bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial results of dose finding in a first-in-human phase 1 study of a novel Claudin 6 (CLDN6) targeted antibody drug conjugate (ADC) TORL-1-23 in patients with advanced solid tumors.
Authors: Konecny Gottfried E. , Wahner Hendrickson Andrea Elisabeth , Winterhoff Boris , Chander Cinthiya , Bilic Sanela , Davenport Simon , Chung Adrine , Miller Lei-Lani , Press Michael F. , Letrent Stephen P. , Slamon Dennis J. 
Published: June 2023

3082 Background: CLDN6, a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies and has little to no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of new therapeutics. TORL-1-23 is first-in-class ADC targeting the tumor-specific antigen CLDN6. Methods: TORL123-001 (NCT05103683) is an ongoing, 2-part, first in human study to characterize the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of TORL-1-23 monotherapy in participants with advanced solid tumors. Serum pharmacokinetics (PK), immunogenicity and clinical efficacy are also assessed. TORL-1-23 is administered as a 30-minute IV infusion once every 3 weeks in 21-day cycles. During Part 1 (Dose Escalation), cohorts of 1 to 6 participants are evaluated at each dose level according to an accelerated titration design. In Part 2 (Dose Expansion), several cohorts of patients with CLDN6-expressing cancers will be evaluated to confirm the RP2D in ovarian cancer, NSCLC, and other CLDN6-expressing cancers using a CLDN6 IHC companion diagnostic. Results: As of 01FEB2023, 22 patients with ovarian (n=18), testicular (n=3), and endometrial (n=1) cancers were enrolled and treated across 8 dose levels ranging from 0.2 to 2.4 mg/kg IV every 3 weeks. 95% of pts had received ≥ 3 prior lines of treatment in the metastatic setting. The most common treatment-related adverse events were Gr1/2 fatigue (n=5), Gr1 peripheral neuropathy (n=4), and Gr1 nausea (n=3). No DLTs have been reported and no dose reductions have been required. Preliminary PK data demonstrate sustained exposure of TORL-1-23 ADC over the 21 day dosing interval and low levels of serum MMAE indicating low off-target MMAE exposure outside of tumor. Partial responses (PR) were observed in 4/17 efficacy evaluable participants with CLDN6+ disease (3 ovarian, 1 testicular). Dose escalation is ongoing and updated results will be presented. Conclusions: TORL-1-23 has a favorable safety/tolerability profile and PK characteristics with preliminary antitumor activity in pts with heavily-pretreated CLDN6-expressing ovarian and testicular cancers. Doses above the historic MTD for MMAE containing ADCs may be explored given the safety/tolerability and PK data observed up to 2.4 mg/kg. Dose finding is ongoing to identify the MTD and optimal doses for subsequent development. Clinical trial information: NCT05103683 .
Safety, pharmacokinetics and anti-tumor activity of RP12146, a PARP1/2 inhibitor, in patients with locally advanced or metastatic solid tumors.
Authors: Wysocki Piotr Jan , Lubaś Maciej Tadeusz , Łobacz, Mateusz , Kalinka-Warzocha Ewa , Tomczak Piotr , Kwiatek Michal , Lugowska Iwona A. , Smakal Martin , Chraniuk Dominik , Melichar Bohuslav , Markiewicz-Bialek Beate , Routhu Kasi V. , Barde Prajak J. , Nair Ajit 
Published: June 2023

3097 Background: RP12146 is an orally bioavailable, potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and PARP 2. Pre-clinically, RP1246 demonstrated anti-proliferative activity in both BRCA and non- BRCA mutant cancer cell lines of different tumor types as well as in xenograft models. The first-in-human of RP12146 as a single agent is underway to determine the safety, pharmacokinetics and anti-tumor activity. Methods: The phase I/Ib study was designed as two-part study. Phase I was a dose escalation, 3+3 design, MTD determination study and would enroll pts who have tumors which are known to harbour DNA repair deficiencies. Phase Ib is dose expansion at the MTD/ optimal dose and would enroll thirty-six pts (12 pts each of advanced/metastatic ovarian cancer (OC), breast cancer (BC), and castration-resistant Prostate cancer (mCRPC) having a confirmed deleterious HRR mutation. RP12146 was administered orally in a 28-days cycles until disease progression. Safety were the primary outcome and the investigator-assessed ORR, CBR and PFS assessed using RECIST v1.1, are the secondary outcomes. Predictive biomarker analysis included inhibition of PARP enzyme as measured by gH2AX levels in PMBCs. Results: As of 31-Jan-2023, 9 pts in the dose escalation at 3 dose levels (100 mg QD, 200mg BID and 400 mg BID) and 13 pts (with 5 CHEK2, 4 BRCA2, 2 ATM, 1 CDK12, and 1 RAD51C mutations) in dose expansion have been enrolled. No DLTs were reported in dose escalation. The dose of 400mg BID was considered for dose expansion. Out of 22 pts enrolled, 13 pts had PC, 3 pts had OC, and 2 pts had BC. Most of the related AEs reported were mild in severity except one event of Grade 3 anaemia which resolved, and patient continues to be on therapy. None of the pts developed related SAEs or discontinued due to an AE. Eleven patients (50%) in the expansion group continue to be on RP12146 treatment. RP12146 exhibited rapid absorption achieving maximum concentrations in 1 hr, with an elimination half-life of ~ 4 hrs. Out of the 7 efficacy evaluable PC patients, 5pts showed stable disease and 2pts showed progressive disease. Out of 3 OC pts, 2 pts showed stable disease, and one pt had progressive disease. Among two BC pts, one showed stable disease and the other had progressive disease. Overall, out of 16 efficacy evaluable patients, 8 patients (50%) showed stable disease. Conclusions: RP12146 showed a differentiated safety profile so far with limited hematological toxicities reported as compared to the first-generation PARP inhibitors. Updated safety and efficacy data will be provided at the time of presentation. Clinical trial information: NCT05002868 .
Phase 1 results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) or gemcitabine (gem) in advanced solid tumors.
Authors: Lynch Ryan C. , Munster Pamela N. , Falchook Gerald Steven , Burness Monika Leigh , Yap Timothy A. , Shapiro Geoffrey , Spigel David R. , Patel Manish R. , Moore Kathleen N. , Juric Dejan , Doleman Susan , Bradley William D. , O'Shea Thomas J. , Englert Judson M. , Renschler Markus F. , Beri Nina 
Published: June 2023

3099 Background: The MCT inhibitor CYT-0851 blocks lactate transport resulting in glycolytic cancer cell death. Monotherapy clinical activity has been previously reported in lymphoma and solid tumors. Preclinical studies assessing CYT-0851 with chemotherapy identified enhanced growth inhibition when combined with 5-FU or gem supporting clinical evaluation. Methods: Patients (pts) with solid tumors were treated with CYT-0851 + standard dosing of cape or gem in 21- and 28-day cycles, respectively, following a 3+3 design. The primary objective was to determine the MTD. Secondary objectives included: safety, PK, and anti-tumor activity by RECIST. Results: As of Feb 1, 2023, 14 pts (pancreatic n=9; ovarian n=5) were treated in 4 cohorts (100 - 400 mg QD) with cape. No DLTs occurred, and 400 mg QD was selected as the RP2D. 8 pts (57%) experienced a treatment-related adverse event (TRAE), including 2 (14%) with a G3/4 AE. The most common related AEs were primarily G1/2 and included fatigue (21%), nausea, decreased appetite, dry skin, mucosal inflammation and maculopapular rash (all 14%). 10 pts (sarcoma n=6; HNSCC n=1; ovarian n=1; pancreatic n=2) were treated in 2 cohorts (100, 200 mg QD) with gem. No DLTs occurred. Escalation is ongoing with up to 2 further cohorts. 9 pts (90%) experienced a TRAE, including 5 (50%) with a G3/4 AE which were primarily cytopenias. The most common TRAEs were fatigue (50%), anemia (50%), neutropenia (40%), thrombocytopenia (30%), nausea, pruritus, ALT/AST increased, neutrophil decreased and WBC decreased (all 20%). CYT-0851 exposure was similar between combination therapy and monotherapy. 8 pts in the cape cohorts were response-evaluable, including 3 with ovarian cancer. 1 pt with platinum-resistant ovarian cancer had a confirmed PR with treatment ongoing at 174 days. 7 pts had SD. 6 pts in the gem cohorts were response-evaluable. 1 pt with sarcoma had a confirmed PR, 4 pts had SD and 1 had PD. Conclusions: 400 mg QD was selected as the RP2D in combination with cape as no MTD was identified. Escalation of gem + CYT-0851 is ongoing to identify the MTD. Both combinations have demonstrated an acceptable safety and tolerability profile with no unanticipated toxicities at clinically active doses. Encouraging antitumor activity has been observed in heavily pre-treated pts with both regimens including pts with ovarian cancer in the cape combo. The cape cohort is being expanded with additional pts with ovarian cancer and will be presented. Clinical trial information: NCT03997968 .
Discovery of gene fusions in driver-negative NCI-MATCH screening samples.
Authors: Kaluziak Stefan T , Iafrate A. JOHN , Karlovich Chris Alan , Williams P. Mickey , Sklar Jeffrey , McShane Lisa , Codd Elizabeth , Purohit Rashi , Kirkpatrick Grace 
Published: June 2023

3112 Background: NCI-MATCH aimed to determine the treatment efficacy of identifying actionable genetic alterations, irrespective of cancer histology, and to tailor treatment to the putative molecular drivers of tumors. Leveraging next-generation sequencing (NGS) and ThermoFisher’s Oncomine assay, this phase II trial genotyped 5,540 patient samples during active screening. Reviewing the genotyping statistics, we noted that NCI-MATCH identified fusions in 164 tumors, only 2.96%. This result is substantially lower than expected, given that clinical assays used at MGH’s and Yale’s diagnostic laboratories identified fusions in 8.5% of the 7,500 sequenced cases, 2.5% of which were novel. Notably, the Oncomine assay, based on multiplexed PCR, is unable to detect driver fusion events when either of the gene partners are unknown, or a novel breakpoint is involved. Cross-referencing identified fusions from MGH’s cohort with Oncomine’s primers, 5-30% of these fusions were potentially missed, suggesting that we could detect up to 30% more fusions than originally identified. Developed at MGH’s Molecular Diagnostics Laboratory, Anchored Multiplex PCR (AMP) interrogates 138 known fusion partners, enabling unbiased fusion detection when only one partner is known. With a high likelihood of identifying novel fusion drivers using AMP technology, we sequenced 663 cases that had no identified mutations of interest (MOI) from the NCI-MATCH cohort. Methods: A total of 200ng of RNA per sample was shipped from ECOG-ACRIN’s repository at MD Anderson Cancer Center to MGH (n = 319) and Yale (n = 349). Samples were processed with ArcherDX’s FusionPlex Pan Solid Tumor v2 kit and sequenced on the NextSeq500 with 150 base pair (bp) Paired-End (PE) kits. Data analysis was completed with ArcherDX’s analytics platform in conjunction with custom Python and R code. Reported fusions were manually verified on a case-by-case basis. All statistical tests were conducted in R. Results: Of the cases sequenced, most (663/693, 95.7%) were successfully processed with AMP. We identified 142 cases with at least one gene fusion out of 663 MOI-Negative cases (21%; 95% CI [18%, 25%]), with 90 as unique fusions, significantly more than the 8.5% observed at MGH (P < .001). Of the 142 fusion-positive cases, 36 have potentially actionable driver events, 27 contain novel fusions not previously described, and in 63 cases no drugs are available to target either component of the fusion. Additionally, we identified fusions in (12/34, 35%) Cholangiocarcinoma and (38/101, 37.6%) Sarcoma cases, 9 and 3 of which were potentially actionable respectively. Conclusions: As hypothesized, we identified fusions that the NCI-MATCH screening had missed, detailing sequencing technology improvement that could be broadly applicable to many clinical laboratories sequencing tumors. Clinical trial information: NCT02465060 .
The relationship between the change with neoadjuvant chemotherapy in the tumor-infiltrating lymphocyte (TIL) expressions and pathological response in breast cancer patients.
Authors: Bilici Ahmet , Goktas Aydin Sabin , Cakir Asli , Olmez Omer Fatih , Erol Vedat Bugra 
Published: June 2023

3114 Background: Many prognostic biomarkers for survival have been studied in the neoadjuvant setting for locally advanced breast cancer (LABC). Our study assessed the correlation between the change in tumour-infiltrating lymphocytes (TIL) before and after neoadjuvant chemotherapy (NAC) in breast tissue and its impact on survival in patients with LABC. Methods: Eighty-four LACB patients were retrospectively analysed in this study. TIL was assessed by means of immunohystochemistry (Eclipse Ni, Nikon, Japan) in paraffin-embedded blocks obtained by core-needle biopsy or surgical specimen with respect to the 'TIL working group' criteria. Results: TIL scores were grouped as 0%, <10%, 10-50%, and >50%, the median TIL percentage was 17.5% before NAC and 5% after NAC, and the difference was statistically significant (p<0.001). Postop-Ki-67 (p=0.005), molecular subtype (p=0.027), pre-NAC TIL score (p=0.006), post-NAC TIL score (p<0.001), postop-Ki-67 (p=0.005) and preoperative residual cancer burden tumour-infiltrating lymphocyte (RCB-TIL) (p<0.001) were significantly correlated with pCR. Higher TIL scores were significantly associated with higher PCR rates. Univariate analysis for disease-free survival (DFS) and overall survival (OS) revealed that postop-Ki-67 level and presence of pCR and postoperative ki-67 score (p=0.031) were significant prognostic factors, respectively. The independent prognostic factor for DFS were postop-Ki-67 score (p=0.012, RR: 6.16, 95% CI: 1.48-9.12), post-NAC TIL score (p=0.041, RR: 0.42, 95% CI: 0.16-1.06) and the presence of pCR (p=0.038, RR: 0.10, 95% CI: 0.01-0.87). Logistic regression analysis showed that a preoperative ki-67 score greater than 14% (p=0.001, OR: 4.55; 95% CI: 0.11-1.49), a postoperative ki-67 score equal to or lower than 14% (p=0.011, OR: 1.10; 95% CI: 0.42-2.29), preop-grade 3 (p=0.01, OR: 2.65; 95% CI: 0.85-3.14), low postop-TIL score (p<0.001, OR: 3.14; 95% CI: 0.79-4.11) were significant predictive factors for pCR. Conclusions: Our study confirms the hypothesis that TIL expressions may be therapeutic targets, especially in specific molecular breast cancer subtypes.
Novel deep learning–based prognostic prediction model for colorectal cancer using hematoxylin and eosin–stained whole slide images.
Authors: Konishi Teppei , Grynkiewicz Mateusz , Saito Keita , Kobayashi Takuma , Goto Akiteru , Umakoshi Michinobu , Iwata Takashi , Nishio Hiroshi , Katoh Yuki , Fujita Tomonobu , Matsui Tomoya , Sugawara Masaki , Sano Hiroyuki 
Published: June 2023

3119 Background: Previous studies have shown that the presence or absence of genetic mutations is critical for colorectal cancer prognosis. However, genomic testing can be expensive and difficult to perform on all samples. In contrast, hematoxylin and eosin (H&E) staining is relatively inexpensive and can be performed on all tissue specimens. In this study, we designed a novel prognostic method using spatial image features extracted from H&E–stained whole slide images (WSIs) and genetic mutation prediction neural networks. Methods: We obtained H&E–stained WSIs and data on Microsatellite Instability ( MSI), BRAF, TTN and APC gene mutations from a clinical cohort of 548 patients with The Cancer Genome Atlas (TCGA) Colon adenocarcinoma and rectum adenocarcinoma. We divided them into training (n=361), validation (n=90), and test (n=115) groups. Classification models were trained to predict the presence or absence of MSI, BRAF, TTN, and APC mutations. The model input comprised features of the H&E–stained WSIs, as obtained via a deep learning–based feature extractor. All resultant models were incorporated into a prognostic model (overall survival: > 60 months (low risk)/< 60 months (high risk)). Our prognostic model’s performance was evaluated against TCGA colorectal dataset, and a survival analysis was performed on the model using the Kaplan–Meier method. Finally, we compared our model’s performance with the end–to–end prognostic prediction of a convolutional neural network (CNN) that also used H&E–stained WSIs as input and provided prognostic prediction as output. Results: Our deep learning–based prognostic prediction model achieved an AUC score of 0.834 with a 95% confidence interval (CI) of 0.734–1.000 alongside TCGA dataset; the survival analysis compared the survival distributions of low–risk and high–risk groups, as predicted by our model; a p–value < 0.01 was obtained. The model could classify low– and high–risk patients and accurately predict patient status as alive (low risk) or deceased (high risk) at 60 months. In contrast, the CNN–based model achieved an AUC score of only 0.502 (95% CI: 0.315–0.690) on the same TCGA dataset, and the p–value obtained for it under the Kaplan–Meier log–rank test was greater than 0.5. The CNN–based method was unable to distinguish between low– and high–risk patients, confirming that our method using spatial imaging features extracted from WSIs was a more effective approach. Conclusions: We developed a novel prognostic prediction method using spatial image features extracted from WSIs and genetic mutation prediction neural networks. Our results demonstrated the advantage of using image features over gene mutation data for prognostic prediction in colorectal cancer patients.
Tumor agnostic efficacy and safety of erdafitinib (erda) in patients (pts) with advanced solid tumors with prespecified FGFR alterations (FGFRalt): RAGNAR primary analysis.
Authors: Pant Shubham , Schuler Martin H. , Iyer Gopa , Witt Olaf , Doi Toshihiko , Qin Shukui , Tabernero Josep , Reardon David A. , Massard Christophe , Welsh Liam , Lugowska Iwona A. , Carranza Omar , Stuyckens Kim , Liao Huimin , Najmi Saltanat , Hammond Constance , Thomas Shibu , Triantos Spyros , Sweiti Hussein , Loriot Yohann 
Published: June 2023

3121 Background: FGFRalt are present across malignancies at various frequencies and may act as oncogenic drivers across tissue histology. Erda is an oral selective pan-FGFR tyrosine kinase inhibitor with activity and safety in pts with prespecified FGFR-altered locally advanced or metastatic urothelial carcinoma (UC) and cholangiocarcinoma . RAGNAR (NCT04083976) is an ongoing phase 2 open-label, single-arm tumor agnostic trial of erda in pretreated adult and pediatric pts with FGFRalt advanced solid tumors. Interim results showed erda clinical benefit, with an objective response rate (ORR) of 29.2%. Here we report results of the primary analysis. Methods: Pts aged ≥12 y with advanced or metastatic (non-UC) tumors of any histology with predefined FGFR1-4alt (mutations/fusions per local/central test), 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 was ORR by independent review committee (IRC). Secondary end points included duration of response (DOR), disease control rate (DCR [CR + PR + SD]), clinical benefit rate (CBR [CR + PR + SD >4 mo]), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Results: At data cutoff, 217 pts were treated, median age was 57.0 y (range, 12-79), median prior systemic tx was 2 (46%; ≥3 lines of tx) with an ORR to last line prior to study entry of 10.1%. ORR to erda tx by IRC was 29.5% (95% CI, 23.5-36.0) with 6 CRs (2.8%) and 58 PRs (26.7%) in 16 distinct tumor types, including advanced CNS, thoracic, gastrointestinal, gynecologic, and rare tumors. ORR was comparable across FGFR1-3 mutations (25.3% [95% CI, 16.0-36.7]) and fusions (32.6% [95% CI, 25.1-40.9]). Median DOR, PFS, and OS were 6.9 mo (95% CI, 4.4-7.1), 4.2 mo (95% CI, 4.1-5.5), and 10.7 mo (95% CI, 8.7-12.1), respectively; DCR was 73.7% and CBR was 45.6%. 99.5% of pts experienced TEAEs, including 70.0% with grade ≥3. Treatment-related serious AEs occurred in 8.3% of pts with no treatment-related deaths. Conclusions: Primary analysis results from RAGNAR, the largest tumor agnostic trial of targeted tx to date, confirm efficacy of erda in heavily pretreated pts with FGFRalt advanced solid tumors. Erda activity was observed in adults and adolescents across tumor types, and across FGFR1-3 gene mutations and fusions. Erda tolerability was consistent with its known safety profile. Clinical trial information: NCT04083976 . [Table: see text]
Homologous recombination deficiency (HRD) in non-small cell lung cancer: Genomic analysis using an RNA-based HRD algorithm.
Authors: Thiede Stephanie , Berginski Matthew , Mitra Akash , Taxter Timothy J. , Stein Michelle M. , Ben-Shachar Rotem , Nimeiri Halla , Aggarwal Charu , Patel Jyoti D. 
Published: June 2023

3123 Background: Recent evidence has suggested that some patients with non-small cell lung cancer (NSCLC) harbor a HRD signature that represents a distinct genomic subtype that could be targeted by PARP inhibitors (PARPi). However, there is little data on HRD prevalence in NSCLC or its genomic associations. Here, we evaluated the co-occurrence of driver mutations and established immune biomarkers with an RNA-based HRD signature in a large, real-world NSCLC cohort. Methods: We analyzed data from 5119 NSCLC patients that underwent sequencing via the Tempus xT test (DNA-seq of 648 genes; RNA-seq with whole exome capture). HRD status was predicted by the Tempus HRD-RNA test, a pan-cancer logistic regression classifier that uses an RNA gene expression signature optimized to distinguish between BRCA-biallelic loss and homologous recombination repair (HRR)-WT samples (Leibowitz et al, 2022). Cohort samples were excluded from model training. All comparisons were tested via chi-squared or Fisher’s exact tests. Results: An RNA-derived signature of HRD (HRD-RNA+) was observed in 3.53% (n=181/5119) of patients. HRD-RNA+ prevalence was higher in squamous cell carcinoma (84/1331, 6.3%) relative to adenocarcinoma (68/3015, 2.3%; p < 0.001). The prevalence of select alterations by HRD-RNA status are shown in Table. Alterations in BRCA1/2 and HRR genes (inclusive of BRCA1/2) were enriched in HRD-RNA+ vs. HRD-RNA- cases (8.8% vs. 2.5%, p < 0.001; 22% vs. 15%, p = 0.008 respectively). Notably, 141 (78%) HRD-RNA+ patients had no alterations in HRR genes. Of all NCCN targetable driver mutations assessed, KRAS G12C and ALK fusions were the only targetable drivers with significantly different prevalence in HRD-RNA+ vs. HRD-RNA- patients. Across the entire cohort, NCCN driver mutations were depleted in HRD RNA+ patients (18% in HRD-RNA+ vs. 30% in HRD-RNA-, p < 0.001). Immune biomarkers (TMB, PD-L1) did not vary by HRD-RNA status. Conclusions: Compared to HRD-RNA- NSCLC, HRD-RNA+ NSCLC represents a unique, molecularly defined subset that has a decreased prevalence of NCCN-driver mutations and is not enriched for TMB-H or PD-L1 expression. Further, this signature increases the number of patients classified as HRD-RNA+ compared to HRR gene alterations alone. Functional characterization (e.g. RAD51 foci immunofluorescence assay) and clinical benefit of targeted HRD therapies such as PARPi should be explored in this HRD-RNA+ population. [Table: see text]