bluuebunny/crossref_metadata_2025 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]
Caveat emptor: A descriptive analysis of guideline-recommended biomarker inclusion in targeted NGS panels for metastatic non-small cell lung cancer (mNSCLC).
Authors: Fox John Leonard
Published: June 2023

3124

Background: Next generation sequencing (NGS)-based panels are routinely used in the diagnosis of mNSCLC, guidelines recommending assessing 12 genes for small variants (SV), (EGFR, BRAF, KRAS, MET, ERBB2); fusions (F), (ALK, ROS1, RET, NTRK1, NTRK2, NTRK3); and copy number variants (CNV), (MET) to assess eligibility for targeted drug therapies. Reimbursement is often limited to targeted panels; yet, a comprehensive review of targeted panels’ ability to capture all recommended biomarkers has not been reported. Methods: Targeted panels were classified as ≤50 and 51-100 genes. We searched the DEX Diagnostics Exchange Registry for NGS-based lung cancer and solid tumor targeted panels. Each panel was compared against the 12 recommended genetic variants. If the type of genetic analysis (SV/F/CNV) was unclear, labs were contacted for clarification. Fusion assays by PCR or FISH with reflex testing to NGS were included. Results: 30 targeted NGS panels from 21 commercial labs were identified; 13 (43%) were specific to lung cancer. Six of 13 panels assessing fusions used FISH or PCR not NGS alone. 12 panels reported only SV, 8 small SV/F, 5 SV/CNS, and 5 all three variant types. Only 1 of the 30 panels (51-100 genes) captured all 12 biomarkers with correct variant types. Of 20 panels reporting ALK, RET, and ROS1, only 11(55%) reported fusions. Of the 5 reporting all three variant types, NTRK fusions were most commonly absent. On average, solid tumor panels sequenced twice as many genes (51 vs. 24) but were no more likely to capture all recommended biomarkers ((1/17 (6%) vs. 0/13 (0%), (p>0.05)). The average biomarkers captured in lung vs. solid tumor panels were 7.9 and 6.6, respectively (p>0.05), while in ≤50 gene panels vs. 51-100 gene panels, 7.0 and 7.6, respectively (p>0.05). Conclusions: Of 30 commercially available NGS panels with <100 genes, only one captured all recommended gene variant types for mNSCLC. Failure to capture all biomarkers was independent of panel size or specificity to lung cancer. NGS panels including small variants, fusions, and copy number variants assessed more biomarkers. Medical oncologists and clinical pathologists ordering targeted NGS panels for the management of patients with mNSCLC must ensure they assess all biomarkers relevant to targeted therapies. Insurers reimbursing targeted panels should acknowledge the inadequacy of <100 gene panels alone to provide guideline-concordant molecular diagnostic testing. [Table: see text]
Patient access to precision medicine: Identifying barriers to biomarker testing in non-small cell lung cancer.
Authors: Levent Ayse , De Richter Pieter , Bender Hope
Published: June 2023

3131

Background: The growing number of targeted therapies approved to treat non-small cell lung cancer (NSCLC) has anchored biomarker testing in clinical practice. Despite general concordance across international guidelines recommending advanced NSCLC patients be tested for oncogenic alterations and immune biomarkers, this is not always the case. This study uses real-world data to explore the barriers to testing across US, Japan, Germany and China. Methods: Ipsos’ Biomarker Testing Rate Monitor is a multi-stakeholder, physician-reported syndicated patient record database. 206 cancer-treating physicians (US=69, Japan=37, Germany=41, China=59) were screened for seniority and caseload and submitted data on 990 NSCLC patients (aggregate) in which biomarker testing had not taken place. Data were collected online January – December 2022. Results: Analyzing physician cited barriers why patients were not tested, choosing not to test at patient’s current stage was highest in the reported US patient cohort, guidelines not calling for testing at this point was more frequently cited in the Japan (27%) and Germany (25%) patient cohort and patient’s co-pay was more frequently cited in the China cohort (34%). The Japan cohort had higher mentions of tissue not being available. Country disparities in the reported metastatic (IIIB-IV) cohort included lack of tissue in Japan (48%) and Germany (25%), deferring testing to a later point in the US (21%) and high co-pay in China (50%). The top cited reasons are shown. Conclusions: Results from this study indicate that, despite guidelines, not all oncology patients receive biomarker testing. While reimbursement structures are difficult to overcome, a concerted effort is needed to raise awareness of the clinical utility of biomarker testing and of the importance of collecting sufficient tissue during the biopsy to allow patients the chance of benefiting from precision medicines. Similarly, calls for earlier testing would support efforts that ensure the best available treatment options are available to patients throughout their journey. Further investigation using comparator cohort is warranted. [Table: see text]
Pathway enrichment analysis in tumors with high mutation burdens and interferon-γ signature expression: A pancancer analysis.
Authors: Li Xuanyi , Park Ben Ho , Balko Justin M. , Johnson Douglas Buckner
Published: June 2023

3138

Background: Tumor mutation burden (TMB) correlates with immunotherapy response, but outcomes still vary in high TMB cancers, and many high TMB tumors lack T cell infiltration. Here, we assessed gene expression signatures of high TMB, including both inflamed and non-inflamed tumors (defined by interferon-γ [IFN-γ] gene signatures). Methods: Gene set enrichment analysis (GSEA) was assessed from RNA-sequencing data in tumors in TCGA. TMB and IFN-γ signature score were assessed by previously published methods. We performed GSEA on high vs low TMB tumors, and further stratified by high vs low IFN-γ signature expression within high TMB tumors. We validated results in Tempus RNA-sequencing data from 264 patients at Vanderbilt. Results: 4020 TCGA cases in non-small cell lung, melanoma, bladder, head and neck, kidney, and colorectal cancer were included. Major signatures upregulated in the high TMB group included cell cycle signaling, nuclear protein/mRNA export, cholesterol biosynthetics, and ubiquitin signaling. High TMB/high IFN-γ signature tumors were enriched in immune-related pathways (neutrophil and monocyte chemotaxis, T cell activation and proliferation, and interleukin-1 secretion), and non-immune pathways including cAMP metabolic process and phosphatidylinositol signaling. High TMB/low IFN-γ signature tumors had enriched pathways in nonsense mediated decay, electron transport chain/oxidative phosphorylation, and mitochondrial translational disassembly. 264 tumors from Vanderbilt were used for validation; pathways including cholesterol biosynthetics also correlated with immunotherapy response. Conclusions: High TMB tumors were enriched in pathways such as ubiquitin signaling, which could regulate immune cell function in antitumor immunity. Within high TMB cancers, tumors with higher IFN-γ signatures have enriched immune-related, and metabolic pathways, which could suggest novel therapeutic targets to make high TMB/ low IFN-γ tumors more immunogenic.
A four-tier classification system for studying homologous recombination repair gene reversion mutations as a mechanism of resistance to PARP inhibitors and platinum chemotherapy.
Authors: Ou Qiuxiang , Wu Miao-fang , Ma Yutong , Wu Xiaoying , Shi Yan , Zhu Minyi , Shao Yang , Li Jing
Published: June 2023

3140

Background: Pathogenic mutations in homologous recombination repair (HRR) genes are highly associated with the oncogenesis of multiple cancers and represent favorable biomarkers for platinum (Pt)-based chemotherapy and poly ADP ribose polymerase inhibitors (PARPi). While the development of drug resistance by restoring protein function via secondary mutation is commonly observed, a thorough analysis of the landscape of HRR gene reversion mutation is lacking. Methods: A real-world database with ~13,000 pan-cancer patients who underwent targeted next-generation sequencing and contained a primary germline or somatic pathogenic mutation of 25 pre-defined HRR genes, including ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, ERCC3, FANCA, FANCC, FANCD2, FANCI, FANCL, MRE11A, NBN, PALB2, RAD51, RAD51C, RAD51B, RAD51D, RAD54L, and WRN, was used to identify HRR secondary mutations, which were further classified into four tiers by mutation type and intended reversion mechanism. Patient’s clinical data and treatment history were retrospectively reviewed. Results: The potential mechanism of HRR gene reversion was categorized into four tiers, including Tier 1 (single nucleotide variation, SNV), Tier 2 (frameshift), Tier 3 (deletion), and Tier 4 of other mutation types that were not further discussed in this study. A total of 42 patients were identified with Tier 1/2/3 secondary HRR gene mutations in the presence of a primary pathogenic germline (N = 32) or somatic (N = 10) mutation. BRCA1 (15/42, 35.7%) and BRCA2 (23/42, 54.8%) were most frequently observed in this cohort with significant enrichment of exon 11 aberrations of both genes. The other HRR genes identified of Tier 1/2/3 reversion mutations included PALB2 (N = 3, Tier 3) and RAD51D (N = 1, Tier 1). More specifically, a majority of BRCA1 reversion mutations (8/15) were Tier 1 SNV, while the most prevalent reversion mechanism for BRCA2 was Tier 3 deletion, which accounted for 60.9% (14/23) of all BRCA2 cases with a median deleted length of 1164 bp (range: 153 – 6745 bp). Furthermore, we reported the treatment history data of three cancer patients (pancreatic, prostate, and lung, respectively) demonstrated the acquisition of BRCA2 reversion mutations (Tier 2 and Tier 3) at post-Pt/Olaparib in the presence of a primary germline BRCA2 pathogenic mutation, strongly suggestive of the role of reversion mutations in driving resistance to Olaparib or Pt-chemotherapy. Conclusions: Owing to a large-scale real-world dataset, we retrospectively investigated the landscape of the reversion mechanism of HRR genes and established a four-tier classification system for secondary HRR mutations in the presence of primary germline/somatic pathogenic HRR mutations. This study is of great clinical value in studying mechanisms of drug resistance to Pt-chemotherapy and PARPi.
Long-term outcome of neoadjuvant mFOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: A multicenter, randomized phase III trial.
Authors: Zhang Jianwei , Chi Pan , Lan Ping , Cui Long , Wei Hongbo , Zhao Ren , Huang Zhongcheng , Zhang Hao , Cai Yue , Wang Jianping , Deng Yanhong
Published: June 2023

3505

Background: Pevisous results of phase III FOWARC trial demonstrated that mFOLFOX6, with or without radiation, did not significantly improve survival versus fluorouracil with radiation in patients with locally advanced rectal cancer at 3 yeas. Here, we presented the data of long-term disease free survival (DFS) and overall survival (OS). Methods: In this multicenter, phase III trial, patients with stage II/III rectal cancer were randomly assigned (1:1:1) to receive 5 cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil adjuvant treatment, mFOLFOX6 plus radiotherapy, or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Results: Totally, 495 patients were enrolled,165 pateints in each group. 445 patients underwent surgery. After a median follow-up of 9.5 years, DFS events were observed in 56, 54, and 55 patients in fluorouracil plus radiotherapy, mFOLFOX6 plusradiotherapy, and mFOLFOX6 goups. The 10-year DFS rate were 55.5%, 63.0% and 62.8% (P = 0.934 by the log-rank test). OS evets were reported in 39, 38, and 40 patientts in the 3 group. The 10-year OS rate was 66.2%, 73.2% and 73.0% (P = 0.919 by the log-rank test), respectively. Conclusions: With long-term follow up, no significant difference in was found in survival outcome between mFOLFOX6, with and without radiation. Comparing with fluorouracil plus radiation, mFOLFOX6 plus radiation also failed to improve long-term survival. Clinical trial information: NCT01211210 .
Transcriptional metabolic profiling young onset colorectal cancer (CRC) patients.
Authors: Vadehra Deepak , Rosario Spencer , Wang Jianmin , Zhang Yali , Hsiao Hua-Hsin , Kolesar Jill , McDonald Patricia , Spakowicz Daniel , Ibrahimi Sami , Tabung Fred , Owen Dwight Hall , Mukherjee Sarbajit
Published: June 2023

3509

Background: Patients diagnosed with colorectal cancer (CRC) at age < 50 years typically present with more advanced disease, resulting in poor therapeutic response and clinical outcomes. Therefore, there is an unmet need to understand the differences in transcriptional profiles between younger (<50) and older ( > 50) CRC patients. Methods: Using TCGA (n = 397; > 50 = 349; < 50 = 48) and Oncology Research Information Exchange network (ORIEN) CRC datasets (n = 460; > 50 = 364 ; < 50 = 96), patients were separated into younger and older populations. Baseline characteristics of the patients in this analysis are provided in the accompanying table. Subsequently, their transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), gene set enrichment analysis (GSEA), immune deconvolution (TIMER2.0), and metabolic pathway analysis (MetaPhOR). These pathways were then mapped to assess transcriptional dysregulation, and patterns of predicted metabolic flux. Results: Comparisons of older and younger groups revealed a large number of significantly differentially expressed transcripts (n = 2629), enrichment in younger groups of metabolic pathways (amino acids and lipids), oncogenes (MYC targets and NRAS targets), and cellular processes. In the older group we found enrichment of methylation and histone modification, immune response, and other metabolic pathways, like androgens. Metabolic pathway analysis revealed consistent alterations in steroid hormone metabolism and kynurenine metabolism, which were largely upregulated in the over 50 group. Additionally, pathways associated with response to both CTLA4 and PDL1 treatment were largely upregulated in the over 50 group. This transcriptional signature may be associated with a pre-disposition to different clinical outcomes and therapeutic response for agents targeting these pathways. Conclusions: Overall, this study has revealed differences in transcriptional metabolic profiles and other drivers of disease, as well as immune profiles, between younger and older CRC populations. This biology should be explored in the future, as new avenues for treatment in younger CRC populations. [Table: see text]
15-month safety and efficacy data after intraperitoneal treatment with 224Radium-labelled microparticles after CRS-HIPEC for peritoneal metastasis from colorectal cancer.
Authors: Larsen Stein G , Graf Wilhelm , Sørensen Olaf , Mariathasan Anthony Burton , Spasojevic Milan , Ghanipour Lana , Cashin Peter , Bruland Øyvind
Published: June 2023

3518

Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by extensive cytoreductive surgery (CRS), frequently used together with hyperthermic intraperitoneal chemotherapy (HIPEC), with median time to recurrence around 12 months. Radspherin is a novel treatment principle based on the delivery of short range and cytotoxic alpha particles emitted during the decay of 224Ra. Alpha particles have high linear energy transfer and a radiation range less than 100 µm (3-10 cell diameters), generating highly localized and effective radiation with non-repairable double-strand DNA breaks in affected cells. Our hypothesis is that Radspherin produces an alpha-particle radiation field exclusively to the surfaces and liquid volumes of the peritoneum, delivering lethal doses to remaining micrometastasis in the peritoneal linings and eradicate free-floating tumor cells after surgical resection, thus assumingly prolonging time to recurrence and potentially overall survival. Methods: A phase 1/2a study (EudraCT 2018-002803-33) is ongoing to evaluate safety, tolerability and signal of efficacy of Radspherin injected intraperitoneally two days after CRS-HIPEC. After completion of dose escalation (1-2-4-7 MBq), an activity-dose of 7 MBq was recommended. Assessment of safety and efficacy (diagnostic imaging) was performed every three months. Safety data and progression-free survival (PFS) at 15 months are presented. Results: Twenty-three patients (pts) were enrolled across cohorts (safety population), of these 12 pts received the recommended dose of 7MBq, 9 pts single dose and 3 pts split dose (3,5 MBq x2). Twelve pts had synchronous PM and 11 metachronous PM. Median age was 64 years (28-78), 70 % were female and median peritoneal cancer index was 7 (3-19). To date, 271 adverse events (AE) were reported, whereof only 7 (all grade 1-2) were deemed related to Radspherin. Fourteen serious adverse events (SAEs) in 8 pts have been reported, none considered related to Radspherin. At 15 months, 9 out of 23 pts (39 %) had recurred, whereof 4 pts recurred in the peritoneum. In the expansion cohort (7MBq), 3 out of 12 pts (25 %) had recurred and none of these pts had peritoneal recurrences. Median PFS was not reached in the two populations. Conclusions: Radspherin was well tolerated with no related SAEs reported. At 15 months median PFS has not been reached and none of the patients at recommended dose had peritoneal recurrences. The results are encouraging and warrant further exploration of Radspherin as a novel treatment principle in clinical trials. Clinical trial information: NCT03732781 .
HPV integration as a prognostic biomarker for metastatic anal cancer: A next-generation sequencing ctDNA-based approach.
Authors: Johnson Benny , Pelicano Helene , Huey Ryan W , Wolff Robert A. , Wistuba Ignacio Ivan , Duose Dzifa Yawa , Mallampati Saradhi , Luthra Rajyalakshmi , Morris Van K.
Published: June 2023

3525

Background: Anal cancer is an HPV-associated malignancy with increasing prevalence in the United States. Immune checkpoint blockade demonstrates limited efficacy in patients with metastatic squamous cell cancer of the anal canal (mSCCA), and no prognostic or predictive biomarkers have demonstrated clinical utility in this population. Available circulating tumor DNA (ctDNA) assays have utilized ddPCR methodologies to report only the most common HPV types (HPV-16 and HPV-18) and HPV copy numbers. To extend the utility of an HPV ctDNA assay, we created a novel next-generation sequencing HPV ctDNA assay to analyze HPV integration as a prognostic biomarker for patients with mSCCA. Methods: Using an IRB-approved protocol, ctDNA isolated from the plasma of patients with mSCCA was sequenced using a 1.4Mb hybrid-capture target-enrichment panel covering the whole genome sequences of all 193 HPV types. HPV type, HPV copy number, and HPV integration status/locus were determined using a bioinformatic pipeline developed in-house. A Fisher's exact test was used to compare radiographic and ctDNA changes in response to systemic treatment. Unpaired t-tests were used to compare demographics between patients with HPV integration (I) or no integration (NI) status in the ctDNA. Median survival was estimated (Kaplan Meier) and compared according to integration status using a log-rank test. Results: 68 plasma samples from 27 patients with mSCCA were analyzed. While HPV-16 was detected in ctDNA of all 27 patients, five patients had additional oncogenic HPV types [HPV-18 (2), HPV-45 (2), HPV-73 (1)]. Radiographic changes in metastatic disease volume were concordant with HPV copy number changes in the ctDNA (odds ratio 12.2, 95% confidence interval (CI) 2.0-75; p = .007). HPV integration events were detected in the ctDNA for 16 (59%) patients (median 2, range 1-7 unique events per patient). For the 23 patients with mSCCA who received anti-PD1 immunotherapy (15 I, 8 NI), there were no differences in age (60 vs 59 years, p = .88) or prior lines of treatment (3.0 vs 3.5, p = .72). There was a trend towards improved median progression-free survival for NI ctDNA status (5.8 vs 3.2 months, hazard ratio (HR) 1.8, 95% CI .71-4.5). Relative to NI status, I status was associated with worse overall survival rates (OS) (22.5 vs 44.9 months, HR 5.0, 95% CI 1.5-17, p = .005). Conclusions: Detection of HPV integration status for all HPV types is feasible using a ctDNA-based approach for patients with SCCA. HPV integration was prognostic for worse OS in patients with mSCCA. Identification of HPV integration as a novel prognostic biomarker for survival outcomes in mSCCA warrants further evaluation in larger clinical trials.
A prospective, cross-sectional, multicentre study to evaluate the clinical performance of the ColoSTAT in vitro diagnostic for the detection of biomarkers associated with colorectal cancer.
Authors: He Emily , Van Hazel Guy A. , Sloss Andrew , Pianko Stephen , Brown Gregor , Clingan Philip R. , Singh Rajvinder , Solterbeck Ann , Traficante Robert , Lockett Trevor , Formby-Miller Louise , Macrae Finlay
Published: June 2023

3529

Background: Colorectal cancer (CRC) survival rates could be improved if more cancers were detected early. The ColoSTAT blood test and algorithm combines concentrations of 5 protein biomarkers with age and sex to provide an alternative to current CRC screening methods like the faecal immunochemical test (FIT). We compared the performance of ColoSTAT to colonoscopy in detecting CRC. Methods: Patients in this Australian study were either recently diagnosed with CRC using colonoscopy and progressing to surgery or neoadjuvant treatment (Cohort 1) or had no CRC history and were scheduled for colonoscopy (Cohort 2). Due to COVID-19 pandemic-related recruitment delays, the samples from Cohort 1 were supplemented with bio-banked blood samples (BBS) from patients with clinically confirmed CRC. Patients provided a 17 mL blood sample and were followed until start of cancer treatment or colonoscopy. All blood samples were de-identified prior to testing by an independent laboratory. The primary endpoints were ColoSTAT sensitivity of ≥73% (lower 95% confidence limit [LCL] > 60%), and specificity ≥90% (LCL > 80%). Sensitivity by TNM stage was an exploratory endpoint (ACTRN12619000301167). Results: Cohort 1 enrolled 29 patients, Cohort 2 enrolled 768 patients and 192 BBS were included. Patient demographic characteristics were similar in Cohorts 1, 2 and BBS. Overall, the median age of the patients (n = 989) was 64 years (range 40 to 88) and 53.4% were female. Definitive ColoSTAT results were obtained for 22 patients in Cohort 1, 554 in Cohort 2 and 81 in BBS. Overall, the estimated sensitivity of ColoSTAT for detection of CRC compared with colonoscopy was 81.3% (95%CL 73.0%-87.4%) and estimated specificity 91.0% (95%CL 87.7%-93.5%) (Table). Conclusions: The ColoSTAT test met the primary endpoints of performance based on sensitivity and specificity in detecting CRC compared to colonoscopy. ColoSTAT sensitivity and specificity for CRC were comparable with published performance parameters for FIT which range from 74-93% (sensitivity) and 85-96% (specificity).1 Clinical trial information: ACTRN12619000301167 . Clinical trial information: ACTRN12619000301167 . [Table: see text]