bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of pembrolizumab in people with HIV and cancer.
Authors: Uldrick Thomas S. , Goncalves Priscila Hermont , Abdul Hay Mohammad Maher , Claeys Alisa J , Emu Brinda , Ernstoff Marc S. , Fong Lawrence , Kaiser Judith C , Kohrt Holbrook Edwin , Lacroix Andreanne , Lee Steve Young , Lundgren Lisa , Lurain Kathryn Anne , Parsons Christopher , Peeramsetti Sharavi , Ramaswami Ramya , Sharon Elad , Wang Chia-Ching Jackie , Yarchoan Robert , Cheever Martin A.
Published: May 2019

2500

Background: People with HIV have been excluded from immuno-oncology (IO) studies. Anti- PD-1/PD-L1 therapies are approved for a growing number of cancers. We evaluated pembrolizumab (pembro) in people with HIV and cancer. Methods: CITN-12 is a multicenter phase 1 trial. Key eligibility: advanced cancer; ECOG ≤1; CD4 ≥100 cells/μL; ≥4 weeks antiretroviral therapy (ART), HIV viral load (VL) < 200 copies/mL. Exclusion: uncontrolled HBV/HCV, autoimmune disease. Participants (pts) accrued into CD4 based cohorts (C): C1 100-199; C2 200-350; C3 > 350 CD4 cells/μL. Pembro 200 mg IV administered Q3W for up to 35 doses. Adverse events (AE) evaluated by CTCAE. Immune related AE ≥ grade (Gr) 2 were events of clinical interest (irECI). Clinical benefit (tumor shrinkage or stable disease [SD] ≥24 weeks) was estimated. Data were locked for safety analysis and publication once C2 and C3 completed accrual and all pts completed ≥2 cycles. Accrual continued for 6 C1 pts and a new phase 1b Kaposi sarcoma (KS) cohort (C4). Results: 30 pts, characteristics: C1 (6), C2 and 3 (12 each), median (med) age 57 years (range 39-77), 28 men, 2 women, 60% White, 30% Black, 10% Hispanic. Med CD4 285 cells/μL (132 - 966). Cancers: KS (6), non-Hodgkin lymphoma (NHL) (5), non-AIDS defining (19) – most common: anal (6) and squamous cell skin (3). Prior radiation (19), med prior systemic therapies 2 (0-8). Safety observed over 183 cycles, med 5 (1-32). Treatment emergent AE ≥ possibly attributed to pembro mostly Gr 1-2, with 20% of pts having Gr 3. irECI: hypothyroidism (6), elevated AST/ALT (1), pneumonitis (3), rash (2), musculoskeletal (1).1 KS pt developed KSHV-associated multicentric Castleman disease (KSHV-MCD) and died of the AE. HIV was controlled and increasing CD4 counts were observed. Best response: complete (lung, 1), partial (NHL, 2), SD ≥24 weeks (KS, 2), SD < 24 weeks (13), progressive disease (10), not evaluable (2). Conclusions: Pembro has acceptable safety in cancer pts with HIV on ART and > 100 CD4 cells/µL, similar to patients without HIV. Anti-PD-1 may unmask KSHV-MCD and such KSHV-viremic patients should be excluded. Clinical benefit was noted in several tumor types. Anti-PD1 is appropriate for FDA-approved indications in this population. Patients with HIV meeting appropriate eligibility criteria should be included in IO studies. Clinical trial information: NCT02595866.
Determination of the recommended phase II dose of birinapant in combination with pembrolizumab: Results from the dose-escalation phase of BPT-201.
Authors: Schilder Russell J. , Albertella Mark , Strauss James Fredric , Sydvander Malin , Le Dung T. , Norin Stefan , Mita Monica M. , Boström Emma , Fu Siqing , Basse Linda , Bethell Richard
Published: May 2019

2506

Background: Birinapant is a bivalent SMAC mimetic targeting cIAP1. Synergistic effects of combining birinapant with immune checkpoint inhibitors have been demonstrated in preclinical models. Based on these observations, a clinical trial with birinapant and pembrolizumab was initiated (NCT02587962). Methods: Patients ≥18 years with advanced solid tumors without further suitable standard therapeutic options were eligible for inclusion. Birinapant (5.6-22 mg/m2) was administered IV on day 1 and 8 in addition to pembrolizumab 200 mg on day 1 in a 21-day cycle until disease progression using standard 3+3 dose-escalation. The primary objective was to determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant in combination with pembrolizumab. Secondary and exploratory objectives included antitumor activity assessed by RECIST 1.1 and iRECIST, pharmacokinetics and assessment of biomarkers including serum cytokines, cIAP1, PD-L1 expression and tumor infiltrating lymphocytes. Results: Nineteen patients were enrolled at 4 dose levels of 5.6 (n = 3), 11 (n = 3), 17 (n = 6) and 22 (n = 7) mg/m2. Most common tumors were pancreatic (n = 5), colorectal (n = 4), ovarian (n = 3) and sarcoma (n = 3). Median prior therapies were 4 (0-12). The most common AE related to any of the study drugs was rash occurring in 3 patients. Ten patients had 17 SAE's of which only one (stomatitis) was judged related to birinapant. Increased ALT/AST (G3/G2) leading to missed day 8 dose constituted a DLT at 22 mg/m2. Grade 2 lipase increases were seen in 2 patients. No cases of Bell’s palsy were detected. ORR by RECIST 1.1 was 5.6% (n = 1) in 18 evaluable patients. The responding patient had microsatellite stable colorectal carcinoma (MSS-CRC)) and remains on therapy 13+ months after first dose. By iRECIST, ORR was 11.1%. CBR (PR+SD) by RECIST was 22.2%. The exposure to birinapant generally increased with dose. The RP2D was determined to be 22 mg/m2. Conclusions: Birinapant and pembrolizumab is a safe and tolerable combination that has shown encouraging signals of efficacy. A phase 2 study evaluating efficacy of this combination in MSS-CRC is ongoing. Clinical trial information: NCT02587962.
Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.
Authors: Meric-Bernstam Funda , Sandhu Shahneen Kaur , Hamid Omid , Spreafico Anna , Kasper Stefan , Dummer Reinhard , Shimizu Toshio , Steeghs Neeltje , Lewis Nancy , Talluto Craig C. , Dolan Sinead , Bean Andrew , Brown Robert , Trujillo Damian , Nair Nitya , Luke Jason J.
Published: May 2019

2507

Background: MIW815 (ADU-S100) is a novel synthetic cyclic dinucleotide that activates the STimulator of INterferon Genes (STING) pathway impacting tumor cells, tumor microenvironment, vasculature, tumor-associated fibroblasts, and priming APC and CD8+ T cells. Spartalizumab is a humanized IgG4 mAb that blocks the binding of PD-1 to PD-L1/2. Preclinical data support synergistic antitumor effects when MIW815 (ADU-S100) is combined with checkpoint inhibitors. Methods: In this Phase Ib dose escalation study, pts with advanced/metastatic solid tumors or lymphoma received MIW815 (ADU-S100) (intratumoral injections [50–800 µg] either weekly [3 weeks on/1 week off] or Q4W) and spartalizumab (400 mg IV Q4W). Injected and non-injected tumor biopsies were obtained at baseline and on treatment. Primary objectives are to determine safety and identify a dose/schedule for future studies. Preliminary activity, pharmacokinetics (PK), and pharmacodynamics (PD) are also being explored. Results: As of Jan 11, 2019, 66 pts (median age: 61 y) with various solid tumors or lymphomas have been treated. Treatment was discontinued in 49 pts (74%) due to disease progression (n = 28), pt/physician decision (n = 18), AE (n = 2), or death (n = 1). No DLTs were reported during the first cycle at any dose level. Most common (≥5 pts) treatment-related AEs (TRAEs) were injection site pain (12%), pyrexia (11%), and diarrhea (9%). Grade 3/4 TRAEs (in ≥2 pts) were increased AST and ALT (3% each). Serious TRAEs were pyrexia (3%), increased amylase, increased lipase, diarrhea, fatigue, hyperthyroidism, partial seizures, dyspnea, and pneumonitis (all 2%). Partial responses in pts with PD-1–naive TNBC and PD-1–relapsed/refractory melanoma have been observed. MIW815 (ADU-S100) plasma exposure generally increased in a dose-dependent manner with a rapid terminal half-life. Response data, PK and PD analyses will be presented. Conclusions: Thus far, MIW815 (ADU-S100) + spartalizumab has demonstrated antitumor activity in PD-1–naive TNBC and PD-1–relapsed/refractory melanoma. The combination is well tolerated, with no DLTs reported to date. The MTD has not been reached and dose escalation is ongoing. Clinical trial information: NCT03172936.
First-in-human study of REGN3767 (R3767), a human LAG-3 monoclonal antibody (mAb), ± cemiplimab in patients (pts) with advanced malignancies.
Authors: Papadopoulos Kyriakos P. , Lakhani Nehal J. , Johnson Melissa Lynne , Park Haeseong , Wang Ding , Yap Timothy A , Dowlati Afshin , Maki Robert G. , Lynce Filipa , Ulahannan Susanna Varkey , Kelly Karen , Sims Tasha Nicholle , Bredlau Amy-Lee , Bramble Derrick , Gonzalez Ortiz Ana , Zhu Min , Chen Huanyu , Karasarides Maria , Kroog Glenn
Published: May 2019

2508

Background: We present initial safety, pharmacokinetics (PK), and efficacy from the dose escalation study of R3767, alone (mono) or in combination with cemiplimab (REGN2810), a PD-1 mAb (combo), in pts with advanced malignancies (NCT03005782). Methods: Pts who had progressed on prior therapy(ies) and/or for whom no therapy with clinical benefit was available were enrolled; most pts had received no prior anti-PD-1/PD-L1. Pts received R3767 1, 3, 10, or 20 mg/kg every 3 weeks (Q3W) ± cemiplimab 3 mg/kg or 350 mg Q3W IV for ≤51 weeks. Crossover from mono to combo was allowed at progression. R3767 PK were evaluated. Tumor measurements were performed Q6W for the first 24 weeks and subsequently Q9W. Data cut-off date was Aug 25, 2018. Results: Mono: 27 pts (median age: 66 yr; ECOG PS: 0 [n=4], 1 [n=23]) were treated. There were no dose-limiting toxicities (DLTs). The most common treatment-emergent adverse event (TEAE) was nausea (22.2%). Grade ≥3 immune-related adverse events (irAEs) of increased alanine and aspartate aminotransferases (each 3.7%) were reported. By investigator-assessment (per RECIST 1.1; INV), best response was stable disease in 11 pts. Combo: 42 pts (median age: 60 yr; ECOG PS: 0 [n=15], 1 [n=27]) were treated. One pt treated with R3767 3 mg/kg Q3W + cemiplimab 3 mg/kg Q3W experienced DLT of grade 4 elevated blood creatine phosphokinase, associated with grade 3 myasthenia syndrome and grade 1 elevated troponin. The most common TEAEs were fatigue (33.3%) and nausea (21.4%). Grade 3 irAE of hypothyroidism (2.4%) was also reported. By INV, 2 (both small cell lung cancer) combo pts and 2 (endometrial cancer and cutaneous squamous cell carcinoma) of 12 additional pts who crossed over from mono to combo had partial responses. PK: R3767 concentrations in serum increased in a dose-dependent manner and were unaffected by combo. Conclusions: The safety profile of R3767 ± cemiplimab was generally tolerable; PK was linear. Early efficacy signals were detected despite the difficult-to-treat pt population. Biomarker studies are ongoing. R3767 20 mg/kg or 1600 mg fixed dose equivalent Q3W as mono and combo were selected for further evaluation. Clinical trial information: NCT03005782.
Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma.
Authors: Zhan Xianbao , Wang Bin , Li Zonghai , Li Jie , Wang Huamao , Chen Longpei , Jiang Hua , Wu Meihong , Xiao Jun , Peng Xiaobo , Ma Hong , Feng Dan , Wang Dakun , Fu Qiang , Wang Mei , Shen Fengping , Hao Qiang , Zhang Linli , Xu Jing , Zhang Yingyi
Published: May 2019

2509

Background: As a promising approach for some cancers, chimeric antigen receptor T cell therapy has limited success in solid tumors. Claudin18.2 (CLDN 18.2) is a stomach-specific isoform of Claudin-18, and highly expressed in gastric and pancreatic adenocarcinoma, the advanced form of both of which have urgent unmet medical needs. We previously developed and demonstrated ability of CLDN 18.2-specific CAR (CAR-CLDN18.2) T cells to eradicate CLDN 18.2-positive gastric cancer xenografts without obvious on-target off-tumor toxicity (Huang J. JNCI 2018). Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03159819) to investigate the safety and explore the efficacy of the autologous CAR-CLDN18.2 T cells, patients with confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma aged 18 to 70 years received 1 or more cycles of CAR-CLDN18.2 T cell infusion(s) after lymphodepletion pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) until disease progression or presence of intolerable toxicity. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Results: As of November 30th, 2018, 12 subjects with metastatic adenocarcinoma (7 gastric and 5 pancreatic) were treated with 1–5 cycles (total of 0.5 - 55 X 108) of CAR-positive T cells infusions. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. No grade 4 AEs except for decreased lymphocytes, neutrophils and white blood cells. All cytokine release syndromes observed were grade 1 or 2. Among the 11 evaluable subjects, 1 achieved a complete response (gastric adenocarcinoma), 3 had partial responses (2 gastric adenocarcinomas and 1 pancreatic adenocarcinoma), 5 had stable disease and 2 had progression of disease. The total objective response rate was 33.3%, with median PFS of 130 days estimated using Kaplan-Meier method [95% CI (38, 230)]. Conclusions: This clinical study indicated that CAR-CLDN18.2 T cell therapy were safe and well tolerated and may have promising therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma. Clinical trial information: NCT03159819.
CX-072, a PD-L1 Probody therapeutic, as monotherapy in patients with advanced solid tumors: Preliminary results of PROCLAIM-CX-072.
Authors: Naing Aung , Thistlethwaite Fiona C. , Spira Alexander I. , Garcia-Corbacho Javier , Randhawa Manreet , Eskens Ferry , O'Neil Bert , Lavernia Javier , Uboha Nataliya Volodymyrivna , Hamid Omid , El-Khoueiry Anthony B. , Benson Beverly A. , Garner William , Huels Vanessa Jessica , Arkenau Hendrik-Tobias , LoRusso Patricia
Published: May 2019

2513

Background: Anti-programmed cell death ligand 1 (PD-L1) immunotherapies have improved survival in many cancers, but immune-related adverse events (irAEs) have been observed, especially in combination therapy. CX-072 is an investigational Probody therapeutic directed against PD-L1, designed to be preferentially activated in the tumor microenvironment and to reduce irAEs. Methods: This is an ongoing phase 1/2a study (PROCLAIM-CX-072; NCT03013491) evaluating CX-072 in patients (pts) with metastatic or unresectable solid tumors with no further standard curative treatment options and with no prior anti-PD1, PD-L1 or anti-CTLA4 treatment. Pts were unselected for PD-L1 expression. We report preliminary results from expansion cohorts in anal squamous cell carcinoma (SCCA), cutaneous squamous cell carcinoma (cSCC), small bowel adenocarcinoma (SBA), triple-negative breast cancer with skin lesions (TNBC), or undifferentiated pleomorphic sarcoma (UPS). Pts were treated with CX-072 monotherapy 10 mg/kg intravenously every 14 days. Results: As of 30 Nov 2018, 51 pts received CX-072 10 mg/kg monotherapy: SCCA (n = 9), cSCC (n = 5), SBA (n = 9), TNBC (n = 9), and UPS (n = 19). Median age was 63 y (range, 32-80), 67% were female, and pts had a median of 3 prior regimens (range, 1-12). Median treatment duration was 1.8 mo (range, 0.3-14.7). A grade 3/4 treatment-related adverse event (AE) was observed in 1 pt (2%; gr 3 generalized rash). No grade 3/4 irAEs were observed. Two pts discontinued treatment due to AEs: nausea (pt with SCCA) and sepsis (pt with SBA), neither treatment-related. Partial responses (confirmed and unconfirmed) were observed in cSCC (n = 1), TNBC (n = 2), and UPS (n = 1) (Table). Conclusions: CX-072 10 mg/kg monotherapy demonstrated anticancer activity in heavily pretreated pts with advanced solid tumors, including responses in cSCC, TNBC with skin lesions, and UPS, with a safety profile that compares favorably to historical controls. Clinical trial information: NCT03013491. [Table: see text]
Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603).
Authors: Fukuoka Shota , Hara Hiroki , Takahashi Naoki , Kojima Takashi , Kawazoe Akihito , Asayama Masako , Yoshii Takako , Kotani Daisuke , Tamura Hitomi , Mikamoto Yuichi , Sugama Ayako , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Togashi Yosuke , Nishikawa Hiroyoshi , Shitara Kohei
Published: May 2019

2522

Background: Immune suppressive cells such as regulatory T cells (Tregs) or tumor-associated macrophages (TAMs) may contribute to resistance to anti-PD-1/PD-L1 inhibitors (A-PD1). Regorafenib, a potent inhibitor of angiogenic and oncogenic kinases, reduced TAMs in tumor models. The combination of regorafenib plus A-PD1 exhibited superior tumor growth suppression compared to either treatment alone in murine models. Methods: In this study, we enrolled patients (pts) with previously treated, advanced GC or CRC. The pts received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase to further establish the safety and determine the preliminary efficacy. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one (4 weeks) to estimate the MTD and the recommended dose. Results: Fifty pts were enrolled (25 GC; 25 CRC) until October 2018. The median prior treatment line was 3 (range 2-8). During dose-escalation, 3 DLTs were observed with regorafenib 160 mg, including grade (G) 3 maculopapular rash, mucositis and proteinuria, while there was no DLT with 80 or 120 mg. In the dose expansion cohort with regorafenib 120 mg, the dose was reduced to 80 mg owing to frequent G3 skin toxicities. Grade ≥ 3 treatment related adverse events occurred in 17 pts; the common events ( > 5%) being rash (14%), palmar-plantar erythrodysesthesia (10%), and proteinuria (8%). Objective tumor response was observed in 19 pts (38%) including 11 MSS GC, 7 MSS CRC and 1 MSI-H CRC for response rates of 44% in GC and 29% in MSS CRC. Three of the 7 A-PD1 pretreated GC pts achieved a partial response. The pre- and post-treatment tumor samples showed a reduction of FoxP3hiCD45RA-Tregs fraction at the tumor response. Conclusions: The combination of regorafenib 80mg plus nivolumab had a manageable safety profiles and encouraging anti-tumor activity in MSS GC and CRC pts, which warrants further investigations in a larger cohort. Updated biomarker analysis will be presented. Clinical trial information: NCT03406871.
Tumor responses and early onset cytokine release syndrome in synovial sarcoma patients treated with a novel affinity-enhanced NY-ESO-1-targeting TCR-redirected T cell transfer.
Authors: Ishihara Mikiya , Kitano Shigehisa , Hattori Hiroyoshi , Miyahara Yoshihiro , Kato Hidefumi , Mishima Hideyuki , Yamamoto Noboru , Funakoshi Takeru , Kojima Takashi , Sasada Tetsuro , Sato Eiichi , Okamoto Sachiko , Tomura Daisuke , Chono Hideto , Nukaya Ikuei , Mineno Junichi , Ikeda Hiroaki , Watanabe Takashi , Kageyama Shinichi , Shiku Hiroshi
Published: May 2019

2530

Background: Adoptive transfer of TCR-redirected T cells has been reported to exhibit efficacy in some of melanoma and sarcoma patients. However, there have not been well known about cytokine release syndrome (CRS) or its relations to tumor responses. This study evaluates clinical responses in association with the cell kinetics and CRSs after transfer of high-affinity NY-ESO-1 TCR-gene transduced T cells in NY-ESO-1-expressiong cancer patients (NCT02366546). Methods: We developed a novel-type affinity-enhanced NY-ESO-1-specific TCR and an originally-developed retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1/TCR sequence is mutated for high affinity with replacements of G50A and A51E in CDR2 region. This is a first-in-man clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It was designed as a cell-dose escalation from 5 x108 to 5 x109 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3+3 cohort design. Cyclophosphamide (1,500mg/m2) were administered prior to the TCR-T cell transfer as pre-conditioning. Results: 9 patients were treated with the NY-ESO-1/TCR-T cell transfer. The TCR-T cells expanded in peripheral blood with a dose-dependent manner, associated with rapid proliferation within 5 days after the cell transfer. 3 patients receiving 5x109 cells developed early-onset CRSs, with elevations of serum IL-6, IFN-γ. The CRSs developed on day1 or 2 after the cell transfer. They were well managed with tocilizumab treatment. 3 synovial sarcoma patients exhibited tumor shrinkages of partial responses, and they all had high-expression of NY-ESO-1 in the tumor samples, namely, 75% or more. Exploratory analysis revealed that multiple chemotactic cytokines including CCL2 and CCL7, and IL-3 increased in the serum from the patients with CRS. The proportions of effector-memory phenotype T cells in the infused cell-product were significantly associated with CRS development. Conclusions: The affinity-enhanced NY-ESO-1/TCR-T cell transfer exhibited early-onset CRS in association with in vivo cell proliferation and sequential tumor responses in the patients with high-NY-ESO-1-expressing synovial sarcoma. Clinical trial information: NCT02366546.
Effect of minimal lymphodepletion prior to ACT with TBI-1301, NY-ESO-1 specific gene-engineered TCR-T cells, on clinical responses and CRS.
Authors: Butler Marcus O. , Saibil Sam , Bonilla Luisa , Franke Norman , Hakgor Sevan , Boross-Harmer Sarah , Majeed Habeeb , Nelles Megan , Ohashi Pamela S , Ross Kendra , Sacher Adrian G. , Scheid Elizabeth , Sotov Valentin , Trang Aileen , Vakili Koosha , Van As Brendan , Takahashi Shuichi , Tanaka Shinya , Nguyen Linh T. , Hirano Naoto
Published: May 2019

2537

Background: Adoptive transfer of T cell receptor (TCR) gene-engineered T cells can induce durable anti-cancer responses. Post-infusion cytokine release syndrome (CRS) has been associated with clinical utility. Pre-infusion lymphodepletion (LD) may influence CRS, graft persistence, and clinical responses. While the optimal LD regimen is not yet defined, most include both cyclophosphamide (CY) and fludarabine (FLU). TBI-1301 is a novel gene therapy produced by engineering autologous lymphocytes to express an NY-ESO-1-specific TCR using a retrovirus vector that encodes siRNA to silence endogenous TCR. Since less intensive LD may be sufficient with the use of this novel vector, we are conducting a study where patients are treated with TBI-1301 following LD with CY alone. Methods: Eligibility includes informed consent, HLA-A*02:01 or A*02:06 haplotype, and NY-ESO-1 expression by immunohistochemistry. Eligible patients undergo harvest of PBMC which are then processed locally to generate engineered TBI-1301 cells. The study design is to infuse 5x109 cells (day 0) to patients following LD with CY (750 mg/m2 on day -3 and -2). Endpoints include safety, efficacy, and biological correlates for persistence of NY-ESO-1-specific T cells post infusion. Results: Thus far, 9 patients have been treated, and 8 have received the target dose. To date, 8 patients are evaluable for response and toxicity, and no DLTs have been observed. Despite LD with CY alone, all 4 patients with synovial sarcoma and 1 with melanoma experienced clinical and laboratory evidence of grade 1-2 CRS with increased CRP, ferritin, and IL-6 levels. CRS resolved spontaneously in all but one patient who required tocilizumab due to grade 2 nausea/vomiting. Two subjects experienced grade 3 tumor-associated pain. Other treatment-associated grade 3 or 4 toxicities included neutropenia and hypophosphatemia. Best overall response by RECIST is as follows: 2 partial responses, 5 stable disease, and 1 progressive disease. Biomarker analysis demonstrates persistence of transferred TBI-1301 cells, > 100 days in some patients. Conclusions: TBI-1301 appears to be safe and to possess anti-tumor activity. Despite LD with CY alone, grade 1-2 CRS is induced. Additional cohorts to this study will examine the role of repeat infusions to enhance anti-tumor activity. Clinical trial information: NCT02869217.
Comprehensive report of anti-CD19 chimeric antigen receptor T cells (CAR-T) associated non-relapse mortality (CART-NRM) from FAERS.
Authors: Anand Kartik , Burns Ethan , Sano Dahlia , Pingali Sai Ravi , Westin Jason , Nastoupil Loretta J. , Lee Hun Ju , Samaniego Felipe , Parmar Simrit , Wang Michael , Hawkins Misha , Adkins Sherry , Fayad Luis , Steiner Raphael , Nair Ranjit , Ahmed Sairah , Fowler Nathan Hale , Neelapu Sattva Swarup , Iyer Swaminathan Padmanabhan
Published: May 2019

2540

Background: CAR-T cells targeting CD19 positive B-cells have improved outcomes for relapsed/refractory non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). CAR-T emergent toxicities for FDA approved therapies leading to non-progression related death have been reported in the pivotal studies. However, they are underreported and there remains a need to obtain a comprehensive report of NRM emergent with anti-CD19 CAR-T. Methods: We retrospectively searched FDA adverse events reporting system (FAERS) for all adverse events (AE) related to “Tisagenlecleucel(T)” and “Axicabtagene ciloleucel(AC)” reported from 2013-2018. FAERS contains AEs from clinical trials and standard of care patients. All cases with the outcome of death were analyzed. Results: Total numbers of anti-CD19 CAR-T pts reported were 636, out of which 288 cases received “T” and 348 received “AC”. Out of total 129 total deaths, 95 died due to non-disease progression. Patient characteristics are summarized in Table. CART-NRM for entire cohort was 15%; 21% for “T” and 10% for “AC”. Major toxicities reported include CRS, hematological, cardiovascular, neurological and infectious. Difference in mortality is likely related to different patient population, diagnoses and the CAR-T construct. Conclusions: CART-NRM remains considerably high at 15%. Our analysis highlights the major toxicities and informs the potential opportunities for interventions to reduce mortality. We will present updated data with comparative analysis of published clinical studies at the upcoming ASCO Meeting in Chicago. [Table: see text]
ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer.
Authors: Moding Everett J , Liu Yufei , Nabet Barzin , Chabon Jacob J. , Chaudhuri Aadel , Hui Angela B. , He Jianzhong , Qiao Yawei , Heymach John , Tsao Anne S. , Liao Zhongxing X. , Gomez Daniel Richard , Ramchandran Kavitha , Neal Joel W. , Wakelee Heather A. , Loo Billy W. , Lin Steven H. , Alizadeh Ash A. , Diehn Maximilian
Published: May 2019

2547

Background: Detection of molecular residual disease via circulating tumor DNA (ctDNA) analysis after chemoradiation (CRT) in localized non-small cell lung cancer (NSCLC) predicts risk of relapse. We explored the hypotheses that (1) patients with undetectable ctDNA after CRT may not require consolidation immunotherapy (CI) and (2) ctDNA analysis could monitor the effectiveness of CI in patients with residual ctDNA after CRT. Methods: We applied CAPP-Seq ctDNA analysis to 88 plasma and matched leukocyte samples collected pre-CRT, post-CRT but pre-CI, and mid-CI in 22 patients with Stage IIB-IIIB NSCLC treated with CRT followed by CI. Identification of patient-specific tumor variants was performed using tumor tissue or pretreatment plasma, and ctDNA was quantified using a tumor mutation-informed bioinformatic strategy. Freedom from progression (FFP) defined radiographically by RECIST 1.1 criteria was compared in patients with ctDNA detected or not detected at pre-CI and mid-CI landmarks. Results: Median follow up from the start of CRT was 11 months. ctDNA detection was associated with inferior rates of FFP when compared to patients with ctDNA not detected both pre-CI (12-month 33% vs. 76%, P = 0.015, HR 7.51, 95% CI 1.47-38.24) and mid-CI (12-month 0% vs. 86%, P < 0.0001, HR 123.3, 95% CI 16.21-937.8). In patients with undetectable ctDNA after CRT, FFP was similar to a historical cohort of patients with undetectable ctDNA after CRT alone (12-month 88% vs. 87%, P = 0.56, HR 0.55, 95% CI 0.07-4.18), suggesting that such patients may not benefit from CI. All patients with detectable ctDNA pre-CI in whom ctDNA increased mid-CI developed progressive disease. Finally, in 2 patients with ctDNA detected after CRT, CI led to elimination of ctDNA at the mid-CI timepoint. One of these patients developed an isolated local recurrence 22 months after CRT and the other patient is currently disease free at 11 months, suggesting clinical benefit from CI. Conclusions: Our results suggest that ctDNA analysis may allow personalization and response monitoring of CI following CRT for NSCLC. Validation in more patients followed by prospective testing in clinical trials will be required to establish clinical utility of such an approach.
Re-evaluating eligibility criteria: Analysis of factors leading to nonparticipation and outcomes of patients (pt) with advanced cancer who signed consent but were not treated in early-phase immunotherapy (IO) trials.
Authors: Carmagnani Pestana Roberto , Subbiah Ishwaria Mohan , Hess Kenneth R. , Huang Le , Liu Shuang , Beltran Kimberly , Harrison Holly , Bryant Angela , Eshon Jennifer , Yap Timothy A , Pant Shubham , Naing Aung , Hong David S. , Meric-Bernstam Funda , Subbiah Vivek
Published: May 2019

2552

Background: Eligibility criteria protect the safety of trial pt and delineate the study population. Excessively restrictive criteria, however, can negatively impact accrual and prevent access to beneficial investigational treatments. Recently, ASCO issued a statement on the need to broaden eligibility criteria and make trials more representative. We aim to characterize the factors leading to non-participation and the outcomes of pt who signed consent for phase I IO trials but ultimately did not receive any therapy on that trial. Methods: We identified 696 consecutive pt w/ advanced cancer who consented to participate on IO phase I trials from 10/2015-12/2017, and collected pt characteristics as well as clinical outcomes, and compared participants (P) to non-participants (NP). Results: Among the 696 pt who initially consented to participate on IO phase I trials, 178 (25.6%) were never treated. Median age was 60 in both groups, and there were no differences regarding median number of metastatic sites (n = 2 vs 2 ) or sex distribution (F 53% vs 54%); NP had received less lines of therapy (median = 3 vs 4, p = 0.016). Reasons for non-participation were: 48 (26%) alternate therapy (for 18, geography was the main reason), 29 (16%) clinical progression/ decline in PS, 14 (8%) did not have enough biopsy tissue, 13 (7%) new lab abnormality, 11 (6%) new brain mets, 63 (35%) had other reasons (death, concurrent medications, financial factors). Median time from signature of consent to final exclusion of trial was 19 days (0-82). 54 of NP eventually enrolled in other trial, including 29 in immunotherapy trial. Median overall survival (OS) was significantly lower for NP vs P (median 6.9 vs 18.0, HR 0.5; p < .0001). Conclusions: One quarter of patients who signed consent for early-phase immunotherapy trials were unable to start on study. NP had significantly decreased OS. Detailed examination of these reasons can lead to recognition of modifiable factors and streamline the pretrial period, to guarantee this vulnerable population has maximal access to start therapy on study.
Preliminary results with tislelizumab, an investigational anti-PD-1 antibody, in Chinese patients with nasopharyngeal cancer (NPC).
Authors: Wang Siyang , Huang Xiaoming , Bai Yu-Xian , Yuan Ying , Li Jian , Wang Zuobai , Wei Chenlu , Li Xin , Liu Tianshu
Published: May 2019

2556

Background: Epidemiology of NPC is characterized by a unique geographic distribution, with China having one of the highest incidence rates of NPC worldwide. Tislelizumab is an investigational monoclonal antibody with high affinity and specificity for PD-1. Tislelizumab was engineered to minimize binding to FcɤR 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 this phase 1/2 study (CTR20160872) have shown that single-agent tislelizumab was generally well tolerated and demonstrated preliminary antitumor activity in Chinese patients (pts) with advanced solid tumors. In the dose-verification part of this study, the recommended dose was established as 200 mg IV Q3W. Here we present preliminary results from the NPC cohort of this study. Methods: Chinese pts with advanced or metastatic, histologically or cytologically confirmed WHO type II-III NPC were enrolled in the indication-expansion phase of this study. Enrolled pts received tislelizumab 200 mg IV Q3W until unacceptable toxicity, consent withdrawal, or no evidence of continued clinical benefit. Antitumor activity (per RECIST v1.1) and safety/tolerability (per NCI-CTCAE v4.03) were assessed. Results: As of 11 May 2018, 20 NPC pts (median age 49 yr [range 35–61]) were enrolled. Most pts were male (85%) and non-smokers (65%). All pts received prior radiotherapy; 19 pts (95%) received ≥1 line of systemic treatment and the median number of prior lines of systemic treatment was 2 (range 0–10). At the cut-off date, 15 pts remain on treatment and the median study follow-up was 5.5 mo (range 0.46–9.0). Of 15 response-evaluable pts, 3 achieved a confirmed partial response (PR) and 9 achieved stable disease; 1 patient had an unconfirmed PR. Seven patients experienced ≥1 treatment-related AE (TRAE); hypothyroidism (n = 3) was the only TRAE that occurred in ≥2 pts. No grade ≥3 TRAEs or serious AEs were reported. Furthermore, no AEs led to either treatment interruption or discontinuation. Conclusions: Tislelizumab was generally well tolerated and demonstrated antitumor activity in previously treated pts with advanced NPC. Clinical trial information: CTR20160872.
Understanding contribution and independence of multiple biomarkers for predicting response to atezolizumab.
Authors: Shah Parantu K. , Kaczmarczyk Jan , Myronov Alexander , Gruba Katarzyna , Stępniak Piotr , Rolfe P. Alexander
Published: May 2019

2567

Background: No biomarker satisfactorily predict response to anti-PD-L1 therapies. Biomarker studies suffer from small sample size, presence of disease subtypes, and lack of simultaneous measurement of multiple biomarkers. The IMvigor210 dataset (Mariathasan et al., Nature 2018) provides baseline measurements for multiple biomarkers of response to atezolizumab (n range: 105-298) coupled with genomewide RNAseq profiles. We examined predictive performance of individual biomarkers and combined information from multiple biomarkers to measure changes in predictive performance. Methods: We built classification models (PR/CR vs. PD/SD) using genes and gene sets that provide information on pathways (mSigDB), immune components (xCell, Cibersort), and predictors of response (IMPRES, Immunophenoscore, and TIDE). Prognostic features were removed based on survival association in TCGA. All experiments were done with repeated five-fold double cross validation. Predictions from the gene sets model were used as a single biomarker. PD-L1 expression by IHC in tumor core and immune cells, tumor mutation burden(TMB), neo-antigen burden (NB), location of metastatic disease, immune phenotype and genomic subtypes were then systematically merged with the gene set based model. Results: NB was the best predictor of response (AUC 0.77), while a model combining NB, TMB, ECOG and expression signatures was marginally better (AUC 0.81) with a chance of over fitting. Chi-square tests for independence suggested that examined biomarkers do not provide independent information explaining lack of increase in AUC. Signatures for TP53 mutations, M1 macrophages, CD8+ T effector cell and DNA repair, among others, were present frequently in classification using gene expression information (AUC 0.71), suggesting their independent contributions to response. Adding gene expression information to NB didn’t improve AUC for response but provided better survival stratification. Conclusions: Integration of examined biomarkers with machine learning did not improve response prediction significantly. We are now examining sizes of subgroups defined by combination of low NB/TMB with these biomarkers.
Tumor mutational burden (TMB) and response rates to immune checkpoint inhibitors (ICIs) targeting PD-1, CTLA-4, and combination.
Authors: Osipov Arsen , Popovic Aleksandra , Hopkins Alexander , Frampton Garrett M. , Albacker Lee A. , Azad Nilofer Saba , Laheru Daniel A. , Zheng Lei , Jaffee Elizabeth M. , Yarchoan Mark
Published: May 2019

2578

Background: ICIs targeting PD-1/L1 and/or CTLA-4 have activity against many different cancers. We and others have previously shown that a higher TMB, a surrogate for an increased number of expressed tumor neoantigens, is an important biomarker for response to anti-PD-1/L1 monotherapy. Whether the relationship between the TMB and response to ICIs extends beyond anti-PD-1/L1 is unknown. Methods: We identified 30 major solid tumor types for which TMB has been described using a genomic profiling assay performed by Foundation Medicine. We conducted searches of MEDLINE (from Jan 1, 2010 to Jan 20, 2019), as well as abstracts presented at ASCO, ESMO, AACR Annual Meetings 2010-2018 to identify the objective response rate (ORR) for anti-PD-1/L1, anti-CTLA-4 and combination anti-PD-1/L1 plus anti-CTLA-4, in each of these cancer types. We pooled the response data from the largest published studies that evaluated the ORR. We excluded studies that; enrolled < 10 evaluable patients, investigated ICI therapies in combination with other agents, and studies that selected patients based on immune-related biomarkers. Across tumor types, median TMB was compared to ORR utilizing the coefficient of determination (r2) derived from simple linear regressions. Results: TMB is strongly associated with response to anti-PD-1/L1 monotherapy (n = 8798, r2= 0.4704, p < 0.001), and combination anti-PD-1/L1 plus anti-CTLA-4 (n = 2280,r2= 0.4082, p = 0.004). Available ORR data were more limited with CTLA-4 monotherapy and the relationship between ORR and TMB did not meet statistical significance (n = 1377, r2= 0.2606, p = 0.1086). The additional ORR benefit of adding a CTLA-4 inhibitor to anti-PD-1/PDL1 therapy increased with increasing TMB. In tumor types with a lower TMB ( < 10 mutations/MB), combined ICI therapy led to an average improvement of 5.5% in ORR over PD-1/L1 monotherapy, versus 21.8 % ORR improvement in high TMB tumors (≥10 mutations/MB). Conclusions: A strong relationship exists between TMB and clinical activity of both PD-1/L1 monotherapy and combination ICIs with PD-1/L1 plus CTLA-4. The clinical benefit of adding anti-CTLA-4 to anti-PD-1/L1 is greatest in high TMB tumors and limited in low TMB tumors.
Using machine learning algorithms to predict response and toxicity to immune checkpoint inhibitors (ICIs) in melanoma patients.
Authors: Johannet Paul , Coudray Nicolas , Jour George , Donnelly Douglas MacArthur , Bajaj Shirin , Moran Una , Dawood Zarmeena , Nomikou Sofia , Kim Randie H , Pavlick Anna C. , Weber Jeffrey S. , Tsirigos Aristotelis , Osman Iman
Published: May 2019

2581

Background: There is growing interest in optimizing patient selection for treatment with immune checkpoint inhibitors (ICIs). We postulate that phenotypic features present in metastatic melanoma tissue reflect the biology of tumor cells, immune cells, and stromal tissue, and hence can provide predictive information about tumor behavior. Here, we test the hypothesis that machine learning algorithms can be trained to predict the likelihood of response and/or toxicity to ICIs. Methods: We examined 124 stage III/IV melanoma patients who received anti-CTLA-4 (n = 81), anti-PD-1 (n = 25), or combination (n = 18) therapy as first line. The tissue analyzed was resected before treatment with ICIs. In total, 340 H&E slides were digitized and annotated for three regions of interest: tumor, lymphocytes, and stroma. The slides were then partitioned into training (n = 285), validation (n = 26), and test (n = 29) sets. Slides were tiled (299x299 pixels) at 20X magnification. We trained a deep convolutional neural network (DCNN) to automatically segment the images into each of the three regions and then deconstruct images into their component features to detect non-obvious patterns with objectivity and reproducibility. We then trained the DCNN for two classifications: 1) complete/partial response versus progression of disease (POD), and 2) severe versus no immune-related adverse events (irAEs). Predictive accuracy was estimated by area under the curve (AUC) of receiver operating characteristics (ROC). Results: The DCNN identified tumor within LN with AUC 0.987 and within ST with AUC 0.943. Prediction of POD based on ST-only always performed better than prediction based on LN-only (AUC 0.84 compared to 0.61, respectively). The DCNN had an average AUC 0.69 when analyzing only tumor regions from both LN and ST data sets and AUC 0.68 when analyzing tumor and lymphocyte regions. Severe irAEs were predicted with limited accuracy (AUC 0.53). Conclusions: Our results support the potential application of machine learning on pre-treatment histologic slides to predict response to ICIs. It also revealed their limited value in predicting toxicity. We are currently investigating whether the predictive capability of the algorithm can be further improved by incorporating additional immunologic biomarkers.
Real-world outcomes of underrepresented patient populations treated with immune checkpoint inhibitors (ICIs): African American descent, poor ECOG performance status, and chronic viral infections.
Authors: Shah Neil J. , Blackburn Matthew , Cook Michael R , Belouali Anas , Serzan Michael , Kelly William , Bikas Athanasios , Kim Chul , Madhavan Subha , Liu Stephen V. , Atkins Michael B.
Published: May 2019

2587

Background: ICIs have now become standard of care treatment for multiple malignancies. However, patients (pts) who are African American decent (AA), have a poor ECOG performance status (PS) or chronic viral infections [human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV)] were underrepresented in early clinical trials with ICIs and outcome data in these pt populations is not well reported. Methods: We performed a retrospective analysis of pts treated with ICIs (anti-PD(L)-1, anti-CTLA-4, or combination ICIs) across five MedStar Health hospitals from January 2011 to April 2018. Investigator-assessed best responses were noted. CTCAE v4.03 was used to capture immune-related adverse events (irAEs). Results: We identified 765 pts treated with 829 unique ICIs therapies across different malignancies. A total of 203 AA pts, 178 pts with a pre-treatment ECOG PS ≥2, 21pts with HIV, and 50 pts with HBV/HCV were noted. Any grade and grade ≥ 3 irAEs in the HIV cohort were 24% and 10% with an ORR of 29%. Any grade and grade ≥ 3 irAEs in HBV/HCV were 50% and 26% with an ORR of 21%. No viral reactivation or changes in pts anti-viral medications were noted during ICIs treatment. The ORR in AA pts was 35%. Any grade and grade ≥ 3 irAEs in the AA cohort were 27% and 8%, respectively. The ORR in pts with ECOG PS ≥2 was 14%. Any grade and grade ≥ 3 irAEs in this cohort were 20% and 4%. Similar trends were seen in the subset of patients with NSCLC treated with anti-PD(L)1 monotherapy (Table). Outcomes of NSCLC pts treated with anti-PD(L)-1 monotherapy. Conclusions: ICI therapy was not associated with any new safety signal in the above underrepresented populations. Prospective studies are needed to validate this data.[Table: see text]
Association of the imbalance between early and late differentiated intra-tumor CD4 T cells with mutational burden in non-small cell lung cancer.
Authors: Ghorani Ehsan , Reading James L. , Henry Jake Y. , Robert De Massy Marc , Rosenthal Rachel , Furness Andrew J.S. , Ben Aissa Assma , Jamal-Hanjani Mariam , Birkbak Nicolai , Wilson Gareth , Salgado Roberto , Lund Tom , Hiley Crispin T. , Loi Sherene , Hackshaw Allan , McGranahan Nicholas , Chain Benjamin M. , Peggs Karl S. , Swanton Charles , Quezada Sergio A.
Published: May 2019

2590

Background: CD4 T helper cells are key orchestrators of immunity in states of persistent antigen exposure. In chronic viral infection, loss of immune control is associated with CD4 differentiation skewing (CD4ds) resulting from decline of early progenitors and gain in abundance of exhausted and terminally differentiated subsets. Here, we set out to identify whether a similar process occurs within the tumour microenvironment, contributing to immune dysfunction. Methods: Multiregional samples of tumour and non-tumour lung tissue from patients with untreated, surgically resected non-small cell lung cancer (NSCLC) within the first 100 recruited to the prospective lung TRACERx study were analysed by high dimensional flow cytometry of tumour infiltrating lymphocytes (TILs) and paired bulk tumour exome and RNA sequencing. We additionally reanalysed publically available single T cell and bulk tumour RNA sequencing from patients with NSCLC. Results: Unsupervised clustering and dimension reduction revealed a heterogenous landscape of CD4 TILs, with evidence of CD4ds in association with tumour mutational burden. Loss of PD1-CCR7+ T central memory enriched early differentiated cells was accompanied by gain in abundance of PD1+ populations with exhausted (CD57-ICOShiCTLA4hi) and terminally differentiated effector (CD57+Eomes+) phenotypes. Further characterisation of these populations by single cell RNA sequencing revealed differential expression of key genes involved in transcriptional regulation, co-inhibition and co-stimulatory pathways. A validated gene signature of CD4ds was associated with worse outcomes in TRACERx and TCGA cohorts. Conclusions: Our findings reveal remodelling of the CD4 differentiation landscape in association with tumour genomic characteristics, underscoring how mutational burden in the context of chronic stimulation may lead to loss of immune fitness and elucidating key regulatory pathways in potentially clinically relevant CD4 subsets.