tbuckley/cabot-search huggingface dataset:
A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1.
Authors: Noboru Yamamoto, Toshihiko Doi, Manish R. Patel, Ignacio Garrido-Laguna, Sutan Wu, Satoshi Nishioka, Keiko Nakajima, Benedito A. Carneiro
Journal: Journal of Clinical Oncology (2024)

TPS3165 Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (DXd). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Methods: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll up to 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid TA-MUC1-expressing tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS-3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Clinical trial information: NCT05875168 .
Biomarker discordance after neoadjuvant systemic therapy and associated patterns of recurrence.
Authors: Esther G Chong, Bowon Joung, Mengni Guo, Won Jin Jeon, Kevin Bera, Jae Lee, Jin Hyun Floyd Moon, Gayathri Nagaraj
Journal: Journal of Clinical Oncology (2024)

3149 Background: Understanding and addressing intratumor heterogeneity in breast cancer (BC) is crucial for advancing research and improving patient outcomes. The identification of biomarkers for targeted therapies is complex when dealing with heterogeneous tumors, and this heterogeneity complicates cancer outcomes since it affects treatment response, and the development of resistance. Methods: A single institution retrospective review of patients with BC who received neoadjuvant systemic therapy (NAST) followed by definitive surgical resection from 2008 to 2022 was performed. Initial tumor biopsies were tested for hormone receptors (HR) [estrogen receptor (ER) and progesterone receptor (PR)], and HER2 status and repeated on the residual tumor tissue after NAST. HER2 status was categorized into HER2-negative, HER2-low, and HER2-positive and HR status was categorized into ER and/or PR positive or negative based on the 2023 ASCO-CAP guidelines. HER2 and HR concordance and discordance rates were obtained and patients who had disease recurrence were identified and analyzed using descriptive statistics and Fisher’s exact test. Results: 480 patients with BC received NAST, and 143 patients with residual disease had pre and post treatment biomarker data available for analysis with a median post-surgery follow up of 15.2 months. Discordance in either HER2 or HR status was identified in 50% (72/143) of samples. Out of 143 patients, 44 patients had disease recurrence in which 50% (22/44) of tumors exhibited biomarker discordance. Among the changes in biomarker status, a shift in PR expression occurred most frequently in 27% of tumors (12/44). A change from HER2-low to HER2-negative status, as well as changes in ER expression occurred in 11% of tumors (5/44). 14% (6/44) of tumors had changes in both HER2 and HR. In patients who did not have recurrence, 51% (50/99) of tumors exhibited biomarker discordance. A HER2-low to HER2-negative status occurred most frequently in 18% (18/99). A change in ER expression occurred second most frequently, in 14% (14/99) of tumors. There was no statistical significance of discordance rates in the recurrence group and non-recurrence group (p-value=0.96). Conclusions: Tumor heterogeneity plays a role in shaping the distinct tumor biology of each patient. While the rates of biomarker discordance were comparable between samples with and without recurrence, the importance of HR discordance in this group requires extensive long-term monitoring. Our research highlights the importance of biomarker changes in a curative setting. Considering the implications for treatment, further investigation into additional biological and tumor-related factors associated with recurrence is warranted. [Table: see text]
Comprehensive molecular profiling of newly diagnosed advanced, high-grade ovarian cancer: Unveiling <i>BRCA1/2</i> mutations and genomic instability scores to advocate for public insurance coverage of genetic testing—Insights from the Hellenic Society of Medical Oncology (HeSMO) national program.
Authors: Emmanouil S. Saloustros, Michael Liontos, Eleni Timotheadou, Charalampos Andreadis, Efthymia Skafida, John Syrios, Antonia Kalykaki, Konstantinos Koutsoukos, Georgios Kesisis, Ioannis Boukovinas, Anastasios L. Boutis, Pavlos Papakotoulas, Dimitrios C. Ziogas, Sofia Karageorgopoulou, Stylianos Giassas, Evangelos Lianos, Natalia Chatzifoti, Fotini Papageorgiou, Zacharenia (Zenia) Saridaki
Journal: Journal of Clinical Oncology (2024)

3146 Background: Homologous recombination deficiency (HRD) in ovarian cancer, indicative of impaired DNA repair, contributes to genomic instability (GIS). Beyond mutations in BRCA1/2 genes, GIS is particularly significant for identifying patients who may benefit from PARP inhibitors. Equivalence between Myriad Genetics' myChoice CDx and the standard diagnostic tests OncoScan and Amoy Diagnostics has been published, prompting HeSMO to launch a national program addressing GIS and BRCA 1/2 mutations in newly diagnosed advanced high grade ovarian cancer patients, with the utilization of these more economically advantageous tests, in order to guide effective therapeutic strategies, since official reimbursement is not yet applicable in our country. Methods: Patients with locally advanced or metastatic high-grade stage III/IV ovarian cancer were eligible for the HeSMO program, submitting an FFPE tissue tumor sample. The evaluation focused on HRD detection (positive or negative) and GIS assessment (high or low), combining results from OncoScan and Amoy Diagnostics. Results: Between August 2022 and December 2023, 511 patients from Greece underwent testing. 48.14% (n=246) tested HRD positive, 46.58% (n=238) HRD negative. High GIS score was observed in 44.81% (n=229), low GIS in 49.71% (n=254). Potential pathogenic mutations in BRCA1/2 genes were found in 19.96% (n=102). BRCA1 mutations (13.70%, n=70) included key mutations: c.190T&gt;C p.(Cys64Arg), c.3700_3704delGTAAA p.(Val1234GlnfsTer8), c.4065_4068del p.(Asn1355LysfsTer10). BRCA2 mutations (6.26%, n=32) comprised of c.1129G&gt;T p.(Glu377Ter), c.3650_3659del p.(Arg1217IlefsTer8), c.7150C&gt;T p.(Gln2384Ter). In 27 samples (5.28%) no result was produced. Conclusions: HRD and GIS are vital genomic instability biomarkers in high-grade ovarian cancer. These metrics provide valuable insights into tumor aggressiveness, guiding therapeutic decisions, including the use of PARP inhibitors. In this study of 511 patients from 50 centers across Greece, 48.14% tested positive for HRD, emphasizing PARP inhibitors' significance and suggesting hereditary implications. Our commitment to enhance patient access to reliable diagnostic biomarker testing in Greece is unquestionable. Furthermore, we believe, our results will strengthen our efforts towards official state reimbursement, paving the way for local HRD testing solutions. [Table: see text]
A multi-center, open-label phase 1/1b dose finding, safety, and pharmacokinetic study of MBRC-101, an Anth-EphA5 monomethyl auristatin (MMAE) antibody drug conjugate, in advanced refractory solid tumors.
Authors: Shiraj Sen, Mohamad Adham Salkeni, Costantine Albany, Neel Jitendra Gandhi, William Jeffery Edenfield, Kellogg Parsons, Isan Chen, John D. Powderly
Journal: Journal of Clinical Oncology (2024)

TPS3161 Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .
Selpercatinib in non-MTC, RET-mutated tumors: Efficacy in MEN-associated and other tumors.
Authors: Philippe Alexandre Cassier, Filippo G. De Braud, Mabel M. Ryder, Bruce Robinson, Pascale Tomasini, Masahiro Morise, Nehal J. Lakhani, Sylwia Szymczak, Patrick Peterson, Scott Barker, Vineeth Sukrithan
Journal: Journal of Clinical Oncology (2024)

3150 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. Current indications for RET mutant disease are limited to MTC. This analysis examined if selpercatinib was effective in non-MTC, RET mutation positive tumors and whether certain RET mutations demonstrated better activity (n=23; data cut-off: 13Jan2023). Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC. Mutations must be known to be activating based on activity in MTC or other published evidence. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Fourteen different tumor types were identified among the 23 pts with non-MTC RET-mutated tumors. This included 8 tumors from the Multiple Endocrine Neoplasia (MEN) syndrome spectrum; adrenal (pheochromocytoma; n=5), paraganglioma (n=2), neuroendocrine (n=1) (Table). Most of the mutations were located in extracellular cysteine-rich domain (CRD) and in the tyrosine kinase domain (TKD) of RET. In 23 efficacy-evaluable pts, confirmed ORR by IRC was 21.7% (5/23, 95% CI: 7.5, 43.7). ORR by IRC for pts with MEN-associated tumors (n=8) was 37.5% while five of these pts (62.5%) had stable disease lasting at least 16 weeks (SD16+). ORR by IRC for the sub-population with pheochromocytoma (n=5) was 40.0% and for pts with tumors manifesting RET extracellular cysteine mutations (n=5) was 60.0%. Of the 15 pts with non-MEN-associated tumors, 2 pts (8.7%; mutation in TKD) had a partial response (both with NSCLC adenocarcinoma, of which one had co-existent MTC). For the overall pts, the median DoR was 12.2 months (95% CI: 3.8, NE) and median PFS was 5.5 months (95% CI: 1.8, 19.4). No new safety signals were identified compared to previous reports. One grade 5 AE, general physical health deterioration, was observed and deemed by INV as not related to selpercatinib. Conclusions: This study suggests that RET-mutated, MEN-associated cancers (adrenal, paraganglioma, neuroendocrine) may benefit from selpercatinib treatment, which could be mediated through mutations in the extracellular CRD. The non-MTC RET-mutated tumor types appear not to derive benefit from selpercatinib. Clinical trial information: NCT03157128 . [Table: see text]
Clinicopathological characteristics and survival in metastatic colorectal cancer with short-form APC mutations.
Authors: Hiroki Osumi, Akira Ooki, Ippei Fukada, Koichiro Yoshino, Mikako Tamba, Shohei Udagawa, Shota Fukuoka, Takeru Wakatsuki, Mariko Ogura, Daisuke Takahari, Keisho Chin, Yoshiaki Nakamura, Hideaki Bando, Takayuki Yoshino, Naomi Hayashi, Shunji Takahashi, Kensei Yamaguchi, Hiroyuki Seimiya, Eiji Shinozaki
Journal: Journal of Clinical Oncology (2024)

3555 Background: Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli ( APC) gene and plays a key role in tumorigenesis in colorectal cancer (CRC). Tankyrase inhibitors, which cause degradation of β-catenin, are expected to have a promising therapeutic effect for CRC, and the short-form APC mutations predict the sensitivity of CRC cells to tankyrase inhibitors (Tanaka et al. Mol Cancer Ther 2017; Chen et al. Br J Cancer, in press).However, clinicopathological characteristics and survival in metastatic CRC (mCRC) with short-form APCmutations remain unclear. Methods: Patients with mCRC who were treated with chemotherapy between 2010 and 2021 and have tissue or circulating tumor DNA-based next-generation sequencing results were enrolled. Short-form APC mutations were defined as those truncated at amino acid 1,256 or shorter, lacking all seven 20-amino acid repeat (20-AAR) regions. Non-short-form APC mutations were defined as those possess more than one 20-AAR. Short-form and non-short-form heterozygous mutations were classified as non-short-form APC mutations. We confirmed incidence of mCRC with short-form APC mutations and compared clinicopathological characteristics and overall survival (OS) between mCRC patients with short-form and non-short-form APCmutations. Results: Of 177 patients (median age, 56.0 years) included in this study, 44 (25%) and 79 (45%) had short-form and non-short-form APC mutations, respectively. Patients with short-form APC mutations were not likely to have lung metastasis (P = 0.15). Logistic regression multivariate analysis, lung metastasis was related to mCRC patients with short-form APC mutations (Odds ratio: 0.46, P = 0.047). Patients with short-form APC mutations had significantly shorter overall survival (OS) than did those without (n = 133), with a median OS of 34.7 vs 50.5 months ( P Log-rank = 0.035, hazard ratio (HR), 1.59; 95% confidence interval (CI), 1.03-2.45). In multivariate analysis, short-form APC mutation was independent factor related to OS (hazard ratio (HR): 1.68, P = 0.02), as well as the BRAF V600E mutation, liver metastasis and peritoneal metastasis. Conclusions: Short-form APC mutation is more common in mCRC patients without lung metastases and is independently associated with a short prognosis.
A phase 2 study evaluating response and biomarkers in patients with microsatellite stable (MSS) advanced colorectal cancer (CRC) treated with nivolumab/relatlimab.
Authors: Eric Christenson, Jennifer N. Durham, Madelena Brancati, Heather Davis Bruning, Susan Petrie, Hao Wang, Jiayun Lu, Katherine M. Bever, Dan Laheru, Ana De Jesus-Acosta, Ross C. Donehower, Michael J. Pishvaian, Nilofer Saba Azad, Qingfeng Zhu, Nicolas Jose Llosa, Franck Housseau, Robert Anders, Drew M. Pardoll, Dung T. Le
Journal: Journal of Clinical Oncology (2024)

3554 Background: Lymphocyte-activation gene 3 (LAG-3) is an immunosuppressive signal, impairing T effector (Teff) activation. Pre-clinical studies suggest LAG-3 inhibition promotes anti-tumor immunity by enhancing Teff function. Correlative studies linked increased LAG-3 levels with reduced overall survival (OS) in CRC. These data prompted optimism that combined LAG-3/PD-1 inhibition might promote anti-tumor responses in MSS CRC. Methods: We conducted a phase 2 study of nivolumab (Nivo) (aPD1)/relatlimab (Rela) (aLAG3) in patients with previously treated advanced MSS CRC. This study enrolled patients onto 1 of 3 arms. Arms A and B used a Composite PD-L1 and acellular Mucin (CPM) score to define patients as CPM(+) in Arm A (CPM≥ 15%) and CPM(-) in Arm B (CPM&lt; 15%). Patients in Arm A and B received Nivo 480mg/Rela 160mg IV q4 weeks. Arm C enrolled patients without biomarker selection who received Nivo 480mg/Rela 960mg or Rela 480mg/Nivo 480mg. The primary endpoint was objective response, and each arm was powered to detect an objective response rate (ORR) of ≥20%. Results: Fifty nine evaluable patients were enrolled (Arm A: 12, Arm B: 15, Arm C: 32). Patient characteristics and responses are outlined. Treatment was well tolerated with no new safety signals over aPD1 alone. Three (5%) patients achieved a partial response (PR), 6 (10%) stable disease (SD), and 50 with progression of disease (PD) as best response. The median progression-free survival was (Arm A: 2.2 mo., Arm B: 2.8 mo., Arm C: 2.6 mo.) while median OS was (Arm A: 4.3 mo., Arm B: 14.2 mo., Arm C: 12.4 mo.). In N=6 patients with lung-only metastases, 2 (33%) experienced a PR, and 1 (17%) a SD, for a clinical benefit rate of 50%. The trial incorporated translational correlates. We will report mass cytometry on PBMCs, RNAseq on baseline biopsies, and imaging mass cytometry on pre- and on-treatment biopsies. Conclusions: This combination did not meet the primary endpoint of 20% ORR for any of the 3 cohorts, but there was intriguing possible activity in patients with lung only metastases, consistent with emerging data. Clinical trial information: NCT03642067 .
A phase I/II, first-in-human study of VLS-1488, an oral KIF18A inhibitor, in patients with advanced cancer.
Authors: Stephanie Gaillard, Alexander Starodub, Bert O'Neil, Cara Amanda Mathews, Ecaterina Elena Dumbrava, Claire Frances Friedman, Paul Swiecicki, Cindy Oh, Celia Andreu, Linda Lee, Jacqueline Campbell, Timothy Geoffrey Bowler, Scott Drutman, Patricia LoRusso
Journal: Journal of Clinical Oncology (2024)

TPS3181 Background: Chromosomal instability (CIN) is a hallmark of cancer characterized by high rates of chromosomal segregation errors during mitosis. This creates structural and numerical changes to chromosomes, driving genetic heterogeneity and cancer evolution. KIF18A is a mitotic kinesin protein shown to be important for successful division of cancer cells with CIN but not required for mitosis in normal diploid cells. Pre-clinical studies demonstrated that treatment of chromosomally unstable cancer cells in vitro and in xenograft models (HCC15 and OVCAR-3) with a KIF18A inhibitor resulted in failure of chromosomal congression, mitotic arrest, cell death and dose-dependent inhibition of tumor growth. VLS-1488 is an oral small molecule inhibitor of KIF18A that is being examined in an open-label, phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity in advanced solid tumors with high prevalence of CIN. Methods: Key eligibility criteria include specific histologically confirmed metastatic or advanced tumor types with at least one site of measurable disease per RECIST 1.1, adequate organ function, and mismatch repair proficient/microsatellite stable.Eligible tumor types include high grade serous ovarian/fallopian tube/primary peritoneal cancer, squamous non-small cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, gastroesophageal cancer, esophageal cancer, colorectal adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian or uterine carcinosarcoma, and uterine serous carcinoma. Subjects will receive VLS-1488 monotherapy continuously for 28-day cycles once daily. The study consists of two parts, Dose Escalation and Dose Expansion. Utilizing a Bayesian Optimal Interval (BOIN) design, Dose Escalation will examine the safety and tolerability of VLS-1488 at various dose levels (DLs) to identify the Maximum Tolerated Dose (MTD) and to select DLs for Dose Expansion. Dose Expansion may commence after the MTD or DLs of interest are identified. Dose Expansion will examine the safety, tolerability, preliminary efficacy and preliminary drug-drug interaction (DDI) and food effect risk of VLS-1488 in selected tumor types. Subjects enrolled to specific tumor type cohorts may be randomized to DLs of interest. Enrollment to Dose Escalation began in September 2023 and is ongoing. Clinical trial information: NCT05902988 .