bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid expansion of M-MDSCs and association with high levels of plasma TSLP and primary resistance to PD-1 inhibitors in metastatic NSCLC.
Authors: Lau Sally CM , Wong Stephanie WY , Wang Ben X , Patel Devalben , Fares Aline Fusco , Tsao Ming-Sound , Bradbury Penelope Ann , Liu Geoffrey , Leighl Natasha B. , Shepherd Frances A. , Ohashi Pamela S , Sacher Adrian G.
Published: May 2020

3084

Background: Elevated frequency of peripheral myeloid cell populations has consistently been associated with poor response to immune checkpoint inhibitors (ICI) in metastatic non-small cell lung cancer (mNSCLC). The mechanisms underlying this relationship remains poorly understood. Thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation, has been implicated in a complex feedback loop leading to tumor growth and expansion of myeloid populations. We hypothesized that TSLP levels directly correlate with the presence and expansion of myeloid derived suppressor cell (MDSC) populations and sought to explore their association with response to PD-1 inhibitors in mNSCLC. Methods: mNSCLC patients treated with ICIs underwent baseline and serial blood collection. Peripheral blood mononuclear cells (PBMC) were analyzed by high-dimensional flow cytometry using validated panels to evaluate T/B/NK-cell, Treg and myeloid populations. Plasma cytokines including TSLP were analyzed using ELISA and Luminex assays. Cox and logistic regressions were utilized to correlate biomarkers with progression-free survival (PFS), overall survival (OS) and radiographic response. Results: 30 mNSCLC patients treated with single-agent ICI were included in the analysis. TSLP level was significantly associated with expansion of monocytic(M)-MDSCs in response to ICI treatment (p=0.02). M-MDSC frequency after a median of 20 days of ICI treatment was significantly associated with progressive disease (PD), reduced PFS and OS (all p<0.05) whereas no correlation was seen with baseline M-MDSC frequency. Patients with a doubling of M-MDSCs (n=11) after treatment had a primary PD rate of 64% vs 24% (OR 7.0, p=0.04) and significantly worse median PFS (2.5 vs 7.8 months, HR 2.6 p=0.04). Conclusions: Early expansion of circulating M-MDSCs after treatment with PD-1 inhibitors is associated with elevated baseline TSLP levels and primary disease progression following ICI therapy in mNSCLC. These findings suggest that elevated TSLP and early expansion of myeloid populations may represent an important mechanism of primary resistance to PD-1 inhibitors in mNSCLC.
Relationship of infusion duration to safety, efficacy, and pharmacodynamics (PD): Second part of a phase I-II study using VSV-IFNβ-NIS (VV1) oncolytic virus in patients with refractory solid tumors.
Authors: Merchan Jaime R. , Patel Manish , Cripe Timothy P. , Old Matthew O. , Strauss James Fredric , Thomassen Amber , Diaz Rosa M , Peng Kah Whye , Russell Stephen J. , Russell Luke , Reckner Monica , Wiegert Erol , Bexon Alice Susannah , Powell Steven Francis
Published: May 2020

3090

Background: VV1 (Voyager V1) is derived from VSV, an RNA virus with low human seroprevalence, engineered to replicate selectively in and kill human cancer cells. In Part 1 of this study, we demonstrated the safety of intratumoral VV1 and dose-response, using serum IFNβ as a biomarker; we observed viral replication in tumor and concomitant lymphocyte/neutrophil trafficking (SITC 2018). 2 other studies suggested greater efficacy and higher IFNβ levels with IV administration. Longer infusion durations were reported to mitigate infusion reactions (IRRs) for another oncolytic. Methods: We studied 3 different infusion durations of VV1 monotherapy at the recommended phase 2 IV dose (1.7 x 1010 TCID50) in patients with advanced solid tumors. Endpoints included safety, preliminary anti-tumor activity, viral titers, IFNβ PD and shedding. Patients received IV VV1 once on D1 and were monitored for DLT over 21 days with efficacy assessments every 6 weeks. IRRs were classified using Lee 2014 criteria for CRS as either constitutional symptoms only (G1) or involving hypotension (G2). Results: 18 patients were treated at 30, 60 and 180-minute durations (n = 7, 5 and 6, respectively). No DLTs, deaths or G3-4 related IRR AEs were observed. Most pts were female (67%), white (100%), with ECOG PS 0 (61%) and median 4 lines of prior systemic therapy (range 1-14) for colorectal (CRC; 56%), squamous cell carcinoma (11%), pheochromocytoma (11%), sarcoma (11%) or other (11%) cancers. The table shows results (number of patients) by infusion duration. Conclusions: There was no difference in safety between the 3 infusion durations, while efficacy and PD markers suggested better anti-tumor effect with 30-minute infusion. VV1 is safe for caregivers, with no viral shedding. Part 3 of this study will now treat CRC patients with VV1 in combination with a checkpoint inhibitor (avelumab). A 5-arm phase 2 basket study in combination with cemiplimab is proceeding with 30-minute infusions. Clinical trial information: NCT02923466 . [Table: see text]
Clinical activity of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in HER2 amplified metastatic breast cancer (MBC) patients (pts) who had progressed on anti-HER2 ADCs.
Authors: Hamilton Erika Paige , Petit Thierry , Pistilli Barbara , Goncalves Anthony , Ferreira Ana Alexandra , Dalenc Florence , Cardoso Fatima , Mita Monica M. , Dezentjé Vincent O. , Manso Luis , Graff Stephanie L. , Bidard Francois Clement , Aftimos Philippe Georges , Escrivá Santiago , Afonso Noemia , Wasserman Ernesto , Bol Kees , Stalbovskaya Viktoriya , Vliet Anastasia , Bachelot Thomas
Published: May 2020

3093

Background: MCLA-128 (zenocutuzumab ), a HER3 pathway inhibitor, is a humanized bispecific full-length IgG1 antibody targeting both HER2 and HER3 with enhanced ADCC activity. The unique Dock & Block mechanism inhibits HER3 from interacting with its ligands and targets HER2 at a different epitope than trastuzumab, blocking HER2/HER3 dimerization and downstream PI3K/AKT/mTOR signaling. In MBC, HER3 overexpression and/or HER3 ligand upregulation are important drivers leading to trastuzumab resistance, indicating a role for MCLA-128. Preclinical activity was seen in HER2+ breast models when MCLA-128 was combined with trastuzumab. Furthermore, single agent MCLA-128 showed consistent antitumor activity in heavily pretreated HER2+ MBC pts. A phase 2, open-label study explored the MCLA-128/trastuzumab plus vinorelbine triplet in an MBC population. Methods: This open-label trial planned for up to 40 evaluable women with HER2+/amplified MBC progressing on up to 5 anti-HER2 lines including trastuzumab, pertuzumab and an anti-HER2 ADC. Pts received MCLA-128 (750 mg, 2h IV), trastuzumab (8 mg/kg loading, then 6 mg/kg) and vinorelbine (25 mg/m², D1 and 8), q3w. A safety run-in of MCLA-128 + trastuzumab ± chemotherapy was performed. Disease control rate (DCR; RECIST 1.1, per investigator), best overall response (BOR), overall response rate (ORR), safety, and PK are evaluated. Data cutoff was 14Nov2019. Results: 28 pts with a median 3 lines (range 2-5) of anti-HER2 therapy (metastatic setting) and 3 (range 1-6) metastatic sites, received a median of 5 (range 1-17) MCLA-128 cycles. Among 26 pts evaluable for efficacy, 20 patients had CR/PR/SD as BOR; DCR was 77% (90%CI: 60-89) with 1 confirmed CR and 4 PRs (2 unconfirmed). Common related AEs (all grades; G3-4) were neutropenia/neutrophil count decrease (61%; 46%), diarrhea (61%; 4%), asthenia/fatigue (46%; 0), nausea (29%; 0). No clinically significant LVEF decline was seen. At the end of cycle 1, mean trough levels of MCLA-128 was 19.1 µg/mL, and mean terminal half-life was 112 h (n = 8-11). Data on the primary endpoint, clinical benefit rate at 24 weeks, and biomarkers will be provided. Conclusions: The triplet MCLA-128-based combination is active in heavily pretreated pts with HER2+/amplified MBC. The regimen is safe and well tolerated with a manageable AE profile mostly related to the chemotherapy component. Clinical trial information: NCT03321981 .
A phase I, open-label, multicenter, single-dose escalation and multi-dose study of a monoclonal antibody targeting CEACAM1 in subjects with selected advanced or recurrent malignancies.
Authors: Shapira Roni , Weber Jeffrey S. , Geva Ravit , Sznol Mario , Kluger Harriet M. , Wong Deborah J.L. , Liang Bertrand C.
Published: May 2020

3094

Background: The carcinomembryonic antigen cell adhesion molecule 1 (CEACAM1, CD66a) is a member of the CEA gene family. CEACAM1 interacts homophilically and heterophilically with CEACAM5, and is involved in various anti-proliferative activities. CEACAM1 is expressed on a variety of epithelial and hematological cells, including multiple types of cancer and activated lymphocytes. High CEACAM1 expression in some tumor types is known to be associated with poor disease prognosis. Recently it was demonstrated CEACAM1 is co-expressed on exhausted lymphocytes with other immune checkpoints such as TIM-3 and may regulate downstream activity. CM24 is a novel humanized α-CEACAM1-specific antibody with nM affinity to the N terminal domain of CEACAM1, which blocks intercellular CEACAM1 interactions. Methods: The primary objective was to test the safety and tolerability of CM24 in adult patients with advanced or recurrent cancer. Secondary objectives included assessment of CM24 PK and PD profiles, anti-tumor response and the recommended Phase 2 dose. Patient received IV infusion of CM24 at 7 dose levels ranging between 0.01 and 10 mg/kg in a cycle of 4 doses administered q2wks followed by a 6-week observation only period and additional 6 cycles. Results: 27 patients (median pretreatment of 4 prior regimens; range 2-8, 11 colorectal, 7 melanoma, 4 ovarian, 3 gastric, 2 NSCLC; 13 males, 14 females, mean age of 60 years), were included. Treatment with CM-24 was overall well-tolerated without DLTs up to 10 mg/kg. The most frequent AE was grade 1-3 increased alanine aminotransferase (7 subjects) and the most severe AE was grade 3/4 increase in gamma-glutamyltransferase (4 subjects). Drug-related AEs were observed in 63% of the subjects with grade 3-5 occurred in 3.7%. Eight subjects (29.6%) had stable disease as the best overall response. Median overall survival was 4 (3.4, 8.0) and 6.2 (2.7, 10.2) months for the 3 and 10 mg/kg doses, suggesting dose response. Cmax, AUC and t1/2 increased with increasing dose with the longest t1/2 of 11.2 days obtained at 10mg/kg. The average target occupancy of CM24 at 3mg/kg and 10mg/kg were 75% and 93%, respectively. Conclusions: PK and target-mediated drug disposition analysis suggest that doses higher than 10mg/kg are needed for target saturation at a q2 week regimen while a q3 week regimen is less optimal. A phase 1/2 clinical trial testing CM24 in combination with anti-PD-1 therapy in patients with NSCLC including assessment of CEACAM1 expression is warranted. Clinical trial information: NCT02346955 .
First-in-class microbial ecosystem therapeutics 4 (MET4) in metastatic solid cancer patients treated with immunotherapy: MET4-IO.
Authors: Araujo Daniel Vilarim , Oliva Bernal Marc , Tan Tira Jing Ying , Heirali Alya Abbas , Schneeberger Pierre H.H. , Pimentel Muniz Thiago , Chen Bo , Stayner Lee-Anne , Xia Kathy , Hansen Aaron Richard , Wang Ben X , Hogg David , Cochrane Kyla , Langer Shawn , Mashiach Nissim , Xu Wei , Siu Lillian L. , Coburn Bryan , Spreafico Anna
Published: May 2020

3098

Background: Therapeutic augmentation of the intestinal microbiome to improve immunotherapy outcomes is an active area of investigation. Microbial Ecosystem Therapeutics (METs) are consortia of human-derived bacteria designed to be reproducible, scalable and safe alternatives to fecal transplant. MET4 is a first-in-class consortium of taxa associated with immune checkpoint inhibitor (ICI)-responsiveness. Here we describe preliminary results of MET4-IO, an interventional trial assessing the safety and ecological effects of MET4 in ICI recipients. Methods: MET4-IO is a randomized investigator-initiated trial, evaluating MET4 in solid cancer patients treated with ICI. MET4-IO involves 3 cohorts of 65 total patients: Group A, a safety cohort of 5 patients already on ICI; Group B, patients starting ICI, randomized 3:1 to receive MET4 or not; Group C, patients on ICI who experience radiological progression but not clinical deterioration, randomized 1:1 to receive MET4 or not. Stool and blood samples are collected at baseline and 4-5 additional time-points. For this interim analysis, 16S rRNA gene sequencing was performed on fecal specimens. Shannon diversity, relative abundance (RA), number and fold-change of MET4 taxa > RA 0.01 were assessed and compared to controls. Results: As of January 26, 2020, 21 patients were enrolled (A = 5,B = 12,C = 4), and 15 (71%) received MET4. The mean age was 65.9 years, 40% were females, 52% had head and neck cancer and 19% melanoma. Sixteen patients (76%) were treated with an anti-PD1 agent as monotherapy and 5 with a combination of anti-PD1 and anti-CTLA4 antibodies. G3-4 toxicities (CTCAEv5.0) attributed to ICI were observed in 13% vs. 17% of MET4 exposed and control patients, respectively. Three patients (20%) experienced toxicities attributed to MET4, all grade 1 except G2 dyspepsia in 1 patient. A greater number of MET4-associated taxa were detectable in MET4 recipients than controls (p < 0.01), with a trend towards higher cumulative RA (p = 0.10). No significant change in Shannon diversity after MET4 was observed, however controls were more likely to lose diversity overtime than MET4 recipients (p = 0.05). Colonization with MET4 varied by recipient and by taxon. Bifidobacterium, Collinsella and Enterococcus were significantly more common and abundant in MET4 recipients than controls. Conclusions: In this cohort, MET4 treatment was safe and associated with higher MET4-associated taxa in recipients than controls. Further analyses including peripheral blood immunophenotyping are ongoing. Clinical trial information: NCT03686202 .
Initial results from a phase II study (TACTI-002) in metastatic non-small cell lung or head and neck carcinoma patients receiving eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab.
Authors: Felip Enriqueta , Doger Bernard , Majem Margarita , Carcereny Enric , Krebs Matthew , Peguero Julio Antonio , Roxburgh Patricia , Forster Martin , Bajaj Pawan , Clay Timothy Dudley , Triebel Frederic
Published: May 2020

3100

Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and then CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses than observed with pembrolizumab alone. We hereby report initial results of a phase II trial (NCT03625323). Methods: A predefined number of patients (pts) are recruited into this 3-cohort trial irrespective of PD-L1 expression; part A: 1st line, PD-X naïve NSCLC; part B: 2nd line, PD-X refractory NSCLC and part C: 2nd line PD-X naive HNSCC. The study has a Simon's 2-stage design, with objective response rate (ORR) as primary endpoint. Secondary endpoints include disease control rate, progression free and overall survival, PK, PD and immunogenicity. Additional pts (N2) will be recruited for each part if pre-specified thresholds for ORR are met. Up to 109 pts will be enrolled. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). The study was approved by ethic committees and institutional review boards. Results: Between 04 Mar 19 and 31 Jan 2020, 48 pts were enrolled and evaluated for safety and exposure. The median age was 66 yrs (range 48-84) and 73 % were male. The ECOG was 0 in 50 % and 1 in 50 % of pts, respectively. Pts received a median of 5 (7) and in total 311 (413) pembrolizumab (efti) administrations, respectively. Three pts (6.3 %) discontinued study treatment due to AEs. The most common ( > 10%) adverse events (AEs) being cough (31 %), asthenia (23 %), decreased appetite (19 %), fatigue (19 %), dyspnea (17 %), diarrhea (15 %) and constipation 13 %). From part A all pts (n = 17) were evaluated. Eight pts (47 %) had a partial response (iPR) and six (35 %) had stable disease according to iRECIST representing an ORR (DCR) of 47 % (82 %). irPRs were observed in all different PD-L1 groups ( < 1%; ≥ 1 % ≤49 %; ≥ 50 %). Ten (10; 59 %) pts are still on therapy (8+ months). In part C stage 1 15/18 pts are evaluable and six (40 %) had an iPR to date. Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in all comer PD-L1 1st line NSCLC and 2nd line HNSCC. Stage 2 has opened for both parts. Clinical trial information: NCT03625323 .
A phase I study to evaluate the T-cell engager AMV564 alone and in combination with pembrolizumab in subjects with advanced solid tumors.
Authors: Starodub Alexander , Piha-Paul Sarina Anne , Karim Raghad , Ruegg Curtis , Smith Victoria , Chun Patrick Youngwhan
Published: May 2020

3101

Background: Overcoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. AMV564 is a bivalent, bispecific T-cell engager that binds CD3 and CD33. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data (Cheng 2017; Blood;130:51) and an ongoing clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to deplete MDSC while sparing monocytes and neutrophils. Methods: In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection for 2 out of 3 wks per cycle, alone or in combination with pembrolizumab (200 mg every 3 wks). Key objectives are to evaluate AMV564 safety, identify a maximum tolerated or recommended phase 2 dose, and evaluate PK, immunophenotype of myeloid and T cell compartments, and preliminary efficacy. Results: Eleven patients have been enrolled: 8 monotherapy (3 at 15 mcg/d, 5 at 50 mcg/d) and 3 combination (5 mcg/d). Tumor types include ovarian (n = 2), small bowel, gastroesophageal junction, endometrial, rectal, penile, urothelial, squamous cell carcinoma (skin), appendiceal, and non-small cell lung. AMV564 was associated with grade (G) 1-2 injection site reactions and G1-2 fevers, which were manageable with acetaminophen and diphenhydramine, as well as G2 weight gain and G3 anemia. No dose-liming toxicity has been observed in any cohort. Three monotherapy patients (15 mcg/d) were evaluable for efficacy with ≥1 on-treatment scan; 2 had SD and 1 PD per RECIST 1.1 criteria. T cell activation, as shown by redistribution from the periphery (margination), was apparent in the first week of dosing for most patients. Compensatory myelopoiesis led to initial expansion of MDSC which were then depleted by AMV564. Increased cytotoxic T cell activation and T-helper (Th) 1 response was evidenced by increased T-bet positive CD4 and CD8 cells and controlled or decreased regulatory T cells. In some patients, effector memory CD8 cell populations (Tem and Temra) were expanded. Conclusions: AMV564 is safe and tolerable when administered SC at doses of 15 mcg/d alone and 5 mcg/d in combination with pembrolizumab. AMV564 depleted MDSC populations and altered T cell profiles consistent with activation of cytotoxic T cells and a Th1 response. Clinical trial information: NCT04128423 .
An increase in serum choline levels to predict progression-free survival (PFS) in patients (pts) with advanced cancers receiving pembrolizumab.
Authors: Watson Geoffrey Alan , Zhang Wenjiang , Liu Zhihui (Amy) , Spreafico Anna , Hansen Aaron Richard , Bedard Philippe L. , Lheureux Stephanie , Abdul Razak Albiruni Ryan , Cescon David W. , Butler Marcus O. , Xu Wei , Mak Tak , Siu Lillian L. , Chen Eric Xueyu
Published: May 2020

3102

Background: Recent work from our laboratory demonstrated that T cell-derived acetylcholine induces vasodilation and increases T cell migration to infected tissues in response to viral infection (Cox et al. Science 2019). Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study is the first reported attempt to correlate serum choline levels in patients (pts) with advanced solid tumors receiving pembrolizumab with treatment outcomes. Methods: Blood samples were collected pre-treatment in 106 pts treated with pembrolizumab 200 mg IV Q3W in the investigator-initiated INSPIRE study (NCT02644369). Of these, 81 pts had on-treatment blood samples collected at week 7 (pre-cycle 3). Serum choline was analyzed with an HPLC-tandem mass spectrometry assay. PD-L1 staining was performed in baseline tumor tissues using 22C3 antibody and scored using modified proportion score. Tumor mutational burden (TMB) was calculated based on number of nonsynonymous mutations detected using whole exome sequencing. Multivariable Cox models were used to assess the impact of choline on PFS and OS, while adjusting for cohort, PD-L1 expression and TMB. Results: This pan-cancer group of 106 pts (median age 55, 62% females) comprised of 5 cohorts: squamous cell carcinoma of the head and neck = 19 pts, triple negative breast cancer = 22, high grade serous ovarian cancer = 21, melanoma = 19, mixed solid tumors = 32. With a median follow-up of 11 months, the median PFS = 1.9 months and median OS = 13.9 months for the entire cohort. In univariable analysis adjusted by cohort, baseline serum choline levels in 106 pts did not correlate with PFS or OS. However, an increase in serum choline level at week 7 compared to pre-treatment (D choline) in 81 pts was significantly associated with a better PFS (aHR 0.49, 95% CI 0.28-0.85, p = 0.01), and a trend towards a better OS (aHR 0.57, 95% CI 0.32-1.03, p = 0.064). In multivariable analysis, D choline remains significantly associated with an improved PFS (p = 0.0087) after adjustment for cohort, PD-L1 and TMB. Conclusions: This is the first exploratory report of serum choline levels in pan-cancer pts receiving pembrolizumab. The association between improved PFS and D choline suggests a possible role for the cholingeric system in the regulation of antitumor immunity. Further nonclinical and clinical studies are required to validate this finding.
A phase I, dose-escalation study of ADG106, a fully human anti-CD137 agonistic antibody, in subjects with advanced solid tumors or relapsed/refractory non-Hodgkin lymphoma.
Authors: Zhang Li , Zhao Hongyun , Ma Yuxiang , Zheng Xin , Jiang Ji , Zhang Yang , Hong Shaodong , Liu Guizhong , She Xiaohong , Ni Qingjiang , Zhu Lvyu , Zhu Yi , Du Fangyong Felix , Luo Peter
Published: May 2020

3105

Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody, targeting a unique epitope of CD137 with novel mechanism of actions for CD137 agonism, CD137 ligand antagonism and potent cross-linking via FcgRIIb. This phase 1 study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and preliminary efficacy. Methods: Eligible patients with age 18 to 75, ECOG ≤1, measurable lesion received intravenous infusion of ADG106 every 3 weeks for a maximum of 24 months. Accelerated titration was applied in 0.1mg/kg dose level and traditional Fibonacci 3+3 method was applied in 0.5, 1.5, 3.0, 5.0 and 10.0 mg/kg dose levels. A dose-expansion cohort will be started for dose levels that have been proved tolerable and with evidence of clinical or biological activity. Results: Data cutoff at Jan 17 2020, 15 patients [5 adenoid cystic carcinoma (ACC), 5 non-small cell lung cancer (NSCLC), 3 nasopharyngeal carcinoma, 1 malignant pleural mesothelioma and 1 follicular lymphoma] were enrolled and received treatment: 0.1mg/kg (n = 1), 0.5mg/kg (n = 3), 1.5mg/kg (n = 5), 3mg/kg (n = 3), and 5mg/kg (n = 3). Of these 15 patients, 6 with ongoing treatment, 9 discontinued (8 progression disease, 1 lack of clinical benefit). Medium treatment duration was 2 cycles (range 2-8). No dose limiting toxicities were observed. Seven (47%) patients experienced treatment-related AEs (TRAEs): rash (13%), pruritus (13%), nausea (7%), pyrexia (7%), hemoptysis (7%), mouth ulceration (7%), vomiting (7%), chest discomfort (7%), LDH increased (7%). All TRAEs were grade 1, no grade ≥3 occurred. One serious adverse event (anemia, not related) was observed. Pharmacokinetic analysis of ADG106 showed a half-life ranging from 5~10 days, with dose-dependent increase of systemic exposure. Treatment induced anti-drug antibodies were developed in 3 (20%) patients. No objective response was observed among the 14 evaluated patients. Disease control rate was 57% (8 stable disease), tumor shrinkage was observed in 3 (21%) patients (2 ACC, 1 NSCLC). Conclusions: ADG106 is safe and tolerable at doses up to 5 mg/kg in solid tumors and non-Hodgkin lymphoma. The dose expansion cohorts have started at selected doses. Clinical trial information: NCT03802955 .
The prevalence of HLA LOH across 10 cancer types in Chinese patients.
Authors: Huang Jian'An , Hu Jie , Fu Xiaorui , Zhang Xiuqing , Tong Fan , Du Xinhua , Luo Ziwen , Yi Yuting , Guan Yan-Fang , Xia Xuefeng
Published: May 2020

3124

Background: Recognition of tumor neoantigen is the key to generating immune response. The expression and integrity of human leukocyte antigen (HLA) are the prerequisites for neoantigen presentation, and loss of heterozygosity in HLA (HLA LOH) may facilitate immune evasion. However, the incidence of HLA LOH in Chinese cancer patients is unknown. Methods: In this study, 45 samples sequenced with both 1021-gene panel and whole-exome sequencing(WES) were used to evaluate the consistency of HLA LOH in the two testing strategies. The prevalence of HLA LOH analysis was performed in 1546 advanced patients across 10 diverse cancer types and 114 early-stage lung cancer patients who had undergone tumor profiling using 1021-gene panel. Exon 2, exon 3 and bilateral introns of HLA-A/B/C genes were well covered in 1021-gene panel. HLA LOH were analysis using LOHHLA algorithm (McGranahan, et al. 2017). Results: In the HLA LOH analysis of 45 samples, the consistency of 1021-gene panel and WES was 95.6% (43/45). Among the 1660 samples, 1.3% (21) were detected as HLA homozygous at all of the three site. HLA LOH was found in 45.1%(697/1546) of all the advanced patients, range from 24.1% to 59.7%. In colorectal cancer, the HLA LOH ratio of MSS samples was significantly higher than that of MSI-H samples (46.2%, 61/132 vs 16.7%, 3/18 p =0.0214). For NSCLC, the proportion of HLALOH in early-stage (I-IIIa) lung adenocarcinoma and lung squamous cell carcinoma was 25.7% (18/70) and 65.9% (29/44), respectively, consistent with the report. However, advanced (IIIa-IV) lung adenocarcinoma and lung squamous cell carcinoma were 49.4%(168/340) and 58.7%(179/305), respectively. The reason for the difference between early-stage lung adenocarcinoma and advanced lung adenocarcinoma needs further study. In 43.8% of cases (326/744), LOH occurred simultaneously in HLA-A, B and C,suggesting that the Class I locus was often lost together. Conclusions: We can use multi-gene panel for HLA LOH analysis, provided that the relevant regions are well captured. The prevalenceof HLA LOHpresent differences among cancer types.Understanding these distributions may provide more information for immunotherapy research. [Table: see text]
Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) in combination with PD-1 monoclonal antibody and/or antiangiogenic treatment in patients with metastatic solid tumors.
Authors: Wei Jia , Liu Qin , Sha Huizi , Qian Hanqing , Shao Jie , Zhu Lijing , Wang Lifeng , Li Rutian , Liu Baorui
Published: May 2020

3134

Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Nanotechnology has been reported to enhance immune responses of vaccines. Moreover, immunizing patients against such neoantigens, in combination with checkpoint inhibitor (CPI) and/or antiangiogenic drugs may elicit greater anti-tumor responses. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) is an amphiphiles nanovaccine loaded with personalized vaccine encoding multiple neoantigens designed to induce neoantigen specific T cells responses. Patients will receive PVAC in combination with PD-1 monoclonal antibody and/or antiangiogenic drugs. Primary end points include safety and tolerability. Results: 13 microsatellite stability (MSS) patients, which had relapsed from standard treatments, are enrolled in this study. 5 patients (1 gastric cancer, 1 liver cancer, 1 cervical carcinoma, 1 soft tissue sarcoma, 1 renal carcinoma) received PVAC in combination with PD-1 mAb, and another 8 patients (3 gastric cancer, 2 colon cancer, 1 NSCLC, 1 renal carcinoma) received PVAC in combination with PD-1 mAb and antiangiogenic therapy. No DLTs were reported. Five patients developed grade 1 and one patients developed grade 2 subcutaneous indurations in the injection sites, which collected with nanovaccine. One patient had grade 2 rash caused by antiangiogenic drug. No drug related SAEs have been observed. There are 1 CR, 6 PR, 4 SD and 2 PD. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: PVAC is safe and well tolerated. Clinical responses have been observed in combination with PD-1 mAb and antiangiogenic drugs and neoantigen-specific T cell response have been observed after vaccination. Clinical trial information: ChiCTR1900022986 .
Safety and tolerability of intratumorally administered OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: A phase I dose escalation clinical study.
Authors: Huang Jing , Zhang Bo , Tang Jialin , Chang Qing , Zhang Rui , Geng Chengyun , Wu Dawei , Qi Ling , Gu Xiangyong , Liu Binlei
Published: May 2020

3139

Background: There have been limited reports concerning treatment outcomes of oncolytic viruses in solid tumors other than melanoma. OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express GM-CSF to enhance tumor-specific immune responses. Methods: We conducted an open-label, single-center, phase 1 study. Eligible pts were 18-75 years of age; had histologically confirmed advanced solid tumor; had progressed after standard systemic treatments. Pts were required to have tumor(s) deemed safe to inject, with a longest diameter of at least 0.5cm. Other eligibility criteria included measurable lesion as per RECIST v1.1; ECOGPS score of 0-1 and adequate organ functions. A 3+3 dose-escalation strategy was used in the study and 3 dose levels (106, 107 and 108 CCID50/mL) of OH2 were assessed. OH2 was administered intratumorally every 3 weeks for the first cycle and every 2 weeks.Treatment may continue afterwards in ptswith potential clinical benefit at the discretion of the investigators. The primary objective was the safety and tolerability of OH2 injection as defined by the dose limiting toxicities (DLTs) within the first 3 weeks of therapy, and the maximum tolerated dose (MTD). Secondary objectives included efficacy and immunogenicity of OH2. Results: 11 pts were enrolled between April 17, 2019 and November 4, 2019. The median follow-up duration was 8.36 months (95%CI: 5.64-11.08). OH2 was well-tolerated as no DLTs were reported and no MTD reached. Before the end of the DLT assessment period,1 pt withdrew consent, and 1 pt died of arrhythmia unrelated to OH2, with negative OH2 DNA copies in serum, urine and saliva samples. Most treatment-related adverse events (TRAEs) observed were of grade 1-2, except that 1 pt in the 108 CCID50/mL group developed grade 3 fever. The most common TRAEs were fever (n =5) and blood bilirubin level increase (n = 4). There were no grade 4 or 5 TRAEs. One pt(rectal cancer) had PR and 2 (appendix cancer and ovarian cancer) had SD as per RECIST v1.1. One patient (esophageal cancer) achieved iPR as per iRECIST criteria. The duration of follow-up for the 2 responders were 9.70 months and 8.36 months, respectively, and both had ongoing responses. Notably, regression of a non-injected lesion was observed in 1 patient. Conclusions: OH2 had a favorable safety profile with no DLTs and MTD. The dose expansion study in selected tumor types is currently underway. Clinical trial information: NCT03866525 .
Analysis of mutation detection of POLD1/pole in pan-cancer.
Authors: Yang Gao , Huang Jian'An , Zu Yukun , Zhang Yan , Dai Pingping , Han Yaqian , Geng Guojun , Zhu Xiaolei , Chang Ruimin , Huan Jiaojiao , Chen Chen , Guan Yan-Fang , Yang Ling , Yi Xin , Xia Xuefeng
Published: May 2020

3142

Background: Previous studies proved that mutation of POLD1 and POLE elevates base-substitution mutations and lead to the elevation of tumor mutation burden (TMB). Other signature needs to explore to identify driver mutations in these two genes. Methods: Using gene-panel target-capture next generation sequencing, we analyzed the TMB and POLD1/POLE mutation in 17383 tumor tissue or plasma ctDNA samples from different patients. Results: Tumor mutation burdens were calculated of all the 17383 samples. According to the present research and our panel, we use 10 and 100 Mut/Mb to define hypermutation and ultra-hypermutation. Samples with hypermutation possessed 18.8% (n = 3268) and ultra-hypermutation possessed 0.3% (n = 58). In unselected, hypermutation and ultra-hypermutation group, POLD1 or/and POLE mutations were identified in 3.5% (n = 625), 56.1% (n = 32) and 87.9%(n = 372) samples. There were 0.5% (n = 81), 17.0% (n = 73) and 87.7%(n = 51) identified more than one mutation. These results showed that POLD1 or/and POLE mutations were enriched in samples with high TMB. We screened every known POLE and POLD1 driver mutations. There were 22 ultra-hypermutation samples identified these mutations, including A456P(3), P286R(10), V411L(6), M444K(1), S459F(1) in POLE and R1016H(1) in POLD1. Interestingly, all of them were identified in microsatellite stable (MSS) samples, which suggest that driver mutation may enriched in MSS samples. These already known driver mutation was not detect in 24 high-level microsatellite instability (MSI-H) and ultra-hypermutation samples. We further analyzed 10 POLD1/POLE mutations in other 5 MSS and ultra-hypermutation samples. POLE L424V was a pathogenic germline mutation but not defined as a driver mutation clearly before. POLE P286C had not been biochemically characterized but had different residue with P286R in the same position. Others had not been biochemically characterized (R232H, A234T, V945M, S1064I, Y467H in POLD1, D462N and R749Q, E1956D in POLE). These mutations were potential driver mutations and further research need to be support. Conclusions: We found that not only POLD1 or/and POLE mutations were enriched in samples with high TMB, but also driver mutations were enriched in microsatellite stable tumors. Further researches need to continue to identify more driver mutations of POLD1 and POLE.
CX-2029, a PROBODY drug conjugate targeting CD71 (transferrin receptor): Results from a first-in-human study (PROCLAIM-CX-2029) in patients (Pts) with advanced cancer.
Authors: Johnson Melissa Lynne , El-Khoueiry Anthony B. , Hafez Navid , Lakhani Nehal J. , Mamdani Hirva , Rodon Ahnert Jordi , Sanborn Rachel E. , Ho Thang , Li Rachel , Waldes Jana , Spira Alexander I.
Published: May 2020

3502

Background: CX-2029 is a PROBODY drug conjugate (PDC) of MMAE, a potent microtubule inhibitor, directed against CD71 (transferrin receptor 1). In addition to being an abundant tumor antigen, CD71 is highly expressed on normal cells, precluding targeting by a traditional antibody drug conjugate (ADC). PDCs are masked ADCs, unmasked predominantly by tumor-associated proteases, thereby restricting target engagement to tumors. Both a CD71 PDC and ADC displayed broad activity in multiple xenograft tumor models; in toxicology studies, the PDC was tolerable at doses consistent with efficacy in non-clinical tumor models while the ADC was not. Methods: In a phase 1/2 first-in-human study of PDC CX-2029 in advanced solid tumors (N CT03543813 ), pts with ECOG 0–1 and ≥1 prior systemic therapy were enrolled into escalating dose cohorts of the PDC CX-2029 given IV every 21 days. Endpoints included evaluation of MTD, safety, antitumor activity, and potential biomarkers; plasma and tissue samples were collected for PK/PD analyses. Preliminary results are reported. Results: As of 30 November 2019, 34 pts were enrolled (median age 59 y; 59% male; 71% ECOG 1; median [range] of 3 [1–16] prior therapies). Pts received a median of 3 (1–12) CX-2029 doses. Starting dose for escalation was 0.1 mg/kg. Following a single CX-2029 dose, median molar ratio of masked CX-2029 to total CX-2029 for AUCtau was 0.938 (0.864–0.942); the ratio of free MMAE to total CX-2029 was <0.03. Infusion-related reactions were the most common treatment-related AE (TRAE) of any grade (88%; primarily low grade and with first infusion), followed by anemia (56%), fatigue and nausea (24% each), neutropenia (21%), and leukopenia (12%). Grade 3+ TRAEs in ≥10% pts were anemia (35%) and neutropenia (18%). In 32 response-evaluable pts, 1 pt had a confirmed partial response (squamous NSCLC); 9 had stable disease including 1 pt with ocular melanoma treated for 36 weeks. Conclusions: The observed safety profile for CX-2029 effectively reduces on-target toxicity for this previously undruggable target, supporting the PROBODY platform. Evidence of anti-tumor activity was observed. Dose escalation continues. Clinical trial information: NCT03543813 .
Pen-866, a miniature drug conjugate of a heat shock protein 90 (HSP90) ligand linked to SN38 for patients with advanced solid malignancies: Phase I and expansion cohort results.
Authors: Falchook Gerald Steven , Bendell Johanna C. , Ulahannan Susanna Varkey , Sen Shiraj , Vilimas Rasa , Kriksciukaite Kristina , Mei Laura , Jerkovic Goran , Sarapa Nenad , Bilodeau Mark , Bloss Jeffrey , Thomas Anish
Published: May 2020

3515

Background: PEN-866 is a miniature drug conjugate which links a HSP90 binding small molecule to a SN-38 cytotoxic payload. HSP90 is highly expressed in advanced malignancies. PEN-866 targets and binds to activated tumor HSP90 protein, releases its cytotoxic payload, and results in complete tumor regressions in multiple xenograft models. This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-866. Methods: Patients (pts) with progressive, advanced solid malignancies were enrolled in escalating cohorts of 2-9 pts. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PEN-866 given weekly (3 out of 4 weeks in a 28-day cycle). Results: 30 pts were treated in 8 cohorts (range 30-360 mg flat dosing or 150–200 mg/m2 BSA-based dosing). As of 9Jan20, the total median/mean exposure was 7.05/12.4 weeks. No dose limiting toxicities (DLTs) occurred in the first 4 cohorts (30-240 mg; 14 pts). In cohort 5 (360 mg), 1 of 3 pts had a DLT of grade (G) 3 transient diarrhea, and 2 other pts had G3 uncomplicated transient neutropenia. A change to BSA-based dosing was instituted for cohort 6 (175 mg/m2), on which no DLTs were observed, although 1 pt experienced G3 uncomplicated transient neutropenia. At 200 mg/m2, 2 of 5 pts experienced DLTs (G5 dehydration, G3 fatigue). The MTD and RP2D were determined to be 175 mg/m2. The most frequent (≥20% pts) related adverse events were nausea (50%), fatigue (43%), diarrhea (40%), vomiting (27%), and anemia (23%). PK was nonlinear. Plasma exposures increased greater than dose proportionally. Median t1/2 ~7 h. Cleaved SN38 never exceeded 3% of PEN-866 plasma AUC at all dose levels. Tissue PK confirmed tumor accumulation and retention of both the conjugate and released payload. As of 9Jan20, 26 pts were evaluable for response. 11 pts had stable disease at 8 weeks, of which 7 lasted 12–58 weeks. One pt with anal squamous cell carcinoma achieved a confirmed partial response. Decreased target lesion size was observed in 6 additional pts. Conclusions: PEN-866 was well tolerated and demonstrated preliminary evidence of antitumor activity. PEN-866 will be evaluated in Phase 2a expansion cohorts enrolling multiple solid tumors (NCT03221400). Clinical trial information: NCT03221400 .
Pan-tumor analyses of kinase fusions detected in circulating tumor DNA (ctDNA) and concordance with paired tissue.
Authors: Lee Jessica Kim , Lieber Daniel , Madison Russell , Chung Jon , Schrock Alexa Betzig , Creeden James , Venstrom Jeffrey , Alexander Brian Michael , Hazar-Rethinam Mehlika
Published: May 2020

3517

Background: Oncogenic kinase gene fusions are targetable with approved and investigational therapies and can also emerge as acquired resistance (AR) to targeted therapy. To understand the clinical validity of liquid biopsy comprehensive genomic profiling (CGP) to detect kinase fusions, we compared patient-matched plasma and tissue-based CGP. Methods: Hybrid capture-based CGP was performed on 28,743 plasma and 325,131 tumor tissue samples in the course of clinical care. Complete exonic regions of 13 kinases involved in oncogenic fusions plus select introns in ALK, EGFR, FGFR2/3, PDGFRA, RET, and ROS1 were sequenced to capture fusions with well characterized breakpoints. ctDNA fraction was estimated by maximum somatic allele frequency (MSAF). Results: 86% of cases had detectable ctDNA in plasma (MSAF > 0). Kinase fusions were detected in 2.1% of ctDNA cases (478/23,294) and were most prevalent in patients (pts) with bladder cancer (4.5%), non-small cell lung cancer (NSCLC) (4.3%), and cholangiocarcinoma (3.9%). The most commonly rearranged kinases were ALK (60%, 162/271) and RET (19%, 51/271) in NSCLC, FGFR2 (85%, 11/13) in cholangiocarcinoma, and FGFR3 (88%, 7/8) in bladder cancer. ALK fusions were detected in 26% (54/207) of fusion+ non-NSCLC cases. Paired tissue and ctDNA samples where ≥1 sample harbored a kinase fusion were available for 147 pts; median time between sample collection was 150 days (interquartile range: 444 days). Positive percent agreement (PPA) to tissue and liquid biopsies was 76% and 80%. Median MSAF in concordant and discordant ctDNA samples was 2.3% and 0.41% (p = 0.04) and median time between specimen collection for concordant and discordant pairs was 110 and 344 days (p = 0.04). PPA to tissue and liquid was 86% and 88% for pairs collected < 60 days apart (n = 53), versus 70% and 74% for pairs collected > 60 days apart. 6 pts with paired samples all collected > 196 days apart (median 593 days) had initial tissue samples with EGFR driver mutations and had an acquired kinase fusion (4 ALK, 1 FGFR2, 1 FGFR3) in the 2nd ctDNA sample, likely representing AR. Conclusions: Kinase gene fusions identified by tissue-based CGP were detected by liquid biopsy CGP in 85% of temporally-matched plasma samples. Kinase fusion detection by liquid biopsy CGP is feasible and had high PPA to tissue-based CGP. Subsequent sampling by liquid biopsy identified acquired fusions in EGFR driver positive cases consistent with known mechanisms of resistance to EGFR inhibitors suggesting utility of liquid biopsy at progression to identify targetable mechanisms of AR.
Demonstrating the value of liquid biopsy for lung cancer in a public health care system.
Authors: Juergens Rosalyn A. , Ezeife Doreen Anuli , Laskin Janessa J. , Agulnik Jason Scott , Hao Desiree , Laurie Scott Andrew , Law Jennifer H. , Le Lisa W , Kiedrowski Lesli Ann , Shepherd Frances A. , Cohen Victor , Shokoohi Aria , Vandermeer Rachel , Li Janice Juanning , Hanson Inna , Fernandes Roxanne , Salvarrey Alexandra Maria , Lanman Richard B. , Leighl Natasha B.
Published: May 2020

3546

Background: Given the challenges of molecular profiling in patients with advanced lung cancer, this prospective study examines clinical outcomes and utility of liquid biopsy in treatment naive stage IV lung adenocarcinoma patients (Cohort 1) and in the setting of resistance to targeted therapy (Cohort 2; not reported here). Methods: This study is being conducted at 6 Canadian centres (NCT03576937) using Guardant 360 (G360), a validated cell-free DNA next-generation sequencing assay that identifies variants in 74 cancer-associated genes, including fusions and copy number gain. Cohort 1 (N = 150) includes patients with treatment-naïve advanced non-squamous lung carcinoma, ≤10 pack-year smoking history, and measurable disease. Patients received standard of care tumour tissue (TT) molecular profiling ( EGFR, ALK +/- ROS1) and liquid biopsy (LB). The primary endpoint was response rate to first-line therapy (RECIST 1.1); secondary endpoints include incremental targetable alterations identified through G360 ( EGFR, ALK, BRAF, ERBB2, KRAS (G12C), NTRK, MET (amplification, exon 14 skipping), RET, ROS1), turn-around time (TAT) and successful molecular profiling rates. Results: To date, 84 eligible patients with clinical data have been accrued to Cohort 1. Median age is 64 (range 23-91), 64% are female, 85% never smokers, 96% have adenocarcinoma. Actionable targets have been identified in 55% of patients using G360 ( EGFR/ALK in 37%), 39% using standard TT profiling. Eight EGFR/ALK aberrations were identified in TT but not LB, while 6 were identified in LB but not TT. TT profiling for EGFR/ALK was unsuccessful in 8% of patients (insufficient tissue, failed biopsy). Fourteen patients (17%) had no ctDNA alterations detected by G360 (low disease burden vs. non-shedding). Of 75 patients receiving first-line treatment, 57% received targeted therapy, 28% chemotherapy combinations, 11% checkpoint inhibitors and 4% were observed. Treatment decisions were informed by G360 alone in 37% and by G360+TT results in 27% (by physician report). Among 46 evaluable patients, ORR was 54% (25/46). Using G360, ORR was 75% (15/20) in those with actionable alterations and 38.5% (10/26) in those without. Using TT, ORR was 67% (14/21) in those with actionable alterations and 44% (11/25) in those without. Mean TAT was 7.9 days (SD+/-1.7) for LB vs 19.9 days (SD+/- 9.8) for TT. Conclusions: Liquid biopsy using G360 identifies actionable targets beyond tissue profiling alone in newly diagnosed lung cancer patients, has faster TAT and yields similar outcomes with targeted and non-targeted therapy. Clinical trial information: NCT03576937 .