Ad Board Research Articles

543. An Integrated Safety Analysis Comparing Once-Daily Doravirine (DOR) to Darunavir+Ritonavir (DRV+r) and Efavirenz (EFV) in HIV-1-Infected, Antiretroviral Therapy (ART)-Naïve Adults

543. An Integrated Safety Analysis Comparing Once-Daily Doravirine (DOR) to Darunavir+Ritonavir (DRV+r) and Efavirenz (EFV) in HIV-1-Infected, Antiretroviral Therapy (ART)-Naïve Adults

LB1. Doravirine/Lamivudine/Tenofovir DF Continues to Be NonInferior to Efavirenz/Emtricitabine/Tenofovir DF in Treatment-Naïve Adults With HIV-1 Infection: Week 96 Results of the DRIVE-AHEAD Trial

BackgroundDoravirine (DOR) is a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI). In the phase 3 DRIVE-AHEAD trial in HIV-1-infected treatment-naïve adults, DOR demonstrated noninferior efficacy to efavirenz (EFV) and favorable profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96.MethodsDRIVE- AHEAD (Clinical Trials Registration: NCT02403674) is a phase 3, multicenter, double-blind, noninferiority trial that compared DOR with EFV. Eligible participants were HIV-1-infected treatment-naïve adults with pre-treatment HIV-1 RNA ≥1,000 copies/mL. Participants were randomized (1:1) to a fixed-dose regimen of DOR 100 mg, lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF) QD or EFV 600 mg, emtricitabine 200 mg and TDF 300 mg (EFV/FTC/TDF) QD for up to 96 weeks. Randomization was stratified by screening HIV-1 RNA (≤/>100,000 copies/mL) and hepatitis B/C co-infection (yes/no). The efficacy endpoint of interest at week 96 was HIV-1 RNA <50 copies/mL with predefined noninferiority margin of 10%. Safety endpoints of interest included occurrence of pre-specified neuropsychiatric adverse events and mean change from baseline in fasting lipid levels at week 96.ResultsOf 734 participants randomized, 728 received study drug and were included in analyses (mean age 33 years, 85% male, 48% white, 19% black, 34% Hispanic). At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF recipients vs. 73.6% of EFV/FTC/TDF recipients (difference 3.8%, 95%CI [−2.4, 10.0]). No additional phenotypic resistance to DOR was observed between weeks 48 and 96, while two additional participants in the EFV/FTC/TDF group developed resistance to EFV. Dizziness, sleep disorders/disturbances, altered sensorium, and rash were less frequent in DOR/3TC/TDF recipients than in EFV/FTC/TDF recipients. Fasting LDL-C and non-HDL-C increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group, while change in total cholesterol/HDL-C ratio was similar.ConclusionWeek 96 results support non-inferiority of DOR/3TC/TFD to EFV/FTC/TDF established at Week 48 with no additional DOR resistance between week 48 and 96. DOR/3TC/TDF was safe and well-tolerated with fewer neuropsychiatric and rash events and favorable lipid profile compared with EFV/FTC/TDF.Disclosures C. Orkin, AbbVie, Abbott, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, ViiV: Grant Investigator and Research Contractor, Research grant and Research support. K. Squires, Merck & Co., Inc.: Ad Board, Ad Board. Gilead Sciences: Grant, Ad Board. VIIV: Ad Board, Ad Board. Bristol Myers Squibb: Ad Board, Ad Board. Janssen: Ad Board, Ad Board. J. M. Molina, Gilead: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. ViiV: Scientific Advisor, Consulting fee. Teva: Scientific Advisor, Consulting fee. P. Sax, Gilead: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. ViiV Healthcare: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Merck: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Janssen: Consultant, Consulting fee. BMS: Grant Investigator, Grant recipient and Research grant. W. Wong, Merck & Co., Inc.: Research Contractor, Research grant. G. Lin, Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.: Employee and Shareholder, May hold stock/stock options in the company and Salary. S. Kumar, Merck & Co., Inc.: Employee and Shareholder, Salary. G. Hanna, Merck & Co., Inc.: Employee and Shareholder, Salary. C. Hwang, Merck & Co., Inc.: Employee and Shareholder, Salary. E. Martin, Merck & Co., Inc.: Employee and Shareholder, Salary. H. Teppler, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA: Employee, May hold stock/stock options in the company and Salary.

LB2. Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial

BackgroundDoravirine is a novel, non-nucleoside reverse-transcriptase inhibitor (NNRTI) that has demonstrated efficacy in two Phase 3 trials in treatment-naïve adults with HIV-1.MethodsThis open-label, active-controlled, noninferiority (NI) trial evaluated a once-daily single-tablet regimen of doravirine 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF) vs. continuation of current therapy in adults with HIV-1 virologically suppressed for ≥6 months on a stable regimen of two NRTIs plus a boosted protease inhibitor (PI), boosted elvitegravir, or NNRTI. Participants with screening HIV-1 RNA <40 copies/mL, no history of virologic failure on any regimen, and no resistance to DOR/3TC/TDF were randomized (2:1) to start DOR/3TC/TDF on Day 1 (immediate switch group, ISG) or after 24 weeks (delayed switch group, DSG). The primary endpoint was the proportion (%) of participants with HIV-1 RNA <50 copies/mL (FDA snapshot approach), with the primary comparison between ISG at Week 48 and DSG at Week 24 and a secondary comparison between the groups at Week 24; the NI margin was -8%. The % of participants with HIV-1 RNA ≥50 copies/mL was also analyzed (FDA snapshot approach; NI margin 4%).ResultsA total of 670 participants (447 ISG, 223 DSG) were treated and included in the analyses; 84.5% were male, 76.4% were white, and mean age was 43.3 years. At Week 24, 93.7% (419/447) of ISG vs. 94.6% (211/223) of DSG had HIV-1 RNA <50 copies/mL (difference −0.9% [−4.7, 3.0]), and 1.8% of each group had HIV-1 RNA ≥50 copies/mL. At Week 48, 90.8% (406/447) of ISG maintained HIV-1 RNA <50 copies/mL (vs. 94.6% of DSG at Week 24; difference −3.8%, 95% CI [−7.9%, 0.3%]), and 1.6% of ISG had HIV-1 RNA ≥50 copies/mL. In the ritonavir-boosted PI stratum, mean changes in fasting LDL-C and non-HDL-C at Week 24 were significantly lower (P < 0.0001) in ISG vs. DSG (table). Rates of any AE and of drug-related AEs at Week 24 were higher in ISG vs. DSG. AEs were mild in most ISG participants (64% of those with any AE; 80% of those with drug-related AEs).ConclusionA once-daily single-tablet regimen of DOR/3TC/TDF demonstrated non-inferior efficacy and acceptable safety compared with continuing therapy, and is an option for maintaining viral suppression in patients considering a change in therapy.Disclosures P. Kumar, Merck, Pfizer, Janssen,: Grant Investigator and Shareholder, Research grant. GSK, Gilead, Teratechnologies, TaiMed,: Grant Investigator, Scientific Advisor and Shareholder, Consulting fee and Research grant. J. M. Molina, Merck GIlead ViiV Janssen Teva: Ad Board and Speaker’s Bureau, Consulting fee. Gilead Sciences: Grant Investigator, Research support. G. Rizzardini, ViiV, Gilead Science, MSD, Angelini, and Abbvie: Board Member and Speaker’s Bureau, Speaker honorarium. Gliead, ViiV, and MSD: Research Contractor, Research grant. P. Cahn, Abbvie: Grant, Research grant. Merck: Grant, Advisory Board. ViiV Healthcare: Grant, Advisory Board. M. Bickel, Merck & Co., Inc.: Research Contractor, Research grant. Y. Zhou, Merck & Co., Inc.: Employee, Salary. C. Morais, Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.: Employee and Shareholder, May hold stock/stock options in the company and Salary. S. Kumar, Merck & Co., Inc.: Employee and Shareholder, Salary. P. Sklar, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.: Employee and Shareholder, Salary. G. J. Hanna, Merck Sharp & Dohme, a subsidiary of Merck & Co., inc.: Employee and Shareholder, May hold stock/stock options in the company. and Salary. C. Hwang, Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.: Employee and Shareholder, Salary. W. Greaves, Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.: Employee, May hold stock/stock options within the company.

LBA3 - Maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial

Background: Pts with newly diagnosed advanced OC are treated with cytoreductive surgery and platinum-based chemotherapy. Most relapse within the first 3 years and have further chemotherapy, but once relapsed are largely not curable. SOLO1 (NCT01844986) is the first Phase III trial to evaluate PARP inhibitor (olaparib [Lynparza®]) maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced OC with a BRCAm. Methods: SOLO1 is a randomized, controlled, double-blind trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal and/or fallopian tube cancer with a BRCAm, had received platinum-based chemotherapy and were in clinical complete or partial response. Pts were randomized 2:1 to olaparib tablets 300 mg bd or placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1). Results: Of 391 randomized pts, 260 received olaparib and 130 placebo (one pt did not receive placebo). Median follow-up was 41 months. Baseline characteristics were well balanced. Primary PFS analysis showed a significant 70% reduction in the risk of progression or death with olaparib versus placebo (Table). PFS sensitivity analyses, second PFS and time to first subsequent therapy or death support the primary analysis. Overall survival datTableLBA3Median, monthsHR (95% CI)Olaparib (N = 260)Placebo (N = 131)Between-group differenceP valuePFS, investigator assessedNR13.8NC0.30 (0.23–0.41)P < 0.0001(51% maturity)PFS, BICR*Sensitivity analysis using BICR BICR, blinded independent central review; HR, hazard ratio; NC, not calculable; NR, not reached; PFS, progression-free survival; PFS2, time from randomization to second progression or death; TFST, time to first subsequent therapy or deathNR14.1NC0.28 (0.20–0.39)(38% maturity)P < 0.0001TFST51.815.136.70.30 (0.22–0.40)P < 0.0001PFS2NR41.9NC0.50 (0.35–0.72)(31% maturity)P = 0.0002* Sensitivity analysis using BICR BICR, blinded independent central review; HR, hazard ratio; NC, not calculable; NR, not reached; PFS, progression-free survival; PFS2, time from randomization to second progression or death; TFST, time to first subsequent therapy or death Open table in a new tab a are immature. Adverse events were mostly low grade. The most common grade ≥3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no change from baseline in health-related quality of life scores with olaparib. Conclusions: Maintenance olaparib led to a substantial, unprecedented improvement in PFS, with an estimated difference in median PFS for olaparib versus placebo of approximately 3 years. Editorial acknowledgement: Gillian Keating, MBChB, from Mudskipper Business Ltd, funded by AstraZeneca and Merck & Co., Inc. Clinical trial identification: NCT01844986, 26 August 2013. Legal entity responsible for the study: AstraZeneca. Funding: AstraZeneca. Disclosure: M. Friedlander: Personal fees for advisory boards: AZ and MSD. K. Moore: Consultancy: Tesaro, Genentech Roche, Clovis, Immunogen, VBL Therapeutics, Janssen (honorarium, ad board), AstraZeneca - honorarium, ad board (for agents not involved in the SOLO-1 study). N. Colombo: Honoraria: Genentech, Astra Zeneca, PharmaMar; Consulting or advisory role: Genentech, PharmaMar, AstraZeneca, Clovis Oncology, Pfizer, MSD, Tesaro; Research funding: AstraZeneca. G. Scambia: Fees for advisory role: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro. A. Oaknin: Fees for advisory board: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro; Travel/accommodation: Roche, AstraZeneca, PharmaMar. A. Floquet: Fees for advisory board: Astra Zeneca, Roche, Tesaro; Support travel: Roche. A. Leary: Ad boards: Clovis, AstraZeneca, Gamamabs, Pfizer, Gridstone; Travel costs: AstraZeneca; Preclinical research support: Merus, Gamamabs, Sanofi. G.S. Sonke: Institutional research support: AstraZeneca, Merck, Novartis, Roche. C. Gourley: Fees for advisory role: Roche, AstraZeneca, Tesaro, Nucana, Clovis, Foundation One; Lecture fees: AstraZeneca; Research funding (to my institution): Novartis, Aprea, AstraZeneca, Nucana, Tesaro. S. Banerjee: Research funding: AstraZeneca; Advisory boards: AstraZeneca, Tesaro, Clovis. A.M. Oza: Steering committees for trials: AstraZeneca, Clovis, Tesaro (all non-compensated); Honoraria: Intas Pharma. A. González-Martín: Grants as speaker/advisory board participants (last 36 months): AstraZeneca, Tesaro, Roche, Clovis, Pharmamar. C. Aghajanian: Consultancy: Tesaro, Cerulean, Bayer, VentiRx (honorarium, ad board); Mateon Therapeutics (honorarium steering committee meetings); Clovis (honorarium ad boards and steering committee meeting). W. Bradley: Fee for advisory role: Celsion E.S. Lowe, R. Bloomfield: Employee and stockholder: AstraZeneca. P. Disilvestro: Consulting fees: AstraZeneca and Tesaro (over last 2 years). All other authors have declared no conflicts of interest.

1488P - Vemurafenib in patients (pts) harboring BRAF V600 mutation: Results of non-small cell lung cancer (NSCLC) cohort from the AcSé trial

Background: BRAF mutations are found in 2-3% of NSCLC. BRAF inhibitors reportedly have antitumor activity. The French National Cancer Institute (INCa) launched a program giving nationwide access to vemurafenib for cancer pts with BRAF-mutated tumors and supporting molecular screening. We report here the results of the NSCLC cohort. Methods: BRAF mutational status was assessed on INCa molecular genetic centers by direct sequencing or NGS. Pts with BRAF V600E mutation, progressing after ≥1 standard treatment were proposed vemurafenib 960 mg BID. Objective Response Rate (ORR) was assessed using RECIST v1.1 every 8 weeks. A sequential Bayesian approach was planned to allow early stopping using an inefficacy boundary for ORR of 10%. If no early stopping occurred, the treatment was considered worthy for further evaluation if there was a 90% probability that the estimated ORR is ≥ 30%, the efficacy boundary. Results: From 10/2014 to 10/2017, 101 NSCLC pts harboring BRAF V600E were enrolled. Median age: 68 years (range 41–85), 68% smokers, 50% females, 100% non-squamous histology and 19% with ECOG PS 2. Most frequent grade ≥3 adverse events (AEs) were asthenia (10% of pts), epidermoid carcinoma (7%), dermatitis (6%) and increased GGT (6%). Three toxic deaths were reported: 1 nausea and vomiting leading to dehydration, 1 pneumonia and 1 neutropenic sepsis. Among the enrolled pts, 100 BRAF V600E NSCLC pts evaluable for the best overall response (BOR), 43 PR, 21 SD, 16 PD, 12 deaths before assessment and 8 not evaluable (no tumor assessment) were observed. The mean objective response rate was 44.9% (95% CI: 35.2; 54.8), the efficacy boundary was reached with a predictive probability greater than 90%. Median duration of response was 6.5 months (5.1-7.3). Median progression-free survival (PFS) was 5.2 months (3.8-6.9) and median OS was 9.3 months. Nine pts were still on treatment at the cut-off date, 91 have stopped vemurafenib (55 PD, 23 AEs, 3 deaths, 1 doctor’s decision, 9 patient’s decisions). Conclusions: Vemurafenib provided reasonable response rate and prolonged PFS in BRAF V600E pretreated NSCLC. These results confirm the activity of BRAF inhibitors in these pts and underline the need of integrating BRAF V600E in biomarkers routine screening. Clinical trial identification: NCT02304809. Legal entity responsible for the study: UNICANCER. Funding: ARC Foundation French National Cancer Institute (INCa) Roche. Disclosure: J. Mazières: Ad Board, Research grant: Roche, BMS, Astra Zeneca. F. Barlesi: Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. V. Avrillon: Advisory Board: Roche, BMS. G. Ferretti: Speaker conference: Boehringer, Roche, GEMS. J.Y. Blay: Advisory Board: Roche, Lilly, Ignyta, Deciphera, Novartis, Bayer, BMS; Corporate-sponsored Research: Roche, Lilly, Ignyta, Deciphera, Novartis, Bayer, Novartis, GSK, AstraZeneca, MSD; Other Substantive Relationships: Surveillance committee of Innate Pharma. All other authors have declared no conflicts of interest.

940O - OVPSYCH2: A randomised study of psychological support versus standard of care following chemotherapy for ovarian cancer

Background: Ovarian cancer (OC) treatment is associated with psychological morbidity. We prospectively studied the impact of a brief course of psychological support on self-reported depression, fear of progression (FoP) and quality of life (QOL) in patients (pts) following chemotherapy for primary or recurrent OC. Methods: Pts consented at their first post-chemotherapy appointment and were eligible if they scored from 5-19 on PHQ9 questionnaire. They were randomised 1:1 to Intervention or Control. Intervention comprised 3 standardised 90-minute sessions of psychological support given 6 -12 weeks after chemotherapy. Control was standard of care in which support was provided where indicated; unblinded block randomisation was used for primary or recurrent OC and 3 levels of PHQ9 as stratification factors. Pts completed PHQ9, FoP-Q-SF, EORTC QLQ C30 and OV28 questionnaires up to 2 years. Primary endpoint was change in PHQ9 score at 3 months compared to baseline. Results: Oct 2015 - Nov 2017: 182 pts were registered; 107 were eligible and randomised; 54 to Intervention and 53 to Control; mean age of 59 yrs; 75 (70%) primary and 32 (30%) relapsed disease; 63 pts completed baseline and 3-month questionnaires and were included in the analysis: 31 control, 32 intervention. At 3 months there was an improvement in the PHQ9 and the Global Health Status/QOL scale for pts in both arms compared to baseline but no significant difference between Intervention and Control. However, there was a significant improvement on FoP-Q-SF scores in the Intervention arm whilst, for pts in the Control arm, FoP-Q-SF scores deteriorated at 3 months (Intervention effect = -5.2, 95%CI (-8.45-1.9) p = 0.003). Conclusions: Overall, although symptoms of depression improved following completion of chemotherapy for patients in both arms of the study, Fear of Progression did not. This is the first randomised trial of a survivorship intervention in OC and demonstrates that Fear of Progression is a prominent concern for pts but it can be overcome with provision of psychological support immediately after chemotherapy. Clinical trial identification: UKCRN ID 15363. Legal entity responsible for the study: Imperial College London. Funding: Imperial College Healthcare Charity, Maggie's Centres. Disclosure: S. Blagden: Advisor: Ellipses; Director of RNA Guardian Ltd, Ad boards: Clovis, Novartis; Research funding: Nucana plc. R.M. Glasspool: Advisory boards: Clovis, Tesaro, Roche, AstraZeneca; Institution receives research funding: Ignyta, Boehringer Ingelheim, AstraZeneca, Tesaro. S. Nicum: Advisory boards: Roche, Tesaro, Clovis, AstraZeneca; Research funding: AstraZeneca. All other authors have declared no conflicts of interest.

A Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 20 Gy Involved-Site Radiotherapy in Early Stage, Unfavorable Risk Hodgkin Lymphoma

A Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 20 Gy Involved-Site Radiotherapy in Early Stage, Unfavorable Risk Hodgkin Lymphoma

A Case of Immunotactoid Glomerulopathy (ITG) Associated with Monoclonal B-Cell Lymphocytosis (MBL) with Chronic Lymphocytic Leukemia (CLL) Phenotype Treated with Obinutuzumab

Abstract Introduction: Although 44 to 90% of CLL cases have kidney infiltration on autopsy, renal involvement generally goes undetected and renal failure is unusual (Da'As N et al, Eur J Haematol 2001). There is no standard therapy for nephrotic syndrome (NS) in CLL. Treatment of CLL itself may result in regression of NS in most patients and treatment with alkylating agents, cyclosporine A, fludarabine and even splenectomy have been shown to be effective. Controversy exists regarding effectiveness of rituximab in CLL-associated nephrotic syndrome. (Yahata et al, Am J Nephrol 2000). Here we report the first case, to our knowledge, of MBL/CLL-associated NS successfully treated with obinutuzumab. Case Report: 71 years old female presented to ER with hypertensive urgency and anasarca. Past medical history was relevant for progressive hypertension (HTN) for 1 year prior. Creatinine (Cr) was 1.9mg/dL, BUN 45mg/dL, urine protein was >300mg/dl on urinalysis and subsequent 24hr urine protein was 9824mg/24hrs. Patient (pt) had renal ultrasound revealing morphologically normal kidneys without evidence of renal artery stenosis. Echocardiogram was normal. CBC revealed anemia (Hgb 9.2mg/dl) and mild thrombocytopenia (plt 121), WBC count was 7.6 x 10e3/mcl with relative lymphocytosis (47.46 %, ALC 3.594 x10e3 /mcl). On left kidney core biopsy 25 glomeruli were seen by light microscopy, 1 of which was globally sclerotic. The remaining glomeruli showed diffuse duplication of basement membranes with cellular interposition and mild to moderate intracapillary hypercellularity with endothelial cell swelling and/or leukocyte accumulation (Figure 1). Proximal tubules displayed patchy degenerative and regenerative changes including loss of apical brush border, nuclear enlargement and prominent nucleoli, and few interstitial foam cells (Figure 2). By immunofluorescence microscopy, glomeruli stained for IgG, C3, C1 and kappa light chain. There was no staining for lambda light chain. Stains for IgG heavy chain subtypes were positive for IgG1 only (Figure 3), consistent with monoclonal IgG1-kappa deposition. Electron microscopy revealed electron dense deposits in the mesangium, also in subendothelial and subepithelial locations in the capillary walls. On high-power magnification, these deposits revealed a microtubular substructure (i.e., with a central lumen) (Figure 4). These pathologic findings were consistent with ITG. Findings of ITG with IgG1 deposit as well as bicytopenia with relative lymphocytosis warranted further workup for gammopathy. SPEP revealed nonselective protein loss (total protein was 4.5g/dL, Albumin 2.9g/dL, total globulin 1.6g/dL, Albumin/Globulin ratio 1.8) with non-detectable M spike. UPEP was negative. IgG was 203mg/dL, IgA 45mg/dL, IgM 50mg/dL. Serum free kappa light chain was 35.79mg/L with normal Lambda light chain level of 20.08 mg/L with Kappa/Lambda ratio 1.78. Beta-2 microglobulin level was 6.4mg/L. Peripheral blood flow cytometry was ordered, which revealed 20% monoclonal B-cells (CD5+/CD23+) with CLL phenotype. Pt was started on prednisone 60mg daily for 7 days for ITG and decision was made to start CLL-targeted treatment with Obinutuzumab for 6 cycles, with the intent of improving the glomerulopathy, as pt did not meet IWCLL-2008 criteria for initiation of treatment for CLL. Obinutuzumab was given in the usual schedule of 100 mg on day 1, 900 mg on day 2 and 1000 mg on day 8 and 15 of first month, followed by 1000 mg every 28 days for 5 additional cycles. Repeat flow cytometry in 6 months after diagnosis showed complete response of monoclonal lymphocytosis (minimal residual disease negative). There was complete normalization of kidney function (Cr 0.73mg/dl and glomerular filtration rate 78ml/min) and no further evidence of proteinuria or edema. Hypertension has fully resolved, without additional need for anti-hypertensives. 30 months post treatment pt remains in remission for both MBL and nephrotic syndrome. Discussion: Treatment with obinutuzumab may lead to complete resolution and sustained remission of nephrotic syndrome associated with CLL. The more efficient B-cell depletion achieved with obinutuzumab may make this a better treatment choice for CLL associated NS than rituximab. Further evaluation with clinical trials is warranted. Download : Download high-res image (128KB) Download : Download full-size image Disclosures Skarbnik: Novartis: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau.

Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma

Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma

Active Surveillance for Newly Diagnosed Nodular Lymphocyte-Predominant Hodgkin Lymphoma

▪BackgroundNodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare disease. In the absence of consensus guidelines, treatment is controversial. Here, we describe the characteristics and outcomes of consecutive NLPHL patients diagnosed at Memorial Sloan Kettering Cancer Center (MSKCC) with a focus on active surveillance (AS) as a first-line management strategy.MethodsWe included consecutive patients aged 16 years (y) or older who were diagnosed and followed at MSKCC between 1974 and 2016. All cases were confirmed by a MSKCC hematopathologist as NLPHL without evidence of transformation. We excluded composite lymphomas and patients with any prior hematological malignancy or concomitant active cancer. We compared outcomes between patients followed expectantly (AS) and those treated actively (AT), which included radiotherapy (RT) only, chemotherapy (+/- Rituximab) (CT), combined modality (+/- Rituximab) (CMT), and rituximab monotherapy (R). Progression-free survival (PFS) was defined as time from diagnosis to a biopsy-proven disease progression or relapse, initiation of further treatment or death. PFS2 was defined as time from diagnosis to second biopsy-proven disease progression or relapse, initiation of 3rd-line treatment or death. AS was considered a 1st-line treatment. We used univariable and multivariable survival analyses stratifying patients by disease stage.ResultsIn total, 163 patients were included. The median follow-up was 5.7y (Min-Max: 0.3 - 42.7) with 24.5% (n=40) of patients followed for 10y or more. Patient characteristics for all, AS and AT patients are shown in Table 1. Patients were treated with RT only (n=75, 46.0%), AS (n=37, 22.7%), CT (n=26, 15.9%), CMT (n=19, 11.7%) or R alone (n=6, 3.7%).Overall, outcome of patients was excellent, with 10-year PFS, PFS2 and overall survival (OS) estimates of 71.2% [95%-CI: 59.3-80.1], 92.5% [95%-CI: 83.7-96.6] and 96.6% [95%-CI: 87.6-99.1], respectively. Seven patients died, 3 deaths were likely treatment related and only one lymphoma related death occurred after progression. Twelve transformations to aggressive lymphomas occurred after a median of 7.0y (Min-Max: 0.4 - 15.6). The transformation rate was 0.99% per patient year. Twelve secondary cancers occurred after a median of 7.8y (Min-Max: 1.1 - 24.8).Only bulky disease ≥ 5 cm (n=21, HR: 3.1 [95%-CI: 1.3-7.2], p=0.008) and extranodal disease (n=11, HR: 7.7 [95%-CI: 2.1-28.5], p=0.002] were risk factors for a shorter PFS in the final multivariate model after correcting for received treatment.In pairwise comparison, PFS with CMT (p=0.038) and RT (p=0.032) was superior to AS, but CT was not (p>0.999). PFS2 and OS were not significantly different between groups.Patients, who received AT (n=126) overall tended to have superior PFS than those in the AS group (n=37) (5-year PFS 97.2% [95%-CI: 79.2-92.2] vs. 76.5% [95%-CI: 55.7-88.5], p=0.068), though this benefit was mainly seen in early stage disease (Ann Arbor I/II) (5-year PFS 94.2% [95%-CI: 86.7-97.6] vs. 65.1% [95%-CI: 43.5-80.2], p<0.001). This did not translate into better PFS2 (p=0.568) or OS (p=0.303) (Figure 1) and was confirmed in a multivariate model controlling for potential confounders that influenced the initial treatment decision. Comparing results in the AS and AT group, death occurred in 0 vs. 7 (0.0% vs. 5.6%), transformation in 2 vs. 10 (5.4% vs. 7.9%) and secondary cancers in 2 vs. 10 (5.4% vs. 7.9%) patients. Only 24.3% (n=9) of the 37 AS patients required treatment after a median of 5.1y (Min-Max: 0.3 - 23.2). Treatments after initial AS were localized radiation (n=4), R-CHOP (n=4) and R monotherapy (n=1) given for local symptoms (n=3), transformation (n=2), progressing nodes (n=2), systemic symptoms (n=1), adrenal insufficiency due to adrenal mass (n=1) and change of management strategy in stable disease (n=1).ConclusionNLPHL has an excellent prognosis. Bulky and extranodal disease were identified as potential risk factors for progression. With the limitations of a retrospective analysis, it can be concluded that AS is a viable management strategy in NLHPL. The majority of AS patients require no treatment after multiple years of observation and those that do, can be adequately managed with established treatments. Additionally, no evidence was found for an increased rate of transformation or worse PFS2 or OS in AS patients. Treatment related deaths exceeded deaths from lymphoma. [Display omitted] DisclosuresMoskowitz:Celgene: Consultancy; Genentech BioOncology: Consultancy; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Merck: Consultancy, Research Funding; Pharmacyclics: Research Funding. Zelenetz:Genentech/Roche, GSK, Gilead, Celgene, Janssen, Hospira, Amgen, Takeda Pharma, Novartis, Nanostring Technologies, Portola Pharmaceuticals, Adaptive Biotechnology: Consultancy; GSK, Janssen, Roche, Gilead, Bristol Myers: Research Funding; Boehringer Ingelheim: Other: DMC Membership. Kumar:Seattle Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding.

260TiP - Phase 3, randomized, double-blind, placebo-controlled study of PEGylated recombinant human hyaluronidase PH20 (PEGPH20)+nab-paclitaxel/gemcitabine in patients with previously untreated, hyaluronan-high, stage IV pancreatic ductal adenocarcinoma (PDA)

Background: Poor outcome in PDA is associated with stromal hyaluronan (HA) accumulation, which may compromise treatment access. In animal models, PEGPH20 degrades tumor HA. Key data from a Phase 2 study showed that PEGPH20 plus chemotherapy improved efficacy over chemotherapy alone in tumors retrospectively identified to accumulate HA (“HA-High”). The objectives of this phase 3 study are to compare efficacy and safety of standard-dose nab-paclitaxel (NAB) and gemcitabine (GEM) combined with PEGPH20 or placebo in patients with HA-High, previously untreated, stage IV PDA. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints are objective response rate, duration of response, and safety. Trial design: 420 patients ≥18 years with untreated HA-High metastatic PDA, ECOG PS 0-1 are randomized (stratified by North America/Europe/other) 2:1 to NAB 125 mg/m2 + GEM 1000 mg/m2 + PEGPH20 3.0 μg/kg or to NAB + GEM + placebo, respectively. Patients with HA-High tumors are prospectively identified by the co-developed VENTANA HA RxDx Assay, which identifies HA in the extracellular matrix. HA-High status (indicating patients who may achieve clinical benefit) was determined by Halozyme to be ≥ 50% HA staining based on clinical outcome data from a Phase 2 study. Treatment is provided in 4-week cycles (Wk 1-3, Wk 4 rest) until disease progression, unacceptable toxicity, death, or consent withdrawal. PEGPH20 or placebo is given twice weekly (Cycle 1) then weekly (Cycles 2+), NAB + GEM once weekly for all cycles. Dexamethasone is given before and after PEGPH20 to reduce treatment-related musculoskeletal symptoms and enoxaparin is given to minimize thromboembolic events. Tumor response will be assessed by an independent central imaging vendor using RECIST v1.1. Adverse events will be graded per NCI CTCAE v4.03. An independent Data Monitoring Committee will evaluate safety and efficacy (PFS and OS) data. Trial initiated Q12016. Clinical trial indentification: EudraCT 2015-004068-13; NCT02715804. Legal entity responsible for the study: Halozyme Therapeutics Funding: Halozyme Therapeutics Disclosure: D-Y. Oh: Research funding from AstraZeneca, Array BioPharma. Y-J. Bang: Research funding: AstraZeneca, Novartis, Roche, MSD, Merck Serano, Bayer, GSK, BMS, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, CKD, Ono, Otsuka, Taiho, Takeda, BeiGene, Hanmi, Green Cross, Curis Ad board member: AstraZeneca, Novartis, Roche, Genentech, MSD, Pfizer, Bayer, BMS, Eli Lilly, Merck Serano, FivePrime, Merrimack, Taiho, Ono, ADC Therapeutics, GreenCross, Samyang Biopharm. E. Van Cutsem: Research funding: Halozyme. A. Hendifar: Consulting or Advisory Role: Xbiotech, Novartis (self) Research Funding: Ipsen, Halozyme (institution). L. Zheng: Employment: Roche, Stock or Other Ownership: Roche, Honoraria: Roche, Travel, Accommodations, Expenses: Roche. M. Ducreux: Honoraria/Consultation Fees: Roche, Celgene, Merck Serono, Amgen, Novartis, Sanofi, Pfizer, Lilly, Servier, Halozyme; Grants/Research funding: Roche, Chugai, Pfizer Spouse: Head of BU, Sandoz. W. Harris: Consulting or Advisory Role: Neotherma Oncology, Bayer (self); Research Funding: Halozyme, BMS, Exelixis, Arqule, Polaris, Medimmune, BTG (institution). P. Corrie: Honoraria: Roche, Novartis, Bristol Myers Squibb, Merck Sharpe & Dohme, Pierre Fabre Research funding: Celgene; Ad hoc honoraria for lectures/meeting presentations: Novartis, Celgene, Merck Sharpe & Dohme. T. Seery: Consulting or Advisory Role: Bayer (self) Speakers' Bureau: Ipsen, Bayer (self). D. Chondros: Employment: Halozyme (self) Leadership: Halozyme (self) Stock or Other Ownership: Halozyme, Roche (self) Travel Accommodations, Expenses: Halozyme, Roche/Genentech (self). A. Bullock: Consulting or advisory board participation support: Halozyme, Celgene, and EMD Serono (self). All other authors have declared no conflicts of interest.

872P - Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib (c) vs everolimus (e) in advanced renal cell carcinoma (rcc)

Background: C inhibits tyrosine kinases that promote oncogenesis and resistance to antiangiogenic therapy in RCC, including MET, AXL, and VEGF receptors. In the phase 3 METEOR trial (NCT01865747), C significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs E in patients (pts) with advanced RCC after prior VEGFR-targeted therapy (Choueiri, Lancet Oncol 2016). The current study evaluated outcomes based on plasma biomarker levels. Methods: Plasma samples collected at baseline and during treatment from 621 of 658 randomized pts were analyzed for HGF, MET, Gas6, AXL, VEGF, VEGFR2, CA9, and IL-8 by ELISA (Assay Gate, Ijamsville, MD). PFS and OS were analyzed based on low vs high (< median vs ≥ median) biomarker levels at baseline. Results: Analyses of PFS and OS based on baseline biomarker levels showed improvement with C vs E (hazard ratio <1) for all analyses of both low and high levels. PFS improvement for C vs E was most pronounced for low baseline levels of AXL and VEGF, while OS improvement for C vs E was most pronounced for low baseline levels of HGF, Gas6, AXL, and VEGF (Table). For a subset of biomarkers, medians for PFS and OS were longer for low baseline levels vs high for both treatment arms. Differences in OS medians for low vs high levels were largest for HGF (not reached [NR] vs 15.4 mo for C; 19.4 mo vs 13.0 mo for E), Gas6 (NR vs 17.2 mo for C; 18.4 mo vs 13.9 mo for E), VEGF (NR vs 16.1 mo for C; 18.4 mo vs 14.9 mo for E), and IL-8 (NR vs 17.2 mo for C; 19.4 mo vs 13.0 mo for E).Table872PPlasma BiomarkerC vs E, Hazard Ratio (95% CI) for OSLow BiomarkerHigh BiomarkerHGF0.48 (0.32, 0.70)0.74 (0.56, 0.99)MET0.67 (0.48, 0.94)0.62 (0.46, 0.84)Gas60.53 (0.37, 0.75)0.76 (0.56, 1.02)AXL0.54 (0.38, 0.76)0.78 (0.58, 1.06)VEGF0.51 (0.36, 0.74)0.78 (0.58, 1.04)VEGFR20.63 (0.46, 0.86)0.68 (0.49, 0.94)IL-80.62 (0.43, 0.88)0.69 (0.51, 0.93) Open table in a new tab Conclusions: PFS and OS improved with C irrespective of baseline plasma biomarker levels in previously treated pts with advanced RCC vs E. However, low baseline levels of a subset of biomarkers were associated with better clinical outcomes with C. Clinical trial identification: NCT01865747 Legal entity responsible for the study: Exelixis, Inc. Funding: Exelixis, Inc. Disclosure: T. Powles: Consultant/advisory: Exelexis Novartis GSK; Research funding: Exelexis Novartis GSK Genetech. R.J. Motzer: Consulting Role: Exelixis, Eisai, Pfizer, Novartis; Research Funding (institution): Exelixis, Eisai, Bristol-Myers Squib, Pfizer, Novartis. D.J. George: Ad Board: Bristol-Myers Squib, Exelixis, Genentech/Roche, Novartis, Pfizer; Corporate-sponsored Research: Bristol-Myers Squib, Exelixis, Genentech/Roche, Novartis, Pfizer Other: Acceleron – IDMC. E. Jonasch: Research funding: Exelixis, Pfizer, Novartis; Honoraria: Bristol-Myers Squib, Eisai, Exelixis, Novartis, Pfizer. S. Pal: Honoraria: Novartis, Medivation and Astellas Pharma; Consulting fees: Pfizer, Novartis, Aveo, Genentech, Exelixis, Bristol-Myers Squib, Astellas and GSK. N.M. Tannir: Ad Board: Bristol-Myers Squib, Exelixis, Nektar, Novartis, Pfizer, Argos, Calithera; Corproate-sponsored Research: Bristol-Myers Squib, Exelixis, Epizyme, Novartis, Miranti. S. Signoretti: Consulting Role: AstraZeneca, Merck; Research Funding (institution): AstraZeneca, Exelixis Patents/Intellectual Property: Biogenex. C. Scheffold: Employee: Exelixis. E. Wang, D.T. Aftab: Employee: Exelixis, Inc. B. Escudier: Honorarium: Bristol-Myers Squib, Novartis, Pfizer, Ipsen, Roche, Bayer, Calithera, Acceleron, EUSA, Eisai. T.K. Choueiri: Research Funding: Pfizer, GSK, Novartis, Bristol-Myers Squib, Merck, Exelixis, Roche, AstraZeneca, Tracon, Peloton; Consulting Role: Pfizer, GSK, Novartis, Merck, Bayer, Eisai, Roche, Prometheus Labs Inc, Bristol-Myers Squib, Foundation Medicine Inc. All other authors have declared no conflicts of interest.

325O - Nivolumab (nivo) in combination with radiotherapy (RT) ± temozolomide (TMZ): Updated safety results from CheckMate 143 in pts with methylated or unmethylated newly diagnosed glioblastoma (GBM)

Background: Prognosis is poor for pts with GBM, as nearly all have recurrence after standard-of-care therapy. Nivo, a fully human IgG4 mAb inhibitor of the programmed death-1 receptor, is approved for the treatment of multiple cancers. Exploratory cohorts 1c and 1d of CheckMate 143 (NCT02017717) assessed the safety/tolerability of nivo in combination with RT ± TMZ in pts with newly diagnosed GBM. Methods: In cohort 1c, pts received nivo 3 mg/kg Q2W + standard RT + concurrent TMZ (75 mg/m2 daily) followed by adjuvant TMZ (150-200 mg/m2; 5 days/28-day cycle for ≥ 6 cycles). In cohort 1d, pts received nivo 3 mg/kg Q2W + standard RT without TMZ. All pts continued to receive nivo until confirmed progression/unacceptable toxicity. Pts (n = 58) were initially assigned to 1c or 1d based on MGMT methylation status (1c, methylated or unmethylated; 1d, unmethylated). Following the initial evaluation, a second group of 55 pts with unmethylated MGMT were randomized 1:1 to 1c or 1d. Pooled safety data for all 113 pts are described here. Results: Twelve pts with methylated and 43 pts with unmethylated MGMT were treated in 1c, and 58 pts with unmethylated MGMT were treated in 1d. Pts discontinued treatment in 1c (67% each arm) and 1d (83%) mostly due to radiographic progression (1c, 50% [methylated], 37% [unmethylated]; 1d, 64%), study drug toxicity (8%, 9%; 10%), or pt decision (8%, 14%; 0%). AEs (all cause) are summarized in Table. The most common (≥ 30% of pts in any arm) neurological AEs were headache (42%, 47%; 41%) and seizure (25%, 16%; 31%). No deaths due to study drug toxicity were reported.Table325O Summary of AEs (all cause)Pts, n (%)1c: Nivolumab + RT + TMZ1d: Nivolumab + RTMethylated MGMTUnmethylated MGMTUnmethylated MGMTn = 12n = 43n = 58AEs in ≥ 30% of pts in any armFatigue9 (75)22 (51)25 (43)Headache5 (42)20 (47)24 (41)Nausea6 (50)13 (30)10 (17)Seizure3 (25)7 (16)18 (31)Constipation2 (17)14 (33)4 (7)Alopecia4 (33)4 (9)7 (12)Other neurological AEs in ≥ 15% of pts in any armCognitive disorder2 (17)3 (7)6 (10)Dizziness2 (17)4 (9)5 (9)Visual field defect2 (17)2 (5)1 (2)Immune-mediated AEs in > 2 pts in any armALT increased3 (25)8 (19)7 (12)Rash1 (8)7 (16)9 (16)AST increased3 (25)7 (16)5 (9)Diarrhea06 (14)8 (14)Hypothyroidism1 (8)4 (9)6 (10)Rash maculopapular3 (25)2 (5)4 (7)Bilirubin increased1 (8)1 (2)3 (5)Creatinine increased03 (7)2 (3)Grade 3/4 AEs in > 2 pts in any armLymphocytes decreased2 (17)5 (12)2 (3)Lipase increased03 (7)4 (7)ALT increased1 (8)2 (5)3 (5)Seizure1 (8)3 (7)2 (3)Tumor flare01 (2)4 (7)Hyponatremia1 (8)03 (5)Muscular weakness01 (2)3 (5)Serious AEs in > 2 pts in any armSeizure3 (25)4 (9)7 (12)Malignant neoplasm progression2 (17)2 (5)3 (5)Pyrexia1 (8)3 (7)2 (3)Tumor flare02 (5)4 (7)Headache04 (9)1 (2) Open table in a new tab Conclusions: Nivo with RT ± TMZ was well tolerated, with the frequency of neurological AEs consistent with that in other reports in this disease. These data support continued development of nivo + RT ± TMZ in newly diagnosed GBM in the ongoing CheckMate 498 (NCT02617589) and CheckMate 548 (NCT02667587) trials. Clinical trial identification: CA209143; Revised Protocol 04d, dated September 15, 2016 Legal entity responsible for the study: Bristol-Myers Squibb Funding: Bristol-Myers Squibb Disclosure: G. Vlahovic: Ad Board: Bristol-Myers Squibb, Genentech, Merck. A. Omuro: Ad Board: Bristol-Myers Squibb, AstraZeneca, Merck, Alexion Therapeutics & Juno Therapeutics. Consulting: Stemline. D.A. Reardon: Honoraria, & Consulting: Abbvie, Amgen, Bristol-Myers Squibb, Genentech/Roche, Merck, Juno. Speakers Bureau: Genetech/Roche, Merck. Research funding: Celldex, Incyte, Inovio, Midatech. M. Lim: Honoraria & Consulting: Bristol-Myers Squibb, Merck, Agenus, Oncours. Research funding: Bristol-Myers Squibb, Agenus, Accuray. Patents/Royalty: John Hopkins. S. Sahebjam: Consulting: Bristol-Myers Squibb, Merck. Research funding: Bristol-Myers Squibb, Cortice, Merck. T. Cloughesy: Consulting: Bristol-Myers Squibb, Pfizer, Tocagen, Roche, Novocure, Nektar, VBL, Abbvie, Upshire Smith, Notable Labs, Oxigene, NewGen, Agios, Cortice, MedQia, ProNai, Wellcome, Merck, Insys, Human Longevity, Sunovion, Boston Biomedical, Alexion, Novogen. V. Potter, P. Paliwal, M. Carleton: Employee of Bristol-Myers Squibb. R. Zwirtes: Employment & stock holder with Bristol-Myers Squibb. J. Sampson: Royalties: Celldex. Shares/Equity: Istari Oncology. Consulting: Bristol-Myers Squibb. A.A. Brandes: Travel grant to ASCO by Roche. All other authors have declared no conflicts of interest.

1064P - High-dose versus low-dose cisplatin with definitive concurrent radiotherapy for squamous cell carcinoma of the head and neck (SCC): An analysis of veteran’s health registry data

Background: Radiotherapy (RT) with concurrent high-dose cisplatin (HDC) improves outcomes for patients (pts) with SCC. Weekly low-dose cisplatin (LDC) is a widely used alternative approach. The comparative effectiveness and safety of these approaches is unknown. We compared the outcomes of pts treated with HDC and LDC within the Veteran’s Administration Corporate Data Warehouse (CDW). Methods: We identified stage III-IVb SCC patients treated non-surgically with RT and HDC or LDC from 2002 to 2014 in the CDW. Pts were grouped by the dose of their first cycle (HDC vs LDC; intent-to-treat). Variables including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression models, adjusting for PS. We also determined the risk of toxicities using PS-adjusted logistic regression models. Results: A total of 2,820 pts were included in the analysis: 69.7% received HDC (mean initial dose 96 mg/m2). The mean initial dose of LDC was 30 mg/m2. HDC pts were younger (p < 0.001), with lower creatinine (p = 0.002), and lower incidence of baseline neuropathy (p = 0.02). In an unadjusted analysis, HDC was associated with improved OS (Table). After PS adjustment, this difference was no longer statistically significant (p = 0.06). On primary site sub-analysis, HDC provided a benefit only for oropharyngeal primaries (OP). Adjusting for PS, HDC was associated with more renal failure (OR 2.2, 95% CI 1.6-3), neutropenia (OR 2, 95% CI 1.1-3.5), dehydration/electrolyte disturbance (OR 1.3, 95% CI 1.04-1.6), and hearing loss (OR 1.6, 95% CI 1.3-2).Table1064P OS of HDC vs LDCGroupUnadjusted HR for OS95% CIPS Adjusted HR for OS95% CIAll patients (n = 2,820)0.850.77-0.940.890.80-1.01Oral Cavity (n = 182)0.770.56-1.10.720.50-1.10Hypopharynx/Larynx (n = 1,026)1.000.86-1.201.10.90-1.30Oropharynx (n = 1590)0.780.70-0.900.810.69-0.96 Open table in a new tab Conclusions: While HDC does not improve OS over LDC for the overall cohort of patients with SCC receiving RT with definitive intent, it is associated with a survival benefit for patients with OP. HDC is associated with more adverse events. Legal entity responsible for the study: Keith Sigel Funding: None Disclosure: J. Bauml: Research Support: Merck, Bayer, Novartis, Carevive Systems Consulting: Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Celgene, Genentech, Merck, Guardant Health. C. Aggarwal: Roche, Bristol-Myers Squibb, Eli Lilly: Ad boards Takeda, Macrogenics, Roche: Research support to institution. C.J. Langer: Research: Pfizer, Lilly, Genentech, OSI; GSK; Clovis; Merck; Nektar; Advantagene; Inovio; Takeda; AbbVie Advisor: Bristol-Myers Squibb, ImClone, Pfizer, Lilly; AstraZeneca; Merck; Novartis; Genentech; Bayer; Celgene; Abbott; Biodesix; Clariant; Caris; ARIAD; Boehringer Ingelheim; Synta; Clovis; Amgen; Synta; Peregrine; Incyte. R.B. Cohen: Takeda scientific ad board Zymeworks, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

611TiP - Nivolumab, ipilimumab and COX2-inhibition in early stage colon cancer

Background: For the 4% of patients with metastatic mismatch repair deficient (dMMR) colorectal cancers, impressive responses are seen with anti-PD1 monotherapy, with response rates up to 40%. Data in patients with non-metastatic colon cancers (CCs) are lacking. Both MSS and MSI early stage CCs show a higher proportion of T-cell infiltration, when compared to metastatic disease. Also, preclinical work has shown improved responses to anti-PD1 therapy by addition of COX (2)-inhibition, suggesting this could be a useful adjuvant that might help induce responses in MSS CRCs. Trial design: The NICHE trial is a single center, investigator-initiated study, in which patients with newly diagnosed colon cancer who have no signs of distant metastases will be treated with short-term immunotherapy ± COX2-inhibition. Treatment will be given in the window period until surgical resection of the tumor. In this exploratory study, the primary objective will be to determine the safety and feasibility of pre-operative immunotherapy in CC. Secondary objectives include exploring the immune activating capacity of immunotherapy in early stage CCs and the added effects of COX2 inhibition, changes in immune suppressive pathways and the correlation of mutational load to putative markers of response. After additional tumor biopsies are taken via endoscopy, patients with dMMR tumors will all be treated with a single dose of ipilimumab 1mg/kg on day 1 and two cycles of nivolumab 3mg/kg on day 1 and 15. Patients with MSS tumors will be randomized to receive celecoxib 200mg once daily in combination with abovementioned treatment. After 5-6 weeks, patients will undergo surgery, where tumor and normal tissue will again be harvested. When deemed advisable by the pathology report, standard adjuvant treatment with chemotherapy will be offered. A total of 30 patients with MSS tumors and 30 patients with MSI tumors will be enrolled. Recruitment for this study is ongoing and currently two patients have been enrolled. Conclusion: This is, to our knowledge, the first study exploring pre-operative immunotherapy in patients with non-metastatic CC and will hopefully help identify mechanisms that interfere with clinical activity of immunotherapy, and to develop future strategies and combinations for CRC. Clinical trial identification: 2016-002940-17. Release date: January 2017 Legal entity responsible for the study: Netherlands Cancer Institute Funding: Bristol-Myers-Squibb Disclosure: D. Cullen: Employment with BMS. J.B. Haanen: Ad board BMS. All other authors have declared no conflicts of interest.

Post-Operative Anticoagulation and the Incidence of Left Ventricular Assist Device Thrombosis

IntroductionAnticoagulation is critical for patients with durable left ventricular assist devices (LVADs) in order to protect against life threatening thromboembolic events. An increase in the incidence of pump thrombosis between 2009 and 2014 prompted examination of our anticoagulation practices following device implants. As the majority of pump thromboses occurred within six months of implant, we hypothesized that anticoagulation strategies employed immediately after implant might play a role. We describe the initial post-operative anticoagulation management of 105 patients implanted with a Heart Mate II (HM II) LVAD by a single surgeon at our academic center. Although patients with more severe clinical compromise were more likely to be bridged, we found no difference in overall pump thrombosis incidence based on the use of a post-operative parenteral anticoagulation bridge compared to unopposed warfarin.MethodsWe performed a retrospective review of 105 patients undergoing primary implant of a HM II LVAD at our center from 2009 through 2014 with follow up through May 31, 2015. Data included demographics, clinical status at time of implant, intra-operative practices, and initial post-operative anticoagulation management. A parenteral bridge was defined as initiation of a parenteral anticoagulant prior to achieving an INR ≥2.0. A parenteral bridge was further defined as early if initiated within ≤3 days of device implant and therapeutic if a goal PTT was achieved during each of the first 0-24, 24-48, and 48-72 hours of the bridge duration. A parenteral bridge was considered sub-therapeutic if at least one but not all PTT measurements were at goal and non-therapeutic if no PTT measurements were at goal. Unopposed warfarin was defined as initiation to reach a therapeutic INR without the use of parenteral anticoagulants. Pump thrombosis was defined as detection within the device, inflow cannula, or outflow conduit at the time of pump replacement, pump explantation, heart transplantation, or autopsy. Pump thrombosis within 186 days of implant was defined as early. Fisher’s exact test and the Wilcoxon rank-sum test were used to compare categorical and continuous variables between groups. Cumulative incidence of pump thrombosis was compared using the Gray test with reimplantation, explantation, transplantation, or death as a competing risk.ResultsAmong 105 HM II implants, 73 (70%) were treated with any parenteral bridge, 50 (48%) with an early bridge, and 29 (28%) with an early therapeutic bridge. Median time to bridge initiation was 3 days (range 1 to 7) and median bridge duration was 6 days (range 1 to 45). A total of 32 patients (30%) received unopposed warfarin. Time to warfarin initiation and therapeutic INR were shorter in patients who received unopposed warfarin compared to a parenteral bridge, with median values of 1 vs. 2 days and 5 vs. 8 days, respectively (p<0.001 for both). Patients who received a parenteral bridge had more severe preoperative clinical compromise (p=0.039) and longer intensive care unit length of stay (p=0.005).Pump thrombosis occurred in 25 patients (24%) and 14 (13%) were early. Hypertension was the only clinical variable that differed by group (p=0.012) and was more prevalent in patients with pump thrombosis.Cumulative incidence analyses showed no significant difference in the incidence of pump thrombosis between patients who did and did not receive a parenteral bridge (p = 0.25), an early parenteral bridge (p=0.37), or a therapeutic parenteral bridge (p=0.87) (Figure 1). At 6 months the cumulative incidence (95% confidence interval) of pump thrombosis was 7.9% (2.0, 19.3) for those who received a therapeutic bridge and 16.4% (8.7, 26.3) for those who did not. At 24 months these values were 22.7% (9.4, 39.5) and 24.3% (14.6, 35.3), respectively.Among patients who did not receive a parenteral bridge, there was no difference in the time to initiation of warfarin (p=0.23) or therapeutic INR (p=0.13) according to the outcome of pump thrombosis.ConclusionsPost-operative parenteral bridging was more common than initiation of unopposed warfarin. Indices of more severe clinical compromise were associated with the use of a parenteral bridge. Our data suggest that post-implant bridging does not affect overall incidence of LVAD thrombosis. Further analysis will be performed to determine if parenteral bridging prevents early pump thrombosis. [Display omitted] DisclosuresConnors:Thoratec (St Jude's): Other: Consultant; Bristoml Meyer Squibb: Consultancy, Other: Scientific Ad Boards/Consultant; Boehringer Ingelheim: Consultancy, Other: Scientifc Ad Boards.

3302 Safety and Activity of Combined Radiotherapy (RT) and Anti-PD-1 Antibodies (PD-1) in Patients (pts) with Metastatic Melanoma

Conclusions: Updated OS analysis confirmed improvement in OS favoring D+T over Vem with medians of 25.6 versus 18 months. Two-year OS rates and additional efficacy and safety analysis will be presented. Conflict of interest: Ownership: J Legos reported equity ownership with GSK. B Mookerjee reported equity ownership with GSK, Incyte Corporation, and AstraZeneca. Advisory Board: P Rutkowski participated in an Advisory Committee for Novartis, Roche, BMS, and MSD. R Dummer participated in an Ad Board with Roche, BMS, GSK, MSD, Novartis. V Chiarion-Sileni participated in an Advisory Committee for BMS, GSK, Roche, and Merck. I Krajsova participated in an Advisory Committee for BMS. Board of Directors: P Rutkowski was a member of the board of directors for Novartis, Roche, BMS, and MSD. V Chiarion-Sileni was a member of the board of directors for BMS, GSK, Roche, and Merck. I was a member of the board of directors for BMS. Corporatesponsored Research: M Lichinitser received research funding from GSK. R Dummer received research funding from Roche, BMS, GSK, MSD, Novartis. K Drucis received research funding from GSK. A Hauschild received research funding from Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma. Other Substantive Relationships: C Robert acted as a consultant for GSK, Novartis, Merck, BMS, Amgen, and Roche. P Rutkowski received honoraria from Novartis, GSK, Roche, Amgen, Pfizer, BMS, MSD, and Bayer and participated in a speakers bureau for Novartis and Pfizer. L Mortier reports personal fees from GSK, during the conduct of the study. A Hauschild acted as a consultant for Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche and received honoraria from Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche. B Mookerjee and J Legos are employees of GSK. D Schadendorf acted as a consultant and received honoraria from, and participated in a speakers bureau for GSK, Novartis, Roche, Amgen, BMS, Boehringer Ingelheim, and Merck/MSD.

Mass Cytometric Analysis of AML Stem and Early Progenitor Cells Reveals Karyotype and Genotype-Specific Immunophenotypes That May Represent Targets for Antibody-Directed Therapies

Introduction: Leukemic stem cells (LSCs) are recognized as important mediators of leukemia relapse. Thus, therapeutic antibodies are in development to target antigens present on these cells. The success of this approach relies on a detailed understanding of the surface marker expression patterns of LSCs. To address this, we applied multi-parametric single-cell mass cytometry (MCM) to deeply profile the surface marker expression of all major immunophenotypic populations in bone marrow aspirates (BM) from patients with acute myeloid leukemia (AML).Methods: BMs from 41 leukemia patients (30 AML, 4 APL, 2 high-risk MDS, 5 AML in CR) and 5 healthy donors and were processed immediately after aspiration (<1min) and stored for pooled analysis with two overlapping 39-antibody MCM panels (50 markers total). All samples were barcoded, such that 20 samples (leukemia and healthy) could be combined into a single tube for simultaneous antibody staining and analysis, resulting in high precision (coefficient of variation = 10-20%).Results: Distinct AML subtype-specific patterns of cell frequencies across immunophenotypic populations were detected. Patients with core binding factor (CBF) AML (n=5) and those with adverse-risk karyotpic abnormalities (n=6) exhibited the greatest expansion of immunophenotypic hematopoietic stem cells (HSCs) and early progenitors (MPP, CMP), while patients with APL (n=4) and FLT3-ITD normal karyotype AML (NK-AML; n=11) exhibited reduced expansion of early progenitors and expansion in more mature myeloid progenitors (GMP, myelo-monoblasts).As a result of barcoding, high resolution (2-3 fold changes) measurement of surface marker expression detected multiple aberrancies across almost all identifiable immunophenotypic populations. Specifically, several genotype- and karyotype-specific trends in aberrant marker expression were observed in hematopoietic stem and progenitor cell populations (HSPCs; CD34+CD38low). FLT3-ITD samples were characterized by increased CD7, CD33, CD123, CD45, CD321, and CD99, as well as decreased CD34, CD117, and CD38. FLT3wt NK-AML samples (n=6) were characterized by increased CD99 as well as decreased CD71, CD47, CD34, and CD45. Adverse-risk karyotype samples (n=6) were characterized by increased CD99 and decreased CD47. All p values were significant (ranging from 0.02 to 4.5x10-7).While all 36 samples (AML or APL) displayed immunophenotypic abnormalities within the CD34+CD38low gated population (3.6 abnormalities on average), there were 9 samples in which an unambiguous separation into normal and leukemic populations was observed among the cells in this gate. Interestingly, among these samples, some markers were aberrantly high in leukemic cells of one subtype, and aberrantly low in leukemic cells of another, e.g. HLA-DR was extremely high in HSPCs of sample #22 (MLL rearrangement), and aberrantly low in all 4 APL samples. CD99 was most consistently elevated in the AML samples (28/36), but was normal in 6 samples, including a majority of those with t(8;21).These results suggest that therapeutic antibodies directed against molecules such as CD33 may be less effective for AML subtypes such as FLT3wt NK-AML (~40% decrease in CD33), and more effective for other subtypes such as FLT3-ITD NK-AML (7-fold increase in CD33). HSPCs from patients with FLT3-ITD mutations also displayed a 20-fold increase in CD123, which could also be therapeutically targeted. These findings, combined with our recent observation that HSPCs from FLT3-ITD NK-AML patients have an extremely low S-phase fraction, may provide a mechanistic basis for the improved disease-free survival recently reported for FLT3-ITD NK-AML patients treated with fractionated gemtuzumab ozogamicin in combination with standard therapy.Conclusions: We have developed an innovative MCM approach for the analysis of hematologic malignancies and demonstrated that different genotypic and karyotypic subsets of AML are highly varied in their immunophenotypic properties, particularly within the stem and progenitor cell compartment. These data also suggest that antigens that distinguish AML stem cells from normal stems cells are likely to be karyotype and genotype-specific. These findings have important implications for the design of therapeutic strategies in AML. [Display omitted] [Display omitted] [Display omitted] DisclosuresBehbehani:Fluidigm: Consultancy. Medeiros:Agios: Consulting - Ad board Other. Nolan:Fluidigm, Inc: Consultancy, Equity Ownership.

AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a Phase I Study in Patients with IDH2 Mutation Positive Advanced Hematologic Malignancies

INTRODUCTION:Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite, R-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in a spectrum of solid tumors and hematologic malignancies. AG-221 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH2 mutant enzyme. Data from the ongoing, first-in-human, Phase I, open-label, dose escalation study of AG-221 are presented here [NCT01915498].METHODS: Patients with advanced IDH2 mutation-positive hematologic malignancies are receiving AG-221 as a single-agent orally once daily (QD) or twice daily (BID) continuously, in 28-day cycles. The dose in the first cohort was 30 mg BID and sequentially higher dose levels are now ongoing at QD and BID dosing regimens; planned expansion cohorts will be enrolled once the recommended Phase II dose is identified. Bone marrow is examined on Days 15, 29, 57, and every 56 days thereafter. The primary objectives are safety and determination of maximum tolerated dose (MTD) and to select a dose and schedule for the expansion cohorts and future Phase II studies. Secondary objectives include clinical activity assessed by investigators using International Working Group Criteria, pharmacokinetics (PK) and pharmacodynamics (PD).RESULTS:Since study start in September 2013, 48 patients have been dosed and 27 are on study drug as of July 24, 2014. Parallel BID and QD cohort regimens are ongoing at doses up to 150 mg and 200 mg, respectively.Therapy has been well tolerated and the MTD has not yet been reached. The majority of adverse events reported have been grade 1 and 2. There have been 9 deaths and 8 within the first 28 days of receiving AG-221. One death reported as possibly related to study drug in a subject with severe pneumonia. Eight subjects have had 11 SAEs reported as possibly related to study drug.Preliminary PK analysis of the 30 mg through 75 mg BID and 100 mg QD doses demonstrated excellent exposure to AG-221, high accumulation after multiple doses, and a mean plasma half-life >40 hours. PD evaluation demonstrated sustained plasma 2-HG inhibition up to 97% in R140Q subjects and up to 50% in R172K subjects after multiple doses.As of July 24, 2014, 48 subjects have been enrolled: 32 are evaluable for efficacy (having had a Day 28 bone marrow), 8 discontinued study prior to Day 28, and 8 are on study but prior to a Day 28 bone marrow assessment. Investigator-assessed objective responses have been observed in 20 subjects (8 CR, 1 CRp, 3 CRi and 8 PR).Five subjects had stable disease and remain on AG-221. Seven subjects have had progressive disease. Responses are durable, including complete remissions of up to 4.5 months and ongoing with subjects on study as long as 8 cycles (1 cycle = 28 days). Five subjects who achieved a CR went on to bone marrow transplantation. Additional and updated safety, PK/PD and efficacy data from the enrolled subjects will be presented.CONCLUSION: AG-221, a potent, selective, oral inhibitor of mutated IDH2, is well tolerated in patients with advanced hematologic malignancies, and triggers the differentiation of leukemic blast cells that ultimately leads to objective durable responses, including complete remissions. These data provide continued validation of mutant IDH2 as a therapeutic cancer target. DisclosuresStein:Janssen Pharmaceuticals: Consultancy. Altman:Astellas: Advisory board Other; Ariad: Advisory board, Advisory board Other; Spectrum: Advisory board, Advisory board Other; Teva: Advisory board, Advisory board Other; Novartis: Advisory board Other; BMS: Advisory board Other; Foundation Medicine: Advisory board Other; Ambit: Advisory board, Advisory board Other. Fathi:Agios Pharmaceuticals: Advisory board participation Other. Medeiros:Agios: Consulting - Ad board Other. Pollyea:Agios: Advisory board membership Other. Roboz:Agios: Consultation Other. Stone:Agios: Consultancy; AbbVie: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Tallman:Seattle Genetics: Personal fee Other; Amgen: Personal fee, Personal fee Other; Medlogix Communications: Personal fee, Personal fee Other; Bioline Rx: Personal fee, Personal fee Other; Boehringer-Ingelheim: Personal fee Other; Celgene: Personal fee Other; Clavis Pharmaceuticals: Personal fee Other; Astex Pharmaceuticals: Personal fee, Personal fee Other; Agios Pharmaceuticals: Non-financial support, Non-financial support Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Fan:Agios Pharmaceuticals: Employment, Stockholder Other. Yang:Agios Pharmaceuticals: Employment, Stockholder Other. Yen:Agios: Employment. de Botton:AGIOS: Grant Other.

Preclinical Activity of a New Proteasome Inhibitor, MLN9708, in Acute Myelogenous Leukemias Expressing NPM1 Mutated Protein

ABSTRACT: The nucleophosmin-1 (NPM1) mutation represents the most common genetic lesion (30-35%) in adult acute myeloid leukemia (AML) with the mutation resulting in the cytoplasmic delocalization of the NPM protein (NPMc+, most commonly mutation type A, c.860_863dupTCTG). Outside of conventional chemotherapy, treatment options for those with relapsed disease are extremely limited. We have previously discovered that leukemic cells expressing NPMc+ are preferentially sensitive to the cytotoxic effects of the first generation proteasome inhibitor, bortezomib, as result of the induction of superoxide in these cells (Huang M, et al., Leukemia, 2013). However, bortezomib has demonstrated only modest anti-leukemic activity as a single agent in early phase clinical trials that have included primarily heavily pretreated patients not stratified according to mutational genotype. In addition, the high incidence of clinically significant peripheral neuropathy in these studies led to early discontinuation of treatment. MLN9708 (Ixazomib) is a novel second generation proteasome inhibitor that is orally bioavailable and has shown promising activity and improved tolerability in early phase clinical trials in lymphoma and in multiple myeloma, where it is currently in a Phase III clinical trial. The efficacy of MLN9708 in relapsed patients with AML has not yet been examined. We have investigated the in vitro effects of MLN9708 on the cytotoxicity, generation of reactive oxygen species (ROS), and cellular glutathione in both cultured NPMc+ AML cell lines and primary leukemic samples. Cultured OCI-AML3 cells (human AML cell line featuring the NPMc+ mutation) were approximately 50-fold more sensitive to MLN9708 with a mean half inhibitory concentrations (IC50 ± SD) of 67 nM ± 1.83 nM at 24 hours than were an AML cell line (THP-1) expressing wild type NPM1. Knockdown of both NPM1/NPMc+ by inducible NPM1 shRNA expression significantly attenuated the MLN9708-mediated cytotoxicity, as determined by MTS colorimetric and flow cytometric apoptosis assays. As with bortezomib, MLN9708 treatment at 75 nM induced a 2.1-fold (p < 0.002) increase in superoxide-specific DHE (PE)-derived fluorescence as compared to controls. Pre-incubation of cells with 25 mM N-acetylcysteine, a ROS scavenger, dramatically reduced cytotoxicity, strongly implicating the generation of ROS in the mechanism of MLN9708-induced cytotoxicity. Knockdown of NPM1/ NPMc+ expression resulted in an increase of glutathione levels of 2.6-fold (p < 0.04) in untreated cells, and 2.3-fold (p < 0.005) and 2.9-fold (p < 0.004) after a 22 hour incubation with MLN9708 at pharmacologically achievable doses of 75 nM and 150 nM, respectively (Figure 1). In addition, a concomitant 4-fold reduction (p < 0.04) in the NADP+/NADPH ratio was observed in the NPM1/NPMc+ depleted OCI-AML3 cells. In vitro apoptosis assays of primary leukemic blasts isolated from five patients with relapsed NPMc+ AML showed an IC50 for MLN9708 ranging from 49.963-467.487nM (183.8 nM ± 176.8 nM). Based on these promising in vitro studies, a Phase 2 clinical trial of single-agent oral MLN9708 (clinicaltrials.gov identifier: NCT02030405) has been initiated for patients with relapsed or refractory NPMc+ AML.We conclude that the expression of NPMc+ renders AML cells more susceptible to MLN9708 toxicity and that this effect results at least in part from the generation of superoxide. Lower glutathione levels in NPMc+ expressing cells suggests an underlying defect in the antioxidant defense pathway. Demonstration of the sensitivity of NPMc+ AML cells to MLN9708 as a single agent may serve as a platform for the development of novel combination strategies with this drug.Acknowledgments: Research was facilitated by the ASH Clinical Research Training Institute and AACR/ASCO Clinical Cancer Research training program. J.S.G is funded by the Leukemia & Lymphoma Society Career Development Award and ASCO YIA award through a grant supported by Mr. Aaron Sasson. J.S.G. is further supported by the Stanford Hematology Fellowship Program. [Display omitted] DisclosuresOff Label Use: MLN9708 is an investigational compound by Millennium Pharmaceuticals, Inc. (MPI). Through an MTA we have secured the compound for in vitro analysis. This data has led to a clinical trial and drug for that study is supplied by MPI.. Medeiros:Agios: Consulting - Ad board Other.