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Authors have calculated the H/V spectral ratios using seismic-noise recordings in the uppermost layers north of the Seymour-Marambio Island, Antarctic. Sixty-seven seismic site-response measurements near and far from the Argentinean Marambio Base runway suggest geotechnical works on the uppermost sedimentary layers due to maintenance, landing, and taxi of large loads and aircraft during decades could contribute to changes in their seismic dynamic response. Two horizontal images of Vp, Vs, and Vp/ Vs ratios at 1.0 m and 35.0 m depth show lateral variations in the permafrost properties. Authors interpret that permafrost is emplaced in rocks with different porosities and contrasting fluids saturation at those depths. In shallow strata, the saturation of gases affects mainly the elastic properties. In deeper strata, where the location of water reservoirs is detected, the primary mechanism of seismic dissipation is anelastic.

Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility is limited to BRAFV600 mutant cancers and NF1 mutant neurofibromas. The limitations of these approved MEK inhibitors are inherently related to a narrow therapeutic window and their inability to completely inhibit MAPK signaling. Specifically, RAS mutant cancer cells have a stronger dependency on CRAF for MAPK signal transduction. The MEK inhibition and the subsequent reduction of phosphorylated ERK (pERK) by the approved MEK inhibitors triggers the relief of the ERK-dependent negative feedback control on CRAF, leading to CRAF mediated MEK reactivation and pERK rebound. In addition, CRAF has kinase independent functions that contribute to its anti-tumor apoptotic activities. We developed IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 stabilizes the MEK-BRAF and MEK-CRAF protein complexes both biochemically and in cells. By trapping MEK in an inactive complex with RAF, it blocks RAF-dependent MEK phosphorylation, limiting CRAF mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS mutant tumors. Importantly, IK-595 demonstrates persistent and further inhibition of ERK phosphorylation than trametinib and VS-6766. This translates to potent inhibition of cell proliferation across a variety of MAPK pathway altered cancer cell lines, including cells with KRAS and NRAS mutations and RAF alterations. Moreover, IK-595 synergizes with KRASG12C, pan-RAF, and mTOR inhibitors in vitro, leading to enhanced anti-proliferation in cancer cells. In addition, IK-595 inhibits MEK and ERK phosphorylation and ERK target gene DUSP6 expression in vivo, driving robust anti-tumor efficacy in multiple KRAS and NRAS mutant, and CRAF amplified, mouse tumor models. Lastly, the pharmacokinetic properties of IK-595 provide a broader therapeutic window compared to available MEK inhibitors. Together, IK-595 is a novel MEK-RAF complex inhibitor that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients. Citation Format: Eric Haines, Michael Burke, Rachel Catterall, Victor De Jesus, Bin Li, Joseph D. Manna, George Punkosdy, Oksana Zavidij, Sarah R. Wessel, Grace Werosta, Jill Cavanaugh, Sheila Newhouse, Aravind Basavapathruni, Lan Xu, Sergio Santillana, X. Michelle Zhang, Sabine K. Ruppel. IK-595, a MEK-RAF complex inhibitor, obviates CRAF mediated resistance resulting in superior RAS/MAPK pathway inhibition and anti-tumor activity in RAS/RAF altered cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR10.

Background Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels. Patients and methods CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate. Results A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, P = 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade ≥3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%). Conclusions Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls. Clinical Trial Registration numbers ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34.

Aristonectines show a highly derived morphology among elasmosaurid plesiosaurs, including some species with large body size. A new postcranial skeleton is described from the uppermost Maastrichtian levels of the Lopez de Bertodano Formation, Seymour Island (= Marambio), Antarctica, being referred to as cf. Aristonectes sp; the most striking feature of the specimen described is its large body size, among the largest elasmosaurids worldwide. The occurrence of this specimen, located approximately 2.3 m or less below the Cretaceous-Paleogene (K/Pg) boundary, indicates the persistence of aristonectines at high latitudes and also it verifies their chronostratigraphical distribution until the end Cretaceous, before the mass extinction. Elasmosaurid diversity in terms of body size, possible relation of this body size, the trophic niche and abiotic drivers in aristonectine evolution are discussed. The body size inferred for MLP 89-III-3-1 seems to indicate an environment with high primary productivity, suggesting that these conditions persisted until the K/Pg mass extinction.

TPS3169 Background: Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activity of multiple innate and adaptive immune cells. Kynurenine, generated from tryptophan by IDO1 and TDO2, is a ligand that binds AHR and leads to a net immunosuppressive tumor microenvironment, making AHR an attractive therapeutic target in multiple cancer types. IK-175 is a selective, small molecule inhibitor of AHR being developed as an oral agent. In preclinical mouse tumor models, IK-175 demonstrates antitumor activity as a single agent or in combination with checkpoint inhibitors. AHR immunohistochemistry (IHC) tumor microarray analysis across 15 different tumor types revealed that bladder cancer has the highest level of AHR protein expression and nuclear localization indicative of ligand-bound and active AHR signaling. Therefore, nuclear AHR in urothelial carcinoma tumors is being investigated for potential predictive clinical benefit with IK-175. Methods: This is a first-in-human, phase 1a/b, open-label, multicenter, dose-escalation and expansion study of IK-175 as a single agent and in combination with nivolumab. The primary objectives are to determine the maximum tolerated dose (MTD) and/or maximum administered dose (MAD), identify the recommended phase 2 dose (RP2D), and evaluate the safety and tolerability of IK-175 alone and in combination with nivolumab. Secondary objectives are to evaluate the pharmacokinetics (PK) of IK-175, evaluate pharmacodynamic (PD) immune effects, and assess preliminary antitumor activity. Key exploratory objectives are to evaluate the PD effects on peripheral immune cells and target gene expression, to assess candidate baseline biomarkers, and correlative analyses of tumor AHR nuclear localization with clinical response. The study is exploring tumor AHR nuclear localization by IHC as a predictive biomarker in patients with urothelial carcinoma. A minimum of 10 patients with a positive AHR nuclear localization test (cutoff for positive AHR is 65% tumor cells positive for 2+/3+ nuclear AHR by a validated IHC assay) will be enrolled in the combination arm. IK-175 is administered daily in 21 or 28 day-cycles as a single agent, and in combination with nivolumab (480 mg q4w on Day 1 of every cycle), in adult patients with advanced solid tumors (dose escalation) and urothelial carcinoma (dose expansion). Key eligibility criteria include patients with histologically confirmed solid tumors (including urothelial carcinoma) who have locally recurrent or metastatic disease that have progressed on or following all standard of care therapies deemed appropriate by the treating physician including prior checkpoint inhibitors. Estimated enrollment is 93 patients; the study began in January 2020 and is ongoing. Clinical trial information: NCT04200963.

Palopolo, Evangelina. Universidad Nacional de Rio Negro. Instituto de Investigacion en Paleobiologia y Geologia. Rio Negro, Argentina.

Conifer fossil woods represent 54% of an assemblage of 116 specimens collected from sediments of the Sobral Formation in Seymour (Marambio) Island, Western Antarctica. These woods are anatomically described in detail and assigned to seven fossil-species of the following fossil-genera: Agathoxylon (Araucariaceae), Podocarpoxylon, Phyllocladoxylon, Protophyllocladoxylon (Podocarpaceae), and Cupressinoxylon (Podocarpaceae/Cupressaceae). The conifer wood assemblage reveals that the most common woods are those of Agathoxylon, therefore indicating a relative abundance of the Araucariaceae in the Antarctic Paleocene forests. This abundance of the Araucariaceae woods is locally continued in the overlying Cross Valley Formation (Paleocene). Podocarpaceae woods are found in almost similar proportions to those of the Araucariaceae. Almost the other half of the fossil woods are dicotyledon woods. The proportions of the identified fossil wood taxa are consistent with those of the palynological studies of the same stratigraphic unit.

Fil: Campos, Lisandro. División Paleontología Vertebrados, Unidades de Investigación Anexo Museo, Facultad de Ciencias, Naturales y Museo. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina. Fil: Fernandez, Marta. División Paleontología Vertebrados, Unidades de Investigación Anexo Museo, Facultad de Ciencias, Naturales y Museo. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina. Fil: Herrera, Yanina. División Paleontología Vertebrados, Unidades de Investigación Anexo Museo, Facultad de Ciencias, Naturales y Museo. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina. Fil: Talevi, Marianella. Universidad Nacional de Río Negro, Instituto de Investigación en Paleobiología y Geología. Río Negro, Argentina. Fil: Concheyro, Andrea. Instituto de Estudios Andinos Don Pablo Groeber, CONICET and Universidad de Buenos Aires. Instituto Antártico Argentino. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina. Fil: Gouiric-Cavalli, Soledad. División Paleontología Vertebrados, Museo de La Plata, Facultad de Ciencias Naturales y Museo, UNLP. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina. Fil: O'Gorman, José. División Paleontología Vertebrados, Museo de La Plata, Facultad de Ciencias Naturales y Museo, UNLP. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina. Fil: Santillana, Sergio. Instituto Antártico Argentino. Argentina. Fil: Acosta-Burlaille, Leonel. División Paleontología Vertebrados, Museo de La Plata, Facultad de Ciencias Naturales y Museo, UNLP. Argentina. Fil: Molly, Juan. División Paleontología Vertebrados, Museo de La Plata, Facultad de Ciencias Naturales y Museo, UNLP. Argentina. Fil: Reguero, Marcelo. División Paleontología Vertebrados, Museo de La Plata, Facultad de Ciencias Naturales y Museo, UNLP. Instituto Antártico Argentino. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina. New ichthyosaur remains from the Upper Jurassic of Antarctica, recovered from the Ameghino (=Nordenskjold) ¨Formation are described. These three new specimens represent the first unambiguous records of ichthyosaurs in this continent. Based on the morphology of the humerus, we refer one of the specimens to Ophthalmosauridae, the dominant ichthyosaur forms from the Middle Jurassic until the extinction of the group during the Late Cretaceous. In addition to the new Antarctic records, we re-evaluate ichthyosaur remains of two individuals from the Upper Jurassic of Madagascar and describe a third new specimen, which is the most complete ichthyosaur from this region of Gondwanaland. These findings provide new insights into the role of the seaways opened during the Jurassic in the dispersion of ichthyosaurs, particularly ophthalmosaurids. Antarctic and Malagasian ichthyosaurs bring additional support to the hypothesis of the Mozambique Corridor acting as a dispersal route connecting the Tethys Sea and the southern Pacific margins of Gondwana, at least since the Late Jurassic.

Elasmosaurids are one of the most frequently recorded marine reptiles from the Weddellian Province (Patagonia, Western Antarctica and New Zealand). Improvements in our knowledge of elasmosaurid diversity have been problematic because of their conservative postcranial morphology. However, recent studies have helped to improved our understanding of the diversity of this group. Here, a new elasmosaurid specimen from the upper Maatrichtian horizons of the López de Bertodano Formation, Antarctica, MLP 14-I-20-16, is described. MLP 14-I-20-16 is one of the youngest non-aristonectine weddellonectian elasmosaurids from Antarctica. We confirm the coexistence of aristonectine and non-aristonectine elasmosaurids in Antarctica until the end of the Cretaceous. MLP 14-I-20-16 shows distinctive short and broad posterior cervical vertebrae, a feature only shared among the weddellonectian elasmosaurids by the Maastrichtian Morenosaurus stocki, although the same vertebral proportions are also recorded for the giant Cenomanian elasmosaurids Thalassomedon haningtoni. Comparison between MLP 14-I-20-16 and other elasmosaurids from the Maastrichtian of Antarctica indicates that at least two different non-aristonectine elasmosaurids were present in Antarctica during the late Maastrichtian., Facultad de Ciencias Naturales y Museo

Purpose To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) –amplified advanced gastroesophageal adenocarcinoma. Patients and Methods Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250 mg or placebo daily. Primary end point was overall survival (OS) in patients with centrally confirmed HER2 amplification in the primary efficacy population. Results A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. Conclusion Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation.

BACKGROUND. Seribantumab (MM‐121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)‐mediated ErbB3 signaling and induce receptor downregulation. This open‐label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non‐small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild‐type tumors and describe the potential predictive power of HRG. MATERIALS AND METHODS. Patients with EGFR wild‐type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. RESULTS. One hundred twenty‐nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression‐free survival (PFS) in the unselected intent‐to‐treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p = .059, HRG‐by‐treatment interaction, p value = .0016). CONCLUSION. The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). IMPLICATIONS FOR PRACTICE. The poor prognosis of patients with non‐small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open‐label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin‐positive advanced adenocarcinoma.

An ichthyofauna recovered from the L opez de Bertodano Formation at Units 9 (uppermost Maastrichtian) and 10 (lowermost Danian) and the Sobral Formation (Danian), in Marambio (Seymour) Island in the James Ross Basin is described and analyzed herein. A review of previously described taxa based on the new material and several new fish records for the L opez de Bertodano Formation is provided, including the youngest record of Enchodus and the first Cretaceous evidence of Pachycormiformes.We also identify the first Paleocene fishes for the continent. The new information and the reinterpretation of previous Cretaceous records show that there was no decline in fish diversity until the CretaceousePaleogene (K/ Pg) boundary in the area and extinction event appears to have been rapid. Finally, we find that the distribution of some chondrichthyans and teleosts in the James Ross Basin appears to be climatically determined., Facultad de Ciencias Naturales y Museo, Consejo Nacional de Investigaciones Científicas y Técnicas

Fossil woods from Paleocene sediments of the Cross Valley Formation (Seymour Island, Antarctic Peninsula) are anatomically studied in detail. We collected 64 samples represented almost exclusively by conifers (95%). Only three samples of not determinable angiosperm fossil wood were found. Preservation of the samples is often poor and 52% of the samples were assigned to a fossil-species. The assemblage is dominated by Agathoxylon (Araucariaceae), particularly Agathoxylon antarcticus. Araucariaceae species are joined by Protophyllocladoxylon, Phyllocladoxylon and Cupressinoxylon. Forests dominated by Araucariaceae are unusual during the Cenozoic. The high dominance of Araucariaceae woods may be a reflection of soil conditions, weather and terrain elevation. Our study supports previous hypothesis that identified differences between the paleofloras in each side of the Antarctic Peninsula during the Paleocene. Fil: Pujana, Roberto Roman. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentina Fil: Marenssi, Sergio Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; Argentina Fil: Santillana, Sergio N.. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina

Purpose CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. Patients and Methods Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m2 per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m2 per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). Results The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, −1.6%; 95% CI, −2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. Conclusion CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

Purpose The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (BC) is unknown. Patients and Methods The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. Results From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). Conclusion As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

A small humerus from Eocene levels of Seymour Island, Antarctica is assigned here to Aprosdokitos mikrotero sp. and gen. nov. (Aves, Sphenisciformes), based predominantly on its small size. An ontogenetic series based on Pygoscelis antartica was established for comparative purposes, and evaluation of pathological conditions was also carried out in order to rule out other possible sources of size variation., Facultad de Ciencias Naturales y Museo

A new collection of 120 fossil wood samples from early Eocene sediments of the La Meseta Formation is studied. Conifers represent 68 % of the total amount of wood samples. The specimens show significant conifer diversity and were placed in seven fossil-species. Samples are assigned to the Podocarpaceae, probably Cupressaceae and Araucariaceae. New fossil-species of Protophyllocladoxylon and Phyllocladoxylon (Podocarpaceae) and two new nomenclatural combinations are proposed. Comments about the systematic position of each genus and species represented are made. The systematic is based on anatomical data and supported by statistical analysis. A PCA of 78 woods and 12 characters was performed to confirm the taxon delimitation and discrete clusters are represented in the plots for most of each species. Phyllocladoxylon antarcticum is the most common wood type followed by Cupressinoxylon, Agathoxylon and other Podocarpaceae. In accordance with previous studies, our samples suggest that during the early Eocene forests of the northeastern part of the Antarctic Peninsula were dominated by conifers, particularly Podocarpaceae. Fil: Pujana, Roberto Roman. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentina Fil: Santillana, Sergio. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina Fil: Marenssi, Sergio Alfredo. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; Argentina

9036 Background: Seribantumab (MM-121) is a human monoclonal IgG2 antibody that blocks the HRG domain of HER3. Preclinical data suggest that seribantumab reverses HRG mediated drug resistance across multiple cancer models. In prior retrospective analyses, addition of seribantumab to standard of care (SOC) appeared to improve outcomes in pts with HRG+ tumors. Here we tested if seribantumab plus SOC improved progression-free survival (PFS) in pts with HRG+ lung adenocarcinoma who had received prior platinum-based therapy. Methods: SHERLOC was a randomized, open-label, multicenter, Phase 2 study in pts with advanced HRG+ adenocarcinoma of the lung. Archival or pre-treatment tumor samples were assessed for HRG+ by RNA in situ hybridization. Eligibility criteria included prior platinum-based therapy for advanced disease with ≤ 2 total prior lines of therapy (prior IO was allowed) and no EGFR or ALK mutations. Pts were randomized 2:1 to receive seribantumab 3000 mg/docetaxel 75 mg IV q3w (experimental; exp) or docetaxel 75 mg IV q3w alone (control). Primary endpoint was PFS. Key secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse event (AEs) profile. Results: At a pre-specified interim analysis of 75% of total PFS events, 108 pts were enrolled (exp n = 71, control n = 37). Median age was 62y (range 34-83y); female 34%; one prior treatment only 39%. Median PFS was 3.0m for exp and 4.0m for control, HR = 1.66m (p = 0.084). Median OS was 7.9m for exp and 8.4m for control, HR = 1.50 (p = 0.235). ORR was 19.7% for exp and 5.6% for control (p = 0.052). Serious AEs were more frequent in the exp arm (40.8%) vs control (24.3%). Most common treatment emergent AEs (TEAEs) in the exp arm were diarrhea (47%), fatigue (37%), and neutropenia (27%). Based on a determination of futility at interim analysis, the study was terminated early. Conclusions: Seribantumab failed to improve PFS when added to docetaxel among previously treated advanced HRG+ NSCLC pts. A higher response rate and a higher incidence of TEAEs were observed in the exp arm. No further study of seribantumab is planned in NSCLC. Clinical trial information: NCT02387216.

Non-communicable diseases, including cancer, are overtaking infectious disease as the leading health-care threat in middle-income and low-income countries. Latin American and Caribbean countries are struggling to respond to increasing morbidity and death from advanced disease. Health ministries and health-care systems in these countries face many challenges caring for patients with advanced cancer: inadequate funding; inequitable distribution of resources and services; inadequate numbers, training, and distribution of health-care personnel and equipment; lack of adequate care for many populations based on socioeconomic, geographic, ethnic, and other factors; and current systems geared toward the needs of wealthy, urban minorities at a cost to the entire population. This burgeoning cancer problem threatens to cause widespread suffering and economic peril to the countries of Latin America. Prompt and deliberate actions must be taken to avoid this scenario. Increasing efforts towards prevention of cancer and avoidance of advanced, stage IV disease will reduce suffering and mortality and will make overall cancer care more affordable. We hope the findings of our Commission and our recommendations will inspire Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies.

2524Background: Seribantumab (MM-121) is an anti-ErbB3 human monoclonal antibody being tested as an anti-cancer therapy for patients with high expression of heregulin mRNA in NSCLC (SHERLOC study, ...

TPS2604Background: Ephrin receptor A2 (EphA2) is expressed in cancer and stroma cells in a wide range of solid tumors. MM-310 is an EphA2-targeting liposomal form of a docetaxel prodrug. Preclinica...

We report and describe two new small diamictite outcrops on Isla Marambio (Seymour Island), Antarctic Peninsula. These rocks rest on an erosional unconformity on top of the Eocene La Meseta Formation and are unconformably covered by glaciomarine rocks of the ?Pliocene–Pleistocene Weddell Sea Formation. The lithology, fossil content and isotopic ages obtained strongly suggest that the rocks belong to the Hobbs Glacier Formation and support a Late Miocene age for this unit. Additionally, the dated basalt clast provides the oldest age (12.4 Ma) for the James Ross Island Volcanic Group recorded up to now. The here described diamictite cannot be confidently correlated with a glaciomarine unit previously assigned to the Late Eocene–Lower Oligocene taken as proof that initial expansion of ice on Antarctica encompassed the entire continent synchronously in the earliest Oligocene. However, it is now evident that there are likely to be more, short but important, stratigraphic sequences of key regional and Antarctic wide interest preserved on the plateau of Isla Marambio.

Palaeostress inferred from brittle mesostructures in Seymour (Marambio) Island indicates a Cenozoic to Recent origin for an extensional stress field, with only local compressional stress states. Minimum horizontal stress (σ3) orientations are scattered about two main NE–SW and NW–SE modes suggesting that two stress sources have been responsible for the dominant minimum horizontal stress directions in the north-western Weddell Sea. Extensional structures within a broad-scale compressional stress field can be linked to both the decrease in relative stress magnitudes from active margins to intraplate regions and the rifting processes that occurred in the northern Weddell Sea. Stress states with NW–SE trending σ3are compatible with back-arc extension along the eastern Antarctic Peninsula. We interpret this as due to the opening of the Larsen Basin during upper Cretaceous to Eocene and to the spreading, from Pliocene to present, of the Bransfield Basin (western Antarctic Peninsula), both due to former Phoenix Plate subduction under the Antarctic Plate. NE–SW σ3orientations could be expressions of continental fragmentation of the northern Antarctic Peninsula controlling eastwards drifting of the South Orkney microcontinent and other submerged continental blocks of the southern Scotia Sea.

Purpose This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m2 per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. Results Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. Conclusion Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.

The biogeographic hypothesis more accepted today is that Antarctica (West Antarctica) and southern South America (Magellan region, Patagonia) were connected by a long and narrow causeway (Weddellian Isthmus) between the Antarctic Peninsula and South America since the Late Cretaceous (Campanian) until the Early Paleogene allowing terrestrial vertebrates to colonize new frontiers using this land bridge. Stratigraphically calibrated phylogenies including large, terrestrial native ungulates Litopterna and Astrapotheria taxa reveal long ghost lineages that extended into the Late Paleocene and provide evidence for the minimum times at which these “native ungulates” were present both on Antarctica and South America. Based on these results we estimate that the Weddellian Isthmus was functional as a land bridge until the Late Paleocene. Our data place the disconnection between Antarctica and South America in the Late Paleocene, indicating that the terrestrial faunistic isolation (Simpson's “splendid isolation”) in South America begun at the end of the Paleocene (~ 56 to 57 m.y.). This faunistic isolation is documented to have occurred at least 25 Ma before the existence of deep-water circulation conditions in Drake Passage (~ 30 m.y.) based on the onset of seafloor spreading in the west Scotia Sea region. We hypothesize that in the early stages of extension (Late Paleocene, ~ 55 m.y.) a wide and relatively shallow epicontinental sea developed between the Antarctic Peninsula and South America drowning the Weddellian Isthmus and preventing the faunal interchange for obligate cursorial terrestrial forms. Fil: Reguero, Marcelo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Departamento Científico de Paleontología de Vertebrados; Argentina Fil: Gelfo, Javier Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Departamento Científico de Paleontología de Vertebrados; Argentina Fil: López, Guillermo Marcos. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Departamento Científico de Paleontología de Vertebrados; Argentina Fil: Bond, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Departamento Científico de Paleontología de Vertebrados; Argentina Fil: Abello, María Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Laboratorio de Sistemática y Biología Evolutiva; Argentina Fil: Santillana, Sergio N.. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina Fil: Marenssi, Sergio Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Basicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Basicas, Aplicadas y Ambientales de Buenos Aires; Argentina

Modern penguins are typically small to medium-sized birds, and nearly all known modern specimens are smaller than the most archaic Paleogene relatives. Here we report an incomplete humerus, associated femur and tibiatarsus of a new spheniscid, Crossvallia unienwillia nov. gen. and sp., from the Late Paleocene (~55 million years, Myr) of Antarctica, extending the record of spheniscids by about 15 Myr. Its large size (length ~140 cm) supports the idea that large body size in penguins was acquired independently at different times (Late Paleocene and Late Eocene) under dramatically different environmental conditions. Comparison of its osteological anatomy suggests that the new taxon is closely related to the extinct Anthropornithinae rather than to other penguin lineages.

Summary. The PML/RARα fusion gene in acute promyelocytic leukaemia (APL) has three subtypes based on the breakpoint site of the PML gene: long (bcr1), short (bcr3) and variable (bcr2) subtypes. The PML/RARα fusion protein is involved in the pathogenesis of APL and the breakpoint site of the PML gene might be associated with aetiological factor(s). Because APL is over-represented in patients that originate in Latin America (Latinos), we evaluated whether the distribution of the PML/RARα fusion mRNA in this population is different to that reported in non-Latinos. Among 52 APL patients (28 from Mexico and Central America diagnosed in Los Angeles and 24 from Peru, South America), bcr1, bcr2 and bcr3 expression was 75%, 10% and 15% respectively. However, bcr1 breakpoints were significantly higher compared with non-Latino patients (340/654, 52%) reported in four studies. Often bcr1 and bcr2 are reported together; 862 (60%) of 1429 non-Latino APL patients reported in nine studies were either bcr1 or bcr2, compared with 44 (85%) in our 52 Latino patients. This difference was also statistically significant when our patients were compared to each of the individual studies from USA and Europe, but not for a small series from China and Japan. These results suggest that the overrepresentation of APL among Latin American patients can be accounted for by an increase of a single subtype – bcr1, and the breakage sites in the PML gene may not be random but possibly influenced by genetic and/or environmental factor(s).

The Eocene La Meseta Formation is the youngest exposed unit of the back-arc James Ross Basin, Antarctic Peninsula, cropping out in Seymour (Marambio) Island. The formation comprises 720 m of clastic sedimentary rocks of deltaic, estuarine and shallow marine origin. It was subdivided into six unconformity-based units (Valle de Las Focas, Acantilados, Campamento, Cucullaea I, Cucullaea II and Submeseta Allomembers) grouped into three main facies associations. Facies association I represents valley-confined deposition in a progradational/aggradational tide-dominated and wave-influenced delta front/delta plain environment. Facies association II includes tidal channels, mixed tidal flats, tidal inlets and deltas, washover and beach environments. Facies association III represents nonconfined tide- and storm-influenced nearshore environments. La Meseta Formation sandstones are quartzofeldspathic with some hybrid arenites (glauconite and carbonate bioclasts-rich). Sandstone detrital modes are subdivided into two distinctive petrofacies: the low quartz petrofacies (petrofacies I, Q 12%), interpreted to retain the original provenance signal, and the high quartz petrofacies (petrofacies II, Q>55% and L 1.4) is clearly dominated by volcanic-derived clasts; it developed at times of high sea level and/or during later stages of the valley fill, when an “energy fence” at the shoreline prevented delivery of sediment from the Antarctic Peninsula, thus enhancing the relative participation of local volcanic sources.

The Eocene of Seymour Island contains the only association of Cenozoic plants and land vertebrates known from anywhere in Antarctica and lies at about latitude 63° south. The late Early to latest Eocene La Meseta Formation fills an incised valley and comprises sediments representing deltaic, estuarine and very shallow marine environments. The Paleogene sequence in southern South America (Patagonia) and the Antarctic Peninsula reveals floristically distinct periods (late Paleocene, early and middle Eocene and latest Eocene), based largely on leaf assemblages. The late Paleocene Cross Valley flora (Seymour Island) contains ferns and other elements suggesting a much warmer climate than at this latitude today. The Middle Eocene Fossil Hill (South Shetland Islands) and the Rio Turbio (Santa Cruz Province, southern Patagonia) floras have a mixture of both Neotropical and Antarctic elements. The La Meseta paleoflora is distinctive in having a predominance of Antarctic taxa especially Nothofagus, podocarps, and araucarian conifers in the Eocene deciduous and evergreen forests. This suggests a cooling trend during the Eocene of Antarctica with mid- to late Eocene seasonal, cool-temperate, rainy climates and latitudinal and altitudinal gradients. The Seymour Island La Meseta Fauna (Cucullaea Allomember, middle Eocene) contains at least 10 mammal taxa, predominantly tiny marsupials (mostly endemic and new taxa). The endemism of these marsupials suggests the existence of some form of isolating barrier (climatic and/or geographic) during the Eocene. Faunal similarity between the La Meseta Fauna and the fauna assigned to the Riochican (late Paleocene) South American Land Mammal Age of Patagonia strongly suggests that the former derived from the latter. The occurrence on Seymour Island of sudamericids, that had become extinct in South America in the Paleocene, also indicates that isolation may have allowed extended survival of this Gondwanan group in the Eocene of Antarctica and the factors that caused their extinction did not affect this continent. Global warming and intercontinental dispersal have been major influences on the timing and magnitude of terrestrial biotic change in the late Paleocene and early Eocene epochs. The faunistic evidence indicates that the La Meseta mammalian fauna derived from late Paleocene/early Eocene Riochican/Vacan faunas. The dispersal and vicariance events may have occurred during the onset of the climatic optimum of the Cenozoic (late Paleocene–early Eocene) when major regressive events are recorded either in the northern Antarctic Peninsula and southernmost Patagonia (between 58.5 and 56.5 Ma). The absence of notoungulates in the La Meseta fauna is noteworthy. We speculate that the notoungulates could have passed into Antarctica during the latest part of the Paleocene when the environmental conditions were warmer, and then became extinct at the onset of the climatic deterioration during the early Eocene.

7050 Background: Ponatinib is approved for pts with refractory CML or Ph+ ALL for whom no other TKI therapy is indicated, or for patients with T315I. Previously (Mueller ASCO ‘16), we reported the positive association of early landmark responses with ponatinib on survival at 3 yrs in heavily pretreated pts with CP-CML in PACE (NCT01207440). Here, we provide an update with survival outcomes at 4 yrs. Methods: The association of molecular (assessed in a central lab) and cytogenetic responses (CyR) at 3, 6 and 12 mo with 4-yr post-landmark PFS and OS was evaluated in CP-CML pts (n = 267). P values: calculated using log-rank test. Data cutoff: 3 Oct ‘16. Results: At baseline, median time from diagnosis: 7 (range, 0.5–27) yrs; median age: 60 (18–94) yrs; median %Ph+: 100% (3–100), ≤10% Ph+: 19 pts (7%); 61% of pts had ≥3 prior TKIs. Among evaluable pts at 3, 6 and 12 mo, MCyR/CCyR was achieved in 48%/39%, 62%/52% and 71%/56% and MMR in 14%, 29% and 39% of pts, respectively. Greater reductions in BCR-ABL1 levels (Table) and CyR at most landmark time points were associated with improved 4-yr post-landmark PFS and OS. Deeper responses at all landmark time points were associated with achievement of MR4.5 over time. Conclusions: As with the 3-yr landmark analysis, CyR and deep reductions in BCR-ABL1 transcripts at early time points correlated with improved 4-yr post-landmark survival in this refractory population. These data continue to demonstrate the prognostic value of early cytogenetic and molecular responses with ponatinib in heavily pretreated pts with CP-CML. Clinical trial information: NCT01207440. [Table: see text]

TPS7073 Background: Ponatinib is an oral TKI with potent activity against BCR-ABL1. The pivotal PACE study (NCT01207440) formed the basis for approval of ponatinib in the US for the treatment of patients with resistant/intolerant CML or Ph+ ALL, or those with the T315I mutation. Long-term follow-up of PACE showed a higher cumulative incidence of vascular occlusive events (VOEs) than reported at the time of approval — dose reductions were later implemented to mitigate VOEs. VOEs comprise arterial occlusive events (AOE) and venous thromboembolic events. The exposure-adjusted incidence of AOEs has not increased over time in PACE; in patients with a history of ischemic disease, the relative risk of serious AOEs was 2.6 in those with ≥2 vs 0 risk factors. The primary objective of this patient registry is to assess VOEs occurring during ponatinib use in routine clinical practice in the US. Methods: OMNI (NCT02455024) is a prospective observational registry of eligible patients (Table) with CML or Ph+ ALL for whom the decision to initiate treatment with ponatinib has already been made for the approved US indications. Patients voluntarily enroll into the registry, which is non-interventional with no protocol-mandated tests/procedures — all treatment decisions are made at the discretion of the health care practitioner in consultation with their patient. Study duration is anticipated as ~30 mo (~18-mo enrollment followed by 12 mo of data collection, which will occur every 3 mo). The primary analysis will be performed 12 mo after last patient enrolled and will estimate the incidence of VOEs by duration of ponatinib exposure. To understand differences between those with and without VOEs, exploratory analyses will be performed, considering factors such as patient demographics, risk factors for developing VOEs, dose and duration of ponatinib treatment, and concomitant medications. VOE outcomes also will be assessed. Enrollment will begin in 2017, with a target of ≥300 patients. Clinical trial information: NCT02455024. [Table: see text]

A fragment of an araucarian ovuliferous cone, araucarian leaves and podocarpaceous wood are described from Upper Cretaceous strata exposed at Cape Lamb, Vega Island, Antarctica. The wood fragment and the reproductive cone come from the middle part of the early Maastrichtian K2 unit whereas the leaves referred to a new species, Araucaria antarctica , were recovered from the younger (mid?) Maastrichtian K3 unit (Sandwich Bluff Member of the Lopez de Bertodano Formation). These are the first plant megafossils to be described in detail for this locality and represent components of a Late Cretaceous forest community growing under cold-temperate conditions. The findings reported herein highlight the potential value of the fossiliferous sequence exposed on Vega Island, which has not yet been fully investigated, and provide insights into the diversity and structure of the high latitude, Late Cretaceous conifer-dominated floras.

The purpose of this ongoing study is to determine the response and safety of a combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus doxorubicin as neoadjuvant therapy for stage IIIB breast cancer. Thirty-nine chemotherapy-naive patients were enrolled in the study. The median age was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 100. Gemcitabine 1,200 mg/m(2) was given on days 1 and 8, and doxorubicin 60 mg/m(2) on day 1, followed by surgery or radiotherapy. Ninety-seven of 117 cycles (83%) were administered at full dose. An overall response rate of 95% was obtained, with a complete response in 18% (seven patients) and a partial response in 77% (30 patients). Twenty-eight patients (72%) underwent breast surgery after a maximum of three cycles of neoadjuvant therapy. World Health Organization grade 3/4 toxicities included leukopenia in nine cycles (8%), neutropenia in 16 cycles (14%), febrile neutropenia in 11 cycles (9%), and anemia in two cycles (2%). The most important nonhematologic toxicity was grade 2/4 mucositis in 16 cycles (14%), and/or grade 2/3 diarrhea in 10 cycles (9%). Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity. Semin Oncol 28 (suppl 10):57-61.

Background: Ponatinib, an oral tyrosine kinase inhibitor with potent activity against native and mutant BCR-ABL1, is approved for patients with refractory chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated, or for patients with the T315I mutation. The efficacy and safety of ponatinib in patients with resistant/refractory hematologic malignancies were evaluated in a phase 1 trial (NCT00660920). Here, we report 4-year follow-up data from chronic-phase (CP)-CML patients; final data (approximately 5-year follow-up) will be presented. Methods: In this open-label, dose-escalation, phase 1 trial, 81 patients with resistant/refractory hematologic malignancies (CP-CML, 43 patients; accelerated-phase CML, 9 patients; blast-phase CML, 8 patients; Ph+ ALL, 5 patients) were enrolled. Patients were treated with ponatinib at a starting dose of 2 mg/d - 60 mg/d; intra-patient dose escalation was permitted. In Oct 2013, dose reduction instructions were provided in response to an observed accumulation of arterial occlusive events (AOEs) with longer follow-up across the ponatinib clinical program. For data presented herein, the data cutoff date is 2 Feb 2015, with median follow-up of 53.1 months (range, 1.7 - 69.9 months) for CP-CML patients. Results: Among CP-CML patients, at baseline, median age was 55 years and median time since diagnosis was 6.6 years; BCR-ABL1 kinase domain mutations were reported in 63% of patients, with T315I confirmed at a central laboratory in 28% of patients. Patients were heavily pretreated, with 37% having received 2 prior TKIs and 60% having received ≥3 prior TKIs. Of 43 CP-CML patients, 22 (51%) remained on ponatinib treatment at data cutoff. Adverse events (AEs; 26%) and disease progression (9%) were the most common reasons for discontinuation of treatment. Cumulative response rates were: major cytogenetic response (MCyR), 72%; complete cytogenetic response (CCyR), 65%; major molecular response (MMR; assessed at a central laboratory), 56%; molecular response 4 (MR4), 42%; MR4.5, 28%. Responses were durable (Table), with median durations of response not reached for MCyR, CCyR, and MMR. Among patients who received ponatinib at starting doses of ≤30 mg/d (n = 15), MCyR was achieved by 67%, CCyR by 53%, and MMR by 47%; ponatinib dose was ≤30 mg/d in all but one of these patients at the time of response. Of 19 patients who were ongoing and in MCyR as of Oct 2013, 13 had their dose reduced; all 13 dose-reduced patients maintained MCyR at data cutoff. Of the 22 ongoing patients at the time of the present analysis, 18 (82%) had CCyR and 17 (77%) had MMR or better (MMR, 6 patients; MR4, 1 patient; MR4.5, 9 patients; MR5, 1 patient) as their response at the data cutoff; 14/22 (64%) ongoing patients were receiving 15 mg/d as their current dose as of the data cutoff. Rash (65%), fatigue (63%), abdominal pain (58%), headache (58%) and arthralgia (53%) were the most common treatment-emergent AEs. The incidence of AOEs (any/serious) was 40%/30% (by subcategory: cardiovascular, 30%/21%; cerebrovascular, 9%/7%; peripheral vascular, 14%/9%). Conclusions: With median follow-up of over 4 years in this phase 1 study, ponatinib continues to provide clinical benefit to heavily pre-treated CP-CML patients, approximately half of whom continue to receive ponatinib, with a majority in deep response that has been long-lasting; final study data will be presented. The most common treatment-emergent AEs were consistent with the AE profile across the clinical program. Potential for long-term benefit, demonstrated herein, versus risk should be considered when using ponatinib in this patient population. Study sponsor: ARIAD Pharmaceuticals, Inc. Disclosures Mauro: BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Shah:ARIAD: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; Plexxikon: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment, Equity Ownership. Santillana:ARIAD: Employment, Equity Ownership. Heinrich:Novartis: Consultancy, Patents & Royalties, Research Funding; Pfizer: Consultancy; Bayer: Research Funding; BMS: Research Funding; Blueprint Medicines: Consultancy; MolecularMD: Consultancy, Equity Ownership; ARIAD: Consultancy, Research Funding; Onyx: Consultancy. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Talpaz:Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding.

Background: Ponatinib is a tyrosine kinase inhibitor (TKI) approved for adult patients (pts) with relapsed/refractory CML or Ph+ ALL and those with the BCR-ABL T315I mutation, which is uniformly resistant to other TKIs approved for the treatment of CML and Ph+ ALL. Prior to the availability of ponatinib, resistant pts with the T315I mutation (T315I+) had worse outcomes than those without the mutation; in a matched pair analysis in chronic phase (CP)-CML pts, median overall survival (OS) was 48.4 mos after development of resistance in T315I+ pts versus not reached in those without the mutation (Nicolini FE, et al. Haematologica 2013). Methods: We evaluated the efficacy and safety of ponatinib in a pooled analysis of a subgroup of CP-CML pts with the T315I mutation (detected in a central laboratory by Sanger sequencing at baseline) from the phase 1 (NCT00660920) and pivotal phase 2 PACE (NCT01207440) trials. In addition, we evaluated the impact of continuation of ponatinib treatment at a 2-yr landmark time point on OS at 1-yr past the landmark in T315I+ CP-CML pts in PACE. The phase 1 trial is an open-label, dose escalation study of ponatinib (starting dose 2-60 mg once daily) in 81 adults with relapsed/refractory hematologic malignancies. PACE is an open-label, single-arm trial of ponatinib (starting dose 45 mg daily) in 449 adults with CML or Ph+ ALL resistant or intolerant to dasatinib or nilotinib or with the T315I mutation. Dose reductions were instructed in Oct 2013 in response to an accumulation of arterial occlusive events (AOEs) reported with longer follow-up across the ponatinib clinical program. Response assessments included major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR; assessed in a central laboratory), and molecular response 4.5 (MR4.5). OS and progression-free survival (PFS) data were only collected in PACE; 3-yr outcomes were examined for all evaluable T315I+ CP-CML pts, along with a log-rank test for OS by treatment status as of the 2-yr landmark time point. Exposure-adjusted incidence rates of new AOEs are reported as number of events/100 pt-yrs. Pooled data as of February 2, 2015 is reported here. Results: There were 76 T315I+ CP-CML pts included in this analysis (phase 1, n=12; PACE, n=64). At the time of analysis, median duration of follow-up in T315I+ CP-CML pts was 40 (range: 1.5-74) mos; 37 pts (49%) remain on study. Median baseline ponatinib dose intensity was 33 (range: 5-56) mg daily; 25/37 (68%) ongoing pts were receiving 15 mg daily as their current dose as of the data cut-off. Primary reasons for discontinuation in T315I+ CP-CML pts were disease progression [10/76 (13%)], adverse events [AEs; 9/76 (12%)], consent withdrawn [5/76 (7%)], physician/administrative decision [4/76 (5%)], death [3/76 (4%)], lack of efficacy [2/76 (3%)], and other [6/76 (8%)]; criteria for disease progression included death, development of advanced phase CML, loss of CHR (in absence of cytogenetic response) and loss of MCyR. Cumulative response rates in T315I+ CP-CML pts (n=76) were: MCyR, 75%; CCyR, 72%; MMR, 61%, and MR4.5, 37%. In PACE, estimated 3-yr PFS/OS rates for 64 T315I+ CP-CML pts were 60%/78% (medians not reached). One yr post-landmark outcomes for T315I+ CP-CML pts by treatment status at the 2-yr landmark time point are displayed in the table. Most common treatment-emergent AEs (≥40%) in the pooled group of T315I+ CP-CML pts (n=76 phase 1 and PACE) were: rash, 55%; dry skin, 49%; headache, 46%; abdominal pain, 43%; nausea, 41%; and fatigue, 41%. Among these pts, the cumulative incidence of any AOE (grade 3/4) was 32% (20%); by subcategory: cardiovascular 20% (15%), cerebrovascular 12% (5%), and peripheral vascular 13% (8%) events. Two T315I+ CP-CML pts had grade 5 AOEs. The exposure-adjusted incidence rate of new AOEs in T315I+ CP-CML pts was 12/100 pt-yrs. Conclusions: Ponatinib continues to provide deep and durable responses with >3 yrs median follow-up in T315I+ CP-CML pts. Survival outcomes with ponatinib treatment in these highly refractory pts were high overall and compare favorably with those observed in T315I+ CP-CML pt populations prior to the availability of ponatinib. Although pt numbers are limited for the landmark analysis, continuation of ponatinib treatment at 2 yrs was associated with a trend for improved OS, where data continue to mature. Updated data in all T315I+ pts will be presented. Study sponsor: ARIAD Pharmaceuticals, Inc. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Baccarani:ARIAD: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Mauro:BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Hughes:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria. Guilhot:ARIAD: Honoraria. Deininger:BMS: Consultancy, Research Funding; Gilead: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shah:ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Plexxikon: Research Funding. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Lustgarten:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Santillana:ARIAD: Employment, Equity Ownership. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

A novel intravenous liposomal formulation of all-transretinoic acid (ATRA) was evaluated in 69 patients with acute promyelocytic leukemia (APL): 32 new diagnoses, 35 relapses, and 2 oral ATRA failures. Liposomal ATRA (90 mg/m2) was administered every other day until complete remission (CR) or a maximum of 56 days. Treatment following CR was liposomal ATRA with or without chemotherapy. In an intent-to-treat (ITT) analysis of all patients, CR rates were 62%, 70%, and 20% in newly diagnosed, group 1 first relapses (ATRA naive or off oral ATRA more than or equal to 1 year), or group 2 relapses (second or subsequent relapse or first relapses off oral ATRA less than 1 year), respectively. In 56 evaluable patients (receiving 4 or more doses), CR rates for the same groups were 87% (20 of 23), 78% (14 of 18), and 23% (3 of 13). Remission failure in newly diagnosed patients was not from resistant disease. Several patients in CR became polymerase chain reaction (PCR) negative for promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARα) after liposomal ATRA alone. Toxicity was generally mild, most commonly headaches (67.5%). Eighteen patients (26%) had ATRA syndrome develop during induction. One-year survival of ITT patients was 62%, 56%, and 20% for newly diagnosed, group 1, and group 2, respectively. The medium duration of CR has not yet been reached and was 18 and 5.5 months in the same groups. These results demonstrate that liposomal ATRA is effective in inducing CR in newly diagnosed or group 1 APL patients. It provides a reliable dosage of ATRA for patients with APL unable to swallow or absorb medications and can induce molecular remissions without chemotherapy.

A new ornithopod dinosaur from Antarctica, Trinisaura santamartaensis n. gen. et n. sp. is diagnosed by a unique combination of characters that includes a scapula with a spike-like acromial process with a strong and sharp lateral crest and longer than other ornithopods, a humerus with a rudimentary deltopectoral crest represented as a thickening on the anterolateral margin of the humerus, and shaft strongly bowed laterally, and an ischium gently curved along its entire length. The holotype specimen comprises vertebral and appendicular elements. The presence of axially elongate distal caudal vertebrae, pubis with long prepubic and postpubic processes, as well as a femur with a distinct anterior trochanter, pendant 4th trochanter and shallow anterior intercondylar groove constitute a combination of characters present in the Late Cretaceous Patagonian Gasparinisaura, Anabisetia and Talenkahuen. The materials were found on the surface enclosed in a hard sandstone concretion collected near the Santa Marta Cove, James Ross Island, from the lower levels of the Snow Hill Island Formation (Campanian). This is the first ornithopod taxon identified from this unit, and the second ornithischian dinosaur, after the ankylosaur Antarctopelta oliveroi. However, other ornithopod reports from nearby localities of James Ross and Vega islands in outcrops of the overlying Lopez de Bertodano Formation suggest that this clade was widely represented in the Campanian and Maastrichtian of the James Ross Basin, Antarctic continent. Fil: Coria, Rodolfo Anibal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Universidad Nacional de Río Negro; Argentina Fil: Moly, Juan J.. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo; Argentina Fil: Reguero, Marcelo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo; Argentina. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina Fil: Santillana, Sergio. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina Fil: Marenssi, Sergio Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; Argentina

A new xanthid crab, Tumidocarcinus foersteri n. sp. is described from the La Meseta Formation on Seymour Island, Antarctica. The fossils were obtained from the Allomember Submeseta of Late Eocene age. As other representatives of the genus Tumidocarcinus were only known from New Zealand and Australia, this finding provides new insights on the palaeobiogeography of high latitude faunas during the Early Tertiary.