Database Lock Research Articles

Therapeutic Management of Dyslipidemia Patients at Very High Cardiovascular Risk (CARDIO TRACK): Protocol for the Observational Registry Study.

BackgroundDyslipidemia is a major modifiable risk factor for atherosclerotic cardiovascular disease. Current South African guidelines recommend titrating lipid-lowering therapy (LLT) to low-density lipoprotein cholesterol (LDL-C) targets stratified by cardiovascular risk. The LDL-C goal for very high-risk patients is <1.8 mmol/L. In international studies, approximately 30% of patients do not achieve this goal despite receiving maximally tolerated statin doses. There is, however, a paucity of data on LDL-C goal achievement in very high-risk South African patients receiving maximal statin doses.ObjectiveThe goal of the research it to assess LDL-C goal achievement in, and clinical characteristics of, very high cardiovascular risk dyslipidemic patients receiving maximal tolerated statin doses with or without ezetimibe.MethodsThis is an observational, cross-sectional South African registry study that plans to include up to 30 sites and 500 study participants. Adult patients with very high cardiovascular risk status receiving stable, maximally tolerated statin doses (with or without ezetimibe) will be eligible for inclusion.ResultsFunding has been awarded and enrollment began on November 15, 2017, and was completed on April 13, 2018, with 507 participants. Database lock was done on June 21, 2018. The statistical analysis has commenced and we expect the final clinical study report to be completed by October 2018.ConclusionsThis study will document the adequacy of LLT in those at highest risk and will thus fill an important data gap in South Africa. This data may be useful in assessing the need for novel LLTs like proprotein convertase subtilisin/kexin 9 inhibitors that substantially lower cholesterol levels in addition to optimal statin therapy.Registered Report IdentifierRR1-10.2196/9248

Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study

Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis. We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759. Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3-54·1]; p<0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred. Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis. Janssen Research & Development.

PRM7 - The Impact of Response at A Landmark on Overall Survival: Implications for the Economic Evaluation of the Value of Immuno-Oncology (I-O) Treatment in Non-Small Cell Lung Cancer (NSCLC)

Treatment with the checkpoint inhibitor nivolumab improved overall survival (OS) versus docetaxel (HR=0.73; 95% CI, 0.59-0.89) in an advanced non-squamous NSCLC clinical trial (CheckMate 057). With limited follow-up, response-based modeling can capture durable OS associated with I-O treatment. We examine the relationship between response status at a landmark and subsequent OS by treatment arm in CheckMate 057. Analysis was conducted on the February 2016 database lock of Checkmate 057. For each study arm and by response status (RECIST 1.1 responder/non-responder) at a 6-month landmark, we performed Kaplan-Meier analysis of subsequent OS and sensitivity analyses. Time-dependent Cox regressions were also performed. Overall response rate was 19% (56/292) for nivolumab and 12% (36/290) for docetaxel. The number of responders (non-responders) at 6 months was 49 and 26 (132 and 149) among nivolumab and docetaxel patients, respectively. For nivolumab, median post-landmark OS was 12.2 months (95% CI: 9.5-15.1) for non-responders and not reached (NR) (95% CI: 23.9-NR) for responders. For docetaxel, median post-landmark OS was 7.1 months (95% CI: 5.4-9.4) for non-responders and 13.8 months (95% CI: 11.1-28.7) for responders. The hazard ratio between responders and non-responders was 0.24 (95% CI: 0.15-0.39) in the nivolumab arm and 0.55 (95% CI: 0.34-0.88) in the docetaxel arm. Time-dependent Cox analyses showed significantly reduced responders’ mortality, and the risk reduction was significantly greater for nivolumab than for docetaxel (p=0.003). Sensitivity analysis using alternative landmarks yielded qualitatively similar findings. In CheckMate 057, response at 6-months was significantly and positively associated with subsequent survival in both arms; however, the relationship was stronger for nivolumab than for docetaxel. Additionally, non-responders to nivolumab showed a longer median post-landmark survival than non-responders to docetaxel. These findings support incorporating separate response-based survival curves by treatment arm in economic models, especially when comparing an I-O to a non-I-O treatment.

Reactogenicity and safety of AS03B-adjuvanted H5N1 influenza vaccine in children: an open-label, one-way, crossover trial

Abstract Background Human cases of highly pathogenic avian-origin influenza A/H5N1 infection continue to be reported to the World Health Organization, and recent outbreaks of human cases of other zoonotic influenza strains highlight the continued need for strategies to mitigate influenza pandemic potential. Methods A Phase II–III randomized, placebo-controlled, observer-blind trial was conducted to assess the immunogenicity, reactogenicity, and safety of two 1.9 μg hemagglutinin doses of AS03B-adjuvanted H5N1 (AS03B-H5N1; A/Indonesia) vaccine in children (6 months to &lt;18 years old) of Thailand, the United States, and Canada (Year 1, published elsewhere). After database lock in Year 1, the trial was unblinded, and children who had been randomized to receive placebo and continued to fulfill the eligibility criteria were invited to participate in an open-label, one-way, crossover safety extension phase, in which they received AS03B-H5N1 vaccine. Here we report the safety analysis in Year 2. Results A total of 155 children were vaccinated in Year 2. The most frequent solicited adverse event (AE) during 7 days post vaccination was injection site pain. Irritability or fussiness was reported in about one-third of younger children (aged &lt;6 years) during 7 days post vaccination and was the most common solicited general AE in this age group. Postvaccination temperature (≥38°C) was reported in 4 (5.1%) children. The most common solicited general AEs in older children (aged ≥6 years) were muscle aches, headache, and fatigue. The AS03B-H5N1 vaccine had a clinically acceptable safety profile up to 385 days post vaccination. Conclusions Safety in the crossover phase was acceptable and consistent with that observed in vaccine recipients in the randomized, blinded phase of the study. Clinical trial registration ClinicalTrials.gov: NCT01310413.

Abstract P5-23-01: Clinical and biological characterization of male breast cancer (BC) EORTC 10085/TBCRC 029/BOOG 2013-02/BIG 2-07: Baseline results from the prospective registry

Abstract BACKGROUND: Through the International Male Breast Cancer Program, a prospective registry for male BC was created with the goals of evaluating 1) the clinical and biological features of this disease and 2) assessing feasibility of a prospective therapeutic clinical trial. METHODS: All men, with any stage histologically proven invasive breast cancer, age 3 18 years, and newly presenting at the participating institutions (within 3 months prior) were eligible. Patients were enrolled for 30 months after activation of the first center, through February 2017. Per the study design, if &amp;lt;100 men enrolled, the study would be considered a failure and therapeutic trials would not be pursued through this network. Epidemiologic data, staging, pathologic features, and BRCA status were collected. Treatment and outcome data collection is ongoing. Optional collection of FFPE tumor samples, blood, and QOL were performed in the US, the Netherlands, and Latin America. Clinical database lock for this report was May 30, 2017. We currently report patient and disease characteristics and will update with patterns of treatment for the presentation. Outcomes and biological samples will be analyzed in the future. RESULTS: 557 patients were enrolled: 75% in Europe, 20% in United States, 5% in other countries. 6.3% of patients had missing forms. Median age was 67 years (range 26-92). 93% were diagnosed 2010-2017. Among patients with complete data, 79% presented with a breast mass. 88% were M0 and 12% M1. Among M0 patients: 47%, 39%, 2%, and 11% had T1, T2, T3, and T4 disease respectively; 52% were N0. Overall, 98% had ER+ disease and 11% had HER2+ cancer. 14% had grade 1, 56% had grade 2, and 30% had grade 3 tumors. Among 112 men who underwent BRCA1 testing, 1 was positive. Among 118 men who had BRCA2 testing, 18 (15%) were positive. 21% of men had prior or concurrent malignancies, with the following most common sites: prostate, non-melanoma skin, colorectal, and melanoma. The prevalence of previously identified possible risk factors for male breast cancer were: overweight/obesity (72%), former/current smoker (51%), current alcohol 31 drink daily (41%), family history of breast cancer (35%), gynecomastia (16%), history radiation exposure (8%), use of anti-androgens (1%), and use of estrogens (1%). CONCLUSION: Through an international collaborative effort, we were able to prospectively accrue 557 patients to a male breast cancer registry. These results demonstrate feasibility of pursuing a therapeutic clinical trial in men with breast cancer. In addition, this study shows the relatively low uptake of BRCA testing, high rates of concurrent/prior malignancy, and the rates of potentially modifiable risk factors in this patient population. Funding from Breast Cancer Research Foundation, Susan G. Komen, Dutch Pink Ribbon Foundation, Swedish Breast Cancer Association (BRO) and EBCC Council. Citation Format: Giordano SH, Schröder CP, Poncet C, van Leeuwen-Stok E, Linderholm B, Abreu MH, Rubio I, Van Poznak C, Morganstern D, Cameron D, Vleugel MM, Smilde TJ, Bozovic-Spasojevic I, Korde L, Russell NS, den Hoed IDM, Honkoop AH, van der Velden AWG, van 't Riet M, Dijkstra N, Bogler O, Goulioti T, Hilsenbeck S, Ruddy KJ, Wolff A, van Deurzen CHM, Martens J, Bartlett JMS, Aalders K, Tryfonidis K, Cardoso F. Clinical and biological characterization of male breast cancer (BC) EORTC 10085/TBCRC 029/BOOG 2013-02/BIG 2-07: Baseline results from the prospective registry [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-23-01.

Abstract P6-12-18: CANTOCHEM: Analysis of chemotherapy practice and early side effects in the 6090 first patients from the prospective CANTO cohort

Abstract Background There is no large prospective trial assessing mid-term adverse effects of adjuvant chemotherapy. In order to address this question, we developed CANTO (CANcer TOxicities - NCT01993498 - http://etudecanto.org/), a prospective trial dedicated to the quantification of side effects after treatment for patients with early breast cancer and to develop predictors of such toxicities. The aim of this presentation is to assess chemotherapy (CT) practice and to report toxicities that persist 3-6 months after CT. Methods CANTO is a prospective study enrolling newly diagnosed invasive cT0-cT3, cN0-3, M0 breast cancer patients (pts) of 26 French comprehensive cancer centers. The study has included 10 500 patients at the time of submission. Pts are assessed at diagnosis, 3-6, 12, 36, 48 and 60 months after treatment completion. CANTO collects &amp;gt;100 items related to toxicities. In the current study, we focus on the first set of data available from the trial (1st database lock, n=6090). We here assess CT practice and toxicities at 3 months. Results Information about (neo)adjuvant CT (NACT/ACT) is available in 5805 pts (96%). Median age at diagnosis was 57y (22-93). Pts had HR+/HER2-, HER2+ or triple negative (TN) tumors in 74%, 15% and 11% of cases. Ki67 was assessed in 70%, and genomic tests in 1% of pts, respectively. Overall, 3074 pts (53%) received CT, either adjuvant (ACT: 76%) or neoadjuvant (NACT: 24%). ACT/NACT pts (84%) received a sequential anthracyclines–taxanes based 6 courses CT schedule. CT was administered in 44.7%, 87.2% and 92.3% of HR+/HER2+/TN tumors, respectively. ACT was administered in 73.2% of pT2+ pts (vs 36.0% in pT0-1 – p&amp;lt;.001)) and in 74.7% in pN1+pts (vs 36.7% in pN0 – p&amp;lt;.001)). After NACT, pts had yPT0 (32.3%) and/or ypN0 (64.6%) for an overall 28.9% pCR rate. We focus here on clinically most relevant patient reported symptoms at 3 m (any grade). side effects at 3m no CT (%)CT (%)p valuePain76.682.1&amp;lt;.001Neurological symptom4768.7&amp;lt;.001GI symptom34.342.1&amp;lt;.001CV sympton8.110.20.011 Pain complaint was recorded in 3596 pts (97.2% of pts with available data), with a median value of 4 on the VAS (range 1-10). In ACT/NACT pts, muscle and joint pain were predominant. Neurological symptoms were seen in 3024 pts (59%), the most frequent pertaining to cognitive disorder (attention trouble, CT: 61.2% vs noCT: 56% - p=.06) and peripheral neuropathy (overall 31%). Paresthesias and sensory neuropathy were much more frequent in CT vs noCT pts: respectively 37.3% vs 20.3% and 25.7% vs 12.8% (both p&amp;lt;.001). Of note, pts receiving paclitaxel had more peripheral neuropathy (92.3% vs 69% in docetaxel pts – p=.07). Diarrhea was the most frequent GI symptom post CT: 44.5% vs 33.2%, p&amp;lt; 0.001. CV symptoms (NOS) were slightly more frequent after CT. Conclusions In this real life, prospective cohort, CT is frequently prescribed and appears in good compliance with current guidelines. Overall, symptoms burden at treatment completion is strikingly high, and much higher in pts receiving CT. A special attention should be given to pain and neurological symptoms. Dedicated questionnaires and sub-studies will explore in depth these side effects. Extended analyses of CT practice and toxicities will be presented. Citation Format: Cottu PH, Amar Y, Pistilli B, Bonsang-Kitzis H, Lesur A, Lerebours F, Vanlemmens L, Tredan O, Levy C, Jouannaud C, Fournier M, Soulie P, Rigal O, Giacchetti S, Arnaud A, Arsene O, Savignoni A, Mesleard C, Andre F, Arveux P. CANTOCHEM: Analysis of chemotherapy practice and early side effects in the 6090 first patients from the prospective CANTO cohort [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-18.

Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): Long-term survival according to prior line of treatment from CheckMate-142.

554 Background: Nivolumab (NIVO) provided durable responses (ORR, 32% per central assessment) and disease control (DCR, 64%) in pre-treated pts with dMMR/MSI-H mCRC (NCT02060188; Overman MJ et al Lancet Oncol 2017). NIVO was approved in the US for pts with dMMR/MSI-H mCRC who progress after standard chemotherapy (SC) with a fluoropyrimidine (F), oxaliplatin (Ox), and irinotecan (Iri). Here we present long-term survival and outcomes by prior chemotherapy with NIVO in CheckMate-142. Methods: Pts with dMMR/MSI-H mCRC received NIVO 3 mg/kg Q2W. The primary endpoint was ORR per RECIST 1.1. Other endpoints were DCR, DOR, PFS, OS, and safety/tolerability. Results: Of 74 pts evaluated, 53 had received F, Ox and Iri (group A); 21 pts had ≤ 2 SC regimens (group B). Median follow-up was 21 mo. Efficacy by central assessment is shown in the Table. In the 74 pts, ORR was 34%; CRs increased from 3% in prior database lock (DBL) to 9%. Numerically higher responses were noted in group B vs group A (Table). Grade 3–4 TRAEs were reported in 20% (all pts), 25% (group A), and 10% (group B) of pts. No treatment-related deaths were reported. Conclusions: NIVO continued to provide clinically meaningful durable responses and long-term overall survival in pts with dMMR/MSI-H mCRC. Of note, CR rate increased with longer follow-up. No new safety signals were reported with long-term follow-up. Enhanced responses in pts with ≤ 2 SC regimens support ongoing evaluation of NIVO combinations in first-line setting. Clinical trial information: NCT02060188. [Table: see text]

Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database.

Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpublished trials. Linear regression was used to explore factors associated with time lag from study database lock to publication for published trials. Results The study cohort included 319 trials. 95 (30%) trials had no matching publication. Thirty (9%) trials were not published in abstract form as well. On multivariable analysis, the most significant factor associated with unpublished trials was industry funding (odds ratio 3.3, 95% confidence interval 1.7-6.6, p=0.019). For published trials, time lag between database lock and publication was longer by 10.9 months (standard error 3.6, p<0.001) for industry funded trials compared with medical center funded trials. Conclusions Timely publishing of early cancer clinical trials results remains unsatisfactory. Industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication. Policies that promote transparency and data sharing in clinical trial research might improve accountability among industry and investigators and improve timely results publication.

Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (cHL): Results from the Phase 2 Checkmate 205 Study

Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (cHL): Results from the Phase 2 Checkmate 205 Study

CA180-372: An International Collaborative Phase 2 Trial of Dasatinib and Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

▪Introduction: Ph+ ALL comprises ~5% of childhood and adolescent ALL. Prior to development of tyrosine kinase inhibitor (TKI) therapy, survival rates were poor. Less than half of patients (pts) survived despite treatment with intensive chemotherapy and frequent use of allogeneic hematopoietic stem cell transplant (HSCT) in first remission (CR1). The Children's Oncology Group (COG) AALL0031 trial (Schultz, JCO 2009) and the EsPhALL trial (Biondi, Lancet Oncology 2012) showed adding imatinib to different intensive chemotherapy backbones improved event-free (EFS) and overall survival (OS) in pediatric Ph+ ALL. Dasatinib is attractive to study in Ph+ ALL because it is a dual ABL/SRC TKI that is 300 times more potent than imatinib in vitro, is active against most ABL1 TKI domain mutations that cause imatinib resistance, and accumulates in the central nervous system (CNS), a sanctuary site for ALL where imatinib penetration is poor.Methods: We conducted a phase 2 trial of dasatinib added to the EsPhALL chemotherapy backbone in pediatric (>1-17.99 years (yrs) of age) Ph+ ALL pts at COG sites in North America and Australia and EsPhALL sites in Italy and the United Kingdom. Protocol therapy added continuous daily dasatinib (60 mg/m2) at day 15 of induction chemotherapy. The study measured minimal residual disease (MRD) by Ig/TCR PCR, flow cytometry, and BCR - ABL1 RT-PCR, with clinical actions based upon a single method, in this hierarchical order. Pts with MRD ≥ 0.05% at the end of block Ib (day 78) and those with MRD 0.005-0.05% at end of Ib who remained MRD positive at any detectable level after three additional high-risk (HR) chemotherapy blocks underwent HSCT in CR1. Dasatinib treatment post HSCT was optional. The remaining pts received chemotherapy plus daily dasatinib for 2 yrs, with cranial irradiation limited to CNS3 pts. The primary study endpoint was 3-year EFS assessed when all patients completed 3 years of follow-up.Results: From April 2012 to May 2014, 109 pts enrolled; 3 did not meet inclusion criteria and received no trial therapy. The median age was 9.0 yrs (range 1-17), 54% were males, and 80% were Caucasian. 71% had CNS1 status at baseline, 24% CNS2, and 5% CNS3. Safety analysis included all treated pts (N=106) and efficacy analysis included all treated Ph+ ALL pts (N=104; 2 pts were retrospectively diagnosed with blast crisis CML). The database lock date was 8/17/16; at this time all pts had completed therapy and 75% had ≥3 yrs of follow-up. Two pts discontinued dasatinib for toxicity (1 allergy and 1 prolonged myelosuppression post HSCT). Nineteen pts met study criteria for HSCT, and 15 received HSCT in CR1 (14.2% of pts). The remaining 91 pts (85.8%) received EsPhALL chemotherapy plus dasatinib without HSCT. Patients tolerated dasatinib combined with chemotherapy well. The primary toxicity was febrile neutropenia and infection: Grade 3+ febrile neutropenia occurred in 75.5% of pts, Grade 3+ sepsis in 18.9%; and Grade 3+ bacteremia in 13.2%. Elevated ALT (21.7%) and AST (10.4%) were the only non-hematologic, non-infectious Grade 3+ adverse events attributed to dasatinib reported in >10% of pts. Relevant Grade 3+ non-hematologic, non-infectious toxicities attributed to dasatinib included pleural effusion (3.8%), edema (3.8%), hemorrhage (2.8%), and cardiac failure (0.8%). No cases of pulmonary hypertension or pulmonary arterial hypertension were reported. All 104 treated Ph+ ALL pts achieved CR. As of the database lock date, 33 events had occurred including 5 deaths (3 in HR3 and 2 in reinduction) due to proven or suspected infection in the 91 patients receiving chemotherapy plus dasatinib, 2 deaths from infection post-HSCT in the 15 HSCT pts, and 26 relapses (chemotherapy 22/86; HSCT 4/12). Sites of relapse included isolated bone marrow (BM; 14), CNS (4), BM+CNS (3), BM+other (2), and other (3). At the time of the interim analysis the 3-yr EFS is 66.0% (95% CI, 54.8-75.0) and the 3-yr OS is 92.3% (95% CI, 85.2-96.1); updated results with all patients having at least 3 years of follow-up will be presented.Conclusions: Addition of dasatinib to the EsPhALL chemotherapy regimen is safe and effective in pediatric Ph+ ALL pts. With only 14% of pts undergoing SCT in CR1, as compared to 80% in the EsPhALL imatinib trial, this trial demonstrates similar outcomes with 3-yr EFS/OS 66.0%/92.3% in this trial vs. published 4-yr EFS/OS 61.9%/72.1% in the EsPhALL imatinib trial. DisclosuresHunger:Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Erytech Pharmaceuticals: Consultancy; Amgen: Consultancy, Equity Ownership. Saha:Shire: Research Funding. Gastier Foster:Bristol-Myers Squibb: Research Funding. Cazzaniga:Italian Association for Cancer Research: Research Funding; Fondazione Tettamanti onlus: Employment. Borowitz:Beckman Coulter: Honoraria; Becton-Dickinson Biosciences: Research Funding; HTG Molecular: Honoraria. Gramatges:Bristol Meyer Squibb: Research Funding. Sun:Baxalta: Consultancy. Swanink:Bristol-Myers Squibb: Employment. Schrappe:Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Healey:Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Equity Ownership.

Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma from the Phase 2 Checkmate 205 Study

Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma from the Phase 2 Checkmate 205 Study

Statistical analysis plan for the \u2018Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage\u2019 (TICH-2) trial

RationaleAside from blood pressure lowering, treatment options for intracerebral haemorrhage remain limited and a proportion of patients will undergo early haematoma expansion with resultant significant morbidity and mortality. Tranexamic acid (TXA), an anti-fibrinolytic drug, has been shown to significantly reduce mortality in patients, who are bleeding following trauma, when given rapidly. TICH-2 is testing whether TXA is effective at improving outcome in spontaneous intracerebral haemorrhage (SICH).Methods and designTICH-2 is a pragmatic, phase III, prospective, double-blind, randomised placebo-controlled trial. Two thousand adult (aged ≥ 18 years) patients with an acute SICH, within 8 h of stroke onset, will be randomised to receive TXA or the placebo control. The primary outcome is ordinal shift of modified Rankin Scale score at day 90. Analyses will be performed using intention-to-treat.ResultsThis paper and its attached appendices describe the statistical analysis plan (SAP) for the trial and were developed and published prior to database lock and unblinding to treatment allocation. The SAP includes details of analyses to be undertaken and unpopulated tables which will be reported in the primary and key secondary publications. The database will be locked in early 2018, ready for publication of the results later in the same year.DiscussionThe SAP details the analyses that will be done to avoid bias arising from prior knowledge of the study findings. The trial will determine whether TXA can improve outcome after SICH, which currently has no definitive therapy.Trial registrationISRCTN registry, ID: ISRCTN93732214. Registered on 17 January 2013.

QLIF-47. HEALTH RELATED QUALITY OF LIFE AND NEUROLOGICAL DETERIORATION FREE SURVIVAL IN INTELLANCE 2/EORTC TRIAL 1410, A RANDOMIZED PHASE II STUDY ON ABT414 IN RECURRENT EGFR AMPLIFIED GLIOBLASTOMA

Treatment options for recurrent glioblastoma are limited. 45-50% of glioblastoma show EGFR amplification. ABT-414 is a tumor-specific antibody-drug conjugate (ADC) combining an antibody (ABT-806) targeting a unique conformation of EGFR bound to monomethyl auristatin F (MMAF), a microtubule cytotoxin. We investigated ABT-414 in glioblastoma at 1strecurrence, besides Overall Survival (OS) the study endpoints included Quality of Life (QoL) and Neurological Deterioration Free Survival Analysis (NDFS). EORTC-1410-BTG (NCT02343406) is a randomized open label phase II study. Eligible were patients with a centrally confirmed EGFR amplified glioblastoma with a first recurrence after combined temozolomide chemo-irradiation, occurring ≥ 3 months after the end of radiotherapy, ≥ 18 years, WHO performance status (PS) 0-2, with adequate organ function, and tissue available for central EGFR and MGMT determination. After stratification for region of the world, WHO status and timing of relapse (< 16 weeks or patients were randomized to either a) treatment with ABT-414 1.0 mg/kg every two weeks intravenously alone, or b) the same treatment in combination with temozolomide 150-200 mg/m2 day1-5 every 4 weeks, or c) either lomustine or temozolomide depending of the time of recurrence in relation to the end of temozolomide treatment in 1stline. QoL was assessed using the EORTC QLQ-C30 questionnaire and the QLQ-BN20 Brain Cancer Module. NDFS was assessed by change in WHO Performance Status; the protocol emphasized the collection of WHO PS beyond progression. Primary endpoint of the study is overall survival (OS); QoL and NDFS are both secondary endpoints. Between Mar 10 2015 and July 22 2016a total of 260 patients were randomized. The per protocol required number of 170 events will be observed in June 2017. The database lock is foreseen for August 2017. At the meeting QOL and NDFS analysis will be presented.

Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial

The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. Astex Pharmaceuticals and Stand Up To Cancer.

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

BackgroundThe BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation–positive metastatic melanoma. We present final OS data from BRIM-3.Patients and methodsPatients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.ResultsBetween 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0–15.4] versus 9.7 months [95% CI 7.9–12.8; hazard ratio (HR) 0.81 [95% CI 0.67–0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0–15.4) versus 10.3 months (95% CI 9.1–12.8); HR 0.81 (95% CI 0.68–0.96); P = 0.01]. Kaplan–Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.ConclusionsVemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.ClinicalTrials.govNCT01006980.

Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis.

Purpose Lenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) demonstrated prolonged progression-free survival (PFS) versus placebo or observation in several randomized controlled trials (RCTs) of patients with newly diagnosed multiple myeloma (NDMM). All studies had PFS as the primary end point, and none were powered for overall survival (OS) as a primary end point. Thus, a meta-analysis was conducted to better understand the impact of lenalidomide maintenance in this setting. Patients and Methods The meta-analysis was conducted using primary-source patient-level data and documentation from three RCTs (Cancer and Leukemia Group B 100104, Gruppo Italiano Malattie Ematologiche dell'Adulto RV-MM-PI-209, and Intergroupe Francophone du Myélome 2005-02) that met the following prespecified inclusion criteria: an RCT in patients with NDMM receiving ASCT followed by lenalidomide maintenance versus placebo or observation with patient-level data available and achieved database lock for primary efficacy analysis. Results Overall, 1,208 patients were included in the meta-analysis (605 patients in the lenalidomide maintenance group and 603 in the placebo or observation group). The median PFS was 52.8 months for the lenalidomide group and 23.5 months for the placebo or observation group (hazard ratio, 0.48; 95% CI, 0.41 to 0.55). At a median follow-up time of 79.5 months for all surviving patients, the median OS had not been reached for the lenalidomide maintenance group, whereas it was 86.0 months for the placebo or observation group (hazard ratio, 0.75; 95% CI, 0.63 to 0.90; P = .001). The cumulative incidence rate of a second primary malignancy before disease progression was higher with lenalidomide maintenance versus placebo or observation, whereas the cumulative incidence rates of progression, death, or death as a result of myeloma were all higher with placebo or observation versus lenalidomide maintenance. Conclusion This meta-analysis demonstrates a significant OS benefit and confirms the PFS benefit with lenalidomide maintenance after ASCT in patients with NDMM when compared with placebo or observation.

Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487. Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment. Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint. PTC Therapeutics.

Abstract CT077: Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors

Abstract Introduction: Prior to the introduction of immunotherapies, treatment options were limited for patients (pts) with NSCLC who progressed after first-line platinum doublet chemotherapy. The majority of pts with advanced disease died within 1 y of diagnosis, and 5-y survival for metastatic NSCLC was ~1%. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, showed encouraging activity in pts with heavily pretreated advanced NSCLC in a phase 1 dose-escalation cohort expansion trial (CA209-003; NCT00730639). Based on improved overall survival (OS) versus docetaxel in 2 phase 3 studies in previously treated advanced NSCLC (CheckMate 017 and 057), nivolumab was approved in this population. Reports of long-term efficacy and safety with immune checkpoint inhibitors are limited. Here we report updated results from CA209-003 based on ~5 y of follow-up, representing the longest survival follow-up for an immune checkpoint inhibitor in advanced NSCLC to date. Methods: Pts with heavily pretreated (1-5 prior systemic regimens) advanced NSCLC received nivolumab (1, 3, or 10 mg/kg) every 2 wk in 8-wk cycles for up to 96 wk. The primary objective was safety and tolerability; secondary objectives included objective response rate and duration of response. OS from the time of first dose was an exploratory objective. The minimum follow-up for the current analysis was 58.25 mo. Results: At database lock, the Kaplan-Meier-estimated 5-y OS rate in all pts (N = 129) was 16% (95% confidence interval [CI]: 10, 23). OS rates at 5 y were similar in pts with squamous (SQ; n = 54; 16% [95% CI: 8, 28]) and non-SQ (n = 74; 15% [95% CI: 8, 25]) NSCLC (excludes 1 pt with unknown histology). Of the 16 pts who survived ≥5 y (median age: 61.5 y [range: 44, 80]), 9 pts were male and 12 were current smokers at baseline (2 former smokers; 2 unknown). In 10 evaluable pts, PD-1 ligand 1 (PD-L1) expression was ≥1% in 7 pts (≥50% in 5) and &amp;lt;1% in 3 pts. Nine of the 16 pts completed the maximum number of nivolumab cycles per protocol; the remainder discontinued due to adverse events (n = 4), disease progression (n = 2), and initiation of a new treatment regimen (n = 1). Twelve of the 16 pts achieved a partial response, and 2 pts each had stable disease (SD) and progressive disease (PD) as best overall response (BOR) to nivolumab. At 5 y, per investigator, 12 pts had received no further therapy after stopping nivolumab treatment and were without evidence of PD. Further details of the disease and treatment course in select pts will be presented. Conclusions: Nivolumab resulted in durable OS in a notable proportion of pts with pretreated advanced NSCLC, as demonstrated by a 5-y OS rate of 16%. Long-term survivors had diverse baseline and on-treatment characteristics including histology, PD-L1 expression level (including pts with &amp;lt;1% PD-L1), and BOR to nivolumab (including pts with SD/PD). Citation Format: Julie Brahmer, Leora Horn, David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, John Powderly, Rebecca Heist, Lecia Sequist, David C. Smith, Philip Leming, William J. Geese, Dennis Yoon, Ang Li, Scott Gettinger. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT077. doi:10.1158/1538-7445.AM2017-CT077

Abstract LB-055: Overall survival and safety experience from an expanded access program (EAP) of nivolumab (NIVO) for patients with advanced melanoma (MEL) who progressed after prior ipilimumab (IPI) treatment

Abstract Background: NIVO (anti-PD-1) was initially approved in the USA as a second-line treatment for MEL based on the results of the phase III CheckMate 037 trial, which enrolled patients (pts) who progressed after prior IPI (anti-CTLA-4) therapy. The results of this trial showed a significantly improved tumor response with NIVO vs. chemotherapy; at a minimum follow-up of 2 years, grade 3/4 treatment-related adverse events (AEs) were reported in 14% of NIVO-treated pts. We report initial overall survival (OS) and safety data from an ongoing EAP of NIVO monotherapy in MEL pts who progressed on IPI therapy (CheckMate 168). Participating countries are Brazil, Canada, the USA, and Argentina. Methods: In CheckMate 168 (NCT02142218), pts with stage III (unresectable) or stage IV MEL who progressed after prior IPI-containing therapy, with an ECOG performance status of 0 or 1, are eligible to receive NIVO 3 mg/kg Q2W for up to 24 months. Key exclusion criteria are active brain metastases, prior immune checkpoint inhibitor therapy other than anti-CTLA-4, and autoimmune disease. For the current analysis, the database lock occurred on November 1, 2016, and included 276 pts with at least 1 year of follow-up (total enrolled: 482). Results: Among the 276 pts included in the current analysis, MEL subtypes were cutaneous (70%), mucosal (8%), acral (5%), uveal (5%), and other or missing (12%). More than half of the pts (55%) had M1c disease (13% with treated brain metastases and 42% without), and 41% had elevated lactate dehydrogenase levels at baseline. Pts had received 1 (21%), 2 (42%) or ≥3 (37%) prior systemic therapies for MEL, which included prior BRAF inhibitor therapy in 24% of pts (in addition to IPI). In the EAP, pts received a median of 8 NIVO doses (range: 1-48), with a median duration of therapy of 3.8 months (range: 0.03-22.1). Median OS in the 276 pts was 14.6 months (95% CI: 11.8-21.2), with a 1-year OS rate of 55.8% (95% CI: 49.2-61.8). Treatment-related AEs of any grade were reported in 69% of pts, most commonly fatigue (24%), diarrhea (17%), nausea (13%), and pruritus (12%), and led to discontinuation of NIVO in 8% of pts. Treatment-related AEs of grade 3/4 occurred in 15% of pts, and led to discontinuation of NIVO in 4% of pts. Any-grade serious AEs related to NIVO treatment were reported in 8% of pts. One death (0.4%) was attributed to study drug (toxic encephalopathy). For treatment-related AEs of potential immunologic origin, those of any grade occurred most commonly in the skin (33%), gastrointestinal tract (18%), and endocrine systems (14%). Conclusions: The initial OS and safety experience from this EAP of NIVO after IPI therapy is consistent with clinical trial data, with no unexpected AEs. These findings suggest that NIVO clinical trial data can be generalized to the advanced melanoma population in a routine clinical practice setting. Citation Format: Milton Barros e Silva, Rafael Schmerling, Andreia Cristina de Melo, Sergio Azevedo, Bernardo Garicochea, Elaine McWhirter, Michael Smylie, Markus Gifoni, Carlos Henrique dos Anjos, Teresa Petrella, Matias Chacón, Martin Greco, Suresh Nair, Alexandre Avila, Sheena Demelo, Joel Jiang, Scott Ernst. Overall survival and safety experience from an expanded access program (EAP) of nivolumab (NIVO) for patients with advanced melanoma (MEL) who progressed after prior ipilimumab (IPI) treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-055. doi:10.1158/1538-7445.AM2017-LB-055

Efficacy of vemurafenib in patients (pts) with non-small cell lung cancer (NSCLC) with BRAFV600 mutation.

9074 Background: BRAFV600 mutations occur in 1–2% of pts with NSCLC. We previously reported the efficacy of vemurafenib, a selective BRAFV600 inhibitor, in BRAF mutation-positive non-melanoma tumors (VE-BASKET study). We now present final data for the expanded NSCLC cohort. Methods: This open-label, histology-independent, phase 2 study included 6 prespecified cohorts (including NSCLC) plus one ‘all-others’ cohort. Pts received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (RECIST v1.1). Secondary endpoints included best overall response rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Because the pre-specified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. ClinicalTrials.gov identifier NCT01524978. Results: Database lock was 12 Jan 2017. Of 208 pts enrolled at 25 centers worldwide, 62 pts had NSCLC: median age 65 years; 56% male; 13% had no prior systemic therapy; 50% had ≥2 prior therapies. Responses were seen in previously treated and untreated pts (Table). The most common all-grade adverse event (AE) was nausea (40%); grade 3–5 AEs included keratoacanthoma (15%) and squamous cell carcinoma of the skin (15%). Six pts discontinued vemurafenib due to AEs; two had non-treatment-related fatal AEs. Conclusions: Vemurafenib showed evidence of encouraging efficacy in pts with NSCLC with BRAFV600 mutation, with prolonged PFS in previously untreated pts; median OS was not estimable due to ongoing responses. The safety profile of vemurafenib was similar to that seen in melanoma studies. Our results suggest a role for BRAF inhibition in NSCLC with BRAF mutations. Clinical trial information: NCT01524978. [Table: see text]