bluuebunny/crossref_metadata_2025 huggingface dataset:
The outcome of checkpoint inhibitor therapy in patients with cancer and solid organ transplant: A systematic review of the literature.
Authors: Hassan Noha Abdelwahab , Abudayyeh Ala , Shah Mohsin , Johnson Daniel Hartman , Suarez-Almazor Maria E. , Diab Adi
Published: February 2018

41

Background: Solid organ transplant recipients have been excluded from Checkpoint inhibitors (CPI) clinical trials because of the concern of allo-immunity and possible organ rejection. Methods: We searched 5 databases through September 2017. Studies describing the use of CPI to treat cancer in solid organ transplant Patients (pts), and provided detailed description of each case were included. Results: Sixteen publications met inclusion criteria, reporting on 19 cases. Median age of pts was 59 (14-77) yrs and 74% were male. Cancer types included melanoma (n=11), cutaneous squamous cell carcinoma (ca) (n=3), non-small cell lung ca and hepatocellular ca (n=2 each), and duodenal ca (n=1). Median time to start CPI after organ transplant was 11 (1-25) yrs. Nivolumab (nivo) was used in 53%, ipilimumab (ipi) in 26%, and pembrolizumab (pem) in 21%. Most pts were maintained on low dose prednisone (≤ 10 mg), mTOR inhibitors, and other immunosuppressives prior to initiating CPI. Graft rejection occurred in 10 of 19 pts (7/12 kidney, 2/5 liver, and 1/2 heart transplants), 90% after receiving anti PD-1, and CPI was discontinued. Median time to rejection was 21 (5-60) days, and obtained biopsies were suggestive of a T-cell mediated rejection process. Only a cardiac transplant recipient with a bioposy proven cellular rejection after nivo, had improved ejection fraction after pulse steroids. Aside from rejection no other immune related adverse events (irAEs) reported. Nivo re-challenge was recommended for a kidney recipient 12 weeks after the rejection process, and the pt had partial tumor response but remained on hemodialysis. Of the 9 pts who had no rejection, 4 had irAEs (hepatitis, colitis, pneumonitis, and dermatitis), including 3 who required high-dose steroids with subsequent improvement, and the remaining 5 pts did not experience any irAEs. Clinical benefit rate was 57% of all pts. Two pts with liver transplants died within 1 month of nivo treatment secondary to acute liver rejection, and 2 others died because of progressive cancer. Conclusions: CPI seem to be associated with high rate of rejection. Multi-institutional collaborative studies are warranted to enhance our understanding of the pathogenesis and plan optiomal therapy that maintain graft tolerance without dampening antitumor clinical benefits.
Efficacy and safety of CetuGEX in recurrent/metastatic squamous cell carcinoma of the head and neck (RM-HNSCC): Results from the randomized phase II RESGEX study.
Authors: Keilholz Ulrich , Kawecki Andrzej , Dietz Andreas , Zurawski Bogdan , Schenker Michael , Kukielka-Budny Bozena , Schafhausen Philippe , Mihailov Anca C. , Ochenduszko Sebastian , Imarisio Ilaria , Mihutiu Simona , Oprean Cristina-Marinela , Folprecht Gunnar , Turcu Alina , Rottey Sylvie , Debourdeau Philippe , Lavernia Javier , Dietrich Bruno , Zurlo Alfredo , Fayette Jerome
Published: February 2018

59

Background: Standard treatment for RM-HNSCC is a combination of cisplatin (P), 5-FU (F), and the epidermal growth factor receptor (EGFR) blocking monoclonal antibody cetuximab. CetuGEX is a new monoclonal antibody sharing the identical EGFR-binding domain with cetuximab, but a modified Fc part by a proprietary glycosylation method to optimize antibody dependent cellular cytotoxicity (ADCC). Methods: Patients with RM-HNSCC without relevant comorbidities were randomized to receive up to 6 cycles of P 100 mg/m2, F 4 x 1000 mg/m2/24hrs and CetuGEX vs. cetuximab. Initial dose of cetuximab was 400mg/m2, followed by weekly 250 mg/m2. CetuGEX was given as 990 mg, followed by weekly 720 mg. After end of combination treatment, patients received single agent antibody maintenance until disease progression or intolerable toxicity. Stratification factors included FcγRIIIa status, primary tumor site, EGFR pretreatment vs. naïve, and recurrent vs. metastatic disease. Primary endpoint was progression-free survival (PFS) by immune related response criteria (irRC). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR) and overall survival (OS) as well as safety and QoL. Results: During Jan 2014 and Feb 2016, 240 patients were accrued in 34 European centers, of which 123 received cetuximab and 117 CetuGEX. The median follow-up was 15 month until May 2017. No difference was observed for the primary endpoint of PFS by irRC [median 27.7 (CetuGEX) and 26.4 (cetuximab) weeks; HR 1.003; 95%-CI 0.738 – 1.363; p = 0.98]. No advantage of CetuGEX over cetuximab was observed for all other secondary efficacy endpoints and subgroup analyses by stratification factors. Infusion related reactions (IRR) were higher for CetuGEX (38.8%) than for cetuximab (5.7%) (Pearson chi2= 37.08; p < 0.0001), but without sequelae. Conclusions: The RESGEX study is the first head-to-head comparison of an ADCC-optimized to a conventional EGFR-directed antibody. The study failed to show superior efficacy of CetuGEX over cetuximab. Both compounds appear to have the same efficacy and a similar safety profile. Glycosylation changes in the Fc part induced more IRRs. Clinical trial information: NCT02052960.
Development of a fully human t-cell engaging bispecific antibody for the treatment of multiple myeloma.
Authors: Buelow Ben , Choudhry Priya , Clarke Starlynn , Dang Kevin , Davison Laura , Force Aldred Shelley , Harris Katherine , Pham Duy , Pratap Payal , Rangaswamy Udaya , Schellenberger Ute , Shah Nina , Trinklein Nathan , Ugamraj Harshad , Wiita Arun , Van Schooten Wim
Published: February 2018

60

Background: T-cell engaging bispecific antibody (T-BsAb) therapies are highly efficacious and well suited for targets with low expression on tumor cells. Recently, T-BsAbs with high activation of CD3 have been shown to overstimulate T cells, leading to toxicity and decreased efficacy. Teneobio has developed a fully human BCMA-specific T-BsAb using a low-activating αCD3 that is highly effective in vitro and in vivo against MM but stimulates minimal cytokine release. Methods: UniRats were immunized with either CD3 or BCMA antigens and antigen-specific UniAbs were identified by Ab repertoire sequencing and high-throughput gene assembly, expression, and screening. Antigen-specific VH sequences with the desired target affinity were selected using recombinant proteins and cells. In vitro efficacy studies included T-cell activation by cytokine- and tumor cell kill by calcein-release assays. In vivo efficacy of the molecules was evaluated in NSG mice harboring myeloma cells and human PBMCs. Results: BCMA-specific UniAbs bound plasma cells with sub-nM affinity. Strong and weak T cell agonists were identified that bound human T cells with high and low affinities respectively. T-BsAbs with a strong and a weak αCD3 demonstrated T-cell activation and tumor-cell cytotoxicity in vitro; T-BsAbs with a weak αCD3 showed markedly reduced cytokine production even at doses that showed maximum tumor cell lysis. In vivo, BCMAxCD3 T-BsAbs reduced tumor load and increased survival when co-administered with human PBMCs as compared to controls. Conclusions: Our results suggest that T-BsAbs with low-activating αCD3 arms may have a favorable toxicity profile while maintaining efficacy in the treatment of MM.
CetuGEX and cetuximab in recurrent/metastatic squamous cell carcinoma of the head and neck (RM-HNSCC): PK/PD results from the phase II RESGEX study.
Authors: Baumeister Hans , Zurlo Alfredo , Fayette Jerome , Dietrich Bruno , Keilholz Ulrich
Published: February 2018

61

Background: Standard treatment for RM-HNSCC is a combination of cisplatin (P), 5-FU (F), and the EGFR blocking monoclonal antibody (mAb) cetuximab (C). The mAb CetuGEX (CG) shares with cetuximab the identical EGFR-binding domain, but harbors a defucosylated glycan at the Fc part to increase antibody dependent cellular cytotoxicity (ADCC) by improved binding at the Fcγ receptors IIIa (FcγRIIIa). Methods: 240 pts with RM-HNSCC were randomized in 34 European centers, of which 123 received C and 117 CG, in combination with P (100 mg/m2) and F (4 x 1000 mg/m2/24hrs) for the first 6 cycles. Initial dose of C was 400mg/m2, followed by weekly 250 mg/m2. CG was administered once 990 mg, followed by weekly infusions of 720 mg. After completion of combination treatment, pts received single agent mAb maintenance until disease progression or intolerable toxicity. The tumor tissues were analyzed for EGFR and p16 expression by IHC staining. Blood samples were withdrawn to analyze the FcγRIIIa phenotypes V/V, V/F and F/F and the FcγRIIa phenotypes R/R, H/R and R/R of each patient. The cellular immune status was analyzed in a subset of about 20 pts per arm before 1st and 5th infusion and 28 days after last infusion (Safety Visit) by flow cytometry. Serum CG concentrations were measured before and after the first ten infusions and for a subset of about 20 pts 5 h, 7 h, 24 h, 48 h, 72 h, and 168 h after the first and 10th infusion. The occurrence of anti-drug antibodies (ADA) was determined before 1st, 2nd, 4th and 10th infusion of CG and at the Safety Visit. Efficacy and safety parameters will be looked at in relation to the biomarkers. Results: While most analyses did not show any difference between CG and C, the subgroup of p16+ pts (N=32) is characterized by a significantly longer overall survival (HR 0.52; 95%-CI 0.29 – 0.86; p=0.009) than that of p16- pts, which remains significant under CG (17 pts; HR 0.43; 95%-CI 0.18 – 0.88; p=0.02) but not C treatment (15 pts), probably due to differences in pts immune status. Conclusion: The RESGEX study is the first head-to-head comparison of an ADCC-optimized to a conventional anti-EGFR mAb. The biomarker assessment may help to understand differences between the two mAbs. Clinical trial information: NCT02052960.
HIV-positive Kaposi sarcoma and immune checkpoint blockade.
Authors: Galanina Natalie , Goodman Aaron , Cohen Philip R , Kurzrock Razelle
Published: February 2018

63

Title: HIV-Positive Kaposi Sarcoma and Immune Checkpoint Blockade Background: Kaposi sarcoma (KS) is an incurable, virally mediated malignancy arising in HIV-positive patients. We report the first observations on the safety and efficacy of checkpoint blockade in these patients. Methods: We identified eight evaluable patients with HIV-related Kaposi sarcoma who received ≥1 dose of checkpoint blockade. Data on demographics, treatment efficacy, and the effects on immune function (HIV and HHV8 viral load, CD4 count) and toxicity were curated. Results: Median age was 45.5 years (range, 38-63); all men; median, one prior regimen; all were treated with nivolumab 3mg/kg IV days 1 and 14 of each 28-day cycle. PD-L1 expression was assessed retrospectively and was low in 3 out of 4 patients with available data. All patients were receiving anti-retroviral therapy. The majority (75%) had preserved CD4 count and undetectable HIV viral load (Table). The response rate (RR) was 62.5% (5 of 8 patients) with 1 complete remission and 4 partial remissions; the remaining 3 patients have stable disease. Median follow up to date is 3.5 months and no patients has discontinued therapy. No grade >2 toxicities were noted. Most common side effects included fatigue, gastrointestinal discomfort, pruritis, and onycholysis. There was an overall increase in CD4 counts. Conclusions: Preliminary observations suggest that checkpoint blockade with nivolumab has low toxicity and high anti-tumor activity in KS. Additionally, patients experienced improvement in CD4 count. [Table: see text]
Natural killer cell activity: A test for immune reactivity with clinical perspectives.
Authors: Nederby Line , Hansen Torben , Raunkilde Louise , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller
Published: February 2018

87

Background: Natural Killer (NK) cells are essential in the biological fight against cancer and the activity of these cells has been suggested as a biomarker for immunological reaction in cancer patients. An assay has been introduced to measure NK cell activity (NKA) in a simple and standardized manner. Following stimulation of NK cells in whole blood with a recombinant protein, it utilizes the concentration of interferon-gamma (IFNγ) in plasma as a surrogate marker for NKA. This study aimed to verify that the test was indeed measuring NKA and whether it could predict the response to cytostatic treatment in metastatic colorectal cancer (mCRC). Methods: Blood was collected in dedicated tubes (NK Vue Promoca) and placed at 37°C. After 24 hours the plasma was analyzed for IFNγ by ELISA (NK Vue ELISA). Blood from patients with mCRC (n = 22) were sampled at baseline and prior to each treatment cycle, and IFNγ levels were compared to response data from first evaluation. The protocol is ongoing hence the results are preliminary. In healthy controls (n = 8), IFNγ was measured intracellularly using flow cytometry at baseline and after 5-, 10-, 15-, 20-, 24-, and 28 hours of incubation. Results: When analyzing the distribution of cells among the IFNγ expressing subset, the proportion of NK cells was significantly different than that of monocytes, T-, and NKT cells at all time points of incubation (p < 0.0001), thus suggesting that the readout of the test was indicative of the NK cells´ ability to mount a response. Using the NKA test, plasma levels of IFNγ in healthy controls were all above 200pg/mL after 24 hours of incubation. The mCRC patients were divided into three NKA groups: 1) IFNγ dropped below 200pg/mL or remained below that level throughout treatment (n = 9), 2) IFNγ remained above 200pg/mL throughout treatment (n = 5), and 3) IFNγ changed from being below 200pg/mL to above that level during treatment (n = 8). The response rates were 11%, 40%, and 100%, respectively, and the difference was significant (p < 0.001). The positive and negative predictive values of increasing IFNγ were 100% and 79%. Conclusions: These data suggest that increasing NK cell activity during treatment has predictive potential in mCRC. The NKA test performs reliably in this setting. Clinical trial information: NCT02705300.
Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer.
Authors: Togashi Yosuke , Tada Yasuko , Kotani Daisuke , Kawazoe Akihito , Doi Toshihiko , Nishikawa Hiroyoshi , Shitara Kohei
Published: February 2018

98

Background: Ramucirumab (RAM), a monoclonal antibody against VEGFR2, was recently approved for the treatment of advanced gastric cancer (GC). However, little is known about the immunological effects in advanced GC patients. Methods: Patients with advanced GC who had been planned to receive chemotherapy containing RAM were prospectively enrolled for this study from January 2016 to September 2016. Paired samples were obtained from peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in primary tumors pre- and post-RAM therapy to investigate immune profiles. Results: A total of 59 PBMCs and TILs from 18 patients were collected. Higher frequencies of FOXP3highCD45RA-CD4+ T cells (effector regulatory T cells: eTregs) were detected in TILs compared with PBMCs (19.05±10.48% vs 1.89±1.0%, P < 0.0001), and the presence of high eTreg in TILs was not reflected in PBMCs. eTregs of TILs, but not of PBMC were significantly decreased after RAM-containing therapies (22.67±11.19% vs. 16.33±8.44%, P = 0.034). Expressions of immune checkpoint (IC) molecules (PD-1, CTLA-4, LAG-3, and ICOS) were much higher in TILs than those in PBMCs, and all these molecules exhibited higher expressions on eTregs than on CD8+ T cells. Among them, ICOS was specifically expressed by eTregs in TILs. PD-1+CD8+ T cells in TILs were significantly decreased after RAM-containing therapies (54.99±19.06% vs. 39.23±17.15%, P = 0.0005), but not in PBMC. Patients with partial responses had significantly higher frequency of eTreg in pre-treatment TIL than those with progression disease (32.56±12.11% vs. 14.83±3.18%, P = 0.036). Furthermore, patients with high eTreg frequency had significantly longer progression-free survival than those with low frequency (161 days vs. 76 days, P = 0.024). Conclusions: There was significant difference in immune profile between PBMC and TIL in GC patients. eTregs and PD-1 expression on CD8+T cells in TILs, not in PBMCs were decreased after RAM-containing therapies. This observation suggests the importance of TIL analyses and might be a rationale to use RAM as an immunomodulator in combination with IC inhibitors.
Phase I/II study of low-dose cyclophosphamide, tumor-associated peptide antigen-pulsed dendritic cell and low dose GM-CSF for solid and hematological tumors.
Authors: Mirandola Leonardo , Figueroa Jose A. , Nguyen Diane Duyen Thuy , Dahlbeck Scott , Chiriva-Internati Maurizio
Published: February 2018

TPS216

Background: Despite advances in understanding the biology of hematologic malignancies (HM) and solid malignancies (SM), and the availability of new treatment options, many patients with HM and SM remain incurable. Since the majority of cancer patients display a defective immune response to tumor antigens, the ex-vivo activation of dendritic cells (DC), through their exposure to tumor associated antigens, is an attractive and active area of investigation. We and others have explored the potential immunotherapeutic targets included our DC vaccine, i.e., SP17, Ropporin, AKAP4, PTTG1, SpanxB, NY-ESO-1, MAGE-1, HM1.24, Her2/Neu. Notably, SP17-pulsed DC have been reported to induce a safe and clinically significant response in patients with multiple myeloma and ovarian cancer. Methods: We hypothesize that treatment of patients with HM or metastatic SM using autologous DC will result in antigen-specific CD4+ T-cell and/or CD8+ CTL responses without significant toxicities. We also hypothesize that the responses generated against specific antigens may translate into clinical anti-tumor activity. Primary Objective: Phase I (6 subjects). To determine safety of intradermal/subcutaneous DC vaccine therapy, low-dose cyclophosphamide and GM-CSF, in patients with metastatic SM or HM who demonstrate a response, or whose disease remains stable, after conventional first-line systemic therapy, or who have failed conventional systemic therapy. Secondary Objective: Phase II (up to 17 subjects). To determine immune responses associated with intradermal/subcutaneous DC vaccine therapy, low-dose cyclophosphamide and GM-CSF, in patients with metastatic SM or HM who demonstrate a response, or whose disease remains stable, after conventional first-line systemic therapy, or who have failed conventional systemic therapy. The study population is currently drawn from patients at various clinical institutions following contractual agreements. Clinical trial information: NCT02709993; NCT02705703; NCT02224599; NCT02223312.
A phase II study of talimogene laherparepvec followed by talimogene laherparepvec + nivolumab in refractory T cell and NK cell lymphomas, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and other rare skin tumors (NCI #10057).
Authors: Silk Ann W. , LeBoeuf Nicole R. , Rabinowits Guilherme , Puzanov Igor , Burgess Melissa Amber , Devata Sumana , Moore Dirk , Goydos James Steven , Chen Helen X. , Kaufman Howard , Zloza Andrew , Mehnert Janice M.
Published: February 2018

TPS219

Background: Talimogene laherparepvec, a modified herpes virus agent, induces a response in 65% of injected melanoma tumors. The combination of talimogene laherparepvec with ipilimumab or pembrolizumab appears promising in clinical trials of advanced melanoma. Talimogene laherparepvec-based therapy may be effective in other cancers of the skin and lymph nodes that are anatomically accessible for intratumoral injection. Methods: This phase II study will evaluate intratumoral talimogene laherparepvec monotherapy in 4 parallel disease cohorts: 1) Refractory T cell and NK cell lymphomas including cutaneous T cell lymphoma, 2) Merkel cell carcinoma 3) Cutaneous squamous cell carcinoma and 4) Other advanced/refractory non-melanoma skin cancers. Lymphoma patients must be refractory to or intolerant of all standard life-prolonging therapies. Skin cancer patients must be advanced/unresectable or refractory to one or more treatments including surgery, radiation therapy, or medical therapy. Prior PD-1-directed therapy is allowed. If an objective response is not achieved by Week 12, the PD-1 blocking antibody nivolumab will be added. The primary endpoint is the response rate with talimogene laherparepvec and secondary endpoints include response rate with the combination and overall survival. Using a two-stage design, if 1 or more response is observed in the first 9 patients in each parallel cohort, 8 additional patients will be accrued for a total sample size of 36 to 68 patients across the 4 disease cohorts. Tumor biopsies of injected lesions are mandatory at baseline and Week 6, and optional at Week 16 and the time of progression. Optional biopsies of non-injected lesions (when applicable) at Week 6 and 16 will be analyzed to identify biomarkers of systemic immunity. Tumor tissue and/or blood will be assayed for PD-L1 expression, RNA profiling, immune cell profiling, HVEM, NECTIN 1/2, IDO, tryptophan and L-kynurenine, mutational load, TIL TCR clonality, and prior exposure to herpes simplex type 1 virus and Merkel cell polyomavirus. Clinical trial information: NCT02978625.
Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).
Authors: Maia Manuel C. , Agarwal Neeraj , McGregor Bradley Alexander , Vaishampayan Ulka N. , Choueiri Toni K. , Green Marjorie C. , Hessel Colin , Scheffold Christian , Schwab Gisela , Powles Thomas , Pal Sumanta K. ,   XL184-021 study group
Published: February 2018

TPS42

Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.
Combination of bemcentinib (BGB324): A first-in-class selective oral AXL inhibitor, with pembrolizumab in patients with triple negative breast cancer and adenocarcinoma of the lung.
Authors: Yule Murray , Davidsen Kjersti , Bloe Magnus , Hodneland Linn , Engelsen Agnete , Lie Maria , Bougnaud Sebastien , D'Mello Stacey , Aguilera Kristina , Ahmed Lavina , Rybika Agata , Milde Naeval Eline , Boniecka Anna , Thiery Jean Paul , Chouaib Salem , Brekken Rolf A. , Gausdal Gro , Lorens James
Published: February 2018

TPS43

Background: Activation of the receptor tyrosine kinase AXL has a profound suppressive effect on the innate immune system. AXL is overexpressed on multiple cell types in the tumour immune microenvironment including dendritic cells, NK cells and tumour-associated macrophages. AXL signalling in immune cells supports tumour immune escape by downregulating dendritic cell activity, modulating efferocytosis as well as favouring an immunosuppressive chemokine profile and M-MDSC expansion. AXL is prevalent in tumours resistant to anti-PD-1 therapy (Hugo, 2016). Axl expression in tumour cells confers resistance to effector T cell cytotoxicity. Bemcentinib (BGB324) is a first-in-class, highly selective and orally bioavailable small molecule AXL inhibitor in phase II clinical development. In pre-clinical models of pancreas, breast and lung cancer, inhibition of AXL signalling with bemcentinib reversed multiple tumour immune suppressive mechanisms as evidenced by increased infiltration of cytotoxic T lymphocytes, NK and NKT cells and decreased infiltration of M-MDSCs (Wnuk-Lipinska, 2017). Bemcentinib enhanced the effect of immune checkpoint blockade via PD-1 or CTLA-4 in lung and mammary adenocarcinoma mouse models and achieved sustained tumour immunity. Methods: BGBC007 (NCT03184558) and BGBC008 (NCT03184571) are open-label, phase II studies designed to assess the anti-tumour activity of bemcentinib in combination with pembrolizumab in patients with previously treated TNBC and adenocarcinoma of the lung respectively. All patients will be treated with bemcentinib in combination with pembrolizumab continuously for up to two years. The primary endpoint is objective response rate, secondary endpoints include duration of response, progression free survival according to RECIST 1.1, pharmacokinetics, safety and tolerability. Pretreatment tumour specimens are scheduled to assess AXL expression/signalling and PD-L1 expression; the levels of circulating immune-related cytokines and soluble AXL receptor will also be measured in longitudinal patient plasma samples. Both studies are open to recruitment. Clinical trial information: NCT03184558.
AIDS malignancy consortium (AMC) 095: A phase I study of ipilimumab (IPI) and nivolumab (NIVO) in advanced HIV-associated solid tumors (ST) with expansion cohorts in HIV-associated solid tumors and classical Hodgkin lymphoma (cHL).
Authors: Rajdev Lakshmi , Chiao Elizabeth , Lensing Shelly , Streicher Howard , Little Richard F. , Dittmer Dirk , Einstein Mark , Haigentz Missak , Sparano Joseph A. , Mitsuyasu Ronald T.
Published: February 2018

TPS44

Background: Immune checkpoint blockade (ICB) using agents that target the priming phase (i.e. CTLA-4) and effector phase (e.g. PD-1) of host immunity, used individually or in combination, has emerged as a therapeutic strategy for cancers. However, little is known about the safety, tolerability and efficacy of ICB in patients (pts) with HIV infection and cancer. Methods: AMC 095 (NCT02408861) is a multicenter, international phase I study of the PD-1 inhibitor, nivo alone or in combination with a CTLA-4 inhibitor, ipi, in 2 cohorts stratified by CD4 counts (Stratum 1: CD4 counts≥200/uL and Stratum 2: CD4 count 100-200/uL) with additional expansion cohorts at the recommended phase II dose in pts with ST and cHL. The primary study objective is to determine the safety and feasibility of nivo alone and the nivo+ipi combination. Secondary objectives are to evaluate the effects of single agent nivo, and ipi+ nivo, on HIV replication and immune function (HIV viral load in plasma using conventional assay, CD4+, and CD8+ cells), and to obtain preliminary information regarding response. The trial was initiated in 8/15, as of 9/30/17, the study is ongoing, and 14 pts have been enrolled. Updated information on the safety and responses will be presented. Clinical trial information: NCT02408861. Funded by the NCI Grant #UM1CA121947.[Table: see text]
Practice-based evidence for factors associated with urinary incontinence following prostate cancer care.
Authors: Li Kevin , Magnani Christopher J. , Bozkurt Selen , Seto Tina , Blayney Douglas W. , Brooks James D. , Hernandez-Boussard Tina
Published: February 2018

106

Background: Urinary incontinence (UI) is a common complication following treatment for localized prostate cancer. Past studies evaluating UI risk factors use surveys or chart abstraction, which may be costly and lack generalizability. Electronic health records (EHR) allow us to examine UI at a population level. We applied data mining methods to EHR data to: (1) evaluate rates of UI following prostate cancer treatment; and (2) evaluate potential risk factors for posttreatment UI. Methods: We conducted a retrospective analysis of patients undergoing prostatectomy or radiation therapy for localized prostate cancer between 2009-2016, and who received follow-up care at our medical center. Our cohort was constructed from the institutional EHR and the California Cancer Registry. The primary outcome was the presence of UI, measured in three-month intervals from the start of first-line treatment. The secondary outcome was UI 12-24 months following treatment (“late UI”). UI was assessed using natural language processing of EHR clinician notes. UI was also assessed with the EPIC-26 quality of life survey, which a subset of patients had prospectively completed. Results: Our cohort consisted of 2783 men, of whom 1907 (69%) underwent surgery and the remainder received radiation; of this cohort, 609 (22%) had data on late UI status. UI prevalence was higher among surgery than radiation patients across all posttreatment time points, and 278 of 434 (64%) surgery patients had late UI compared to 78 of 175 (45%) radiation patients (p < 0.001). Univariable analyses showed an association between pretreatment and late UI among surgery patients as measured in the EHR (OR 2.5, 95% CI 1.0-6.5, p = 0.05) and by EPIC-26 (OR 8.1, 95% CI 1.8-36.5, p = 0.01). Only surgery (compared to radiation) was a significant predictor of late UI (OR 5.8, 95% CI 1.1-32.3, p = 0.05) in multivariable regression with EHR data. Conclusions: Using EHR data, we found that treatment modality was a significant predictor of late UI among prostate cancer patients who underwent prostatectomy or radiation therapy. These results suggest the utility of EHRs in patient-centered outcomes research in prostate cancer care, and should be validated at other sites.
Performance of a clinically validated urine exosome gene expression test to predict high grade prostate cancer in men with a prior negative biopsy.
Authors: Donovan Michael Joseph , Torkler Phillipp , Noerholm Mikkel , Skog Johan , McKiernan James M
Published: February 2018

119

Background: The over-diagnosis of low grade, indolent prostate cancer (PCa) initiates significant patient anxiety regarding treatment options and health risk. To address this clinical need, we developed and subsequently validated a noninvasive, easy to administer, supportive diagnostic test (ExoDx Prostate(IntelliScore), EPI) to guide the initial prostate biopsy decision process for men with PSA 2-10ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GS 7 PCa) from low-grade (GS 6) and benign disease, thereby potentially reducing the number of unnecessary biopsies. As many men have had prior negative/ benign biopsies, we sought to understand the performance of EPI in this selected population. Methods: Utilizing men with prior negative biopsies from two clinical trials we evaluated performance of the EPI test with respect to subsequent biopsy outcomes. We used the previously validated and alternative EPI cut-points of 15.6 and 20, respectively, to assess performance with AUC, sensitivity, and NPV. Results: A total of N = 286 patients with a prior negative biopsy; mean age 65 years, mean PSA 6.2 ng/mL, 22% positive family history, 15% African American; 32% positive biopsy rate: 20% GS6 (ISUP1) and 12% > / = GS7 PCa (ISUP≥2). AUC 0.68 vs. AUC 0.59 for standard of care (i.e. PSA, age, race, family history) and AUC 0.51 for PSA alone. By comparison the EPI initial biopsy AUC was 0.71. Using the previously validated EPI cut-points of 15.6 (or alternative 20) yielded NPVs of 92% and 95%, and number of avoided biopsies of 23% and 32%, respectively, and sensitivity of 85.7% for both cut-points. Notably, EPI in the initial biopsy setting had a sensitivity of 92 vs. 87% and an NPV of 91 vs. 90%, for the 15.6 and 20 cut-points, respectively. Conclusions: The EPI test is a noninvasive, first-catch, non-DRE gene expression array that accurately discriminates low-grade and benign biopsy outcomes from high-grade prostate cancer. The test performs well in both the initial and prior negative biopsy patients and has the potential to reduce the overall number of unnecessary biopsies in both settings.
Hypofractionated, dose escalation radiotherapy for high-risk prostate cancer: The primary endpoint of a group led phase III trial. (PCS5).
Authors: Niazi Tamim , Nabid Abdenour , Bettahar Redouane , Vincent Linda S. , Martin Andre-Guy , Jolicoeur Marjory , Yassa Michael , Barkati Maroie , Igidbashian Levon , Bahoric Boris , Archambault Robert , Villeneuve Hugo , Tsui James M , Mohiuddin MD
Published: February 2018

123

Background: The low α\β ratio of prostate cancer (PCa), 1.5-2, suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (HFRT). Most available data of moderate HFRT have focused on low, intermediate and/or mixed risk groups. We therefore conducted the first randomized trial of moderately HFRT in high-risk PCa patients and present the primary safety analysis of side effects at 2 years. Methods: We conducted a Canadian multi-centric phase III trial of conventional fractionated radiation therapy (CFRT) vs. intensity-modulated HFRT in men with high-risk PCa as per NCCN definition. From February 2012 to March 2015, 329 patients were randomized in a 1:1 ratio to receive either CFRT or HFRT. All patients received neo-adjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. CFRT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. HFRT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy, in 1.8Gy per fraction to the pelvic lymph nodes. The primary endpoint was to compare the toxicities at 6 months and at 24 months using the CTCAE v.4. Results: Of the329 patients, 164 were randomized to HFRT and 165 to CFRT. The minimum, median and maximum follow-up were 24, 40 and 60 months respectively. At 24 months, 12 patients in the CFRT arm and 15 patients in the HFRT arm had grade 2 or worse gastrointestinal (GI)-related adverse events (HR:1.32 [0.62.2.83] 95% CI; P=NS). Similarly, 11 patients in the CFRT arm and 3 patients in HFRT arm had grade 2 or higher genitourinary (GU) toxicities (HR:0.26 [0.07-0.94] 95% CI; P=0.037). In the HFRT arm, there were 3 grade 3 GI and one grade 3 GU related toxicities. In the CFRT arm there were 3 grade 3 GU and no grade 3 GI related toxicities. There were no grade 4 toxicities in either arm. Conclusions: This is the first hypofractionated dose escalated radiotherapy study in high-risk PCa patients treated with contemporary radiation and androgen suppression. Our results indicate that moderate HFRT to high risk PCa patients is equally well tolerated as CFRT at 2 years. Clinical trial information: NCT01444820.
A phase 2 study of olaparib and durvalumab in metastatic castrate-resistant prostate cancer (mCRPC) in an unselected population.
Authors: Karzai Fatima , Madan Ravi Amrit , Owens Helen , Couvillon Anna , Hankin Amy , Williams Monique , Bilusic Marijo , Cordes Lisa M. , Trepel Jane B , Killian Keith , Meltzer Paul S. , Gulley James L. , Lee Jung-min , Dahut William L.
Published: February 2018

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Background: Data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition (PARPi). Immune checkpoint blockade may increase the proportion of patients that respond to PARPi. We hypothesize that increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC (NCT02484404). Methods: Single arm pilot study with accrual of 25 patients (pts) with mCRPC and disease that is amenable to biopsy. Prior treatment with enzalutamide and/or abiraterone is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Core biopsies undergo mutational analysis. Results: In the first 17 pts, median age is 66 (range 45-79 years), median baseline PSA is 79.67 ng/mL [3.93-2356 ng/mL]). Median Gleason score is 8. 6 patients have bone only disease and 11 patients have bone and soft tissue/visceral disease. Median number of cycles is 7 (2-17). Grade 3/4 adverse events include anemia 4/17 (24%), lymphopenia 2/17 (12%), infection 2/17 (12%), thrombocytopenia, leukopenia, neutropenia, nausea, vomiting, UTI, hypertension, hearing impairment, fatigue, syncope, oral mucositis, muscle weakness, and muscle cramps [1/17 each, (6%)]. 8/17 pts (47%) had PSA responses >50%. 6 of these pts had mutations in the DNA damage repair pathways (DNAdr). 2/17 pts (11%) had PSA responses >30% with no known mutations in DNAdr. 4 pts had a PR. The 12 month PFS is 51.5% (95% CI: 25.7-72.3%). Conclusions: Preliminary data shows D+O is well tolerated with activity in an unselected population. Accrual is ongoing with biomarker analysis. Clinical trial information: NCT02484404.
Phase II trial of SM 88 in non-metastatic biochemical recurrent prostate cancer.
Authors: Roach Mack , Gostout Zachary , Zawisny Patricia , Retter Avi S. , Sokol Gerald H. , Hoffman Steve , Del Priore Giuseppe
Published: February 2018

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Background: Despite toxicity and no clear survival benefit, non-metastatic recurrent prostate cancer (nmPC) is typically treated with androgen deprivation therapy (ADT). SM88 is a relatively non-toxic novel combination therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect, with activity in a variety of cancers including prostate (JCO 2017 35, e16567). Phase I and II results demonstrated stable or rising testosterone levels while achieving a reduction of CTCs (circulating tumor cells) and no radiographic progression events (Annal Oncol 2017, 28(5):274-5). We now report results for toxicities typically seen with ADT. Methods: Prospective ongoing Phase Ib/II of SM88 (230mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), detectable CTCs, and no radiographically identified metastases at baseline. Results: Since Sept 2016, there have been 17 consented (of 34 planned) with 10 evaluable (completed > 1 cycle) (median 7, range 1-13). Mean age was 71.2 (53-84); all had prior ADT after curative intent RT (50%) or surgery (50%); with no patient currently on ADT. Mean testosterone level was 307.6 ng/dL before SM88 and 349.2 after (p = 0.07, one-tail T test), rising in (5/10) or remained stable except for one patient who entered the trial castrate ( < 2.5). Overall 70% had some grade 1-2 adverse event (AE) but no drug related serious AE. EORTC-QLQ-C30 relating to mental function domain (Q20-28) and QLQ-PR25 intimacy domains (Q44-50) remained stable, including 9 (90%) reporting no or resolved hot flashes; 7 (70%) reporting an improved or stable “interest in sex”; and 6 (60%) having “excellent” “overall health” and “QOL”. Weight and osteoporosis (measured by Urinary NTX) did not worsen; mean EKG QTc (422 ms); mean arterial pressure (95.1 mmHg); glucose (115.2 mg/dl) and hematocrit (41.5%) were not affected. Conclusions: Toxicities typically associated with ADT were not seen with SM88, a novel non-hormonal anti-neoplastic. Despite the limited follow-up, these data suggest that ADT may be avoided or delayed without progression in selected patients with nmPC. A phase III RCT of SM88 vs patient choice of hormonal or active surveillance is planned for confirmation of these results. Clinical trial information: NCT02796898.
A phase Ia study of safety and clinical activity of atezolizumab (atezo) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kim Joseph W. , Shaffer David R. , Massard Christophe , Powles Thomas , Harshman Lauren Christine , Braiteh Fadi S. , Conkling Paul R. , Sarkar Indrani , Kadel Edward E. , Mariathasan Sanjeev , O'Hear Carol , Schiff Christina , Fasso Marcella , Carroll Susheela , Petrylak Daniel Peter
Published: February 2018

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Background: In the past decade, several therapies have been approved for mCRPC. However, most pts develop resistance and experience disease progression. Thus, there remains a high unmet need. Atezo (anti–PD-L1) blocks the interaction between PD-L1 and its receptors, PD-1 and B7.1, thereby restoring anti-tumor immunity. Atezo has demonstrated clinical efficacy in many tumor types. Here we report the clinical safety and activity of atezo in pts with mCRPC from a Phase Ia study (PCD4989g; NCT01375842). Methods: Eligible pts previously received enzalutamide and/or sipuleucel-T for mCRPC. Pts also had PSA or radiographic progression prior to enrollment. Atezo 1200mg was administered IV q3w. CT and bone scans were performed q6w for 24w and q12w thereafter (q6w if treatment beyond disease progression). Primary objectives were safety and tolerability; OS was an exploratory objective. mCRPC cohort–specific objectives included PSA response, radiographic progression per PCWG2 criteria, soft tissue response per RECIST v1.1 and immune-related response criteria (irRC). Survival follow-up data was collected ≈ every 3 mo until death or loss to follow-up. Results: The 15 pts in the initial mCRPC cohort were evaluated (clinical cutoff: December 31, 2016). 13 pts (87%) had received ≥ 2 prior lines of therapy for mCRPC. Median survival follow-up was 15.8 mo (range, 2.3-23.0). 9 pts (60%) had a treatment-related AE (TRAE); only 1 pt (7%) experienced a Gr 3 TRAE (hyponatremia). No Gr 4-5 TRAEs were reported. The landmark 12-mo OS rate was 55.6% (95% CI: 27.4, 83.7); median OS was not reached (range, 2.3-23.0 mo). Median PFS was 3.4 mo (95% CI: 2.3, 5.7); the 6-mo PFS rate was 26.7% (95% CI: 4.3, 49.1). 1 pt (9%) had a PR per irRC (irPR); 5 pts (45%) had SD per RECIST v1.1 and irRC. 2 pts (13%) had a ≥ 50% decrease in PSA from baseline. The pt who experienced an irPR had increased CD8 expression and expansion of T-cell clones on study treatment. Conclusions: Atezo was well tolerated and demonstrated long-term disease control in pts with heavily pretreated mCRPC, with a 12-mo OS rate of 55.6%. Preliminary biomarker analyses from the pt who experienced an irPR were suggestive of an activated immune response. Clinical trial information: NCT01375842.
Randomized trial of enzalutamide versus bicalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer: A Prostate Cancer Clinical Trials Consortium trial.
Authors: Vaishampayan Ulka N. , Heilbrun Lance K. , Monk Paul , Tejwani Sheela , Sonpavde Guru , Smith Daryn , Jasti Pallavi , Dobson Kimberlee , Heath Elisabeth I. , Cher Michael L. , Chinni Sreenivasa , Fontana Joseph A.
Published: February 2018

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Background: Addition of abiraterone or docetaxel has overall survival (OS) benefit in metastatic hormone sensitive prostate cancer (mHSPC). The clinical outcomes with early enzalutamide in mHSPC are unknown. We compared the combinations of enzalutamide (Arm A) or bicalutamide (Arm B) each with LHRH analogue therapy in mHSPC. Methods: The primary endpoint was PSA nadir < 4 ng/ml after 7 months of therapy, as this has been recognized as a powerful surrogate for overall survival (OS) outcomes. A minimum of 29 African American (AA) patients were required to be enrolled to evaluate the effect of race on the primary endpoint. Secondary endpoints were toxicities, biochemical and radiologic progression free survival (PFS), and OS. Stratification was by presence of bone pain and race; AA or other. PSA was monitored monthly for first 7 months and then every 3 months. The target sample size was 82 evaluable patients but the study was stopped when early abiraterone showed OS benefit in mHSPC. Metastatic site biopsies were mandatory pretherapy and optional post therapy. Results: 71 men; 29 black, 41 white and 1 Asian were enrolled. The median age was 67 years (range 46-87 years) and median baseline PSA was 56.3 ng/ml in Arm A (4.2-10,431 ng/ml) and 60 (4.9-12,030 ng/ml) in Arm B. 27 pts (38.5%) had bone pain and 13 had visceral metastases. No seizures were noted in either arm. Grade 3+ AE’s on Arm A were: Hypertension (13%), infection (7%), and Snycope (7%) and on Arm B were: Hypertension (21%), Fatigue (7%), and Hematuria (7%). By intent to treat PSA nadir < 4ng/ml at month 7 was achieved in 96.3% pts in arm A and 66.7% pts in arm B and in 71.7% of AA men and 89.7% of Caucasians. The 6-month PSA remission duration rates after month 7 on Arms A and B were 86% and 79%, respectively. 53 (75%) biopsy samples had tumor tissue available. Tmprss2-Erg fusion gene expression and androgen biosynthetic enzyme levels were determined in metastatic biopsies and will be correlated with clinical endpoints. Conclusions: Early enzalutamide use in mHSPC has the potential to improve PSA remission rates and subsequently improve PFS and OS outcomes. Clinical trial information: NCT02058706.
Overall survival of patients with metastatic prostate cancer starting androgen deprivation therapy with degarelix, a gonadotropin-releasing hormone antagonist.
Authors: Freedland Stephen J. , Sørensen Per Settergren , Persson Bo-Eric
Published: February 2018

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Background: Morbidity and mortality amongst patients diagnosed with metastatic prostate cancer remains high and androgen deprivation therapy is the mainstay of hormonal treatments for these patients. The gonadotropin-releasing hormone (GnRH) antagonist, degarelix, has a fast and profound onset of action and compares favorably with GnRH agonists in terms of progression-free survival (PFS) and overall survival during the first year of treatment. It is of interest to assess longer term survival data in patients with very advanced disease. Methods: Data from several studies of patients treated with degarelix are available for descriptive analysis from a study repository. We analyzed data from patients with metastatic disease and prostate-specific antigen (PSA) > 50 ng/mL treated with degarelix from 17 controlled and uncontrolled trials for overall survival and PFS. Possible selection bias over time was also estimated. Results: Overall, 519 patients with metastatic disease and PSA > 50 ng/mL were included; median age was 71 (±6) years. Survival at 36 months was 83% for patients with baseline PSA > 50 to < 200 ng/mL and 72% for patients with baseline PSA > 200 ng/mL. The corresponding numbers for PSA-PFS were 29% and 15%, respectively (Table). A delayed separation of Kaplan-Meier estimates was observed between the PSA > 50 to < 200 ng/mL and > 200 ng/mL groups; 6 months for PSA-PFS and 12 months for survival. A Cox regression indicated no significant effect of age (p = 0.20) or BMI (p = 0.33). The data suggest some selection bias over time in the most advanced patients. Conclusions: The data indicate that 77% of patients with metastatic disease and PSA > 50 ng/mL who start degarelix treatment are alive after an observation period of 36 months. This is an analysis of uncontrolled data and a comparative randomized approach is required to allow potential comparison with other treatments. [Table: see text]