bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of pembrolizumab on patients with pre-existing autoimmune diseases.
Authors: Bazerbashi Noor , Muhsen Ibrahim , Burns Ethan , Abdelrahim Maen 
Published: June 2022

2660 Background: Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape across a range of solid and hematologic malignancies. With the mechanistic activation of the adaptive immune response and known unique development of immune-related adverse effects (irAE), there is a theoretical risk of causing detrimental effects on patients with pre-existing autoimmune diseases (AID). However, this patient population was excluded from many clinical trials, and there is limited and conflicting retrospective data speculating upon the impacts of using ICI therapy in patients with AID. This study aims to report the impact of pembrolizumab in patients with AID. Methods: Patients who received pembrolizumab for treatment of any type of cancer between 1/1/2017-8/1/2021 were retrospectively reviewed, and patients with AID (rheumatologic or non-rheumatologic) were identified. Data including age, gender, race, ECOG, and primary cancer diagnosis were collected. AID was characterized by type, activity (symptomatic vs. asymptomatic at ICI initiation), and immunosuppressive treatment (IST) use. Outcomes included flare of AID, irAE, and ICI discontinuation. Results: Out of 810 patients, 12 with pre-existing AID were found and being treated for non-small cell lung cancer (NSCLC) (58% N=7), renal cell carcinoma (RCC) (16.6% N=2), colorectal cancer (CRC) (8% N=1), head and neck cancer (8% N=1), and cervical cancer (8% N=1). Around 67% of these patients were females with a median age of 65 years (50-77). Median ECOG was 1 (0-2). 9 patients (75%) had rheumatologic disease (5 rheumatoid arthritis (RA), 1 systemic lupus erythematosus (SLE), 2 psoriatic arthritis, and 1 systemic sclerosis (SS)). 3 patients (25%) had non-rheumatologic AID (1 multiple sclerosis (MS), 1 autoimmune hepatitis, and 1 Evan’s syndrome). All patients were asymptomatic prior to initiation of therapy. At the time of ICI initiation, 11 patients (92%) were on therapy, including steroids, methotrexate, and other IST. Due to concern for severe flare, pembrolizumab was discontinued in 3 (25%) MS, RA, and SS patients treated for RCC, CRC, and NSCLC, respectively. 3 patients (25%) developed irAE unrelated to their AID (pneumonitis, dermatitis, arthritis, gastritis) and received steroids. 4 patients (33.3%) had documented flares while on pembrolizumab requiring escalation of their ongoing therapy, and 1 NSCLC patient had a severe exacerbation of SS requiring cyclophosphamide and rituximab infusions. Conclusions: This analysis adds to the limited available literature that patients with an AID and on IST appear to have minimal AID-associated flares requiring intervention and tolerate pembrolizumab with a similar rate of irAE compared to patients without AID. Additional larger studies are needed to assess the efficacy of treatment in this population.
Immune-related adverse effects of long-term PD-1/PD-L1 inhibtor treatment.
Authors: Kim Sarah , Colevas A. Dimitrios , Tse Stephanie , On Sandy , Cheung Edna 
Published: June 2022

2661 Background: Immune-related adverse effects (irAE) are autoimmune-like toxicities caused by immune checkpoint inhibitor (ICI) treatment and often necessitate interventions such as corticosteroids, treatment interruptions/discontinuation, or hospital admission. Although ICI related irAEs are well described in literature, data on the toxicity profile associated with long-term ICI use remains limited. Since the optimal duration of therapy with ICI agents is currently unknown, it is crucial to assess the risks of long-term ICI use. Methods: This was a retrospective, observational, single-center study of adult oncology patients who received at least 1 year of programed death 1 (PD-1) inhibitor or programmed death ligand-1 (PD-L1) inhibitor treatment. The objective of this study was to characterize late-onset irAEs defined as greater than 1 year with long-term ICI treatment. Clinically significant irAEs were defined as those requiring corticosteroid treatment, hospital admission, treatment interruption or treatment discontinuation. This study included patients who received at least 1 year of nivolumab, pembrolizumab, atezolizumab or durvalumab between January 2016 and September 2021. Disease states included head and neck cancer, renal cell carcinoma, non-small cell lung cancer, and melanoma. Patients with concurrent exposure to other treatment such as chemotherapy, radiation, surgery, tyrosine kinase inhibitors and monoclonal antibodies while on ICI treatment were included in the study. Exclusion criteria included patients with treatment breaks of greater than 6 months, two malignancies undergoing active treatment, and treatment administration outside of the study center. Results: Of 282 patients assessed, 143 met study inclusion criteria. The median ICI treatment duration was 19 months (IQR 14-27). There was a 30% incidence of late-onset irAEs, of which 22% were clinically significant. Most late-onset irAEs were low in severity, as 45 (90%) were grade 1-2 and 5 (10%) were grade 3. The most common late-onset irAEs were pulmonary (8%) and gastrointestinal (7%). Univariate analysis suggests risk factors potentially associated with late-onset irAEs include concurrent exposure to additional therapies during ICI treatment and past medical history of rheumatologic disease. Conclusions: Although the optimal duration of ICI therapy is unknown, this study suggests that long-term ICI use was associated with a low but notable incidence of toxicities, of which most were low in severity. [Table: see text]
Immune checkpoint inhibitor–induced diabetes mellitus across NCI trials.
Authors: Quandt Zoe E. , Hill Vanessa , Dib Joe E. , Burian Jason , Tessler Sapir , Naqash Abdul Rafeh , Anderson Mark S , Othus Megan , Sharon Elad 
Published: June 2022

2668 Background: Immune checkpoint inhibitors (CPI) are known to rarely cause new onset diabetes (CPI DM). While rare, this adverse event is quite challenging for patients and clinicians to manage. Therefore, it is important to identify risk factors and clinical characteristics. This is the first comprehensive, multi-institutional study of CPI-DM across multiple agents and cancer types. Methods: The NCI Cancer Therapy Program (CTEP) database of adverse events (AEs) was queried for AEs related to diabetes (Grade 3 or 4 hyperglycemia, Acidosis including Diabetic Ketoacidosis (DKA), glucose intolerance and diabetes mellitus) among 6,925 patients who had been treated with a PD-(L)1 inhibitor alone or in combination from 6/2015 to 12/2019. Each AE report was reviewed and classified as due to CPI DM, new onset type 2 diabetes mellitus (T2DM), T2DM exacerbation without medication non-compliance, existing DM with medication non-compliance, or association with steroids (SDM). CPI DM was diagnosed based on: evidence of insulin deficiency either through presentation in DKA or low c-peptide with need for long term basal bolus insulin to maintain euglycemia and/or positive islet autoantibodies. Results: In total, there were 82 cases with at least one of these AEs; 41 had CPI-DM, 22 had SDM, 1 had new T2DM, 4 had T2DM exacerbation, 3 had medication noncompliance and 11 had acidosis not attributable to diabetes or had insufficient data. After excluding non-hyperglycemic acidosis, 57.8% had CPI-DM. Furthermore, if not on steroids and in good compliance with diabetes medications, 89.1% had CPI-DM. The incidence of CPI-DM was 0.59%; it was most common on combination PD-1/CTLA-4 inhibitor therapy (0.85%, 15/1767), followed by PD-(L)1 inhibitor monotherapy (0.54%, 18/3354), followed by CPIs combined with additional agents including chemotherapy and targeted agents (0.44%, 8/1804)(p = 0.25). Hospitalization was required for 87.5% of CPI-DM cases with 74.3% of those requiring an inpatient endocrine consult. All but one CPI-DM case had an endocrine consult at as either an inpatient or outpatient. Conclusions: While rare, this cohort shows the large health care burden of CPI-DM and that any hyperglycemia, and especially marked hyperglycemia, should be treated as CPI-DM until proven otherwise. [Table: see text]
A phase Ia/Ib study of CBP-1008, a bispecific ligand drug conjugate, in patients with advanced solid tumors.
Authors: Wu Lingying , Shen Lin , Hu Xichun , Li Ning , Liu Dan , Zhang Jian , Huang Robert , Teng Yan , Li Li , Zhang Bin , Zhang Youzhong , Huang Yi , Wang Ying , Wu Junyan , Zheng Yulong , Luo SuXia , Ba Yi , Tong Zhongsheng , Wang Xian , Lou Ge 
Published: June 2022

3000 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are overexpressed in many solid tumors hence could be promising therapeutic targets. CBP-1008 is a first-in-class bi-specific ligand drug targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload. Here we report the first-in-human, multicenter, phase Ia/Ib study designed to explore the safety, pharmacokinetics and efficacy of CBP-1008 in advanced solid tumors. Methods: CBP-1008 was administered by intravenous infusion. Phase Ia study included a dose-escalation period initiated by accelerated titration (0.015, 0.03mg/kg d1,15; q28d) and then switched to 3+3 scheme (0.12, 0.15, 0.17, 0.18mg/kg d1,15; q28d) and a dose expansion period. Phase Ib clinical expansion study included 3 cohorts, platinum-resistant ovarian cancer (OC), metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective was to assess the safety and preliminary efficacy. Results: As of January 13, 2022, 106 patients received at least one dose of study drug were enrolled (phase Ia: n = 30; phase Ib: n = 76) and received median 3 prior regimens. Included tumor species were OC (n = 52), TNBC (n = 20), ER+/Her2+ breast cancer (BC) (n = 16), lung cancer (n = 3), pancreatic cancer (n = 2) and others (n = 13). In phase Ia study, DLTs were observed in 3 patients (0.12, 0.15, 0.18mg/kg, n = 1 each), including grade 4 hypophosphatemia, neutropenia, febrile neutropenia, and grade 3 hyperglycemia, alanine aminotransferase (ALT). MTD was not yet reached. Majority of adverse events were mild to moderate. The most common grade 3/4 treatment-emerging adverse events (TEAEs) were neutropenia (37.7%), AST elevation (6.6%), ALT elevation (5.7%), hyperglycemia (2.8%), hypohemoglobinemia (2.8%) and nausea (1.9%). Drug-related death was not observed. A total of 69 patients at dose of 0.15mg/kg or above were evaluable for efficacy assessment. There were 11 patients achieved partial response (PR) (OC n = 8, ER+/Her2+ BC n = 2, TNBC n = 1) and 30 patients achieved stable disease (SD). In 32 advanced platinum-resistant OC patients with FRα and/or TRPV6-positive expression, 6 PR and 16 SD were observed. Moreover, 6/18 PR (33.3%) and 8/18 SD (44.4%) were observed in enriched OC patients who showed high score of FRα/TRPV6 receptor. Conclusions: The preliminary results showed that CBP-1008 has manageable safety profile. Antitumor activity was observed in patients with FRα/TRPV6 receptor expression, especially in platinum-resistant OC cohort with high score of the two receptors. Clinical trial information: NCT04740398.
A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).
Authors: Gounder Mrinal M. , Yamamoto Noboru , Patel Manish R. , Bauer Todd Michael , Schöffski Patrick , Grempler Rolf , Durland-Busbice Sara , Geng Junxian , Maerten Angela , LoRusso Patricia 
Published: June 2022

3004 Background: The highly potent MDM2–p53 antagonist BI 907828 showed antitumor efficacy in vivo, particularly in TP53 wild-type, MDM2-amplified de-differentiated LPS (DDLPS) patient-derived xenografts and syngeneic models. This phase I study (NCT03449381) is assessing BI 907828 monotherapy in patients with advanced solid tumors, including LPS. In Part A (dose escalation), patients received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. Based on previously reported results from Part A (LoRusso ASCO 2021), the MTD was 60 mg q3w and the recommended dose for expansion (RDE) was selected as 45 mg q3w. Methods: In Part B (dose expansion), patients received BI 907828 45 mg q3w. The primary endpoint was PFS. Secondary endpoints/objectives included objective response rate, overall survival, the number of patients with grade ≥3 treatment-related AEs, and PK parameters. Here, we report overall safety data and efficacy data in the subgroup of patients with advanced LPS. Results: As of January 10, 2022, 90 patients had been enrolled; 49 (54.4%) were male, 55 (61.1%)/34 (37.8%) were ECOG PS 0/1, the median number of prior systemic therapies was 2 (range, 0–11), 44 had advanced LPS (28 DDLPS, 16 well-differentiated LPS [WDLPS]). At data cut-off, 31/90 patients (34.4%) had received treatment for ≥6 months. In the 41 evaluable patients with advanced LPS, best response of PR or SD was observed in 24/27 patients with DDLPS (88.9%) and 13/14 patients with WDLPS (92.9%). Two DDLPS and 4 WDLPS patients achieved a PR; all had MDM2-amplified disease. In Part A, 5/11 DDLPS patients and 4/8 WDLPS patients have achieved PFS ≥10.5 months. In the 42 patients who received the RDE of 45 mg q3w, 18 patients (42.9%) had grade ≥3 AEs; the most common grade ≥3 AEs were neutropenia (23.8%), thrombocytopenia (21.4%), and anemia (11.9%). Seven patients (16.7%) had SAEs; the most common were thrombocytopenia (4.8%) and pyrexia (4.8%). PK analysis showed that mean plasma exposures (Cmax and AUC0-inf) increased with dose and showed no significant deviation from linearity in the dose range 10–60 mg. A correlation was observed between exposure and GDF-15 levels in plasma, as a target engagement marker. Conclusions: BI 907828 showed a manageable safety profile, high plasma exposure, target engagement and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. The Part B dose expansion is ongoing. Clinical trial information: NCT03449381.
Tumor agnostic efficacy and safety of erdafitinib in patients (pts) with advanced solid tumors with prespecified fibroblast growth factor receptor alterations (FGFRalt) in RAGNAR: Interim analysis (IA) results.
Authors: Loriot Yohann , Schuler Martin H. , Iyer Gopa , Witt Olaf , Doi Toshihiko , Qin Shukui , Tabernero Josep , Reardon David A. , Massard Christophe , Palmer Daniel , Lugowska Iwona , Coward Jermaine , Corassa Marcelo , Stuyckens Kim , Liao Huimin , Najmi Saltanat , Hammond Constance , Santiago-Walker Ademi E. , Sweiti Hussein , Pant Shubham 
Published: June 2022

3007 Background: Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat locally advanced or metastatic urothelial carcinoma (UC) in adults with susceptible FGFR3/2alt who have progressed during or after ≥ 1 line of platinum containing chemotherapy . FGFRalt are observed across a wide range of malignancies and may function as oncogenic drivers independent of the underlying tumor type. RAGNAR (NCT04083976) is an ongoing phase 2 open label, single arm tumor agnostic trial investigating the efficacy and safety of erda in pretreated adult and pediatric pts with advanced solid tumors and FGFRalt. Here, we report results from a planned IA of RAGNAR. Methods: Pts aged ≥ 6 y with advanced or metastatic solid tumors of any histology (except UC) with predefined FGFR1-4alt (mutations/fusions based on local/central test) and documented disease progression on ≥ 1 prior line of systemic therapy (tx) and no alternative standard tx received oral erda until disease progression or intolerable toxicity. The primary end point is objective response rate (ORR) by independent review committee (IRC). Secondary end points include investigator assessed ORR, duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), PFS, OS, and treatment emergent adverse events (TEAEs). Results: As of the IA data cutoff, 178 pts were treated (median age 56.5 y [range 12-79], median 2 prior systemic tx). Only 9.0% of pts responded to last line of tx prior to study entry. ORR by IRC was 29.2% (95% CI, 22.7-36.5). Investigator assessed ORR was 26.4% (95% CI, 20.1-33.5). Responses were observed in 14 distinct tumor types, including gliomas, thoracic, gastrointestinal, gynecological, and rare tumors (Table). ORR in pts with FGFR mutations vs fusions was comparable (26.8% vs 27.0%, respectively). Median DOR, PFS, and OS were 7.1 mo (95% CI, 5.5-9.3), 5.2 mo (95% CI, 4.0-5.6), and 10.9 mo (95% CI, 7.9-14.3), respectively; DCR was 75.3% and CBR was 48.9%. All pts experienced TEAEs, including 69.1% with grade ≥ 3. Treatment-related serious TEAEs occurred in 7.3% of pts. Conclusions: RAGNAR data show, for the first time, evidence of efficacy for erda in heavily pretreated pts with a variety of hard to treat advanced FGFR+ malignancies, including glioblastoma, pancreatic, and salivary gland cancers. Safety was consistent with the known erda safety profile. Clinical trial information: NCT04083976. [Table: see text]
Expanding clinical actionability in individual patient profiles with the Molecular Oncology Almanac.
Authors: Reardon Brendan Michael , Van Allen Eliezer Mendel 
Published: June 2022

3015 Background: The clinical care of oncology patients is routinely informed by tumor and inherited genetic profiles. This is accomplished by molecular pathologists synthesizing the growing body of clinical guidelines and scientific evidence that associates cancer genome alterations and therapeutic response, and applying that knowledge during case reviews. Many academic medical centers formalize this process in the form of molecular tumor boards. As the number of cases for review and literature continue to increase, there is opportunity to leverage clinical interpretation algorithms to computationally prioritize molecular features and both enhance and automate the sample contextualization process. Here, we present the Molecular Oncology Almanac (MOAlmanac) to enable the rapid assessment of tumor actionability. Methods: Molecular Oncology Almanac is an open source clinical interpretation algorithm and paired knowledge base for precision cancer medicine. It is used to rapidly characterize and identify genomic features related to therapeutic sensitivity and resistance and of prognostic relevance. This is performed by assessing not only individual genomic features (e.g. somatic variants, copy number alterations, germline variants, and fusions) but also interactions between these events as well as secondary features such as mutational burden, mutational signatures, MSI status, and aneuploidy. MOAlmanac summarizes all clinically relevant findings into a web-based actionability report. The underlying knowledge base can be accessed through our API endpoints and web browser, and entries may be recommended through either Github or our browser extension. In addition, we developed a cloud-based web portal on top of the Terra framework to increase accessibility. Results: A total of 32,108 samples from 30,607 patients across 66 cancer types received targeted sequencing to characterize somatic variants, copy number alterations, and fusions from PROFILE’s Oncopanel and were evaluated with MOAlmanac. Based on Oncopanel’s tier 1 and tier 2 criteria for clinical actionability, we observed that 8,285 samples (26%, 0 - 69% by cancer type) of patients harbored at least one alteration suggesting therapeutic sensitivity based on FDA approvals or clinical guidelines. Actionability increases to 18,117 samples (56%, 0 - 85% by cancer type) when considering an expanded set of evidence to include relationships captured from clinical trials, clinical, preclinical, and inferential evidence; consequently providing at least one therapeutic hypothesis to otherwise variant-negative patients. Conclusions: Clinical actionability of molecular tumor data was increased in individual patients by expanding the set of evidence considered. Source code and a web portal for this project are available at moalmanac.org .
Enabling circulating cell-free mRNA theranostics from PD-L1, ALK, ROS1, NTRK to transcriptomic profiling.
Authors: Yeh Chen-Hsiung 
Published: June 2022

3033 Background: Circulating cell-free mRNA (cfmRNA) expression can be considered as a compendium of transcripts collected from all organs. It has the capability of integrating functional and genetic information of tissues, highlighting this analyte’s unique potential as a non-invasive biomarker in early detection, therapy selection and patient follow-up of cancer management. Plasma cfmRNA is usually made up of degraded small fragments of smaller than 200 nucleotides, very low concentration, and with different terminal modification, these properties make it difficult to detect. We have developed, validated and automated a cfmRNA clinical testing workflow for simultaneous measurement of PD-L1 expression, ALK, ROS1 and NTRK fusions. This proprietary real-time qPCR-based process is exosome-free, highly sensitive and requires only half milliliter of plasma with 72-hour turnaround. A plasma cfmRNA profiling database covering 750 genes in 9 major cancer pathways was also established with novel cancer type-specific characteristics. Methods: Circulating cfRNA was extracted from 400 uL of plasma and reverse transcribed to cDNA. The cDNA pool then served as the universal source for multi-biomarker tests. All target primer and probe sets were selected based on RNA secondary structures. Plasma PD-L1 expression, ALK, ROS1, NTRK fusions and transcriptomic profiling were performed by Circulogene CLIA/CAP-complied testing platform. Results: Limit of detection (LOD) for PD-L1, ALK/ROS1 and NTRK were 1.0 copy/uL, 17.5 copies/uL and 28 copies/uL, respectively. For scoring of PD-L1 expression, based on Keynote trials, we used the 30th percentile Ct value as cutoff in qPCR which corresponded to IHC ≥ 50% TPS; while the 66th percentile Ct value corresponded to IHC ≥ 1% TPS. PD-L1 cfmRNA was demonstrated to be an excellent surrogate marker of tissue PD-L1 protein for clinical outcomes with immunotherapy. In a global cfmRNA landscape, a functional transcriptomic databank was also established, including differential gene expression, classification, functional clustering and cancer type-specific signatures. Conclusions: Liquid biopsy qPCR tests targeting PD-L1 expression, ALK, ROS1 and NTRK fusions are commercially available and filling the gap of tissue-based assays and NGS. Our groundbreaking cfmRNA work has research, clinical, and diagnostic value, and provides greater dimensionality to the current knowledge of cfmRNA research and makes a significant jump into understanding and devising strategies to tailor cancer Dx and Rx.