tbuckley/cabot-search huggingface dataset:
Immunotherapy-induced endocrinopathies: A multi-center experience.
Authors: Karine Ronan, Elly Hanis Che Othman, Susan McKenna, Cian Anderson, David Sheehan, Margaret Griffin, Ray McDermott, Jennifer Westrup
Journal: Journal of Clinical Oncology (2019)

e14251 Background: Endocrinopathies account for approximately 10% of immune-related adverse events. 1 Methods: We carried out a retrospective review of 100 patients who received immunotherapy at two hospital sites between 2012 and 2019. Our aim was to ascertain the overall rate of immunotherapy-induced endocrinopathy and assess the impact of immunotherapy on pre-existing diabetes and thyroid dysfunction. Results: 28 out of 100 patients had pre-existing thyroid dysfunction, 36% of these experienced further thyroid dysfunction on immunotherapy. 41 patients had a diagnosis of renal cell cancer, and had treatment with a tyrosine kinase inhibitor prior to treatment with Nivolumab. Eighteen of these patients had a pre-existing thyroid dysfunction. Of these 18 patients, 44% experienced further thyroid dysfunction following immunotherapy. Of the 23 patients who received a tyrosine kinase inhibitor, who had no pre-existing thyroid dysfunction, 17% developed thyroid dysfunction on Nivolumab. 15% of patients without a pre-existing thyroid dysfunction developed a new thyroid dysfunction while on immunotherapy. Seven patients had diabetes mellitus prior to commencing immunotherapy, diabetes control did not disimprove during treatment. One case of diabetes was diagnosed on immunotherapy(1%). One case of adrenalitis(1%) and two cases of hypophysitis(2%) were diagnosed on immunotherapy. The adrenalitis occurred on Nivolumab (1.35%). Both cases of hypophysitis occurred on ipililumab(14%). The overall rate of new immunotherapy-induced endocrinopathy was 15%. Conclusions: The rates of endocrinopathy observed de novo are in line with published rates. 1,2,3,4 In this small study, an increased rate of thyroid dysfunction was observed in patients with pre-existing thyroid dysfunction. Prior treatment with a tyrosine kinase inhibitor did not cause an increase in the rate of thyroid dysfunction. Ipilimumab was observed to be a risk factor for development of hypophysitis. [Table: see text]
Cost and time savings of subcutaneous trastuzumab (SC-T) in a public health system in Mexico.
Authors: Cynthia Villarreal-Garza, Cristel De la O-Maldonado, Héctor Díaz-Pérez, Fernanda Mesa-Chavez, Marisol García-García, Servando Cardona-Huerta, Omar Peña-Curiel
Journal: Journal of Clinical Oncology (2019)

e18387 Background: The subcutaneous presentation of trastuzumab has been recently incorporated into the treatment regimen of HER2-positive breast cancer (BC). Its use has been associated with cost savings and reduced chair time, being especially suitable for public health systems. Aim: To estimate the cost savings of the use of SC-T compared to intravenous trastuzumab (IV-T) according to patient weight, and calculate the infusion time of SC-T in a tertiary healthcare facility at TecSalud from Feb 2018 - Jan 2019. Methods: From a total of 2068 oncological treatments, 756 corresponded to SC-T, either alone or concomitantly with chemotherapy (CT). For cost estimation, we considered $1,103 USD per SC-T vial, $1,162 USD per IV-T vial and $2.6 USD per mg of IV-T, as per governmental rates. We compared the actual treatment cost of 600 mg fixed SC-T dose with the hypothetical cost of administering IV-T at a dose of 6 mg/kg, considering its price per vial and per mg. The total time of SC-T infusion was reported. Results: Median patient weight for the 756 reported SC-T treatments was 72 kg (45 - 127 kg). Of these, 561 consisted of SC-T alone; and 56% had adjuvant, 34% neoadjuvant and 10% palliative intent. The estimated cost of the 756 doses of SC-T was $833,500 USD. Considering patients’ weight, 46% of the infusion treatments would have required 2 IV-T vials, with a total of 1105 vials and an absolute cost of $1,282,374 USD. Likewise, if cost per mg of IV-T is examined, we would have used 338,744 mg of IV-T, with an estimated cost of $894,284 USD. Approximate savings of SC-T use would reach $448,874 USD per vial payment and $60,784 USD per mg payment. The median time of SC-T only infusion was of 3 minutes (1 - 20 minutes); and no adverse effects were documented during its administration. Conclusions: The SC-T fixed dose (irrespectively of patients’ weight) results in significant practical and financial advantages as weight-adjusted dosing is not required. This is specially relevant in countries like Mexico, where &gt; 70% of BC patients are overweight/obese, requiring higher doses of IV-T and resulting in greater expenses. Thus, the use of SC-T not only offers greater convenience to patients, but also reduces overall healthcare costs compared to standard IV infusion.
Uterine corpus invasion as a risk factor in patients with early-stage cervical carcinoma receiving radical surgery.
Authors: Yifan Li, Ning Li, Lingying Wu
Journal: Journal of Clinical Oncology (2019)

e17012 Background: To explore whether pathologically verified uterine corpus invasion (UCI) is a risk factor for patients with early-stage (IB1-IIA2) cervical carcinoma receiving radical surgery. Methods: A mathed-case comparison of early-stage cervical carcinoma patients with pathologically verified UCI to patients without UCI on a 1:1 ratio was conducted. High risk factors (lymph node metastasis, paremetrial invasion, vaginal margin invasion) and intermediate risk factors (lymphovascular space invasion (LVSI) and deep stromal invasion) were completely matched between UCI and non-UCI groups. Kaplan-Meier and Log-rank test were applied for univariate analysis, and COX proportional hazard regression models were used for multivariate analysis. Results: 1320 consecutive patients with cervical carcinoma received surgery in our centerfrom Jan. 1 st 2009 to Dec 31 st 2014. 79 (5.98%) cases with UCI were identified. Median follow-up time was 43 months. There were 22 cases with recurrence. In UCI group, the recurrence rate was 20.3% (16/79), and in non-UCI group the recurrence rate was 7.6% (6/79). On univariate analysis, SCC, neoadjuvant chemotherapy (NACT), lymph node metastasis, parametrial invasion, LVSI, deep stromal invasion, vaginal invasion and UCI were significantly associated with disease free survival (DFS). After multivariate analysis, UCI ( p= 0.02, RR3.832, 95% CI1.235-11.893)and lymph node metastasis ( p= 0.042, RR 2.890, 95% CI1.038-8.045) were still independent risk factors for deceased DFS. Conclusions: Pathologically verified uterine corpus invasion might be an independent risk factor for decreased DFS in patients with early-stage cervical carcinoma receiving radical surgery.
Intravenous administration of ALKS 4230 as monotherapy and in combination with pembrolizumab in a phase I study of patients with advanced solid tumors.
Authors: Ulka N. Vaishampayan, Mayer N. Fishman, Daniel C. Cho, Christopher J. Hoimes, Vamsidhar Velcheti, David F. McDermott, William J. Slichenmyer, Emily Putiri, Heather Losey, Sean Rossi, Marc S. Ernstoff
Journal: Journal of Clinical Oncology (2019)

TPS2649 Background: ALKS 4230 is a fusion protein of circularly permuted IL-2 and IL-2 Receptor (IL-2R) α designed to selectively bind the intermediate-affinity (ia) IL-2R, comprised of IL-2Rβ and γ c , for activation of CD8 + T cells and NK cells, which drive antitumor immune responses. In contrast, unmodified IL-2 activates high-affinity (ha) IL-2R, driving the expansion of immunosuppressive CD4 + regulatory T cells (T regs ) at concentrations below those that activate iaIL-2R expressing cells. Binding of IL-2 to haIL-2R on endothelial cells may contribute to capillary leak syndrome seen with high-dose IL-2. Thus, selective activation of the iaIL-2R by ALKS 4230 has the potential to enhance tumor killing and improve tolerability. ALKS 4230 has previously been shown to improve antitumor activity relative to IL-2 in murine models. In this clinical study, ALKS 4230 will be assessed as monotherapy and in combination with anti-PD-1 therapy. Methods: ALKS 4230 is being studied in adults with advanced solid tumors in a phase I first-in-human trial designed primarily to assess the safety of ALKS 4230 alone and with pembrolizumab. The study will also determine a monotherapy recommended phase 2 dose (RP2D) and characterize pharmacokinetics, pharmacodynamics (PD), immunogenicity, and evidence of anti-tumor activity. It will be conducted in 3 parts: monotherapy dose escalation (Part A), monotherapy dose expansion at the RP2D (Part B), and combination therapy with pembrolizumab (Part C). ALKS 4230 is administered as a 30 minute IV infusion once daily for five days in each 14 or 21 day cycle. Part A is inpatient. Eligibility requires ECOG PS 0-1 and adequate bone marrow, liver and kidney function. Part B will enroll 21 patients each in renal cell carcinoma and melanoma cohorts. Part C will enroll up to 79 patients total into 3 cohorts based on tumor type and prior anti-PD-1 therapy; a 4th cohort will enroll patients from Part A or B who received at least 4 cycles of ALKS 4230 or experienced disease progression on monotherapy. The primary PD endpoint is change from baseline in CD8 + T, NK, and T reg cell counts. Inflammatory cytokine levels will also be measured. Parts A and C are currently enrolling. Clinical trial information: NCT02799095.
AtTEnd/ENGOT-en7: A multicenter phase III double-blind randomized controlled trial of atezolizumab in combination with paclitaxel and carboplatin in women with advanced/recurrent endometrial cancer.
Authors: Nicoletta Colombo, Maria Pilar Barretina-Ginesta, Philip James Beale, Kenichi Harano, Emma Hudson, Frederik Marmé, Christian Marth, Manuela Radaglio, Angeles Alvarez Secord, Roldano Fossati, Anna Roberto, Eliana Rulli, Francesca Tettamanzi, Elena Biagioli
Journal: Journal of Clinical Oncology (2019)

TPS5608 Background: Prognosis of advanced/recurrent endometrial cancer (EC) is poor with median survival of 12-15 months for patients with measurable disease. Treatment options are limited, with primary management being chemotherapy with carboplatin and paclitaxel. EC is known to be one of the tumor types with highest mutational load. Ultra- and hyper-mutated EC, which harbor POLE and mismatch repair gene defects respectively, have shown peri-tumoral T cell infiltration and high expression of PD-1 and PD-L1 proteins, suggesting that immune regulation may enhance specific T cell responses and result in improved anti-tumour immunity. Preliminary data in EC patients have shown tumour control activity of the PD-L1 targeting agent atezolizumab. Methods: 550 patients with newly diagnosed, advanced stage III/IV or recurrent EC will be accrued during a period of 24 months with a 1:2 randomization ratio into two arms: i. control group receiving standard chemotherapy plus placebo IV every 21 days up to 6/8 cycles followed by placebo until progression; ii. experimental group receiving standard chemotherapy plus 1200 mg atezolizumab IV every 21 days up to 6/8 cycles followed by atezolizumab until progression. Standard chemotherapy will consist of 175 mg/m 2 paclitaxel plus AUC5/6 carboplatin. Stratification factors are: histology, disease stage, microsatellite status, country of experimental site. The study is planned to demonstrate a survival increase and is equally powered for PFS. Secondary endpoints include ORR, duration of response, PFS2, quality of life, adverse events and compliance. The study is sponsored by MaNGO group and will involve sites from ENGOT and GCIG networks across Europe, Japan, Australia and New Zealand. Currently, the trial is open in Italy and in Switzerland where a total of 6 patients have been enrolled. Clinical trial information: NCT03603184.
Preliminary effects on the innate immune system with the combination of cetuximab and durvalumab in metastatic/ relapsed head and neck squamous cell carcinoma in a phase II trial.
Authors: Shuchi Gulati, Rachel Vachon, Shireen Desai, Aubrey Steele, Sarah Palackdharry, Vinita Takiar, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2019)

e14273 Background: Cetuximab is a recombinant chimeric monoclonal IgG1 antibody which binds specifically to the epidermal growth factor receptor (EGFR) and stimulates an innate immune response by promoting natural killer (NK) cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab is approved as a single agent in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC). PD-1 check-point inhibitors which release the inhibition of the adaptive immune response, are also approved as single agents in this setting. However the response rates with these drugs, when used individually range from 10-20%. We hypothesized that adding a PD-L1 inhibitor, durvalumab to cetuximab would cause anti-tumor synergy by activating the innate as well as adaptive immune systems without compromising safety in this phase-2 trial in R/M HNSCC patients who have progressed on platinum based therapy. Methods: Blood samples were collected from the first six enrolled patients prior to starting treatment and 4 weeks after the first combined dose of cetuximab and durvalumab. PBMCs were isolated, stained with a live/dead stain as well as CD3, CD4, CD8, CD56, CD16 and NK2GD (natural killer group 2 member D activation receptor) antibodies and analyzed by flow cytometry. Cytokine levels in plasma were measured using standardized ELISA assay kits. Results: Compared to pre-treatment levels, post-treatment samples showed an increase in activated cytokine producing NK cells (CD56 bright /CD16-) in all but one patient. Activated cytotoxic NK cell subpopulations (CD56 dim /CD16+) showed variable results post-treatment. CD8+ T cells were similar pre and post-treatment in 5 patients. TGF-b levels increased in 5 patients and decreased in 1 patient post-treatment. Interestingly, the patient with decreased TGF-b levels post-treatment had an almost doubling of CD8+ T-cells and an increase in activated cytokine producing NK cells (CD56 bright /CD16-). Conclusions: The clinical trial is ongoing and therefore, comparison to clinical response has not yet been analyzed. However, these findings support the combination of cetuximab and durvalumab in R/M HNSCC given the activation of an NK-cell mediated innate immune response in these patient samples. Clinical trial information: NCT03691714.
Association of secondary somatic mutations in <i>BRCA1/2</i> with clinical resistance to PARP inhibitors and chemotherapy.
Authors: Lingjun Zhu, Yan Zhang, Pingping Dai, Ping Zhou, Hui Li, Chunwei Xu, Wen xian Wang, Chi Zhang, Yan-Fang Guan, Xuefeng Xia, Ling Yang, Xin Yi
Journal: Journal of Clinical Oncology (2019)

1087 Background: Somatic reversion mutations in either BRCA1/2 has been reported to lead to the resistance of platinum-based chemotherapy or PARPi. In this study we try to analyze the secondary somatic mutations in BRCA1/2 in patients with germline mutations. Methods: Using gene-panel target-captore next generation sequencing, we analyzed the secondary somatic mutations from 86 patients with BRCA1/2 germline mutations. Results: Eighty-six cases with BRCA1/2 gremline mutations were identified. Secondary somatic mutations restoring BRCA1/2 were identified in 7 patients, including 2 breast cancer, 3 ovarian cancer, 1 prostate cancer and 1cholangiocarcinoma patient. For these seven patients, five had been treated with platinum-based chemotherapy without PARPi and the other two (patient 1 and 2) with PARPi (olaparib). Patient 1 and 2 both received targeting therapy of PARP inhibitor olaparib after the germline BRCA1/2 mutation was detected. About six months later, plasma ctDNA was sequenced. Result showed that the germline mutations remained and additional larger deletions was detected. These secondary somatic mutations are not predicted to significantly affect the BRCA1/2 protein, and are likely to cause resistance to platinum-based chemotherapy or PARPi therapy by restoring BRCA1/2 ORF and DNA repair function. Conclusions: Secondary somatic mutations that restore BRCA1/2 in carcinomas with germline BRCA1/2 mutations predict resistance to platinum-based chemotherapy and PARP inhibitors, some strategies to reverse this type of drug resistance need further investigation. [Table: see text]
Comprehensive geriatric assessment prior to autologous stem cell transplant as a predictor of patient outcomes: A retrospective review.
Authors: Kelsey Sokol, Ruben Rhoades, Benjamin E. Leiby, Adam Binder, Andrew E. Chapman, Pierluigi Porcu, Neal Flomenberg, Dolores Grosso, Neil David Palmisiano
Journal: Journal of Clinical Oncology (2019)

e23023 Background: While autologous stem cell transplant (ASCT) has been shown to be safe and effective in the geriatric population, age alone is not a sufficient predictor of outcomes. Minimal data exists regarding the use of a comprehensive geriatric assessment (CGA) tool prior to ASCT as a predictor of patient outcomes. This study aims to assess our institution’s pre-ASCT CGA on its ability to predict transplant-related outcomes in the elderly. Methods: We retrospectively analyzed all patients age 65 years of age and older (n = 68) who received ASCT at Thomas Jefferson University Hospital between 2012 and 2018 for multiple myeloma (MM) (n = 52), AL amyloidosis (n = 1), combined MM/amyloidosis (n = 2), B-NHL (n = 11), T cell lymphoma (n = 2), and Hodgkin lymphoma (n = 1). The CGA consists of 13 components, culminating in an overall frailty status. Kaplan-Meier survival estimates were used to assess overall survival (OS) and progression free survival (PFS), and multivariable logistic regression and Cox proportional hazard regression were used to determine associations between CGA variables and relevant post-ASCT outcomes. Results: Among the 68 patients (43 males, 25 females) who received ASCT, the median age was 68 years (range 65-78). Fifty-one patients (75%) underwent pre-transplant CGA. Among the entire cohort, 2-year OS and PFS were 95.4% and 79.6%, respectively. Median OS was not reached, and median PFS was 48.5 months. There was no difference in OS between patients who underwent CGA and those who did not (P = 0.937). Multivariate analysis revealed that none of the variables in the CGA were predictive of patient outcomes, such as OS, length of stay on ASCT admission, 30-day readmissions, and falls. Conclusions: This single-institution data suggests that ASCT is safe and highly effective in geriatric patients. Undergoing a CGA was not associated with improved outcomes, and none of the CGA components including frailty status were predictive of outcomes in this preliminary data set. Our data suggest that further refinement of the CGA may improve its predictive ability. Future studies examining additional outcomes, including patient-reported quality-of-life outcomes, are warranted.
Remembering the forgotten child: the role of immune checkpoint inhibition in patients with human immunod eficiency virus and cancer
Authors: Jacob J. Adashek, Pedro Nazareth Aguiar Junior, Natalie Galanina, Razelle Kurzrock
Journal: Journal for ImmunoTherapy of Cancer (2019)

Patients with human immunodeficiency virus (HIV) infection have a high risk of developing virally-mediated cancers. These tumors have several features that could make them vulnerable to immune checkpoint inhibitors (ICIs) including, but not limited to, increased expression of the CTLA-4 and PD-1 checkpoints on their CD4+ T cells. Even so, HIV-positive patients are generally excluded from immunotherapy cancer clinical trials due to safety concerns. Hence, only case series have been published regarding HIV-positive patients with cancer who received ICIs, but these reports of individuals with a variety of malignancies demonstrate that ICIs have significant activity, exceeding a 65% objective response rate in Kaposi sarcoma. Furthermore, high-grade immune toxicities occurred in fewer than 10% of treated patients. The existing data suggest that the underlying biologic mechanisms that mediate development of cancer in HIV-infected patients should render them susceptible to ICI treatment. Preliminary, albeit limited, clinical experience indicates that checkpoint blockade is both safe and efficacious in this setting. Additional clinical trials that include HIV-positive patients with cancer are urgently needed.
A phase I clinical trial of fluorouracil (5-FU) + devimistat (CPI-613) combination in previously treated patients (pts) with metastatic colorectal cancer (MCR).
Authors: Caio Max Sao Pedro Rocha Lima, Angela Tatiana Alistar, Rodwige J. Desnoyers, Steven Sorscher, George Hosni Yacoub, Emily Van Meter Dressler, Timothy S. Pardee, Stefan C. Grant, Sanjeev Luther, Destini Butler, Olivia Ogburn, Kristin Strickland, Boris Pasche
Journal: Journal of Clinical Oncology (2019)

e15054 Background: MCR that failed standard lines of therapy have a poor outcome. Inhibition of glutamine metabolism potentially can synergize with chemotherapy and reverse resistance. Devimistat is a novel anti-mitochondrial agent that alters energy metabolism and redox processes, leading to apoptosis, necrosis, and autophagy. Methods: Phase Ib dose escalation (3+3 design) to determine the MTD of devimistat, when used in combination with fixed doses of bolus and infusional 5-FU, in non-resectable MCR, ECOG PS 0-3, and good organ function who have failed, or could not tolerate, prior standard therapies. A cycle was 2 weeks. Escalating doses of devimistat were given IV over 2 hrs via central line on days 1-4. On Day 2 when both devimistat and bolus 5-FU were given, devimistat was given first, followed by 5-FU bolus (400 mg/m 2 ) followed by infusional 5-FU over 46 hrs (2,400 mg/m 2 ) on Days 2-4. Plasma samples to measure devimistat and metabolites were collected before and after the first and last dose of devimistat on cycle 1. Results: 19 pts enrolled from 1/20/2015 to 1/16/2019. One was never treated with devimistat and was excluded from analyses. Median age was 63 (range 32-83). 10 males and 8 females. Median devimistat cycles were 4 (range 1-8). Dose levels of devimistat: 1 pt treated at 2,000 mg/m 2 , 1 pt treated at 2,250 mg/m 2 , 7 pts treated at 2,500 mg/m 2 , then dose was de-escalated for an additional 9 pts treated at 2,250 mg/m 2 . Two of 7 pts had a DLT at the devimistat 2,500 mg/m 2 dose level; a grade 3 and a grade 4 creatinine level. The dose of devimistat was de-escalated to 2,250 mg/m 2 with a total of 10 pts being treated without DLTs observed (2 still on treatment). Other G1-2 non-hematologic and G1-3 hematologic toxicities were observed but related to 5FU except for two episodes of G1 intravascular hemolysis. No radiologic responses were observed. Four pts had SD and two pts at 2,250 mg/m 2 of devimistat continue on therapy. Median PFS and OS are currently 2.73 and 5.75 months respectively. Conclusions: Devimistat and 5FU combination demonstrated a tolerable safety profile in heavily pretreated MCR pts. Durable SDs observed at the MTD suggest antitumor activity at the 2,250 mg/m 2 devimistat dose level. Clinical trial information: NCT02232152.