bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.