tbuckley/cabot-search huggingface dataset:
BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advBC).
Authors: Josep Tabernero, Jason J. Luke, Anthony M. Joshua, Andrea I. Varga, Victor Moreno, Jayesh Desai, Ben Markman, Carlos Alberto Gomez-Roca, Filippo G. De Braud, Sandip Pravin Patel, Matteo S. Carlino, Lillian L. Siu, Giuseppe Curigliano, Zhaohui Liu, Yuko Ishii, Penny Phillips, Megan Wind-Rotolo, Paul Andrew Basciano, Alex Azrilevich, Karen A. Gelmon
Journal: Journal of Clinical Oncology (2018)

4512 Background: NIVO (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in pts with advBC (Sharma P, et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates development of regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 therapy can upregulate IDO1, supporting the rationale for combining NIVO with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD), oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + NIVO demonstrated a favorable safety profile and antitumor activity in heavily pretreated pts with select solid tumors (Luke J, et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the advBC cohort are reported. Methods: Dose-escalation methods of this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + NIVO 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed [u] responses). Prior IO therapy was permitted in the advBC cohort. Results: As of Dec 15, 2017, 434 pts received BMS-986205 + NIVO. TRAEs were reported in 51% of pts (grade 3‒4, 12%), the most common being fatigue (13%) and nausea (10%); 16 pts (4%) discontinued due to TRAEs, and 1 pt died due to a TRAE (myocarditis). With a median follow-up of 17 wk (range, 4‒53), the ORR among 29 pts with advBC was 34% (1 u CR, 9 PRs [1 u]), and the disease control rate (DCR) was 48%. Of 29 pts, 26 had no prior IO therapy; ORR in these pts was 38% (1 u CR, 9 PR [1 u]), and the DCR was 54%. ORR in pts with tumor PD-L1 ≥ 1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 15) vs < 1% (n = 11) was 47% vs 27%. Conclusions: BMS-986205 + NIVO was well tolerated, with a safety profile similar to that of NIVO monotherapy. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + NIVO. Updated data by dose and subgroup in the advBC cohort will be presented. Clinical trial information: NCT02658890.
Pulmonary sarcomatoid carcinoma (PSC): A 40 year experience at a comprehensive cancer center.
Authors: Priyank P. Patel, Nabeela Khan, Grace K. Dy, Hongbin Chen
Journal: Journal of Clinical Oncology (2016)

e20044 Background: PSC is rare and standard therapy is not well defined. We evaluated experience at our center to identify factors influencing the outcome. Methods: Retrospective review of PSC patients (pts) treated at Roswell Park Cancer Institute between 1972 and 2014. Results: 45 pts were identified; males 55%, Caucasians 91%, median age 63 yrs. 87% were smokers with mean 47 pack-year smoking history. Stage at diagnosis: I - 22%, II - 25%, III – 22%, IV- 31%. All 13 pts tested for EGFR mutation were wild type. Mutations in KRAS were present in 3/11, ROS1 in 0/2, ALK in 0/9, RET in 0/2, BRAF in 0/2 and MET amplification in 1/2 pts. 29 pts underwent surgery – 26 lobectomy, 3 pneumonectomy. 80% had video assisted thoracoscopic surgery. 7 pts (16%) had neoadjuvant chemotherapy (CT). 6 of these received a cisplatin-based doublet (with gemcitabine, etoposide or pemetrexed), 1 received sarcoma-like regimen with cisplatin, paclitaxel and ifosfamide. 6 pts had partial response (PR) and 1 had progressive disease (PD). Adjuvant chemotherapy (AC) consisting of a platinum-based doublet was given in 10 pts. 41% pts who underwent surgery relapsed. Local relapse in the lung was the most common (77%). Systemic CT was given in 19 pts with stage IV or relapsed disease. First line CT was a platinum-based doublet in 74% pts. After a median of 2 cycles, only 1 patient had PR and 1 had stable disease. 88% pts had PD on first-line CT. Second-line CT was given in 11 pts, with combination or single agent (platinum, docetaxel, irinotecan, pemetrexed) or EGFR inhibitors in 3 pts. 5 pts underwent third-line CT. No pts had response to second- or third-line CT. Median progression free survival (PFS) was 4.9 m and overall survival (OS) was 12.2 m and significantly depended on stage at diagnosis. Stage IV pts had PFS of 2.4 m and OS of 3.4 m. Pts receiving AC had significantly improved PFS (37 vs 13 m; p = 0.026) and OS (48 vs 22 m; p = 0.025). Conclusions: PSC heralds a poor prognosis and current management is sub-optimal. In early stage disease, AC is significantly associated with improved survival but local relapses are common. In advanced stage disease, cytotoxic CT is largely ineffective. Newer biomarkers and therapies should be investigated.
Reply to D.M. Green
Authors: David B. Dix, Nita L. Seibel, Yueh-Yun Chi, Geetika Khanna, Elizabeth A. Mullen, James I. Geller, John A. Kalapurakal, Peter F. Ehrlich, Marcio H. Malogolowkin, Conrad V. Fernandez, Jeffrey S. Dome
Journal: Journal of Clinical Oncology (2018)
Nurse practitioner and physician assistant oncology workforce for older adults.
Authors: Lorinda Adaire Coombs, Caroline Stephens, Tatjana Kolevska, Wendy Max
Journal: Journal of Clinical Oncology (2018)

e18514 Background: Cancer is most frequently diagnosed in adults over the age of 65 years in the U.S. Access to cancer care is unequal, and anticipated oncologist shortages could have a further negative impact. The growth of the older population with the corresponding increase in malignancy diagnoses has driven the need to better identify and characterize Nurse Practitioner (NP) and Physician Assistant (PA) contribution to the oncology workforce. We measured the number of NPs and PAs who cared for older adults with cancer, their proportion compared to other providers, and examined the clinical and patient characteristics of those received care from NPs. Methods: A cross sectional ambulatory care analysis using 2013 SEER-Medicare database was conducted. Clinicians were identified using National Provider Identifier taxonomy codes and included all malignancies. The number of patients included in the analysis was 201, 237 and providers numbered 128,971. Results: Over 2.5 million claims for malignancy were included in the analysis; NPs numbered 4,806 and made up 3.7% of the total workforce compared with 3,767 or 2.9% for Physician Assistants (PA), and 6,286 or 5.1% for oncology specialist physicians. Patients who received care from NPs were more often female (56% compared with 44% male) and 70-75 years of age. Compared with patients who did not receive care from NPs, those who did were more likely to have more than 1 malignancy or metastatic cancer (P = .0001). A larger proportion of patients who lived in rural areas received care from NPs and PAs. Conclusions: Our study identified a large number of NPs and PAs providing cancer care for older adults, the magnitude of which has not previously been recognized or measured. Although rural cancer providers comprised a small portion of the total workforce (10%), NPs and PAs made up almost half of those providers. Accurate portraits of the NP and PA cancer workforce has been confounded by a sole reliance upon self-reported measures, and the lack of the ability to identify their specialty care. Our study is the first attempt to quantify their efforts to care for older adults with cancer.
Durvalumab (DURVA) plus daratumumab (DARA) in patients (pts) with relapsed and refractory multiple myeloma (RRMM).
Authors: Paul G. Richardson, William Bensinger, Katja C. Weisel, Kevin Boyd, Karthik Ramasamy, Esther Gonzalez, Linda Favre-Kontula, Teresa Peluso, Lars Axel Sternas, Carl Di Casoli, Mohamed H. Zaki, Thierry Facon
Journal: Journal of Clinical Oncology (2017)

TPS8054 Background: DARA, a monoclonal antibody (mAb) against CD38, is approved for RRMM. Combination treatment (Tx) with DARA + DURVA, a mAb against programmed death ligand-1 (PD-L1), may enhance host anti-MM immunity and response. DARA and PD-L1 mAbs have each demonstrated clinical activity in combination with pomalidomide (POM) + low-dose dexamethasone (LoDEX) in MM. Thus, the phase 2 MEDI4736-MM-003 trial is evaluating DURVA + DARA in RRMM, and, in an exploratory analysis, the addition of POM + LoDEX to DARA + DURVA either upon progressive disease (PD) with DARA + DURVA or as up-front Tx will be assessed. Methods: ≈ 144 pts with RRMM are being enrolled. Pts with measurable MM who received ≥ 3 prior anti-MM Txs, including a protease inhibitor and an immunomodulatory agent, or are double-refractory to these 2 agents will be included. Exclusion criteria include allogeneic stem cell transplant (SCT), autologous SCT ≤ 12 weeks, and prior DARA or other CD38 antibody therapies. Primary endpoints are overall response rate (ORR) and safety. Secondary endpoints are time to response, duration of response, progression-free survival, and pharmacokinetics. The study includes a 3 + 3 safety run-in phase to confirm the tolerability of the recommended phase 2 doses (RP2Ds) of DURVA and DARA. Dose-limiting toxicities will be evaluated during the first Tx cycle. Safety and efficacy will be assessed by a Simon 2-stage design (Table). POM + LoDEX may be added to DARA + DURVA in pts who received ≥ 2 cycles of DARA + DURVA and had confirmed PD. Based on preliminary safety and efficacy, the 4-drug regimen may be explored as up-front Tx. Tx with either the 2- or 4-drug regimens will continue until PD or unacceptable toxicity. Pts treated with POM will be followed for second primary malignancies every 6 mos until the end of the trial. To date, 6 pts have enrolled in the run-in phase. Clinical trial information: NCT02807454. [Table: see text]
Pregnancies during and following trastuzumab (T) and/or lapatinib (L) in patients (pts) with HER2-positive (HER2+) early breast cancer (EBC): Analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.
Authors: Matteo Lambertini, Samuel Martel, Christine Campbell, Sebastien Guillaume, Florentine Hilbers, Uwe Schuehly, Larissa Korde, Hatem A Azim, Serena Di Cosimo, Richard Charles Tenglin, Jens Bodo Huober, Jose Baselga, Alvaro Moreno-Aspitia, Martine J. Piccart-Gebhart, Richard D. Gelber, Evandro De Azambuja, Michail Ignatiadis
Journal: Journal of Clinical Oncology (2018)

10065 Background: Limited data exist on the safety of using targeted agents in pregnant cancer pts. So far, only retrospective studies assessed the prognosis of pts having a pregnancy after prior EBC with no data in HER2+ pts. We aimed to evaluate the outcome of pregnancies occuring during or following T and/or L and the prognostic effect of having a pregnancy in HER2+ EBC pts. Methods: NeoALTTO and ALTTO were randomized phase 3 trials in HER2+ EBC pts. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between pts unintentionally exposed to T and/or L during gestation (exposed group) and those who got pregnant following T and/or L completion (not-exposed group). In the ALTTO trial, disease-free (DFS) and overall survival (OS) of pregnant pts were compared to those of pts ≤40 years without subsequent pregnancy with the Extended Cox Model With Time-Varying Covariates to account for guarantee-time bias. Results: Out of 455 and 8,381 pts included in NeoALTTO and ALTTO, 92 pts (7 in NeoALTTO and 85 in ALTTO) had a pregnancy at a median age of 33 years (range 23-40). Pregnancy outcomes are reported in the table No difference in DFS (HR 1.24; 95% CI 0.58-2.6) or OS (HR 0.53; 95% CI 0.13-2.17) was observed between young pts with (n = 85 pts) or without (n = 1,392 pts) a pregnancy. Conclusions: Despite fewer live births were described in the exposed group, unintentional exposure to T and/or L during gestation does not seem to affect newborns’ outcomes upon treatment discontinuation. Having a pregnancy after HER2+ EBC does not appear to impact on DFS or OS. These data are of high relevance to counsel young EBC pts facing pregnancy-related issues. Clinical trial information: NCT00490139. Exposed Group n = 17 pts Not-exposed Group n = 75 pts Completed pregnancy 7 (41%) 52 (69%) Induced abortion 10 (59%) 7 (9%) Spontaneous abortion 0 10 (13%) Ongoing/unknown 0 6 (8%) Live births 7 (41%) 54 (72%) Congenital anomalies 0 1 (2%) Oligohydramnios 0 0 Gestational week at delivery (range) 38.5 (34-39) 39 (38-40) Apgar score (range) 9 (9-9) 9 (9-10) Newborn weight, g (range) 3,145 (2,880-3,776) 3,440 (3,016-3,710) Newborn length, cm (range) 50 (49-52.5) 51 (49-52.5)
Room for improvement regarding patient involvement in decisions to limit treatment: Results from the EPAL-study (Ethics Policy for Advanced Care Planning and Limiting Treatment).
Authors: Eva Caroline Winkler, Katja Mehlis, Elena Jaeger, Katsiaryna Laryionava, Friederike Mumm, Wolfgang Hiddemann, Pia Heussner
Journal: Journal of Clinical Oncology (2016)

e21504 Background: The aim of this study was to describe the extent to which advanced cancer patients want to be and are actually involved in decisions to limit treatment (DLT) and to investigate factors that impact patient involvement. Methods: This prospective quantitative study recruited 50 cancer patients and 35 of their oncologists from 5/2014-6/2015 in the Dept. of Hematology/Oncology at the University of Munich. Included were advanced cancer patients with treatment limitations. Patients and their respective physician completed a set of validated questionnaires on patient’s information needs, involvement, distress and perceived quality of communication. Results: While 93% (n = 46) of the patients prefer to be involved in DLT, only 61% (n = 30) state they feel sufficiently involved. 88% (n = 44) of the patients had a DNR and 78% (n = 39) a No-ICU order. However, only 34% with DNR and 36% with No-ICU order confirm deciding together with their physician. Those who report a shared decision about DLT evaluated the quality of communication significantly better (p = .004) compared to the non-involved, showed a higher degree of information seeking behavior (p = .037), felt sufficiently involved (p = .001) and agreed more often with their physician on the treatment plan (p = .047). They also had a higher stress level (p = .000), maybe because of their worse prognosis compared to all patients. Conclusions: Given the fact that all patients had decision-making capacity and only one third reported to be involved in their DNR/No-ICU order, there is room to improve patient participation in these crucial decisions – e.g. by focusing on triggers for EOL-communication. We aim for this in the EPAL-Project with a policy for advanced care planning and limiting treatment. A post-implementation study will evaluate the impact of the policy.
Effect of Redd1 loss on proliferation and metastasis of pancreatic cancer cells with KrasG12D-LOH by inhibiting glycolysis.
Authors: Mingyue Hu, Peilin Huang, Yu Ma, Sunkai Ling, Yuan Li, Baoan Chen, Yueshuang Xu
Journal: Journal of Clinical Oncology (2017)

e15741 Background: Aerobic glycolysis, regulated by mammalian target of rapamycin (mTOR) pathway, plays an important role in pancreatic carcinogenesis. Regulated in development and DNA damage response (Redd1) constitutes an important regulator of mTOR signaling. Previously, we observed that the loss of heterozygosity (LOH) status of Kras mutations (e.g. KrasG12D) is associated with an increased Redd1 expression. Here, we investigated the functional relevance of Redd1 in the context of KrasG12D-LOH. Methods: Murine Kras G12D -LOH/Kras G12D pancreatic cancer cells isolated from genetically engineered mice were used in this study. The glycolysis dependence was detected by CCK8 assays after treated by glycolysis inhibitor 2-Deoxy-D-glucose (2-DG). Redd1 expression was down-regulated using shRNA transfection. Cell proliferation was determined by CCK8 and colony formation assays. Cell invasion and migration was measured by transwell and wound-healing assays. The levels of lactic acid and ATP were tested by ELISA kit. Genes related to glycolysis and mTOR signal were evaluated by western-blot and quantitative RT-PCR. Results: Compared with KRAS G12D pancreatic cancer cells, the viability of KRAS G12D -LOH cells decreased significantly in the presence of 2-DG. After Redd1 suppression, the proliferative and invasive potentials of KRAS G12D -LOH cells decreased significantly when compared with blank group and negative group. The levels of lactic acid and ATP were also reduced by Redd1 down-regulation. Furthermore, the signal activity of mTOR pathway and Pkm2 and Hk2 expression were reduced dramatically, while Tsc1 and Tsc2 expression were unaffected. Conclusions: The LOH status of KRAS G12D renders the pancreatic cancer cells additive to glycolysis, which further affect the proliferative and invasive potentials via the function of Redd1/mTOR. These data underscore the importance of KRAS G12D -LOH in regulating cancer glucose metabolism.
Plinabulin (Plin), a small molecule with anti-cancer activity and a novel mechanism of action (MoA) in docetaxel (Tax)-induced neutropenia: Phase (φ) 2 results from a head-to-head comparison with Pegfilgrastim (Peg).
Authors: Douglas W. Blayney, Yuankai Shi, Igor Bondarenko, Qingyuan Zhang, Nadezhda Vitalievna Kovalenko, Jifeng Feng, Ihor Vynnychenko, Mikhail Valeryevich Kopp, Stephan Ogenstad, Lihua Du, Lan Huang, Ramon W. Mohanlal
Journal: Journal of Clinical Oncology (2018)

2528 Background: Plin has clinical anticancer activity in combination with Tax (Mohanlal ASCO-SITC 2017,18). Plin prevented Tax-induced neutropenia in a post-hoc analysis of a φ 2 trial (Blayney ASH 2016). Plin is being studied in the prevention of chemotherapy(chemo)-induced neutropenia (CIN) induced by Tax/ adriamycin/ cyclophosphamide in BC, by gemcitabine/ abraxane in PC, by carboplatin/ pemetrexed/ pembrolizumab in NSCLC , and irinotecan in CRC. We report final results of the φ 2 portion of a prospective φ 2/3 trial of Plin for CIN compared with Peg (NCT03102606; Study BPI-2358-105). The 105 study is designed to demonstrate non-inferiority (NI) of Plin vs Peg for duration of severe neutropenia (DSN) in φ 3. Methods: Patients (Pts; n = 55) with lung cancer (NSCLC) were randomized to Tax 75 mg/ m2 day (D)1, and either Peg 6 mg D2 or Plin 5, 10, or 20 mg/ m2 D1. Plin was dosed on the same day of (30 min after) chemo. Absolute Neutrophil Count (ANC) was collected D1,2,3,6,7,8,9,10,15 and 21. Primary endpoints were DSN and grade (Gr) 4 neutropenia to establish recommended phase 3 dose (RP3D). The NI margin for DSN is 0.65 D. Hypertension (HT) was evaluated by semi-continuous BP measurement on D1. Results: DSN for Peg was 0.51 D and for Plin 0.54 D. Gr 3 HT was transient and not different among all groups (p < 0.18). Bone Pain occurred in 33% of pts with Peg and 11% with 20 mg/ m2 Plin. Clinical trial information: NCT03102606. Conclusions: Plin 20 mg/ m2, given 30 min after chemo is well tolerated, has less bone pain, and has similar myeloprotective effect vs Peg. Its post chemo recovery curve is shallower, broader and later than Peg, with median ANC staying within normal range, suggesting a different MoA to prevent CIN. Plin 20 mg/m2 is the RP3D based upon its protection against Gr 4 neutropenia and safety profile. Dose Pts Median ANC (cell count x10E9/L)* Gr 4 CIN % D1 D6 D7 D8 D9 D10 D15 Peg 6 mg 14 9.43 4.65 5.82 12.1 15.7 16.7 11.4 14 Plin 20 mg/m2 14 7.39 4.25 3.57 2.69 2.25 2.41 3.97 14 Plin 10 mg/m2 13 7.93 4.13 1.91 1.76 1.94 2.30 4.69 23 Plin 5 mg/m2 14 7.63 3.57 1.73 1.33 1.42 1.95 3.21 21 * Normal range of ANC: 1.8 to 7.7 X 10^9 cells/L
Does immune checkpoint inhibitor-induced thyroid dysfunction impact on side effect profile? A restrospective cohort study.
Authors: Jack Patrick Gleeson, Haley Ellis, Lisa Mary Prior, Geoffrey Alan Watson, Killian Nugent, Marvin Chang Jui Lim, Emily Harrold, Connor Gerard O'Leary, Deirdre Kelly, Catherine Margaret Kelly, John McCaffrey
Journal: Journal of Clinical Oncology (2016)

e14535 Background: The immune checkpoint inhibitors have the reported class effects of inducing hypo- or hyperthyroidism in a small but significant number of patients. However, the reported rates of these vary by study. Anecdotally, we have seen a correlation between thyroid dysfunction and adverse side effect profile. We aimed to determine the rates of immune checkpoint inhibitor-induced thyroid dysfunction in our centre and assess the impact of this on side effect frequency. Methods: All patients who received one or more of the immune checkpoint inhibitors over a 5-year period, between January 1st 2010 and December 31st 2015 were analysed and their charts reviewed retrospectively. Patients on active unpublished clinical trials were excluded due to data rights issues. Measures recorded included patient demographics, treatment type and cycles, TSH & free T4 , and all side effects recorded during the treatment period, classified by CTC AE v4.0. Thyroid dysfunction was defined as TSH outside the laboratory reference range. Results were analysed using SPSS v22.0. Results: 43 patients received ipilimumab, nivolumab or pembrolizumab. 20 patients met the inclusion criteria and received a total of 27 treatments comprising 155 treatment cycles (Mean: 5.8, Range: 1-15). Thyroid dysfunction was seen in 25% (5/20) of patients. A positive correlation was seen between thyroid dysfunction and increasing number of side effects (R = 0.76), however this was not statistically significant (p = 0.36). Thyroid dysfunction onset immediately preceded discontinuation of treatment due to either progression or serious adverse events in 80% (4/5) of those patients. Conclusions: Immune checkpoint inhibitor use in our institute cause thyroid dysfunction at rates higher than those reported in the literature. Thyroid dysfunction is associated with a higher rate of all grade side effects in these patients. This study supports the hypothesis that immune checkpoint inhibitor-induced thyroid dysfunction impacts the side effect profile of patients on these therapies and may impact disease progression or treatment cessation due to serious adverse events. Further research in this area and a larger study is warranted.