bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma next-generation sequencing (NGS) in advanced non-small cell lung cancer (aNSCLC) patients (pts) treated with immune checkpoint inhibitors (ICIs): Impact of STK11 and TP53 mutations on outcome.
Authors: Pavan Alberto , Zulato Elisabetta , Calvetti Lorenzo , Ferro Alessandra , Nardo Giorgia , Boscolo Alice , Attili Ilaria , Frega Stefano , Dal Maso Alessandro , Pasello Giulia , Guarneri Valentina , Aprile Giuseppe , Conte Pier Franco , Indraccolo Stefano , Bonanno Laura
Published: May 2020

3046

Background: ICIs revolutionized aNSCLC treatment. The next challenge lays on the search for predictive markers. Detection of multiple tumor-related genetic alterations through NGS in cell free DNA is a promising tool, provided the limited availability of tumor tissue in most cases. Methods: Between January 2017 and October 2019, aNSCLC pts consecutively referring to our Institution were prospectively screened with plasma NGS while included in two clinical trials: VISION (NCT02864992) and MAGIC trial, an observational study. In VISION trial NGS was performed in plasma (Guardant360 test) and tissue (Oncomine Focus Assay). In MAGIC Myriapod NGS-IL 56G Assay was used. Aim of the study was to evaluate the impact of STK11, KRAS and TP53 mutations (muts) on outcome of ICI-treated pts, with overall survival (OS) as primary endpoint. A control group of pts not receiving ICIs was also analyzed. Results: A total of 235 NSCLC pts were enrolled and received ICIs. 93 pts were analyzed in plasma at the time of beginning ICIs: median OS was 18.9 m (95% CI: 13.7-24.1) and median immune-related progression free disease (irPFS) 3.8 m (95% CI: 2.5-5.1). 49 (52.7%), 22 (23.7%) and 8 (8.6%) pts carried TP53, KRAS and STK11 pathogenic alterations, respectively. STK11 mutated pts showed a trend for worse OS compared with wildtype counterpart (14.9 m, 95% CI: 6.5-23.3, versus 20.3, 95% CI: 13.4-27.2, p = 0.192) KRAS muts had no impact on outcome. Pts with TP53 or STK11/KRAS co-mut (n = 3) had worse OS (12.3 m, 95% CI: 9.2-15.4; HR = 3, 95% CI: 1.6-5.8, p = 0.001 and 5.9 m, 95% CI: 1.4-7.6; HR = 2.9, 95% CI: 1.4-6.3, p = 0.007) and worse irPFS (2.8 m, 95% CI: 1.7-3.9, HR = 1.8 95% CI: 1.1-3.1, p = 0.03 and 1.2 m, 95% CI: 0.9-1.5, HR = 2.2 95% CI: 1.2-4.1, p = 0.01). Number of muts negatively impacts pts’ OS (HR = 1.2, 95% CI: 1.1-1.3, p = 0.02) and was higher among TP53 mutated pts (p < 0.001, Mann-Whitney test). In multivariate analysis, TP53 and STK11/KRAS retained significance. A control group of pts not receiving ICIs was analyzed (n = 101): median OS was 16.8 m (95% CI: 13-20.6). Nor STK11 (n = 10), nor STK11/KRAS (n = 6) had impact on OS (HR = 1.8, 95% CI: 0.7-4.7, p = 0.267 and 1.4, 95% CI: 0.7-3.0, p = 0.293) while the presence of TP53 muts (n = 41) was associated with shorter OS (11.4 m, 95% CI: 7.3-15.5; HR = 2.2, 95% CI: 1.2-4.2, p = 0.009). Conclusions: NGS performed in plasma might be used to detect predictive markers. TP53 muts in plasma at baseline had prognostic value, while STK11/KRAS muts were associated with worse outcome to ICIs.
TCR clonality and Treg frequency as predictors of outcome in stage III NSCLC treated with durvalumab.
Authors: Lau Sally CM , Soleimani Shirin , Wong Stephanie WY , Pedersen Stephanie , Wang Ben X , Elkrief Arielle , Patel Devalben , Fares Aline Fusco , Jao Kevin , Daaboul Nathalie , Hakozaki Taiki , Bradbury Penelope Ann , Liu Geoffrey , Leighl Natasha B. , Tsao Ming-Sound , Ohashi Pamela S , Pugh Trevor John , Routy Bertrand , Shepherd Frances A. , Sacher Adrian G.
Published: May 2020

3050

Background: Novel blood-based biomarkers evaluating T-cell receptor (TCR) clonality as well as the frequency/activation of immune populations hold significant potential for predicting response and elucidating the biology of anti-tumor immunity in stage 3 NSCLC treated with durvalumab. In this study, we sought to characterize clinical and immunologic predictors of durable response to therapy with a specific focus on TCR clonality and peripheral immune populations. Methods: Stage 3 NSCLC patients undergoing chemoradiation (CRT) and durvalumab were prospectively recruited and underwent baseline and serial blood collections. TCR repertoire analysis was performed on cfDNA using hybrid-capture TCR sequencing and TCR diversity estimated using Shannon’s entropy index. Viably preserved 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. Correlations between cell populations were examined using linear and cox regression. Results: 134 stage 3 NSCLC patients who received durvalumab had a median PFS was 15.4 months, with worse PFS in patients with PD-L1 1-49% (HR 2.4, p = 0.03) and PD-L1 < 1% (HR 2.6, p = 0.03). Smoking and EGFR/ALK mutations were not predictors of PFS. Immune profiling was performed in a pilot of 19 patients. Baseline TCR diversity did not associate with clinical factors or outcome. However, lack of clonal expansion after CRT indicated by a higher Shannon’s index was significantly associated with increased frequency of Tregs after durvalumab (p < 0.05). In turn, this elevation in Tregs was associated with significantly reduced PFS in EGFR/ALK wt patients (p = 0.03) and a trend towards reduced PFS in the overall cohort (HR 5.2, p = 0.1). Conclusions: Clonal expansion of T cells after CRT may influence the likelihood of an anti-tumor immune response following PD-L1 blockade in stage 3 NSCLC. Similarly, expansion of peripheral Treg populations is associated with increased likelihood of disease recurrence. Further characterization of TCR clonality, minimal residual disease and T cell subpopulations using serially collected blood is ongoing.
Phase Ib clinical study of CBP501, cisplatin, and nivolumab administered every three weeks in patients with advanced refractory tumors: Efficacy in dose-escalation and expansion cohorts.
Authors: Matrana Marc Ryan , Tsai Frank , Cleary James M. , Satti Suma , Borazanci Erkut , Estes Jacob , Moser Justin , Do Khanh Tu , Du Lingling , Sharma Sunil , Khemka Vivek , Kolmakov Valentin , Kawabe Takumi , Shapiro Geoffrey
Published: May 2020

3059

Background: CBP501 is a 12-amino acid G2 checkpoint abrogator and calmodulin-modulating peptide that increases platinum influx into tumor cells and induces tumor immunogenic cell death. CBP501 also suppresses platinum-induced release of cytokines by macrophages, lowers cancer stem cell populations, and reduces migration, invasion, and epithelial-mesenchymal transition of tumor cells. We report safety and efficacy outcomes from dose-escalation and expansion cohorts of a Phase Ib study of CBP501 combined with cisplatin and nivolumab (NCT03113188). Methods: An open-label Phase I trial was conducted using a 3+3 design: CBP501 and cisplatin were dosed simultaneously by 1h infusion Q3W at 4 different combined dose levels (CBP501: 16 or 25 mg/m2; cisplatin: 60 or 75 mg/m2) in the dose-escalation cohort. Nivolumab (240 mg) was dosed on the same day as a 1h infusion following CBP501/cisplatin. CBP501 and cisplatin were fixed at 25 and 60 mg/m2, respectively, in the expansion cohort. Eligible patients had pathologically confirmed, locally advanced or metastatic solid tumors, age ≥18 years, ECOG PS 0-1, life expectancy > 3 months. The dose-expansion cohort had pretreated metastatic exocrine pancreatic cancer or microsatellite stable colorectal cancer (CRC). Scans were performed every 6 weeks while on study, then every 3 months. Results: The most common related adverse events (AEs) were infusion-related reaction (rash, itching, hives; n = 32/37 [Gr 1, n = 4; Gr 2, n = 28]; 86%) and anemia (n = 19/37 [Gr 1/2, n = 10; Gr 3, n = 9]; 51%). There were no additional safety signals other than those known for each agent. At January 9, 2020 (interim analysis), efficacy was evaluable in 17/19 patients in the dose-escalation cohort. Unconfirmed partial response was seen in 18% (3/17; 1 pancreatic, 1 colorectal, 1 cholangiocarcinoma), with > 3 months stable disease (SD) in 41% (7/17), disease control in 41% (7/17), and > 8 months overall survival (OS) in 53% (9/17). In the expansion cohort, efficacy was evaluable in 8/13 patients with pancreatic cancer: > 4 months SD was 50% (4/8), median progression-free survival 4.2 months, and median OS 5.9 months (6/8 ≥3rd line). The CRC cohort median OS for all CRC patients (n = 10) including the dose-escalation cohort (n = 5) was 17.5 months (10/10 ≥3rd line). Conclusions: The triple-drug combination is reasonably tolerable with preliminary signs of efficacy in refractory solid tumors, including those in which cisplatin and nivolumab have limited single-agent activity. Clinical trial information: NCT03113188 .
Safety of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors.
Authors: Johnson Melissa Lynne , Patel Manish R. , Cherry Mohamad , Kang Yoon-Koo , Yamaguchi Kensei , Oh Do-Youn , Hussein Maen A. , Kitano Shigehisa , Kondo Shunsuke , Hansen Aaron Richard , Percent Ivor John , George Ben , Arrowsmith Edward , Morimoto Manabu , Duffy Christine , Ge Miaomiao , Rohrbacher Maren , Elgadi Mabrouk M. , Bendell Johanna C.
Published: May 2020

3063

Background: LAG-3, an immune checkpoint receptor involved in T-cell regulation, is frequently co-expressed with PD-1. LAG-3 and PD-1 signaling contributes to immune cell exhaustion and reduces the immune response to tumor cells. Dual inhibition of PD-1 and LAG-3 may reactivate the T-cell response better than blockade of either individual pathway. Here, we report combined safety data from 4 trials investigating BI 754111, an anti-LAG-3 mAb, in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: Data from 2 phase I dose-escalation/expansion trials, 1 phase I imaging trial, and 1 phase II trial were included. Eligible patients had advanced and/or metastatic solid tumors with measurable disease and an Eastern Cooperative Oncology Group performance status ≤1. Patients received BI 754111 (intravenously [iv], 4–800 mg) in combination with BI 754091 (iv, 240 mg fixed dose) every 3 weeks (q3w). Patients remained on treatment until progressive disease or unacceptable toxicity. In each trial, safety was assessed by incidence and severity of adverse events (AEs), and graded according to Common Terminology Criteria for AEs, version 5. Results: Overall, 321 patients were treated with BI 754111 in combination with BI 754091 (200 [62%] male; median age, 63 years [range 18–88]). Median treatment exposure was 85 days (range 9–625). Of these patients, 282 (87.9%) had any AE (G≥3 in 99 [30.8%]). 285 patients received the 600 mg recommended phase II dose of BI 754111 plus BI 754091 240 mg q3w. Median treatment exposure in these patients was 74 days (range, 8–590). The table shows the 3 most common AEs and 4 most common immune-related AEs, and their frequency. 21 (7.4%) patients had AEs leading to study drug discontinuation, most commonly infusion-related reactions (IRRs) in 6 (2.1%) patients. Serious AEs (all-cause) occurred in 77 patients (27.0%), most commonly pleural effusion in 6 (2.1%) and deep vein thrombosis in 4 (1.4%) patients. 2 patients (0.7%) experienced an AE resulting in death (cardiac tamponade and acute kidney injury, both related to underlying diseases). Conclusions: The combination of BI 754111 and BI 754091 had a manageable safety profile, similar to other checkpoint inhibitors. Clinical trial information: NCT03156114, NCT03433898, NCT03697304, NCT03780725 . [Table: see text]
Fecal microbiota transplantation (FMT) for immune checkpoint inhibitor induced–colitis (IMC) refractory to immunosuppressive therapy.
Authors: Wang Yinghong , Ma Weijie , Abu-Sbeih Hamzah , Jiang Zhi-Dong , DuPont Herbert L.
Published: May 2020

3067

Background: ICIs are efficacious treatment for several advanced malignancies. IMC can limit their use, and can be refractory to medical treatment (immunosuppression) with significant morbidity. Gut microbiome alteration affects IMC development. We sought FMT as a novel therapy for IMC refractory to immunosuppressive therapy. Methods: 15 patients who received FMT for IMC after failure of immunosuppressive therapy were included (6/2017-1/2020). FMT was performed via colonoscopy with healthy donor’s stool. Results: Median age was 55 years with 67% males. 5 patients received PD(L)-1, one CTLA-4 and 9 on combination. Majority had genitourinary cancers followed by melanoma. Median time from ICI to IMC was 75 days. 14 patients had grade 3-4 diarrhea and 9 had grade 3-4 colitis. Endoscopy showed mucosal inflammation in 12 patients and normal mucosa in 3 patients. IMC was refractory to 2-3 doses of infliximab or vedolizumab after corticosteroids prior to FMT. Median time from IMC onset to FMT was 75 days. 13 patients received one . 11 patients achieved clinical response within 10 days of FMT (7-14). Symptom remission was maintained for a median follow-up of 13 months. 6 patients resumed non ICI cancer treatments after FMT. 4 patients had persistent symptoms; 2 continued on vedolizumab, 1 had total colectomy, and 1 transferred to hospice. 4-8 weeks after FMT, endoscopic remission was achieved in 64% of the 11 patients who responded to FMT. No adverse events were reported. Conclusions: FMT treatment was successful in 73% of patients with for IMC refractory to immunosuppressive therapy. Controlled clinical trials are warranted to confirm our conclusion. [Table: see text]
Interrogation of neoantigen-specific CD8 T cells in peripheral blood following PD-L1 blockade in patients with metastatic urothelial carcinoma (mUC).
Authors: Holm Jeppe Sejerø , Funt Samuel Aaron , Bjerregaard Anne-Mette , Reading James L. , Maher Colleen Anne , Regazzi Ashley Marie , Wong Phillip , Al-Ahmadie Hikmat , Overgaard Nana Haahr , Tamhane Tripti , Bentzen Amalie Kai , Snyder Alexandra , Merghoub Taha , Wolchok Jedd D. , Nielsen Morten , Rosenberg Jonathan E. , Bajorin Dean F. , Hadrup Sine Reker
Published: May 2020

3075

Background: Proliferation of CD8 T cells can be detected in the blood of cancer patients (pts) following a single dose of immune checkpoint blockade (ICB) and tends to be more robust in responding pts. Furthermore, tumor mutational burden (TMB) is seen to predict outcome to ICB across cancers. Mutation-derived neoepitopes presented on the tumor cell surface is believed to be recognized by T cells and are thus critical for tumor clearance. However, the capacity to mount a neoantigen T cell response and the kinetics in relation to ICB remain poorly understood. Methods: 24 pts with mUC were treated with atezolizumab (anti-PD-L1) 1200mg q3w on IMVigor 210 at MSKCC and included in here. Pt-specific neoepitopes were predicted based on whole-exome and RNA sequencing of pre-treatment archival tumors using the MuPeXI platform. Using DNA-barcode labelled pMHC multimers, we investigated CD8 T cell recognition of mutation-derived neoepitopes by screening pt PBMC samples pre- and post-treatment with atezolizumab (n = 85 PBMC samples). The kinetics of neoepitope-specific CD8 T cells were assessed for association with durable clinical benefit (DCB; defined as progression free survival > 6 mo). Results: Neoepitope peptide libraries of between 200-587 peptides were generated per pt (mean = 260 peptides per pt). 31 out of a combined 56 possible pt HLA types across the cohort were utilized for T cell analyses (mean four HLAs per pt). MHC multimer-based screening of pt PBMCs revealed detection of neoepitope-specific CD8 T cells in 22 of 24 pts pre-treatment (range one to 14 neoepitope responses) and 21 of 22 pts post-treatment (up to 273 weeks after trial start; one to 19 neoepitope responses). There were large inter- and intra-patient variations of neoepitope-specific CD8 T cell responses during treatment with the largest increases occurring at the 3-wk, post-treatment initiation timepoint. We observed that pts with DCB tend to raise a broader neoantigen T cell response than patients without DCB. 38% of pts without DCB and 67% of pts with DCB exhibited an increase in neoepitope-specific CD8 T cell responses within 3 wks of treatment initiation. Conclusions: Using high-throughput screening, pt-specific neoepitope reactive CD8 T cells could be detected pre- and post-treatment in pts with mUC treated with atezolizumab. Phenotypic characterization of neoepitope reactive CD8 T cells is ongoing. These data may help elucidate the dynamics and characteristics of the T cells of highest relevance to the ICB-induced, anti-tumor immune response.
Preliminary results of sintilimab plus different dose of IBI305 (anti-VEGF monoclonal antibody) in patients with advanced hepatocellular carcinoma: A phase Ib study.
Authors: Zhang Wen , Bi Xinyu , Sun Yongkun , Yu Yue , Zhou Jian-guo , Zeng Huiying , Wu Fan , Luo Yang , Yang Yong , Chen Mingxia , Wang Yan , Zhou Hui , Cai Jianqiang , Zhao Hong , Zhou Aiping
Published: May 2020

3079

Background: The study aimed to evaluate the safety and efficacy of sintilimab, a PD-1 blockade, plus IBI305, a biosimilar candidate of bevacizumab, in patients (pts) with advanced hepatocellular carcinoma (HCC). Methods: Adults with histocytologically confirmed advanced or metastatic HCC were enrolled in this two-part study. Part 1 was dose escalation trial, with initial dose of sintilimab 200 mg plus IBI305 7.5 mg/kg, q3w (low-dose group). If tolerable, IBI305 was escalated to 15 mg/kg (high-dose group). In part 2 for extension, at least 20 pts were enrolled to each tolerable dose group. Results: As data cutoff (Jan. 7, 2020), 50 pts were enrolled, 29 in low-dose group and 21 in high-dose group. 41 patients were systemic treatment naïve. The median treatment cycle was 4 (range: 1-19) in low-dose group and 11 (range: 1-16) in high-dose group. Most TRAEs were G1-2 with the most common being hypertension (28.0%) and pyrexia (26.0%). Totally, the grade 3 or more TRAEs were occurred in 6 (12.0%) pts, including hypertension occurred in 2 (4%) pts. The objective response rate (ORR) per RECIST v1.1 was 24.1% (95%CI: 10.3 - 43.5) in low-dose group, and 33.3% (95% CI:13.3 - 59.0) in high-dose group. As with the cutoff date, the median PFS has not been reached and the 6-month PFS rates were 60.5% (95%CI 36.1, 78.0) and 75.8% (95% CI: 47.3, 90.2), respectively. Conclusions: The combination of sintilimab and IBI305 showed promising efficacy and favourable safety profile in advanced HCC in both low-dose and high-dose groups. The preliminary result of this study warrant further exploration of dose selection for anti-VEGF/VEGFR agent when combined with PD-1/PD-L1 antibody. Clinical trial information: NCT04072679 . [Table: see text]
Impact of relacorilant, a selective glucocorticoid receptor antagonist, on the immunosuppressive effects of endogenous cortisol.
Authors: Greenstein Andrew , Munster Pamela N. , Sachdev Jasgit C. , Fleming Gini F. , Grauer Andreas , Shepherd Stacie Peacock
Published: May 2020

3091

Background: Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad transcriptional program that affects T-cell activation, pro-inflammatory cytokine secretion, and immune cell trafficking. By selectively antagonizing GR, relacorilant may reverse the immunosuppressive effects of cortisol in solid tumor cancers. Methods: Immune cells and GR expression were assessed by IHC and calculated based on The Cancer Genome Atlas (TCGA) data. Human PBMCs were stimulated with αCD3+IL-12 +/- cortisol or cortisol + relacorilant. EG7 tumor-bearing mice were treated with anti-PD1 (RMP1-14) ip Q5D +/- relacorilant QD. Whole blood mRNA was measured via Nanostring, hematology was performed using standard complete blood count assays, and cytokines were assessed by immunoassays in study NCT02762981. Results: GR expression was observed in human tumor and immune cells. Its abundance was positively correlated with tumor infiltration of TH2, Treg, and PDL1+ cells ( P< .001) and negatively correlated with TH1 cells ( P< .001). In PBMCs, cortisol inhibited, and relacorilant restored, CD8+ T-cell activation ( P< .001) and pro-inflammatory cytokine secretion (TNFα P= .006, IFNγ P< .05). In the EG7 syngeneic model, relacorilant increased αPD1 efficacy ( P= .007) and decreased circulating IL-10 ( P< .002). In patients with advanced solid tumors, relacorilant + nab-paclitaxel systemically suppressed the expression of canonical GR-controlled genes ( ptgs2 P< .001) and genes encoding candidate-immunomodulatory drug targets ( cxcl8, ptger4, ido1; P< .001). In a small subset of patients (n = 11), sustained clinical response was associated with increased T-cell count ( P= .06) and IFNγ ( P= .03), as well as decreased Tregs ( P= .06) and IL-10 ( P= .03). Conclusions: Evidence of T-cell activation by relacorilant was observed in PBMCs, syngeneic mouse tumors, and patients with sustained response in a Phase 1 study. This supports the hypothesis that relacorilant can reverse immune suppression by endogenous cortisol in solid tumor cancers. Clinical studies with immune checkpoint inhibitors and relacorilant are planned.
A phase I dose-escalation and expansion study of intratumoral CV8102 as single-agent or in combination with anti-PD-1 antibodies in patients with advanced solid tumors.
Authors: Eigentler Thomas , Bauernfeind Franz G , Becker Jürgen C. , Brossart Peter , Fluck Michael , Heinzerling Lucie , Krauss Jürgen , Mohr Peter , Ochsenreither Sebastian , Schreiber Jutta Sylvina , Terheyden Patrick , Weide Benjamin , Weishaupt Carsten , Funkner Fatma , Muth Anke , Kays Sarah-Katharina , Stosnach Claudia , Daehling Angelika , Quintini Gianluca , Gnad-Vogt Senta Ulrike
Published: May 2020

3096

Background: CV8102 is a non-coding, non-capped RNA that activates the innate (via TLR7/8, RIG-I) and adaptive immunity dose-dependently. CV8102 injected intratumorally (i.t.), as a single agent or combined with systemic anti-PD-1 antibody (Ab) led to tumor growth inhibition in animal models and showed synergism with PD-1 blockade. Methods: An open-label, cohort-based, dose escalation and expansion study in patients with advanced cutaneous melanoma (cMEL), cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (hnSCC) or adenoid cystic carcinoma (ACC) is ongoing investigating i.t. CV8102 as single agent and in combination with anti-PD-1 antibodies. [NCT03291002]. Results: As of December 2019, 23 patients in the cohort A (single agent) and 13 patients in cohort C (combination with anti-PD-1 Ab) were exposed to at least one dose of CV8102 at dose levels of 25-600 µg (single agent) and 25-450 µg (combination). No dose limiting toxicities (DLTs) were observed within the first two weeks of study drug treatment. Most frequent TEAEs were G1/2 fatigue, fever, chills and headache. 4 (17%) patients (pts) in cohort A and 3 (23%) pts in cohort C experienced related G3 TEAEs that were manageable with supportive treatment (liver enzyme increases (3), abscess at injection site (1), hypertension (1), asymptomatic elevation of pancreatic enzymes (2)). In cohort A, 2 cMEL patients experienced an objective response according to RECIST 1.1 (1 CR in a PD-1 naïve pt and 1 PR in a PD-1 refractory pt) and 2 further pts (cMEL, hnSCC) showed SD with shrinkage of tumor lesions. Conclusions: CV8102 i.t. was well tolerated without dose limiting toxicities to date and showed evidence of single agent activity. Updated results on safety, efficacy and serum biomarkers will be presented. Clinical trial information: NCT03291002 .
A phase II, open-label study of tomivosertib (eFT508) added on to continued checkpoint inhibitor therapy in patients (pts) with insufficient response to single-agent treatment.
Authors: El-Khoueiry Anthony B. , Tchekmedyian Nishan , Sanborn Rachel E. , Peguero Julio Antonio , Pulver Kerry , Dembla Vikas , Thomas Jacob Stephen , Chiang Gary Gene , Densel Mark , Sankar Neil , Worland Stephen Theodore , Gleich Lyon L. , Sikorski Robert S.
Published: May 2020

3112

Background: Despite the broad activity of checkpoint inhibitors across tumor types, primary or secondary resistance after initial response represents a major challenge. Tomivosertib (T), a potent and highly selective inhibitor of the immunosuppressive kinases MNK-1 and 2, blocks expression of checkpoint proteins PD-1, PD-L1, and LAG-3 as well as immunosuppressive cytokines IL-6 and IL-8. In preclinical models, T was shown to trigger an anti-tumor immune response and enhance the activity of checkpoint inhibitors in a T-cell dependent manner. In prior clinical studies, T had an acceptable safety profile as a single agent and in combination with anti-PD-L1 agent avelumab. Methods: Patients experiencing insufficient response (progression or stable disease for 12 weeks or more) to any FDA-approved checkpoint inhibitor in any approved indication were eligible. T at 200 mg oral (PO) BID was added to the existing checkpoint inhibitor until disease progression or unacceptable toxicity was noted. Results: 39 pts (23 male, 16 female) were enrolled across seven cancer types. Median age was 68 (range 42-85). Median prior therapies were 2 (range 1-6). The most common cancers were lung (N = 17), urothelial (N = 6), renal (N = 5) and head and neck (N = 5). 36 pts continued on anti PD-1 antibody (Pembrolizumab and Nivolumab, 18 each) and 3 on anti PD-L-1 antibody (Durvalumab 2, Atezolizumab 1) . The most common grade 3/4 treatment related adverse events occurring in more than 1 pt were alanine aminotransferase increase (2), blood creatine phosphokinase increase (2) and maculo-papular rash (2). 7 patients discontinued treatment (18%) due to adverse events attributable to either drug. Three partial responses (PR) per RECIST 1.1 were observed in pts with previous progression on checkpoint inhibitor therapy, one each in NSCLC (1/17), gastric (1/1) and renal cancer (1/5). 7 NSCLC pts (41%) were progression free for ≥ 24 weeks. All NSCLC patients entered the study with progression by RECIST 1.1 on single agent checkpoint inhibitor prior to adding T. Conclusions: The addition of T to existing checkpoint therapy was well tolerated and manifested clinical activity including objective responses in pts with progression on existing checkpoint inhibitor. A Progression Free Survival rate at 24 weeks of 41% was noted in NSCLC patients. Additional studies evaluating the addition of T to checkpoint inhibitor therapy after progression on anti PD-1 or PD-L-1 therapy are planned. Clinical trial information: NCT03616834 .
Deep-learning analysis of H&E images to define three immune phenotypes to reveal loss-of-target in excluded immune cells as a novel resistance mechanism of immune checkpoint inhibitor in non-small cell lung cancer.
Authors: Park Sehhoon , Ock Chan-Young , Jang Minje , Shin Jiwon , Lee Sarah , Paeng Kyunghyun , Park Jonghanne , Chae Young Kwang , Choi Yoon La , Mok Tony S. K. , Lee Se-Hoon
Published: May 2020

3120

Background: Discovery of predictive biomarker to enrich the responder of immune checkpoint inhibitor (ICI) in PD-L1-low ( < 50%) non-small cell lung cancer (NSCLC) is still challenging. Recent study showed that loss of heterozygosity (LOH) of HLA led to immune evasion. In the current study, we hypothesized that 3 immune phenotype (3IP): inflamed, excluded and desert would be reliably classified by deep-learning algorithm of H&E image, called Lunit-SCOPE, which would dictate the responder in PD-L1-low NSCLC patients and discover a unique resistance pathway in excluded phenotype. Methods: Lunit-SCOPE was trained with 1,824 H&E Whole-Slide Image (WSI) of NSCLC from Samsung Medical Center (SMC). WSI was divided into patches (~10 high-power fields) which was classified for 3IP, based on both quantity and localization of immune cells. The 3IP was trained and optimized by considering clinical outcome of 119 NSCLC patients with PD-(L)1 inhibitor (training cohort, patches = 25,897), and validated in 62 patients enrolled in LC-biomarker study (NCT03578185, validation cohort, patches = 8,929). Tumor Proportion Score (TPS) of PD-L1 22C3 immunohistochemistry was assessed by pathologists. Tumor Mutational Burden (TMB) was calculated as number of nonsynonymous alterations throughout whole-exome and HLA LOH was called by LOHHLA algorithm. Results: Interactive analysis to classify 3IP in training cohort showed that 8,726 (33.7%), 10,965 (42.3%), and 6,206 (24.0%) patches were classified as inflamed, excluded, and desert, respectively. In validation cohort, median progression-free survival (mPFS) of inflamed phenotype was 10.1 m, significantly prolonged compared to either excluded phenotype (3.0 m, P= 0.0053) or desert phenotype (1.4 m, P= 0.0011). Inflamed phenotype independently dictated favorable ICI outcome in PD-L1-low (TPS < 50%, mPFS of inflamed: 14.3 m vs excluded/desert: 1.4 m, P= 0.0233) as well as in PD-L1-high (TPS≥50%, 10.1 m vs 4.2 m, P= 0.0361), respectively. Excluded phenotype had higher TMB compared to inflamed phenotype had (median 177 vs 107), and HLA LOH was also enriched in excluded phenotype (31.0%) compared to inflamed (17.6%) and desert (16.7%) phenotypes. Conclusions: Lunit-SCOPE based 3IP classification can predict ICI outcome especially in PD-L1-low ( < 50%) patients. Excluded phenotype showed poor ICI outcome even with high TMB, partially explained by HLA LOH resulting in loss-of-target, as a novel resistance mechanism of ICI.
Percutaneous hepatic injection of rose bengal disodium (PV-10) in metastatic uveal melanoma.
Authors: Patel Sapna Pradyuman , Carter Brett W. , Murthy Ravi , Sheth Rahul , Agarwala Sanjiv S. , Lu Gary , Redstone Ellen , Balmes Gener C , Rider Helene , Rodrigues Dominic , Wachter Eric Andrew
Published: May 2020

3143

Background: PV-10 is a small molecule autolytic immunotherapy in clinical development for treatment of solid tumors. When administered by intralesional (IL) injection, PV-10 can produce immunogenic cell death that may induce a T cell-mediated immune response against treatment refractory and immunologically cold tumors. Given this mechanism of action and clinical data that metastatic uveal melanoma (MUM) generates low response rates to immune checkpoint blockade (CB), we investigated treatment of MUM with percutaneously-delivered PV-10. Methods: This open-label Phase 1 basket study (NCT00986661) is evaluating the safety, tolerability, and preliminary efficacy of intralesional PV-10 in patients (pts) with solid tumors of the liver. PV-10 is injected into one or more designated hepatic tumor(s) with a maximum sum of diameters ≤4.9 cm. Response assessments using 2D EASL criteria are performed at Day 28, then every 3 months. Pts with additional injectable tumors are eligible to receive further PV-10 after Day 28. Pts can receive standard of care CB immunotherapy during treatment with PV-10. Results: As of February 1, 2020, the initial cohort of 15 pts with MUM to the liver was fully enrolled. Pts had received at least 1 IL injection of PV-10, with an average of 2 hepatic lesions injected per pt (range 1-4). Of these, 4 pts were refractory to prior CB. Three pts received PV-10 alone, 3 received PV-10 + anti-PD-1 and 9 received PV-10 + anti-PD-1 + anti-CTLA-4. Adverse events (AEs) were consistent with established patterns for PV-10 and CB: AEs attributed to PV-10 were transient and included 3 cases of Grade 3/4 transaminitis that resolved within 72 hrs, injection site pain, photosensitivity, and pink discoloration of skin, urine or feces; AEs attributed to CB included nausea, decreased WBC, and fatigue. Response assessments on 24 injected tumors were: 2 complete response (8%), 7 partial response (29%) and 11 stable disease (46%), per 2D EASL. Among the 4 CB-refractory pts, median overall survival (OS) was 9.2 months (range 5.3 - 11.4 months, with 2 pts alive at 5.3 months each), while among the 11 CB-naïve pts OS was undefined (range 0.5 - 21.9+ months, with 1 death at 7.9 months). Pts receiving PV-10 alone (1 CB-refractory, 2 naïve) achieved a median OS of 7.9 months with one CB-naïve pt alive with partial overall response at 21.9 months. Conclusions: Response indicative of regression or stabilization in a majority (83%) of injected lesions is encouraging in a disease of major unmet need. Enrollment and follow-up for safety, duration of response and survival are ongoing. Clinical trial information: NCT00986661 .
Early plasma circulating tumor DNA (ctDNA) changes to predict response to first-line pembrolizumab +/- chemotherapy in non-small cell lung cancer (NSCLC).
Authors: Ricciuti Biagio , Champagne Christine , Jones Greg , Lazarus Tadd Scott , Adeni Anika E. , Cheng Michael L. , Oxnard Geoffrey R. , Awad Mark M.
Published: May 2020

3518

Background: ctDNA shedding into plasma can be prognostic in lung cancer, and changes in plasma ctDNA levels correlate with response to systemic therapy. However, is unknown whether early detection of ctDNA levels change predicts response to first-line pembrolizumab +/- chemotherapy. We hypothesized that serial assessment of plasma ctDNA by next generation sequencing would enable early detection of response to immunotherapy in NSCLC prior to radiological assessment. Methods: Patients (pts) with advanced NSCLC who received first-line treatment with pembrolizumab +/- platinum doublet chemotherapy at the Dana-Farber Cancer Institute were enrolled in this study. Plasma collected from pts prior to starting therapy and serially after starting therapy was analyzed by NGS using enhanced tagged-amplicon sequencing (eTAm-Seq) of hotspots and coding regions from 36 genes (InVisionFirst-Lung). ctDNA allele fractions (AF) change was correlated with treatment responses. Results: Among 38 pts who received first-line pembrolizumab +/- platinum/pemetrexed, 9 (23.7%) had no ctDNA detected at baseline while 29 had alterations detected. Pembrolizumab was administered as monotherapy in 19 of the 29 pts (65.5%) and in combination with chemotherapy in 10 (34.5%). The median time to the first ctDNA assessment was 21 days (IQR:21-24). Pts who had a decrease in the max AF at the first blood drawn compared to pre-treatment AF had a significantly higher response rate to treatment with pembrolizumab +/- platinum doublet chemotherapy than those with an AF increase (64.5% vs 7.7%, P < 0.01). The median PFS (mPFS) and median OS (mOS) were significantly longer among pts with early AF decrease compared to those with an AF increase mPFS: 13.7 vs 3.4 months, HR:0.20, P < 0.01; mOS: 32.8 vs 14.7 months, HR:0.06, P < 0.01). The median change in allele fraction at the first on-treatment blood draw was -90% (range: -100 to +65), -71% (range: -100 to +100) and +35% (range: +17 to +100) in pts with subsequent radiological response (N = 11), stable disease (N = 11) and progressive disease (N = 7), respectively (P < 0.01). Among the 9 cases with no detected ctDNA at baseline, 2 pts with emergence of cfDNA within 8 weeks developed progressive disease. In the other 7 cases, ctDNA remained undetected. Conclusions: In pts with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.
Longitudinal cumulative dose: A novel measure to assess multiple dimensions of chemotherapy adherence over time.
Authors: Webster-Clark Michael , Keil Alexander P , Sanoff Hanna Kelly , Sturmer Til , Westreich Daniel , Lund Jennifer Leigh
Published: May 2020

3522

Background: Adjuvant chemotherapy regimens take months to complete. Despite this, trials and observational studies evaluate chemotherapy adherence via measures assessed at the end of treatment (e.g. number of patients missing any dose, relative dose intensity [RDI]). This approach misses information that impacts outcomes, like treatment delays. We propose longitudinal cumulative dose (LCD) as a way to integrate the impact of dose reductions, missed doses, and dose delays at each cycle over time. Methods: We obtained data from the 2,246 participants in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC). We evaluated proportions of patients stopping treatment early and reducing (based on protocol), missing, or delaying a dose in each arm for each chemo agent at each visit. We obtained LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each chemo agent. We compared LCD medians over time and at the end of a standard regimen (24 weeks) between treatment arms and by age and performance status. We assessed agreement between oxaliplatin LCD and RDI with Fleiss’ kappa (Table). Results: Participants randomized to FOLFOX were more likely than those randomized to 5FU to stop treatment, reduce doses, miss doses, or delay visits; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. Graphs of median LCD for 5FU showed a clear difference between arms (FOLFOX arm median LCD: 81%; 5FU arm median LCD, 96%). While 5FU LCD decreased with age in the FOLFOX arm (median LCD in those age <40: 85%; 40-64, 82%; 65-75, 76%), it was similar across ages in the 5FU arm (median LCD 94%, 96%, and 96%, respectively), with smaller performance status trends. RDI and LCD showed fair agreement (Fleiss’ kappa=0.34); 19% of those with RDI over 85% had LCD under 60%. Conclusions: Visualizing LCD highlighted the timing and scale of deviations from standard administration, with major differences in 5FU LCD across arms. Next steps include evaluating if LCD predicts clinical outcomes. [Table: see text]
MSK-ACCESS for noninvasive somatic mutation profiling of lung cancers utilizing circulating tumor DNA.
Authors: Lebow Emily S. , Murciano-Goroff Yonina R. , Brannon Angela Rose , Zehir Ahmet , Arcila Maria E. , Benayed Ryma , Chaft Jamie E. , Drilon Alexander E. , Kris Mark G. , Gomez Daniel Richard , Razavi Pedram , Reis-Filho Jorge S. , Jones David Randolph , Rudin Charles M. , Isbell James M. , Solit David B. , Ladanyi Marc , Tsui Dana , Berger Michael F. , Li Bob T.
Published: May 2020

3529

Background: Circulating cell-free DNA (cfDNA) next-generation sequencing (NGS) is a promising strategy for non-invasive molecular profiling of cancers. MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status) is a hybridization-capture targeted NGS assay that detects somatic variants in select exons of 129 genes with matched white blood cell sequencing. We present the initial clinical experience with MSK-ACCESS among patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients with stage IV NSCLC underwent prospective MSK-ACCESS testing at initial diagnosis or progression of disease on targeted therapy between June 2019 and January 2020. A subset of patients had matched tissue-based NGS testing with the MSK-IMPACT 468 gene assay. We assessed oncogenic driver detection, turnaround time, plasma-tissue concordance, and matching to therapy. National Comprehensive-Cancer Network designated driver alterations were included in evaluation of tissue-plasma concordance (EGFR, ALK, KRAS, MET, RET, BRAF, HER2, ROS1, NTRK). Turnaround time was compared by a two-sided Wilcoxon signed-rank test. Results: A total of 201 patients with NSCLC had MSK-ACCESS testing at initial diagnosis (n = 79) or following progression of disease (n = 122). The median turn-around-time from plasma collection to MSK-ACCESS report was 16 days (range: 9 – 36 days) compared to 19 days from lab receipt of tissue to report (range: 12 – 57) for MSK-IMPACT (p < 0.001). Among patients with a driver detected on MSK-ACCESS, 100% (92/92) had an identical driver detected on MSK-IMPACT. Among patients with a driver detected on MSK-IMPACT, 75% (92/123) had an identical driver detected on MSK-ACCESS. This rate was similar among patients who were treatment-naive (74%; 64/86) and had disease progression (76%, 28/37) at the time of MSK-ACCESS. MSK-ACCESS identified driver alterations that directly guided first-line targeted therapy (n = 18) with response in all patients with available radiographic follow-up (n = 10), including a patient without confirmatory tissue testing. MSK-ACCESS identified resistance alterations among patients with disease progression including EGFR T790M, EGFR C797S, ROS1 G2032R, as well as a BRAF fusion. Conclusions: MSK-ACCESS successfully identified driver alterations with high concordance to tissue-based testing, directly guided patients to therapy with clinical responses, and detected known and novel resistance mechanisms. This assay warrants further clinical development to guide and facilitate precision oncology.
Circulating stromal cells as a potential blood-based biomarker for screening invasive solid tumors.
Authors: Adams Daniel , Lin Steven H. , Pass Harvey I. , Chumsri Saranya , Lapidus Rena G. , Edelman Martin , Bergan Raymond C. , Tsai Susan , Aft Rebecca , Pillai Sreeraj , Watson Mark , Kim Amy K. , Chikamatsu Kazuaki , Hayashi Masanori , Loeb David M , Pinto Navin R. , Alpaugh R. Katherine , Tang Cha-Mei , Ho Thai Huu , Marks Jeffrey R
Published: May 2020

3535

Background: Peripheral blood allows for a simple non-invasive method for isolating various cancer associated circulating stromal cells (CStCs) which may predict for cancer presence. Cancer Associated Macrophage-Like cells (CAMLs), a specific CStC, are phagocytic myeloid cells that derive from an immunological response to cancer and emanate from primary tumors. Using a filtration platform we screened the peripheral blood of untreated newly diagnosed cancer patients (n = 308) for CAMLs. In parallel, we screened patients with newly diagnosed non-malignant diseases, i.e. lupus, benign cysts, etc. (n = 39), and healthy control samples (n = 76). We found that CAMLs are highly prevalent (87%) in the blood of cancer patients, but uncommon in non-malignant conditions (20%) & absent in healthy individuals (0%). Methods: Anonymized peripheral blood were taken from 308 cancer patients after confirmation of invasive malignancy [stage I (n = 76), stage II (n = 73), stage III (n = 72), stage IV (n = 65) and unstaged non-metastatic (n = 22)] with pathologically confirmed lung (n = 65), pancreas (n = 53), breast (n = 52), prostate (n = 40), esophageal (n = 30), renal cell (n = 18), hepatocellular (n = 15), neuroblastoma (n = 10), melanoma (n = 8), and other (n = 17). Further, anonymized blood was taken from patients with untreated non-malignant conditions including benign breast masses (n = 19), lupus (n = 11), liver cirrhosis (n = 5), benign prostatic hyperplasia (BPH) (n = 3), and viral infection (n = 1); or from healthy control volunteers (n = 76). CAMLs were isolated from whole peripheral blood by the CellSieve™ microfiltration technique and defined as enlarged, multinuclear cells with cytokeratin and/or CD45/CD14 positive. Results: CAMLs were found in 87% of all cancer patients regardless of stage, ~5.4 CAMLs/7.5mL blood. Specifically, CAMLs were found in 80% of Stage I, 90% Stage II, 89% Stage III, and 97% Stage IV patients. No CAMLs were found in any healthy controls, but were found in 26% of benign breast masses, 18% of lupus, 0% of BPH and 0% of cirrhosis. In total, CAML sensitivity in cancer vs healthy was 87% (CI95% 82-90%), specificity = 100% (CI95% 95-100%), PPV = 100% (CI95% 100%), NPV = 67% (CI95% 58-71%). CAML sensitivity in cancer vs benign was 87% (CI95% 82-90%), specificity = 80% (CI95% 64-91%), PPV = 97% (CI95% 95-98%), NPV = 43% (CI95% 35-51%). Conclusions: CAMLs, a Circulating Stromal Cell subtype, is a sensitive blood based biomarker found in all stages of cancer that is rare in non-malignant conditions and absent in healthy individuals.
Evaluation of Genexus system that automates specimen-to-report for cancer genomic profiling within a day using liquid biopsy.
Authors: Low Siew-Kee Kee , Uchibori Ken , Hayashi Rie , Chan Hiu Ting , Ariyasu Ryo , Kitazono Satoru , Yanagitani Noriko , Nishio Makoto , Nakamura Yusuke
Published: May 2020

3538

Background: Genomic profiling of patients’ tumors using NGS system help in facilitating molecular-guided therapy. The turnaround time from specimen to report by the NGS system is important to deliver result timely for clinical decisions. The Genexus Integrated Sequencer automates all steps of the targeted NGS workflow starting from nucleic acid of formalin-fixed paraffin-embedded tissues or plasma that significantly reduce laborious procedures. Importantly, the whole specimen-to-report workflow delivers results in a single day. In this study, we evaluated detection rate of alteration using Oncomine Precision Assay (OPA) on Genexus system with cell-free DNA (cfDNA) from non-small cell lung cancer (NSCLC). Methods: Among the cfDNA from 48 plasma samples of NSCLC were evaluated, 19 were newly-diagnosed cases with EGFR mutations in cancer tissues and 29 cases were patients who experienced progression of disease after first line of EGFR, ALK or ROS1-targeted therapy. 13-20ng of input cfDNA were subjected to automated Genexus Integrated Sequencer for library construction using OPA panel, templating and sequencing. OPA panel covers actionable hotspot mutations, copy number gains or loss, fusion drivers. The concordance of mutation profiles between the tumor tissue and cfDNA and detection of a resistance mutation(s) during molecular-targeted therapy were evaluated. Results: The sequencing resulted in median overall reads of 8,698,358, median overall depth of 30,648 (range 15,069-48,707) and median molecular coverage of 1,595 (range 859-2,550). Among 48 samples examined, 44 were detected to carry at least one somatic mutation, giving the detection rate of 92%. A total of 17 of 19 newly diagnosed EGFR-positive patients were also detected to carry EGFR mutations. Importantly, these 17 patients carry the same mutation that was found in tissue samples implying complete concordance. In addition, we found novel resistance mutations in plasma of the patients who were under EGFR, ALK or ROS1 targeted therapies. Conclusions: Genexus Integrated Sequencer is a fully automated and highly accurate NGS system with a 1-day turnaround time that could assist clinicians to make more timely decision. Novel actionable, resistance mutations were detected using OPA panel that provide potential options for molecular-guided therapy and may help the better understanding of resistance mechanism of targeted therapy.