilimumab was administered at a dose of 3 mg/kg intravenously every 3 weeks for four cycles to adults with advanced melanoma for whom at least one line of treatment for metastatic disease had failed. Data from the medical records of 108 patients treated within the SA-EAP were collected and statistically analyzed to determine overall (OS) and progression-free survival (PFS) at 1 and 2 years. Results: In the population of 108 patients, a median OS of 8.98 months (95% CI, 7.47 to 10.79 months) was observed. One-year OS was 36% (95% CI, 26% to 45%), and 2-year survival was observed as 20% (95% CI, 12% to 27%). The median survival without progression (ie, PFS) was 3.44 months (95% CI, 2.98 to 4.16 months), and 1- and 2-year PFS were 22% (95% CI, 14% to 29%) and 14% (95% CI, 8% to 21%), respectively. The longest recorded survival was 3.4 years. No independent prognostic variables were identified to predict for OS by multivariate Cox proportional hazards model. Conclusion: In this multicenter South African setting, ipilimumab at a dose of 3 mg/kg was an effective treatment with long-term OS in a subset of patients with pretreated advanced malignant melanoma

Primary results from CECILIA, a global single-arm phase II study evaluating bevacizumab, carboplatin and paclitaxel for advanced cervical cancer

International audienceObjective: Adding bevacizumab to cisplatin-paclitaxel for advanced cervical cancer significantly improves overall and progression-free survival. We evaluated bevacizumab with a widely used carboplatin-paclitaxel backbone.Methods: Patients with metastatic/recurrent/persistent cervical cancer not amenable to curative surgery and/or radiotherapy received 3-weekly bevacizumab 15 mg/kg, paclitaxel 175 mg/m2, and carboplatin AUC 5 until progression or unacceptable toxicity. Maintenance bevacizumab was allowed. Patients with ongoing bladder/rectal involvement, prior cobalt radiotherapy, a history of fistula/gastrointestinal perforation, or recent bowel resection/chemoradiation were excluded. The primary objective was to determine incidences of gastrointestinal perforation/fistula, gastrointestinal-vaginal fistula, and genitourinary fistula.Results: Among 150 treated patients, disease at study entry was persistent in 21%, recurrent in 56%, and newly diagnosed metastatic in 23%. After 27.8 months' median follow-up, median bevacizumab duration was 6.7 months; 57% received maintenance bevacizumab. Seventeen patients (11.3%; 95% CI: 6.7-17.5%) experienced ≥1 perforation/fistula event: gastrointestinal perforation/fistula in 4.7% (1.9-9.4%), gastrointestinal-vaginal fistula in 4.0% (1.5-8.5%), and genitourinary fistula in 4.7% (1.9-9.4%). Of these, 16 were previously irradiated, several with ongoing radiation effects. The most common grade 3/4 adverse events were neutropenia (25%), anemia (19%), and hypertension (14%). Five patients (3%) had fatal adverse events. Objective response rate was 61% (95% CI: 52-69%), median progression-free survival was 10.9 (10.1-13.7) months, and median overall survival was 25.0 (20.9-30.4) months.Conclusions: Bevacizumab can be combined with carboplatin-paclitaxel in the CECILIA study population. The fistula/gastrointestinal perforation incidence is in line with GOG-0240; efficacy results are encouraging

Guideline for the treatment of myelodysplastic syndromes (MDS) in South Africa

INTRODUCTION: Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal haematopoietic disorders characterised by chronic and progressive cytopenias resulting from ineffective haematopoiesis. Treatment is complicated by differences in disease mechanisms in different subgroups, variable clinical phenotypes and risk of progression to acute myeloid leukaemia. RATIONALE: Changes in disease classification, prognostic scoring systems, the availability of novel treatment options and the absence of South African guidelines for the diagnosis and management of these complex disorders underpinned the need for the development of these recommendations. METHODS: These recommendations are based on the opinion of a number of experts in the field from the laboratory as well as clinical settings and came from both the private and institutional academic environments. The most recent literature as well as available guidelines from other countries were discussed and debated at a number of different meetings held over a 2-year period. RESULTS: A comprehensive set of recommendations was developed focusing on risk stratification, supportive management and specific treatment. Novel agents and their indications are discussed and recommendations are made based on best available evidence and taking into account the availability of treatments in South Africa. CONCLUSION: Correct diagnosis, risk stratification and appropriate therapeutic choices are the cornerstones of success in the management of patients with MDS.http://www.samj.org.z

Pattern of rash, diarrhea, and hepatic toxicities secondary to lapatinib and their association with age and response to neoadjuvant therapy: Analysis from the NeoALTTO trial

Purpose We investigated the pattern of rash, diarrhea, and hepatic adverse events (AEs) secondary to lapatinib and their association with age and pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALLTO) phase III trial. Patients and Methods Patients with HER2-positive early breast cancer were randomly assigned to receive lapatinib (Arm A), trastuzumab (Arm B), or their combination (Arm C) for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery. We investigated the frequency and time to developing each AE according to age (≤ 50 v > 50 years) and their association with pCR in a logistic regression model adjusted for age, hormone receptors, tumor size, nodal status, planned breast surgery, completion of lapatinib administration, and treatment arm. Results Only patients randomly assigned to arms A and C were eligible (n = 306). Younger patients (≤ 50 years) experienced significantly more rash compared with older patients (74.4% v 47.9%; P < .0001). Diarrhea and hepatic AEs were observed in 78.8% and 41.2% of patients, respectively, with no differences in rate or severity or time of onset according to age. Early rash (ie, before starting paclitaxel) was independently associated with a higher chance of pCR, mainly in patients older than 50 years (odds ratio [OR] = 3.76; 95% CI, 1.69 to 8.34) but not in those ≤ 50 years (OR = 0.92; 95% CI, 0.45 to 1.88; P for interaction = .01). No significant association was observed between pCR and diarrhea or hepatic AEs. Conclusion Our results indicate that the frequency and clinical relevance of lapatinib-related rash is largely dependent on patient age. © 2013 by American Society of Clinical Oncology.SCOPUS: ar.jinfo:eu-repo/semantics/publishe