bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study to evaluate safety and efficacy of neoadjuvant pembrolizumab and radiotherapy in localized MSS rectal cancer.
Authors: Kossler Thibaud , Nicolas Buchs , Dutoit Valérie , Puppa Giacomo , Tsantoulis Petros , Frossard Jean-Louis , Bichard Philippe , Montet Xavier , McKee Thomas , Di Marco Mariagrazia , Dietrich Pierre-Yves , Roth Arnaud , Zilli Thomas , Ris Frédéric
Published: February 2020

TPS272

Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitors use. This prospective phase II trial will test that hypothesis in addition to confirming safety of this approach using a “window-of-opportunity” study design with the anti-PD-1 agent Pembrolizumab. Methods: This monocentric phase II trial, will enroll patients (pts) with rectal cancer who are undergoing neoadjuvant short course RT (scRT) (25 Gy in 5 fractions). according to the standard of care. Eligible includes pts with MSS stage II-III rectal cancer with adequate organ function and availability of pre-treatment tumor, who are undergoing scRT with intention to proceed to surgical resection. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes 4 doses of Pembrolizumab (200mg IV, once every 3 wks), the first dose being given before the first scRT fraction. Surgery will be performed within 12-16 weeks of the final scRT dose. Primary endpoint is tumor regression grade (TRG) using the Mandard regression grade score targeting a 30% pathological complete response (pCR) compared to 10% in historical controls. Secondary endpoints include OS, DFS, toxicity, local and distant relapse-free survival, negative surgical margins, QoL, quality of surgery and exploratory assessments of tumor infiltrating lymphocytes, profiling of circulating immune cell populations, and molecular predictors of response. A safety stopping rule is planned based on Wald’s sequential probability ratio test for the occurrence of the safety outcome. Enrollment target is 25 pts. Support: MSD. Clinical trial information: NCT04109755 .
Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line therapy in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Xu Rui-hua , Arkenau Hendrik-Tobias , Bang Yung-Jue , Denlinger Crystal S. , Kato Ken , Tabernero Josep , Wang Jin , Li Jiang , Castro Henry , Moehler Markus H.
Published: February 2020

TPS458

Background: First-line standard of care in patients with locally advanced or metastatic G/GEJ adenocarcinoma is fluoropyrimidine- and platinum (plat)-based combination chemotherapy. Despite improved chemotherapy regimens, outcomes remain poor and survival is low. Tislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from early phase studies suggested tislelizumab, as a single agent and combined with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced solid tumors, including G/GEJ cancer. Methods: This randomized, placebo-controlled phase 3 study (NCT03777657) is designed to evaluate plat/fluoropyrimidine + tislelizumab vs plat/fluoropyrimidine + placebo as first-line therapy for patients with locally advanced or metastatic G/GEJ adenocarcinoma. Adult patients (n≈720) from ~160 centers will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo in combination with chemotherapy. Oxaliplatin (130 mg/m² IV Q3W) + capecitabine (1000 mg/m2 orally BID for 2 weeks) or cisplatin (80 mg/m² IV Q3W) + 5-fluorouracil (800 mg/m2/day IV on Days 1-5 Q3W) will be used as backbone chemotherapy on an individual basis. Chemotherapy will be administered for up to 6 cycles; capecitabine maintenance therapy is optional for patients who received capecitabine and oxaliplatin. Progression-free and overall survival are primary endpoints of the study. Secondary endpoints will include overall response rate, quality-of-life outcomes, and the safety/tolerability profile of combination therapy. Exploratory endpoints include disease control rate, time to response, and an analysis of potential predictive biomarkers including PD-L1 expression; the VENTANA PD-L1 (SP263) assay will be used for PD-L1 expression analysis. This study is actively enrolling. Clinical trial information: NCT03777657.
A phase Ib study of alofanib, an allosteric FGFR2 inhibitor, in patients with advanced or metastatic gastric cancer.
Authors: Statsenko Galina , Fedyanin Mikhail , Moiseyenko Vladimir , Vladimirova Liubov Yu , Tsimafeyeu Ilya , Tjulandin Sergei
Published: February 2020

TPS466

Background: Fibroblast growth factor receptor 2 (FGFR2) is amplified or overexpressed in 3% to 61% of patients with gastric cancer and associated with a poor prognosis. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a novel selective allosteric inhibitor of FGFR2. Alofanib could bind to the non-active site of FGFR2 extracellular domain and had an inhibitory effect on FGF2-induced phosphorylation of FRS2α. On preclinical models no severe organ and function test changes were observed. Based on these results, alofanib has advanced into clinical evaluation. Methods: RPT835GC1B is a Phase 1b study, being conducted in at least four sites in Russia, evaluating the safety and preliminary efficacy of alofanib in patients with advanced and metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. This trial consists of two parts. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. The dose-expansion phase accrues additional 20 patients, where comprehensive information to be collected. Secondary endpoints include pharmacokinetic parameters, rate of adverse events, progression-free survival, overall survival, and objective response rate. All patients will receive alofanib until disease progression or unacceptable toxicity. FGFR2 amplification, fusion, and overexpression will be assessed as well. Clinical trial information: NCT04071184.
SOlar: A translational phase II study of single-agent olaparib in the treatment of advanced esophagogastric cancer.
Authors: Cartwright Elizabeth , Fong Caroline Yean Kit , Hubank Michael , Saffery Claire , Kalaitzaki Eleftheria , Young Kate , Coyne Tracy , Musallam Annette , Fotiadis Nicos , Wotherspoon Andrew , Begum Ruwaida , Zerizer Imene , Rao Sheela , Watkins David J. , Gerlinger Marco , Chong Irene Yu-Shing , Lord Christopher J. , Chau Ian , Cunningham David , Starling Naureen
Published: February 2020

TPS471

Background: Oesophagogastric (OG) cancers represent a significant health burden and leading cause of cancer related death. Prognosis in advanced disease is poor and novel therapies are needed to improve outcomes. Molecular features of advanced OG cancer suggest that assessment of DDR (DNA damage repair) targeted agents is warranted. Specifically, ATM and ARID1A defects and mutational scars indicative of homologous recombination defects are present in a subset of OG cancers and are associated with polyadenosine 5’diphosphoribose polymerase inhibitor (PARPi) sensitivity. Methods: SOlar is a multi-centre, open-label, single arm, phase II study of olaparib, a PARPi, in patients with advanced oesophageal, gastro-oesophageal junction and gastric adenocarcinoma. The trial will use a single-arm Simon two-stage design to evaluate the anti-tumour activity of olaparib in advanced OG cancers. The primary endpoint is disease control rate (DCR) at 8 weeks by RECIST v1.1. To rule out a DCR of ≤15% while aiming for DCR ≥30% (alpha = 0.09, power = 89%), 54 patients must be recruited it total. An interim analysis will take place when 27 patients have been accrued, dosed and followed until the 8-week disease evaluation. If 4 or fewer patients have disease control (DC) the study will be terminated. If 5 or more patients have DC, an additional 27 patients will be enrolled to a total of 54 patients. If ≥12/54 have DC in the final analysis then it will be concluded that the treatment has shown anti-tumour activity compatible with 30% and an investigation of potential biomarkers of response will be carried out. Secondary endpoints are ORR, DoR, OS, PFS, time to radiological progression and safety. This highly translational study incorporating serial tumour biopsies will investigate candidate predictive biomarkers of PARPi sensitivity with the aim of identifying responder/non-responder subpopulations. Further exploratory objectives will investigate the predictive role of early FDG-PET/CT in assessing tumour response and the creation of an organoid biobank. The trial opened to recruitment in July 2019 and will recruit up to 54 patients over 3 years. Clinical trial information: NCT03829345.
A phase II study of enterade in neuroendocrine tumor (NET) patients with quality-of-life limiting bowel movement frequency.
Authors: Das Satya , Koyama Tatsuki , Luque Laura , Cheuvront Samuel , Berlin Jordan
Published: February 2020

TPS634

Background: BM frequency in NET pts is a major cause of morbidity. Though typically associated with serotonin excess in pts with carcinoid syndrome (CS), it can also occur in pts without CS due to etiologies such as short bowel syndrome, bile acid malabsorption, steatorrhea from somatostatin analogs (SSAs) and complications from chemotherapy/immunotherapy/biologics. Enterade is an oral rehydration solution, comprised of 5 amino acids, which has demonstrated pre-clinical and clinical potential to improve small intestinal resorption, thereby offering a potential treatment for limiting BM frequency in NET pts. Methods: We are conducting a phase II parallel cohort study in CS and non-CS NET pts (NCT 4073017). To be eligible, pts must be experiencing an average of ≥ 4 daily BM while on standard-of-care (SOC) therapies (SSAs, anti-diarrheals). Pts will be categorized into CS or non-CS cohorts based upon biochemical evaluation which includes plasma 5-HIAA/24-hour urine 5-HIAA, VIP or gastrin levels. Eligible pts will undergo observation during weeks 1-4 (baseline period). During weeks 5-8, pts will consume Enterade twice per day (Enterade period) while during weeks 9-12, pts will stop Enterade and resume observation. Daily stool diaries for each pt will be assessed to compute differences in mean bowel movement number between baseline and Enterade periods. Endpoints: The primary endpoint of the study is reduction in BM frequency in individual pts between baseline and Enterade periods. Based on parameters utilized in a prior study, we will assume that the mean daily reduction in bowel movements from baseline is equal to 1.5 (standard deviation of change = 1.5) representing a large effect size = 1.0. A sample of 12 pts in each cohort will provide nearly 90% power to detect this effect size based on a one-sample t-test (α = .05). An additional 3 pts will be added to each cohort to account for potential dropouts. Key secondary study endpoints include differences in pt-reported QOL outcomes (FACIT-D), pt weight, intravenous fluid requirement and utilization of SOC anti-diarrheals between baseline and Enterade periods. Accrual for the study will be ensuing shortly. Clinical trial information: NCT04073017.
A phase I study of nanoliposomal irinotecan and 5-fluorouracil/folinic acid in combination with interleukin-1-alpha antagonist for advanced pancreatic cancer patients with cachexia (OnFX).
Authors: Atkins Katelyn Mae , Gong Jun , Tighiouart Mourad , Klempner Samuel J. , Tuli Richard , Placencio-Hickok Veronica , Hendifar Andrew Eugene
Published: February 2020

TPS780

Background: Patients with pancreatic cancer have the highest rate of weight loss among all advanced cancers. Of which, the majority develop cachexia, characterized by progressive and involuntary loss of weight and skeletal muscle mass. In preclinical studies, interleukin-1-alpha (IL-1α) antagonism has been found to neutralize tumor angiogenesis and onco-inflammation. Early phase single-agent studies in cancer cachexia have demonstrated increased lean body mass and decreased fatigue, pain, and appetite loss. The present study aims to establish the safety of an IL-1α antagonist (Bermekimab) in combination with nanoliposomal irinotecan (Nal-Iri) and 5-fluorouracil (5FU)/folinic acid (FA) in patients with advanced pancreatic adenocarcinoma and cachexia who have failed gemcitabine-based chemotherapy. Methods: This is a single arm, single center, phase I study. The primary objective is to assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nal-Iri and 5FU/FA. MTD is defined as the dose such that the probability of dose-limiting toxicities at MTD is θ = 0.33. The first cohort of up to 3 patients will receive 7.5 mg/kg Bermekimab, 50 mg/m2 nanoliposomal irinotecan, 2000 mg/m2 5FU, and 400 mg/m2 FA and the subsequent doses will be determined by the escalation with overdose control (EWOC) algorithm. Treatment is administered on days 1 and 15 of each 28-day cycle. Key inclusion criteria include: advanced or locally advanced pancreatic adenocarcinoma that has progressed through or intolerant of gemcitabine-based chemotherapy, cachexia defined as > 5% unexplained weight loss 6 months prior to screening or as documented by physician, ECOG PS 0-2 or KPS ≥ 60%, and normal organ and marrow function. Secondary objectives are to assess weight, lean body mass, inflammatory cytokines, overall survival, progression free survival, patient quality of life, and functional status. Since January 2019, 23 patients have been screened and 21 enrolled. Clinical trial information: NCT03207724.
Atypical Stevens-Johnson syndrome-like reaction in the setting of immune checkpoint inhibition.
Authors: Molina Gabriel E. , Yu Zizi , Foreman Ruth K. , Reynolds Kerry Lynn , Chen Steven T.
Published: February 2020

102

Background: Stevens-Johnson syndrome (SJS) is a rare, life-threatening mucocutaneous toxicity that can occur in patients receiving immune checkpoint inhibitors (ICIs). ICI-induced SJS is scarcely reported in the literature and thus remains poorly understood, particularly regarding features that may distinguish it from classic SJS. Methods: To describe the timing, clinical manifestations, and treatment course of ICI-induced SJS, this multicenter, retrospective study identified seven patients with SJS in the setting of ICI use from January 2011 through May 2019. Results: All seven patients presented initially as benign, limited drug eruptions after a median of 4 ICI cycles (range, 1-7) and 63 days (range, 13-253 days) from ICI initiation. While none of the patients had prior drug allergies, all 7 were receiving new, recently initiated – i.e., within two months – medications at the time of rash onset. Cases demonstrated characteristic histologic findings of SJS, such as epidermal necrosis, and occasional unusual features, including interface dermatitis. All patients responded favorably and rapidly to systemic therapy, primarily intravenous corticosteroids, with near immediate symptomatic resolution and cessation of progressive skin blistering or detachment. Median length of stay was 11 days and no patients died from SJS. Conclusions: Our cohort defines an atypical SJS-like reaction secondary to ICI use, which is distinct from classic SJS in its delayed onset, mild initial presentation, and rare ocular involvement. The association with concomitant medication use suggests a potential mechanism whereby ICIs reduce patient immune tolerance to subsequent drug exposures. Reassuringly, this atypical SJS-like phenomenon exhibits a benign clinical course and favorable response to standard treatments.
Anxiety among immunotherapy patients: Preliminary findings from Immunotherapy & Me.
Authors: Jaisle Alyssa Marie , Power Nicholas James , House Linda S. , Jones Tameka N. , Schwartzberg Lee S.
Published: February 2020

104

Background: Immunotherapy is a relatively new method of cancer treatment which has seen little research into its psychosocial side effects. A clearer understanding of the source of anxiety for those undergoing immunotherapy is crucial as anxiety during cancer treatment can result in decreased treatment adherence, increased mortality rates, and other negative outcomes. This study surveyed 112 cancer patients undergoing immunotherapy to understand their top treatment-related concerns. Methods: RNs in twelve clinics across the U.S. recruited participants into Immunotherapy & Me, a study run by the Cancer Support Community (CSC). Participants were given access to a selection of CSC’s world-class support resources designed to help them and their loved ones manage their treatment. While accessing these resources, participants were encouraged to complete a monthly survey online either at their clinic or at home for seven months. This survey included CancerSupportSource – CSC’s scientifically-validated distress screening tool – as well as some additional questions specifically tailored to immunotherapy patients. Results: The most frequent source of concern related to diagnosis and treatment was “feeling too tired to do things you want to need or do” ( M = 1.21, SD = 1.01), closely followed by “exercising and being physically active” ( M = 1.05, SD = .93). Other concerns included the future ( M = 1.03, SD = .99) and financial ( M = 1.02, SD = 1.16). There were significant differences between age groups in concerns about disruption to life F(4, 97) = 3.52, p < .01; pain F(4,97) = p < .05; finances F(4,97) = 2.86, p < .05; and fatigue F(4, 96) = 2.47, p< .05. Older participants were significantly less concerned about disruption to life as compared to younger participants while younger participants were more concerned about pain than older participants. Conclusions: Cancer patients undergoing immunotherapy do not have a single, outstanding concern. Instead, these patients have several concerns, the level of which varies significantly between age groups and gender. This suggests the need for a subsequent study that explores a more refined list of categories and probes which specific aspects of diagnosis and treatment generate these concerns. Clinical trial information: NCT03347058.
A randomized phase II study with ilixadencel, a cell-based immune primer, plus sunitinib versus sunitinib alone in synchronous metastatic renal cell carcinoma.
Authors: Lindskog Magnus , Laurell Anna , Kjellman Anders , Melichar Bohuslav , Niezabitowski Jacek , Maroto Pablo , Zieliński Henryk , Villacampa Felipe , Bigot Pierre , Bajory Zoltan , Parikh Omi , Vazquez Alba David , Jellvert Asa , Flasko Tibor , Gallardo Diaz Enrique , Ribal Maria Jose , Purkalne Gunta , Suenaert Peter , Karlsson-Parra Alex , Ljungberg Borje
Published: February 2020

11

Background: Ilixadencel is a cell-based allogeneic off-the-shelf product aimed to prime anti-cancer immune response when injected intratumorally. The present randomized Phase II multicenter trial (MERECA; NCT02432846) evaluated intratumoral ilixadencel administration (2 doses 2 weeks apart) pre-nephrectomy followed by sunitinib post-nephrectomy compared with sunitinib monotherapy post-nephrectomy as first-line systemic therapy in patients with newly diagnosed synchronous metastatic renal cell carcinoma (mRCC). Methods: Patients were randomly assigned at two-to-one ratio to the combination (COMBO) or sunitinib (SUN) arm. Overall survival (OS) was assessed from enrollment while progression free survival (PFS) and tumor response was assessed per RECIST 1.1 (independent blinded central review) from start of sunitinib. Results: From April 2014 to January 2017, 88 patients (58 COMBO, 30 SUN) were randomized. In the COMBO arm, 2 patients did not receive ilixadencel, 10 did not receive sunitinib, and 1 did not have any follow up CT-scan. Five patients in the SUN arm never received sunitinib. Five patients (11%) in the COMBO arm had a complete response as best response versus one patient (4%) in the SUN arm. Confirmed ORR was 42.2 % (19/45) versus 24.0% (6/25). Median Duration of Response was 7.1 months versus 2.9 months. Median PFS was 11.8 months versus 11.0 months. Median OS has still not been reached in either group. As of July 2019, 57% and 43% were alive in the COMBO and SUN arms, respectively. Treatment with ilixadencel did not add any treatment-related Grade 3-4 Adverse Events. Conclusions: Compared to sunitinib monotherapy, combined treatment with ilixadencel followed by sunitinib demonstrated higher confirmed ORR, including several complete responses and longer duration of response, in patients with newly diagnosed synchronous mRCC. Clinical trial information: 02432846.
PD-L1 targeted engineered toxin body provides direct cytotoxicity and T-cell mediated tumor targeting.
Authors: Waltzman Roger J. , Brieschke Brigitte , LeMar Sara , Dekker Joseph , Cornelison Garrett , Robinson Garrett L. , Sarkar Asis , Zhao Jay , Iberg Aimee T. , Ramos Hilario J. , Willert Erin K.
Published: February 2020

12

Background: Engineered toxin bodies (ETBs) comprised of a proprietarily engineered Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains work through novel mechanisms of action and can force internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Our PD-L1 targeted ETB includes antigen seeding technology (AST), and additionally delivers a viral antigen for presentation in complex with MHC-I to resident viral-specific cytotoxic T lymphocytes (CTLs). The fusion protein provides a powerful, dual mechanism of action to specifically target and destroy PD-L1+ tumor and inhibitory immune cells. Methods: In vitro activity of ETBs was measured by cell viability and kinetic imaging of labeled target cells in an effector T-cell co-culture assay. Repeat dosing in non-human primates (NHPs) and murine models harboring human PD-L1+ patient derived tumors were used to evaluate tolerability and efficacy. Results: ETBs targeting PD-L1 have potent direct and specific activity across human tumor cell lines and human donor derived monocytes expressing PD-L1 in vitro. In co-culture assays, AST capable ETBs had a deeper response when target cells express both PD-L1 and the appropriate MHC-I allele in the presence of antigen specific CTLs. In vivo, PD-L1 targeted ETBs induced tumor growth delay, regression and survival benefit in multiple PD-L1+ NSCLC PDX models. These ETBs were also tolerated in repeat dosing NHP studies. Conclusions: The potent targeted activity of ETB mediated tumor cell destruction is demonstrated across tumor cell lines from multiple indications, on PD-L1+ immune cells ex-vivo, and by tumor growth and survival benefits in PDX models in vivo. The AST capable, PD-L1 targeted ETBs provide dual novel mechanisms to deplete PD-L1+ cells and control malignancies. Both the SLT-A mediated direct cell kill and activation of viral-specific CTLs circumvents a need for high mutational burden or anti-tumor immune-cell infiltrate at the tumor site, providing a potential treatment option for patients whose disease has progressed after checkpoint therapy.
Sustained, cell-intrinsic versus intermittent, cell-extrinsic checkpoint blockade in solid tumor CAR T-cell therapy.
Authors: Linot Camille , Saini Jasmeen , Adusumilli Prasad S.
Published: February 2020

16

Background: We and others have published that antigen-stress induced functional exhaustion of chimeric antigen receptor (CAR) T cells can be rescued by addition of anti-PD1 agents. To avoid the need for multiple administrations of anti-PD1 agent, we developed CAR T-cell intrinsic PD1 dominant negative receptor (PD1 DNR). Herein, we investigated the anti-tumor efficacy of cell-extrinsic versus intrinsic anti-PD1 strategies. Methods: Human T cells transduced with CD28 costimulated mesothelin-targeted CAR T cells (M28z) with or without anti-PD1 agent, and M28zPD1DNR CAR T cells were investigated against mesothelin-expressing cancer cells with inducible or constitutive PDL1 over expression. In vitro, cytotoxicity upon single and multiple antigen stimulation and proliferation, inhibitory receptor expression (PD1, TIM3 LAG3) were tested. In vivo, tumor burden regression kinetics and median survival were determined in an orthotopic model of pleural mesothelioma. Results: Following single antigen stimulation, both CAR T cells exhibited equivalent cytotoxicity. Following multiple antigen stimulations (antigen stress test), M28z PD1DNR CARs showed sustained and relatively higher cytotoxicity and proliferation compared to M28z CAR T cells, even when combined with anti-PD1 agent. PD1, TIM3 and LAG3 expression upregulation was noticed in both CAR T cells. CAR T cell therapy combined with extrinsic PD1 blockade or intrinsic PD1 DNR demonstrated enhanced and sustained tumor regression and prolonged survival (median survival 66 and 60 days) compared to CAR T cell therapy alone (27.5 days). In mouse model with constitutive PDL1 overexpressing cancer, similar trend is observed (74, 69 versus 28 days). Conclusions: A single dose of M28z CAR T cells with cell-intrinsic PD1DNR demonstrated equal anti-tumor efficacy compared to multiple doses of extrinsic anti-PD1 agent administration in models with inducible and constitutive high-PDL1 expressing cancer with no on-target, off-tumor toxicity with either strategy. This data provides the rationale for our ongoing phase II trial of combination therapy with M28z CAR T cells and anti-PD1 agent, and upcoming M28zPD1DNR CAR T cell trial in 2020.
The impact of pretreatment absolute lymphocyte count (pALC) and neutrophil-lymphocyte ratio (pNLR) on checkpoint inhibitors (CPIs) response rates in renal cell carcinoma (RCC) and bladder urothelial cancers (BC).
Authors: Bah Tonjeh Mary Stella , Sommerhalder David , Haddad Philip A.
Published: February 2020

31

Background: CPIs have been established as essential components of cancer immunotherapy across multiple cancer types with proven clinical benefit, improved outcomes, and less toxicity. Studies in lung and head and neck cancers found that low ALC, a marker of immune exhaustion, was associated with poor response to CPIs and worse progression-free survival. We explored the effect of pALC and pNLR on CPI response rates in patients with RCC and BC. Methods: We retrospectively reviewed every RCC and BC patient that received CPIs at Overton Brooks VA Medical Center and LSUHSC-S between 2015 and 2019. Patients’ pALC and pNLR were calculated. The patients were divided according to pALC into 2 groups: Group A with pALC > 1000 and Group B with pALC < 1000. Similarly, using NLR’s established upper normal limit of 3, 2 groups were created: Group 1 with pNLR < 3 and Group 2 with pNLR > 3. Our primary outcome of interest was defined as the presence or absence of CPI response. Patients who attained stable disease, partial response, and complete response were categorized as responders. Those who progressed on CPIs were labeled as non-responders. The significance of the association between pALC and pNLR groups and the occurrence of any response was analyzed statistically. Results: Twenty patients (13 RCC, 7 BC) were treated with CPIs and had documented responses. Twelve patients had pALC > 1000 (Group A) whereas 8 patients had pALC < 1000 (Group B). Both groups were comparable with respect to age, sex, race, and types of CPIs. Group A had a significantly higher response rate (75% vs 25%, p = 0.027). As to pNLR, 10 patients had pNLR < 3 (Group 1) and another 10 patients had pNLR > 3 (Group 2). Patients with pNLR > 3 had worse response rates to CPIs compared to those with pNLR < 3 (30% vs 80%, p = 0.024). Conclusions: This is the first report from a real-world clinical setting to show a detrimental association between pALC < 1000 and pNLR > 3 and CPI response rates in a retrospective cohort of consecutive non-selected kidney and bladder cancer patients. This association and its clinical utility require further confirmation in a prospective larger cohort.
Correlation of Epstein-Barr virus-specific cytotoxic T lymphocyte precursors (EBV-CTLp) after tabelecleucel with response and survival in rituximab relapsing or refractory EBV+ post-transplant lymphoproliferative disease (PTLD).
Authors: Aftab Blake T. , Shen Rhine R. , Guzman-Becerra Norma , Sun Yan , Forozan Farahnaz , Prockop Susan , Doubrovina Ekaterina , O'Reilly Richard J. , Li Xiaoming , Hiremath Minoti , Gamelin Laurence , Navarro Willis H.
Published: February 2020

38

Background: EBV+ PTLD is often a fatal disease. Tabelecleucel is an investigational off-the-shelf, allogeneic T-cell immunotherapy specific for EBV antigens. Functional in vivo expansion approximated by a limiting dilution analysis of EBV-CTLp has previously been correlated to clinical response. Methods: We conducted analyses of reported peak circulating EBV-CTLp levels following tabelecleucel administration in correlation to response and safety across two studies (N=42) in rituximab refractory or relapsing EBV+ PTLD following HCT or SOT. Results: Two cohorts were defined by the lowest EBV-CTLp quartile (n=11) and the combined upper 3 quartiles (n=31). Twenty-five of 31 subjects (80.6%) in upper quartiles exhibited a clinical response compared to 3 of 11 subjects (27.3%) in the lowest quartile. Eighteen of 20 complete responses and 7 of 8 partial responses demonstrated peak CTLp values in the upper quartiles of the population. Overall survival (OS) rate in subjects exhibiting CTLp values in the upper quartiles was 83.9% (95% CI: 65.5-92.9%) at 1 year and 66.1% (95% CI: 45.9-80.2%) at 2 years, compared to 18.2% (95% CI: 2.9-44.2%) in the lowest quartile over the same periods. OS is commensurate with a hazard ratio of 0.168 in favor of subjects with higher EBV-CTLp (95% CI: 0.067-0.425; Log-Rank Test p-value <0.001). Subjects demonstrating clinical responses experienced median CTLp values of 36.2 CTLp/ml (15.6-155 interquartile range), whereas non-responders exhibited significantly lower (p=0.001, based on Wilcoxon Rank Sum test) median CTLp of 0.07/ml (0.01-5.5 interquartile range). Tabelecleucel was well tolerated across both studies, with a safety profile in each group consistent with the underlying clinical condition of patients. Conclusions: These analyses illustrate the correlation of peak EBV-CTLp to clinical benefit in subjects receiving tabelecleucel. Significant correlation of EBV-CTLp with ORR and OS are consistent with potential use as a functional biomarker for the expansion of EBV-specific T-cells in the treatment of EBV+ PTLD in the rituximab refractory/relapsing setting. Clinical trial information: NCT01498484.
Impact of cachexia in advanced NSCLC patients treated with PD-1 inhibitor.
Authors: Jo Hitomi , Horinouchi Hidehito , Yagishita Shigehiro , Shinno Yuki , Okuma Yusuke , Yoshida Tatsuya , Goto Yasushi , Yamamoto Noboru , Ohe Yuichiro
Published: February 2020

44

Background: Cancer cachexia is known to a multifactorial catabolic syndrome and is observed 15-40% in general cancer population with worse prognosis. A recent study suggested a shorter survival period in non-small cell lung cancer (NSCLC) patients with a higher pembrolizumab clearance associated with cachexia. We here conducted analyses for the clinical impact of cachexia in advanced NSCLC treated with pembrolizumab. Methods: We evaluated consecutive advanced NSCLC patients who received pembrolizumab between March 2017 and December 2018 at the National Cancer Center Hospital. Cachexia was defined as a body weight loss >5% over the past 6 months or >2% in patients with a BMI <20 kg/m2 at the start of treatment. Information on patient age, sex, performance status, histology, driver mutation status, smoking status, disease stage, treatment line, and PD-L1 tumor proportion score were recorded. The overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were investigated according to the presence of cachexia. Univariate and multivariate analyses were performed. Results: A total of 157 NSCLC patients received pembrolizumab during the study period. Of these, 134 patients with information for body weight were included in the final analysis. Patients with cachexia accounted for 35% (47 out of 134) of this cohort. The ORR was 38% among the patients with cachexia and 35% among those without cachexia. The median PFS was significantly shorter for the patients with cachexia than for the patients without cachexia (median PFS, 4.2 months vs. 7.1 months; hazard ratio, 1.63; 95% confidence interval, 1.06 – 2.53; P = 0.02). The median OS was significantly shorter for the patients with cachexia (median OS, 8.6 months vs. NR; hazard ratio, 1.83; 95% confidence interval, 1.03-3.25; P = 0.04). The presence of cachexia was independently associated with a shorter PFS in a multivariate analysis. Conclusions: The presence of cachexia was significantly associated with a shorter PFS and OS in our study cohort. Screening for cachexia may help to identify patients who are more likely to achieve a durable response.
Prognosis of patients developing immune-related adverse events with immune checkpoint inhibitors in melanoma influenced by the ability to resume therapy.
Authors: Song Jung Min , Behera Tapas Ranjan , Demski Kathryn , Yurco Ann , Patil Pradnya Dinkar , Funchain Pauline
Published: February 2020

61

Background: Immune checkpoint inhibitors (ICPis) have improved survival in melanoma patients, however their use is associated with 5-60% patients experiencing severe immune related adverse events (irAEs). Severe irAEs may affect survival benefit imparted by ICPis. Objective: We aimed to analyze disease outcomes with resumption of immunotherapy as compared to non-resumption of immunotherapy in patients with severe irAEs (Grade 3/4 in CTCAE v5.0). Methods: Patients with melanoma being treated with ICPis who developed severe irAEs were discussed in an institutional irAE tumor board (TB). We analyzed all patients discussed in TB from September 2017 to September 2019 for cancer outcome of withholding versus resuming immunotherapy in the face of severe irAEs. Results: Out of 26 total patients with melanoma discussed in TB, 23 had severe irAE. Colitis was the most common irAE 9/23 (39.1%) followed by 2/23 (8.7%) of pneumonitis and hepatitis each. ICPi was resumed in 8 patients (resume group) (median age 53, range 42-67) and withheld in 15 patients (non-resume group) (median age 57, range 42-91). In the resume group all 8 patients (100%) are alive, of which 2/8 (25%) had disease progression (median follow up 106.5wk, range 35wk-131wk); whereas, in the non-resume group 9/15 (60%) progressed, of which 6/15 (40%) died (median follow up 91wk, range 3wk-197wk). Conclusions: Our data suggest that the ability to resume ICPi after an episode of severe irAE is associated with better prognosis in terms of disease progression and survival. Immunotherapy being the mainstay of the management in metastatic melanoma, inability to resume therapy is associated with worse prognosis. Timely management of irAEs should be prioritized in order to resume treatment.
Radiomics to predict response to pembrolizumab in patients with advanced rare cancers.
Authors: Colen Rivka R. , Ahmed Sara , Elshafeey Nabil , Karp Daniel D. , Pant Shubham , Subbiah Vivek , Piha-Paul Sarina Anne , Hong David S. , Yap Timothy A , Fu Siqing , Tsimberidou Apostolia Maria , Stephen Bettzy , Gong Jing , Rodon Ahnert Jordi , Naing Aung
Published: February 2020

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Background: To predict responders versus non-responders to Pembrolizumab, an anti PD-1 monoclonal antibody, in patients with advanced rare cancers. Methods: The study included 58 patients with advanced rare cancers (eg. squamous cell carcinoma of the skin, adrenocortical carcinoma, carcinoma of unknown primary, and paraganglioma) who were enrolled in a phase 2 trial of Pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients were categorized into: 21 responders (stable disease, partial response, and complete response) and 37 non-Responders (progressive disease). Target lesion(s) obtain from standard-of-care, pre-treatment contrast enhanced CT scans were segmented using 3D slicer v4.8.1. A total of 610 features (10 histogram-based and 600 second-order texture features) were calculated from each extracted volume of interest (VOI). Radiomic features were obtained using a feature selection approach based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model, using XGboost, for prediction of tumor response to Pembrolizumab. To evaluate the robustness of the estimates, Leave-One-Out Cross-Validation (LOOCV) was performed. Results: A total of 10 radiomic features were selected; the XGboost-based classification robustly differentiated between responders vs non-responders (area under the curve, sensitivity and specificity were 99%, 100%, and 95%, respectively [p<0.0001]). Conclusions: Our radiomic derived features were able to identify imaging differences that can evaluate patients’ response to Pembrolizumab treatment.
A phase Ib study of troriluzole (BHV-4157) in combination with nivolumab.
Authors: Silk Ann W. , Saraiya Biren , Groisberg Roman , Chan Nancy , Spencer Kristen Renee , Girda Eugenia , Shih Weichung , Manne Veeraswamy , Palmeri Marisa , Berman Robert , Coric Vlad , Vieth Joshua , Chen Suzie , Mehnert Janice M. , Malhotra Jyoti
Published: February 2020

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Background: The Metabotropic Glutamate Receptor 1 (GRM1) is overexpressed in many solid tumors. It activates MAPK and PI3K/AKT pathways and promotes an immune-suppressive tumor microenvironment. In an immunocompetent melanoma mouse model, GRM1 blockade using riluzole or its pro-drug troriluzole (BHV-4157) and PD-1 blockade inhibit tumor growth in an additive manner. We conducted a phase Ib trial of troriluzole and the PD-1 antibody nivolumab. Methods: Patients with advanced or refractory solid tumors were treated with increasing doses of troriluzole. Troriluzole monotherapy was given for a 14-day lead-in period and then patients received troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Results: We enrolled 14 patients with advanced solid tumors (melanoma=3, NSCLC=3, renal cell cancer=2, NSCLC=2, head and neck cancer=2). Eleven patients had prior therapy with anti-PD-(L)1. PK sampling demonstrated that the prodrug was cleaved efficiently without regard to food (Table). The most common TEAEs (all grades) occurring in >40% of patients were transaminitis, increased lipase and nausea. DLT occurred in 3 patients: 1) grade 3 anorexia, 2) grade 3 fatigue and, 3) atrial fibrillation. The MTD was determined to be troriluzole 140 mg QAM + 280 mg PO QHS. The response rate was 7 % (1/14); this occurred in a PD-L1 treated patient. The 6-month PFS rate was 21%. Correlative studies will be presented. Conclusions: The combination of troriluzole and nivolumab was safe and well-tolerated in this highly PD-1 refractory population. Clinical trial information: NCT03229278. [Table: see text]
Incidence and prediction of checkpoint inhibitor immune-related nephrotoxicity.
Authors: Sorah Jonathan D , Rose Tracy L. , Radhakrishna Roshni , Derebail Vimal , Milowsky Matthew I.
Published: February 2020

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Background: Immune checkpoint inhibitors (ICIs), through inhibition of self-tolerance, have the potential to cause immune-related adverse events that can affect any organ, including the kidneys. Our study aimed to better characterize the incidence of and predictive characteristics for immune-related nephrotoxicity. Methods: All patients at the University of North Carolina (UNC) who received ICIs between April 2014 and December 2018 for any malignancy were identified. Patients on dialysis or those who received concurrent platinum-based chemotherapy were excluded. Any patient who subsequently had a clinically significant acute kidney injury (AKI), defined as a doubling or more of baseline creatinine, was included for analysis. A retrospective chart review was performed to determine the cause of AKI. Any uncertain cases were reviewed by two nephrologists for expert consensus (R.R. and V.D.). Results: 1766 patients received an ICI during the study period. 123 (7%) patients had AKI within one year of the first ICI dose. 14 were due to immune-related nephrotoxicity (11% of patients with AKI and 0.8% of all ICI patients). Pre-existing autoimmune disease was more likely in patients with immune-related nephrotoxicity than in those with non-immune AKI (14% vs 3%, p = 0.04). Similarly, concurrent or prior other immune-related adverse events were more common in patients with immune-related AKI (57% vs 6%, p = 0.01). Patients with immune-related AKI were more likely to see a nephrologist (57% vs 23%, p = 0.007) and had a more profound increase in creatinine from baseline (median 2.6 vs 1.6, p = 0.02). Age, sex, urinalysis findings, and primary tumor type were not associated with increased risk. Conclusions: The true incidence of ICI related nephrotoxicity is difficult to ascertain due to the many confounders that contribute to AKI in this population. Severe immune-related nephrotoxicity is rare, but patients with preexisting autoimmune disease or history of immune-related adverse events are at increased risk.
Onset, duration, and clinical impact of immune-related adverse events in Hodgkin lymphoma.
Authors: Higgins Alexandra , Richter Michael D. , Patel Shruti , McCullough Kristen Beth , Habermann Thomas Matthew , Ansell Stephen M. , Thompson Carrie A. , Bennani Nabila Nora , Thanarajasingam Uma , Thanarajasingam Gita
Published: February 2020

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Background: The incidence of immune-related adverse events (irAEs) in patients (pts) with Hodgkin lymphoma (HL) treated with PD-1 antibodies (ICI) is reported at 28 - 36%. However, clinically relevant information on irAE onset, duration, or impact on ability to continue therapy in HL is lacking. Additionally, these incidence rates reflect CTCAE definition and grading, and not ASCO Clinical Practice Guidelines irAE-specific criteria (Brahmer et al, JCO 2018). The objectives of this study were to evaluate the rate and severity of irAEs in HL pts using ASCO criteria, to characterize irAE time profile and to assess their impact on continued therapy. Methods: HL pts who received a PD-1 inhibitor for the treatment of HL at Mayo Clinic Rochester between January 1, 2011 and March 1, 2018 were identified. We conducted a detailed, longitudinal retrospective chart review with definition and grading of irAEs in accordance with ASCO guidelines. Results: Fifty-one pts were identified (35% women, median age at ICI initiation 35 years [range: 19-87]). Median duration of follow up from ICI start was 30 months (range: 1-70). Thirty-one pts (61%) had any irAE. Most common irAEs were inflammatory/bullous dermatoses (23.5%/5.9% any grade/grade3-4; median onset/duration of 81/57 days[d]), followed by thyroiditis (22%/0%; 86/84 d), colitis (14%/8%; 82/106 d), pneumonitis (14%/10%; 241/182 d), and hepatitis (14%/4%; 71/35 d). Fifteen pts (29%) required treatment with steroids. Among the total cohort, ICI was held for an irAE 28 times (50% of 56 total irAEs). Median treatment cycles held was 2.5 and ICI was permanently discontinued due to irAE in 18%. The most common irAE leading to treatment discontinuation was pneumonitis, followed by neuritis (5.9%/3.9%; 179/374 d), colitis, and rash. Conclusions: The rate of irAEs of 61% in this cohort as defined by ASCO consensus criteria was higher than reported in trials. Most irAEs were characterized by delayed onset of several months and prolonged duration, particularly pneumonitis and neuritis. Treatment discontinuation due to irAEs was infrequent overall. Further studies are needed to determine whether the development or duration of irAEs is predictive of treatment outcomes in HL.
Revolutionary Positions
Authors: Chase Michelle , Cosse Isabella
Published: February 2020

This essay opens new perspectives on the Cuban Revolution by considering its global impact through the lens of gender and sexuality. This framework provides important new insights into the rise of the New Left and the anticommunist Right by centering ideas of gender, sexuality, and the family. Locating the Cuban Revolution alongside other contemporary struggles against racism and imperialism, the essay argues that gender and sexuality were crucial terrains of struggle that demonstrate the complexity of the Cold War in the Global South. Moreover, this point of view challenges long-standing perceptions of revolutionary Cuba as “isolated” by showing how the island precipitated and was embedded in transnational networks and flows of people and ideas, including solidarity campaigns, military missions, and forms of cultural diplomacy.
Angela Davis in Cuba as Symbol and Subject
Authors: Seidman Sarah J.
Published: February 2020

This essay examines how gender facilitated the encounters between Angela Y. Davis and the Cuban Revolution in the late 1960s and 1970s. Davis’s multifaceted identity as a black woman and communist shaped both her representation and reception in Cuba. Cubans supported Davis by participating in the global campaign for her freedom and welcoming her to the island several times, often with delegations from the Communist Party, beginning in 1969. The Cuban state propagated an iconography of Davis that cast her as a global signifier for both repression and international solidarity. Furthermore, at a transitional moment when Cuban leadership advocated institutionalization of the revolution, the Federation of Cuban Women provided highly visible opportunities for Davis to speak and be seen not afforded to men in the black liberation movement. Davis’s time in Cuba proved transformative and foundational in shaping her view of global liberation.
Tactical Negrificación and White Femininity
Authors: Bayard de Volo Lorraine
Published: February 2020

At the ideological heart of the Cuban Revolution is the commitment to liberation from oppressive systems at home and abroad. From early on, as it supported anti-imperialist struggles, revolutionary Cuba also officially condemned racism and sexism. However, the state’s attention to racism and sexism has fluctuated—it has been full-throated at times, silent at others. This essay examines gender and race in Cuba’s international liberatory efforts while also considering the human costs of armed internationalism. Focusing on Cuba’s Angola mission (1975–91), it finds that the state approached gender and racial liberation separately and tactically, as means to military, political, and diplomatic ends. Through negrificación (blackening) of national identity, Cuba highlighted race to internationally legitimize its Angola mission. Women were a minor and primarily domestic theme, yet military women’s femininity was racialized, as idealized feminine combatants were typically represented as white, light-skinned women despite a diverse racial composition.