tbuckley/cabot-search huggingface dataset:
Concordance of tissue- and plasma-derived genomic profiling in CheckMate 9LA, using the FoundationOne CDx and GuardantOMNI assays.
Authors: Jonathan F. Baden, Mark Sausen, Natallia Kalinava, William J. Geese, David Balli, Jaclyn Neely, George Green
Journal: Journal of Clinical Oncology (2021)

9010 Background: Blood-based profiling of genomic features including tumor mutational burden (TMB) has generally demonstrated positive correlations with tissue-derived assessments from paired tumor samples. However, both technical and biological factors contributing to discordance between these measurements and underlying sequence alterations need further investigation for the successful adoption of noninvasive tumor profiling. We explored the genomic landscape, including the association between tissue TMB (tTMB) and blood TMB (bTMB), in samples from patients with stage IV non-small cell lung cancer (NSCLC) enrolled in CheckMate 9LA (NCT03215706), a phase 3, randomized clinical trial of nivolumab + ipilimumab in combination with 2 cycles of chemotherapy (chemo) vs 4 cycles of chemo as first-line treatment for NSCLC. Methods: Tissue- (FoundationOne CDx [F1CDx]) and blood-based (GuardantOMNI [OMNI]) genomic data obtained from both treatment arms were utilized for our retrospective analysis of genomic variants and complex biomarkers, including tTMB and bTMB. In total, 692 tissue and 646 plasma samples were analyzed. Results: Following the established criteria for the validated F1CDx and OMNI platforms, 464 tissue and 537 plasma samples passed quality control, resulting in ascertainment levels of 67% for tTMB and 83% for bTMB. Across 344 paired tissue and plasma samples, tTMB and bTMB scores were found to be moderately correlated (Spearman’s r = 0.56; P &lt; 0.001); median tTMB score was 7.7 mutations per megabase (mut/Mb) and median bTMB score was 13.5 mut/Mb. For the prespecified cutoffs of 10 mut/Mb for tTMB and 16 mut/Mb for bTMB, the positive, negative, and overall percentage agreements between assays were 65%, 79%, and 73%, respectively. Interestingly, 2 discordant sample pairs had considerably higher bTMB than tTMB (76.1 vs 3.8 and 172.6 vs 5.0 mut/Mb for bTMB and tTMB, respectively) and both had high microsatellite instability from blood-based assessments. OMNI and F1CDx data from 477 patients were evaluable for the analysis of short sequence variants (single nucleotide variations and indels). OMNI detected 4557 variants, F1CDx detected 4620, and 2903 (46% of total reported variants) were detected by both assays. Conclusions: In CheckMate 9LA, data from paired samples revealed the complementary nature of TMB assessments from tissue and blood and suggest that both approaches may have the potential to identify genomic alterations that may be useful in the management of patients with NSCLC. Further interrogation of the biological and analytical factors affecting tumor- and blood-derived genomic profiling is warranted to support their implementation in clinical settings. Clinical trial information: NCT03215706.
Differentiated activity profile for the PD-1 inhibitor balstilimab.
Authors: Cailin Joyce, Dhan Chand, Benjamin Duckless, Manuel Hidalgo, Joseph Elan Grossman, Remigiusz Kaleta, David M. O'Malley
Journal: Journal of Clinical Oncology (2021)

5529 Background: The development and clinical application of immune checkpoint inhibitors has transformed the therapeutic landscape for cancer treatment in recent years. Balstilimab (AGEN2034) is a fully human, monoclonal IgG4 antibody that binds with high affinity to programmed death 1 (PD-1), thus preventing the interaction between this receptor and its ligands programmed death ligand 1 and 2 (PD-L1, PD-L2). Emerging evidence suggests that balstilimab exhibits a differentiated activity profile compared to currently approved anti-PD-1 agents, including pembrolizumab and nivolumab. Methods: Balstilimab as monotherapy was evaluated in a large phase 2 study in patients (pts) with recurrent/metastatic cervical cancer who had relapsed after a platinum-based treatment regimen for advanced disease. Pts were dosed at 3 mg/kg once every 2 weeks for up to 24 months and antitumor activity was assessed using RECIST v1.1. The tumor cell killing activity of balstilimab was evaluated preclinically in a human co-culture system of (1) primary T cells engineered to recognize NY-ESO-1 and (2) NY-ESO-1 + cancer cell lines, including PD-L1 and/or PD-L2-deficient engineered lines. The co-culture system was maintained for ̃ two weeks to drive partial T cell exhaustion; a state where cytotoxicity is compromised but recoverable with PD-1 blockade. Cytotoxicity of these partially exhausted T cells was quantified against PD-L1/L2 double positive, single positive, or double negative cancer cells in the presence or absence of PD-(L)1 antibodies. Results: In the second-line treatment setting for pts with advanced cervical cancer, balstilimab showed a numerically higher objective response rate (ORR) in subjects with PD-L1 + , squamous cell carcinoma (SCC) tumors (21%, 95% CI, 12.7-32.6%) than those reported for pembrolizumab. Unlike pembrolizumab, balstilimab showed activity in PD-L1(-) pts, and irrespective of tumor histology (ORR 7.9%, 95% CI, 2.7-20.8%). Despite lower overall PD-L1 positivity compared to SCC (41.7 v 72.9%), an ORR of 12.5% (95% CI, 5.9-24.7%) was observed in the subset of pts with a poorer prognosis, those with cervical adenocarcinoma. Concordant with clinical observations, balstilimab demonstrated superior rescue of antigen-specific T cell cytotoxicity in vitro relative to pembrolizumab, nivolumab, or atezolizumab. Balstilimab also induced cytotoxicity against PD-L1 and/or PD-L2 deficient target cancer cells. Conclusions: Taken together, these data suggest functional differentiation of balstilimab from other PD-1 inhibitors with potentially important implications for extending the therapeutic reach of anti-PD-1 therapy. Investigation of the underlying mechanistic basis for these findings is ongoing. Clinical trial information: NCT03104699.
Does order matter? Real-world data on outcomes of successive regimens involving anti-PDx-1 in advanced and metastatic non-small cell lung cancer.
Authors: David Hadley, Shady Gendy
Journal: Journal of Clinical Oncology (2021)

e21159 Background: In 2020, 65% of newly diagnosed advanced (adv)or metastatic (met) NSCLC patients in US started first line (1L) systemic therapy on anti-PDx-1 regimen, 53% of second line (2L). Between broader approvals of anti-PDx-1, increasing use in different therapy lines, and in different regimen combinations, selecting initial and subsequent regimens can be challenging, especially with limited research on outcomes based on order. This analysis uses real-world data to summarize treatment decisions made in a network of oncology centers and relates them to time to second disease progression (PFS2) and overall survival (OS). PRA US medical &amp; prescription claims – 2020 (Jan-Aug). Methods: Deidentified data on adv/met NSCLC patients were selected from Inteliquet’s Cancer Center Research Consortium partners, which comprises academic &amp; community oncology practices as well as integrated delivery networks across the United States. Analysis was limited to patients who started 1L systemic treatment in 2017 &amp; 2018 (index event), progressed and started 2L. Either 1L / 2L / both must have been anti-PDx-1 based regimen. Patients with known actionable driver mutations were excluded. Data from the following 24 months was used to identify regimens and time to progression. PFS2 and OS across the combined 1L and 2L treatment protocols were assessed by proportional hazards regression. The analysis was adjusted for age at diagnosis, gender, PS and treating organization. Results: 132 patients met the study criteria: 53% were female, the median age range at diagnosis was 60-69 years, and 73% were diagnosed with stage IV, and 76% had PS 0-2 at diagnosis. After 24 months, 86% were alive, all had one progression and 44% had a 2nd progression. The most frequently observed treatment patterns are summarized in the table. Conclusions: Same regimens in different order showed different outcomes. There is a significant benefit for both OS &amp; PFS2 by starting with a platinum doublet followed by IO PT, versus the same start followed by IO MT. There is a significant disadvantage in OS by starting with IO MT followed by platinum doublet, versus the reversed order. 1L IO PT versus baseline showed non-significant improvement in PFS2, but not OS.[Table: see text]
COVID-19 and hematologic diseases: Risk factors and long-term follow-up of CHRONOS19 Registry.
Authors: Kristina Zakurdaeva, Olga A. Gavrilina, Anastasia N. Vasileva, Sergei Dubov, Vitaly S. Dubov, Lev S. Butaev, Alena M. Sukhareva, Lubov V. Gavrilova, Inessa Yu. Toropova, Marina O. Popova, Aleksandr A. Siniaev, Kamil D. Kaplanov, Andrei A. Petrenko, Oksana I. Ochirova, Ekaterina Chelysheva, Yulia A. Chabaeva, Yulia V. Sveshnikova, Mikhail A. Kunst, Anzhelika F. Rakhmani, Valery G. Savchenko
Journal: Journal of Clinical Oncology (2021)

e18715 Background: Pts with hem diseases are at high risk of COVID-19 severe course and mortality. Emerging data on risk factors and outcomes in this patient population is of great value for developing strategies of medical care. Methods: CHRONOS19 is an ongoing nationwide observational cohort study of adult (≥18 y) pts with hem disease (both malignant and non-malignant) and lab-confirmed or suspected (clinical symptoms and/or CT) COVID-19. Primary objective was to evaluate treatment outcomes. Primary endpoint was 30-day all-cause mortality. Long-term follow-up was performed at 90 and 180 days. Data from 14 centers was collected on a web platform and managed in a deidentified manner. Results: As of data cutoff on January 27, 2021, 575 pts were included in the registry, 486 of them eligible for primary endpoint assessment, n(%): M/F 243(50%)/243(50%), median age 56 [18-90], malignant disease in 452(93%) pts, induction phase/R/R/remission 160(33%)/120(25%)/206(42%). MTA in 93(19%) pts, 158(33%) were transfusion dependent, comorbidities in 278(57%) pts. Complications in 335(69%) pts: pneumonia (67%), CRS (8%), ARDS (7%), sepsis (6%). One-third of pts had severe COVID-19, 25% were admitted to ICU, 20% required mechanical ventilation. All-cause mortality at 30 days – 17%; 80% due to COVID-19 complications. At 90 days, there were 14 new deaths: 6 (43%) due to hem disease progression. Risk factors significantly associated with OS are listed in Tab 1. In multivariate analysis – ICU+mechanical ventilation, HR, 53.3 (29.1-97.8). Acute leukemias were associated with higher risk of death, HR, 2.40 (1.28-4.51), less aggressive diseases (CML, CLL, MM, non-malignant) – with lower risk of death, HR, 0.54 (0.37-0.80). No association between time of COVID-19 diagnosis (Apr-Aug vs. Sep-Jan) and risk of death. COVID-19 affected treatment of hem disease in 65% of pts, 58% experienced treatment delay for a median of 4[1-10] weeks. Relapse rate on Day 30 and 90 – 4%, disease progression on Day 90 detected in 13(7%) pts; 180-day data was not mature at the time of analysis. Several cases of COVID-19 re-infection were described. Conclusions: Thirty-day all-cause mortality in pts with hem disease was higher than in general population with COVID-19. Longer-term follow-up (180 days) for hem disease outcomes and OS will be presented. [Table: see text]
Healthcare resource use (HRU) by infusion setting of chimeric antigen receptor T-cell (CAR-T) in patients with relapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL): A retrospective cohort study using CMS 100% Medicare database.
Authors: Jing Zhao, Vamsi Bollu, Hongbo Yang, Anand Dalal, Mimi Tesfaye, Qiufei Ma, Angela Lax, Stephen Lim
Journal: Journal of Clinical Oncology (2021)

e19550 Background: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CAR-T therapies that were approved for r/r DLBCL in 2017 and 2018, respectively. While majority of the CAR-T infusions occur at inpatient (IP) setting in clinical trials, CAR-T infusions can also occur in the outpatient (OP) setting. This study aimed to compare the real-world HRU between IP vs. OP infusion of CAR-T among patients with r/r DLBCL. Methods: Adult patients with r/r DLBCL receiving tisa-cel or axi-cel were selected from the CMS 100% Medicare data from 2017 to 2019 and classified into IP and OP cohorts based on CAR-T infusion setting. Number of IP, OP, intensive care unit (ICU) visits, IP days, and ICU days by month post-CAR-T infusion were compared between cohorts using generalized linear models, adjusting for age, sex, race, and National Cancer Institute comorbidity index. Average length of stay (LOS) per IP episode during the first month was also described. Results: A total of 430 patients receiving CAR-T (380 IP and 50 OP) were identified. Among those with CAR-T regimen identifiable in the OP cohort, 90.2% received tisa-cel and 9.8% received axi-cel. Mean age at CAR-T infusion in IP and OP cohorts was 70.8 and 68.4 years, respectively. Most of the CAR-T infusions occurred in 2019 (66.6% in IP cohort and 74.0% in OP cohort). During the first month post-CAR-T infusion, OP cohort had significantly lower number of IP visits, IP days, ICU stays, and ICU days compared to the IP cohort. Average LOS per IP episode was 14.2 days in the IP cohort and 7.1 days in the OP cohort. Number of IP visits, IP days, and ICU days were nominally lower while number of OP visits were nominally higher in the OP cohort compared to the IP cohort in subsequent months (Table). Conclusions: Over 90% of the patients treated with CAR-T in the OP setting received tisa-cel. Patients receiving CAR-T in the OP setting had lower resource use of IP and ICU compared to patients receiving CAR-T in the IP setting.[Table: see text]
Modelling treatment benefit for bexmarilimab (an anti-Clever-1 antibody and a novel macrophage checkpoint inhibitor) using phase I first-in-man trial data.
Authors: Petri Bono, Jussi Ekström, Matti K Karvonen, Jami Mandelin, Jussi Koivunen
Journal: Journal of Clinical Oncology (2021)

e14530 Background: Bexmarilimab, an investigational immunotherapeutic antibody targeting Clever-1, is currently investigated in phase I/II MATINS study (NCT03733990) for advanced solid tumors. Machine learning (ML) based models combining extensive data could be generated to predict treatment responses to this first-in-class macrophage checkpoint inhibitor. Methods: 58 baseline features from 30 patients included in the part 1 of phase I/II MATINS trial were included in ML modelling. Seven patients were classified as benefitting from the therapy by RECIST 1.1 (PR or SD response in target or non-target lesions). Initial feature selection was done using a combination of domain knowledge and removal of features with several missing values resulting in 20 clinically relevant features from 25 patients. The remaining data was standardized and feature selection using variance analysis (ANOVA) based on F-values between response and features was performed. With this approach, the number of features could be further reduced as the prediction performance increased until the most important features were included in the model. Several prediction models were trained, and prediction performance evaluated using leave-one-out cross-validation (LOOCV), with and without SMOTE oversampling of the positive class of the training data inside each LOOCV fold. In LOOCV the prediction model was trained 25 times. Stacked meta classifier with SMOTE oversampling combining three classifiers: elastic-net logistic regression, random forest and extreme gradient boosting was chosen as the best performing prediction model. Results: Seven baseline features were associated with bexmarilimab treatment benefit. Increasing bexmarilimab dose and high tumor FoxP3 cells showed positive benefit. On contrary, high baseline blood neutrophils, CD4, T-cells, B-cells, and CXCL10 indicated negative relationship to the treatment benefit. The ML model trained with these seven features performed well in LOOCV as 6/7 benefitting and 16/18 non-benefitting were classified correctly, and all considered classification performance metrics were good. In feature importance analysis, low baseline CXCL10 and neutrophils were characterized as the most important predictors for treatment benefit with values of 0.19 and 0.16. Conclusions: This study highlights possibility of using ML models in predicting treatment benefit for novel cancer drugs such as bexmarilimab and boost the clinical development. These findings are in line of expected immune activation of bexmarilimab treatment. The generated ML models should be further validated in a larger patient cohort. Clinical trial information: NCT03733990.
Abstract 15701: Pharmacodynamics of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With PCSK9 Gain-Of-Function or ApoB Loss-Of-Function Mutations: An Open-Label Extension Study
Authors: Michel Krempf, Paul N Hopkins, Eric Bruckert, Gerald Luc, Shane Lee, Stephen Donahue
Journal: Circulation (2018)

Introduction: Causes of autosomal dominant hypercholesterolemia include apolipoprotein B (ApoB) loss-of-function mutations (LoFm) and PCSK9 gain-of-function mutations (GoFm; very rare). Alirocumab ...
EMBR-32. INTEGRATED STRESS RESPONSE PLAYS A PRO-SURVIVAL ROLE IN MYC-DRIVEN MEDULLOBLASTOMA
Authors: Sofya Langman, Alberto Delaidelli, Yue Zhou Huang, Poul Sorensen
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) accounts for 20% of diagnosed brain tumors in children. Group 3 (G3) MB subtype is the most aggressive. Molecularly, G3 MB is characterized by MYC overexpression, which drives elevated mRNA translation in tumor cells. PERK is an eukaryotic translation initiation factor 2 (eIF2α) kinase that inhibits mRNA translation under endoplasmic reticulum (ER) stress conditions, such as in response to accumulation of unfolded proteins. When unfolded proteins accumulate in the ER, activated PERK phosphorylates eIF2α. This shuts down global translation and triggers integrated stress response (ISR) to help cells adapt through selective translation of mRNA encoding pro-survival proteins. High mRNA expression of PERK correlates with poor survival in G3 MB patients. In vitro, combination of ER or hypoxic stress with PERK knockdown induces apoptosis in MB cells. ISRIB is an ISR inhibitor that maintains translation rates despite eIF2α phosphorylation. Combining ISRIB with stress such as hypoxia induces apoptosis in MB cells and prevents accumulation of key ISR mediators such as ATF4. In addition, combination of ISRIB and hypoxia induces oxidative stress. Current G3 MB treatment regimens include vincristine, a known ISR inducer. Combination of ISRIB with vincristine amplifies vincristine-induced apoptosis, potentially suggesting novel therapeutic approach for MB. Our findings show that inhibition of ISR in G3 MB represents a powerful inducer of cancer cell death.
Efficacy and safety of vactosertib and pembrolizumab combination in patients with previously treated microsatellite stable metastatic colorectal cancer.
Authors: Tae Won Kim, Keun Wook Lee, Joong Bae Ahn, Jin Lee, Jiyeon Ryu, Bitna Oh, Chan-Young Ock, Sunjin Hwang, Ki Baik Hahm, Seong-Jin Kim, Young Suk Park
Journal: Journal of Clinical Oncology (2021)

3573 Background: Microsatellite stable metastatic colorectal cancer (MSS mCRC) represents a high unmet need since there are currently no approved immunotherapy options. Since the inhibition of the transforming growth factor-β (TGF-β) pathway is known to contribute to the enhancement of immunotherapy efficacy, here, we report the results of vactosertib, a potent and selective TGF-β receptor I kinase inhibitor, combined with pembrolizumab in patients with MSS mCRC. Methods: In this phase 2, open label trial, patients have received vactosertib (300 mg BID, 5 days on / 2 days off) and pembrolizumab (200 mg, every 3 weeks) until confirmed progressive disease (PD), unacceptable toxicity or consent withdrawal. Patients with histologically confirmed mCRC who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan were enrolled. Eligible patients were ≥19 years old, had ECOG status ≤1, and had no prior exposure to immunotherapy. The objectives were to evaluate the safety and efficacy (objective response rate (ORR) per RECIST v1.1). Results: Thirty-three patients with MSS mCRC were enrolled. Median age was 60 (range 33-72), 55% were male, median number of previous lines of chemotherapy was 3 (range 1-7), and 82% were consensus molecular subtype (CMS) 4. The ORR was 15.2% including 5 partial responses (PRs), 7 stable diseases, and 17 PDs as best overall responses; 12 patients remain on treatment. Among 5 patients with PR, 3 patients had confirmed PR and median duration of response was not reached yet. As of 04 Jan 2021, the most common treatment related adverse events (AEs) were increased amylase (21.2%), pruritus (21.2%), rash (21.2%), and increased lipase (18.2%). There were 3 treatment-related SAEs reported; drug induced pneumonitis (3%), nausea (3%), and vomiting (3%). Conclusions: The combination treatment with vactosertib and pembrolizumab showed favorable safety profile with promising efficacy in patients with MSS mCRC. Updated data including pharmacodynamic markers will be presented at the meeting. Clinical trial information: NCT03724851.