tbuckley/cabot-search huggingface dataset:
Response to RAF/MEK/ERK inhibitors in patients with RAS altered and wild-type tumors.
Authors: Mohamed Alaa Gouda, Heather Y. Lin, Lei Kang, Hung Le, Ecaterina Elena Dumbrava, Siqing Fu, Daniel D. Karp, Apostolia Maria Tsimberidou, Aung Naing, Sarina A. Piha-Paul, Paula R Pohlmann, Jordi Rodon Ahnert, Timothy A. Yap, Funda Meric-Bernstam, David S. Hong
Journal: Journal of Clinical Oncology (2024)

3099 Background: The MAPK pathway is frequently activated in different cancers. Inhibitors of different molecules across this pathway have been developed and approved including BRAF, MEK, and ERK inhibitors. However, limited data are available regarding response in patients with upstream RAS alterations. The interplay between RAS and downstream RAF/MEK/ERK has been commonly noted; although distinct conclusions have been debated. In this study, we aimed to explore possible associations between RAS status and therapeutic outcomes to RAF/MEK/ERK inhibition in patients with advanced solid tumors. Methods: We used MD Anderson Cancer Center (MDACC) CHIMERA platform to extract data of patients with advanced solid tumors who were treated with investigational protocols including RAF, MEK, and/or ERK inhibitors in the department of investigational cancer therapeutics at MDACC as part of early phase-clinical trials. We included only patients who had molecular testing annotated by MD Anderson Precision Oncology Decision Support (PODSS) team. Patients who did not complete 30 days of therapy and those who were unevaluable for response were excluded from analysis. Treatment given at cycle 1 day 1 was manually checked to exclude patients who received other drugs in combination protocols that are not inclusive of RAF, MEK, and/or ERK inhibitors, patients who received non-selective RAF, MEK, and/or ERK inhibitors, and patients who received RAS inhibitors. Results: We included 219 patients (107 males and 112 females) who received treatment with investigational RAF, MEK, and/or ERK inhibitors. The majority of patients (58%, n=127) had RAS wild type status. Patients without RAS mutations had higher response rate compared to patients with RAS alterations (18.1% vs 2.2%, p&lt;0.001) (Table). Disease control rate (PR or SD) was also higher in patients with RAS wild-type status compared to patients with RAS alterations (70.1% vs 52.2%, p=0.007). Additionally, progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS) were significantly longer in patients without RAS mutations (median PFS 18 weeks vs 9 weeks, p&lt;0.001; median TTF 19 weeks vs 10 weeks, p&lt;0.001; and median OS 58 weeks vs 42 weeks, p=0.027). Conclusions: RAS alterations are associated with lower efficacy of RAF/MEK/ERK inhibitors. This can be further validated while controlling for potential confounding factors in multivariable analysis. Additional studies are needed to investigate if RAS mutations might confer inherent resistance to treatment with RAF/MEK/ERK inhibition. [Table: see text]
First-in-human study of simmitinib, a novel tyrosine kinase inhibitor targeting FGFR1-3, KDR and CSF-1R.
Authors: Sheng Yang, Yanqiao Zhang, Mingjun Zhang, Yongzhong Wu, Yongsheng Li, Feng Wang, Xin Tian, Suxia Luo, Yuping Sun, Linlin Wang, Jiancheng Li, Da Jiang, Mingxia Wang, Yunchao Huang, Huaqiu Shi, Haiyu Yang, Xiaowen Liu, Wei Ji, Weiqing Pu, Yuankai Shi
Journal: Journal of Clinical Oncology (2024)

3109 Background: Simmitinib, a potent tyrosine kinase inhibitor targeting FGFR1-3, KDR and CSF-1R, was evaluated in a phase I study in patients with advanced solid tumors. Methods: The study included dose-escalation cohorts and dose-expansion cohorts. In the dose-escalation cohorts, patients received simmitinib at doses from 1 to 9 mg orally. The DLT observation period consisted of a single dose over 7 days and multiple doses over 28 consecutive days. Patients were assessed for safety, pharmacokinetics, and efficacy. Results: As of October 31, 2023, 98 patients with a median age of 60 years (range 27-70) were enrolled. 24 patients were enrolled in the dose-escalation cohorts and 74 in the dose-expansion cohorts. One DLT was reported in the 9 mg group (grade 3 hypertension lasted for more than 3 days). The maximum tolerated dose (MTD) was not achieved. Furthermore, 4 mg QD, 6 mg QD and 6 mg 3 weeks on 1 week off dosing regimens were employed for expansion. Treatment-related adverse events (TRAEs) were reported in 88 patients (89.8%); detailed TRAEs of any grade occurring in ≥ 10% patients are listed in the table below. The incidence of TRAEs in the 6 mg 3 weeks on 1 week off group was the lowest among all the dosing regimens, with TRAEs any grade and grade ≥ 3 reported in 18 patients (66.7%) and 4 patients (14.8%), respectively. Of 56 patients with pretreated esophageal squamous carcinoma, the ORR was 16.1% (95% CI, 7.6-28.3%) with DCR of 46.4% (95% CI, 33.0-60.3%) and median PFS of 5.7 months (95% CI, 3.5-6.7); the ORRs for 4 mg QD, 6 mg QD, 6 mg 3 weeks on 1 week off, and 9 mg QD groups were 0 (0/6), 13.6% (3/22, 95% CI, 2.9-34.9%), 19.2% (5/26, 95% CI, 6.6-39.4%) and 50.0% (1/2, 95% CI, 1.3-98.7%), respectively. Based on the results of safety and efficacy, 6 mg 3 weeks on 1 week off was selected as recommended phase Ⅱ dose (RP2D). Statistical analysis using a power model for ln-transformed exposures (C max and AUC 0-∞ ) suggested dose proportionality from 1 to 9 mg (95% CI of the slope estimate included the value of 1). Higher copy numbers of FGF3, FGF4, or FGF19 appeared to be associated with durable disease control in preliminary biomarker analysis, and further exploration is ongoing. Conclusions: Simmitinib showed manageable toxicity in the study and encouraging activity in esophageal squamous carcinoma. Accordingly, 6 mg 3 weeks on 1 week off was recommended for phase Ⅱ trials. Clinical trial information: NCT04058587 . [Table: see text]
Clinical impact of molecular profiling in the national prospective cohort Solving Unknown Primary Cancer (SUPER) study.
Authors: Tharani Sivakumaran, Matthew White, Owen Prall, Catherine Mitchell, Christine Dijkstra, Richard Rebello, Huiling Xu, Joseph Vissers, Sean Grimmond, Hui-Li Wong, Anna DeFazio, Bo Gao, Madhu Sudan Singh, Ian M. Collins, Christopher B. Steer, Mark Andrew Warren, Narayan Vaderahobali Karanth, David Bowtell, Richard W Tothill, Linda R. Mileshkin
Journal: Journal of Clinical Oncology (2024)

3056 Background: Cancer of unknown primary (CUP) is a common cause of cancer death, with a median survival &lt; 12 months. SUPER is a prospective cohort study designed to create a national information and biobank of patients (pts) with no confirmed primary site following diagnostic work-up. We aimed to determine the impact of tumour molecular profiling on treatment decisions. Methods: 449 pts were recruited (2013-2021) over 3 phases from 12 Australian sites. Clinical information collected over 12 months included: demographics, treatments, investigations and clinico-pathological characteristics. Molecular tests were centrally performed and included comprehensive panel (CCP) sequencing and gene-expression tissue of origin (TOO) assays in Phase 1&amp;2 and CCP and whole genome sequencing (WGS) in Phase 3. The number of genes reported on increased over the 3 phases. Molecular results were discussed in a molecular tumour board. Clinicians completed clinical management questionnaires before and after receiving molecular results. A combined retrospective evaluation of therapeutic actionability was applied to all DNA sequencing data using the TOPOGRAPH database. Results: Median age 63 years [19-86], with 81% ECOG 0-1 and 87% classified as unfavourable CUP subtype. Reporting timelines and rates of successful sequencing improved over time (Table). Clinically actionable genomic abnormalities were detected in 95/331 (29%) pts. Moderate or high match results on TOO assay were consistent with a suspected or later confirmed TOO as reported by clinicians in 81/195 (42%) pts in phase 1 + 2. Germline pathogenic mutations were detected in 34/331 (10%) pts. Molecular tests confirmed clinician’s treatment (started while awaiting results) was consistent with the most likely TOO in 170/331 (51%) pts. Clinicians reported that molecular tests resulted in a change in management in 11/118 pts (9%) in phase 1 and 40/213 (19%) pts in phases 2+3, with 17/51 (33%) pts changed treatment based on potential TOO determination. 11/51 (22%) pts could access treatment via standard pathways given a more specific tumour-type diagnosis and 15/51 (29%) pts were potentially eligible for clinical trials; however, only 7 pts were well enough for referral. Conclusions: The clinical impact of molecular testing in CUP improved over time as testing became more sophisticated and turnaround times improved. Clinicians suspected TOO pre-profiling was consistent with molecular results in half of the pts. Routine access to novel therapies in CUP remains a challenge. [Table: see text]
CUPCOMP: A multi-site UK trial in carcinoma of unknown primary: A comparison across tissue and liquid biomarkers.
Authors: Alicia-Marie Conway, Matthew Robinson, Matthew Concannon, Sally Clive, Tania Tillett, Kai-Keen Shiu, Louise C. Medley, Sonali Dasgupta, Eliyaz Ahmed, Kelly Warrington, Zoulikha Zair, Tess Gillham, Aaron Davis, Julie-Anne Scott, Alison Taylor, Mark Stares, Claire Mitchell, Pedro Oliveria, George Burghel, Natalie Cook
Journal: Journal of Clinical Oncology (2024)

3059 Background: Cancer of Unknown Primary (CUP) is a difficult to treat cancer entity for which the tumour origins remain elusive. There is emerging evidence to support a precision medicine approach to aid treatment decisions, however scarcity of tumour tissue for molecular profiling remains a challenge. CUPCOMP sought to compare the feasibility of molecular profiling from both tissue and blood in patients (pts) diagnosed with CUP. Methods: A non-randomised prospective feasibility clinical trial conducted across 7 UK sites between 06/2021-02/2023. Eligible pts had a histological confirmed diagnosis of favourable/unfavourable CUP based on clinical, radiological, and pathological review at a CUP Multi-Disciplinary Team meeting and ESMO Guidelines for CUP. Pts had mutation profiling performed from circulating tumour DNA (ctDNA) (FoundationOne Liquid CDx) and tumour tissue (FoundationOne CDX or whole genome sequencing (WGS)). All results were discussed at a dedicated Molecular Tumour Board (MTB) to evaluate the activation state of oncogenic pathways. Results: Baseline characteristics of the 117 pts recruited are shown (Table). 114/117 (97%) pts had successful blood (109/117; 93% pts) or tissue (69/117; 59% pts) molecular profiling; both methods were performed in 64/117 (55%) pts. WGS was only successful in 15/21 pts where repeat biopsy was obtained. Where targeted tissue and blood profiling was performed using the same panel (49/117; 42%): 421/550 (77%) Single Nucleotide Variants (SNVs) found in tissue were concordant in ctDNA. ctDNA tumour fraction was ≥10% in 41/109 (35%) pts. In ctDNA, 1556 SNVs, across 271 genes, and 42 rearrangements were identified. 73/114 (64%) of cases carried an actionable alteration in blood or tissue, as determined by MTB. The most frequently reported actionable gene alterations were: KRAS (n=11; 10%); ATM (n=9; 8%); ARID1A (n=9; 8%); PIK3CA (n=10; 9%); NF2 (n=7; 6%); BRAF (n=7; 6%); FGFR2-fusion (n=7; 6%). A tumour mutational burden (TMB) of ≥10 mutations/Mb was detected in 25/117 (22%) of pts. Potential germline variants were found in 8% of pts. 80/114 (70%) pts were alive 6 months after consent to trial. Conclusions: Successful tissue-based molecular profiling is challenging in pts with CUP; achieved in only 59% of pts in this cohort. ctDNA analysis was feasible (93% successful) and reliably concordant with tissue. Potentially actionable alterations were found in 64% of pts. ctDNA molecular profiling should be considered as a reliable alternative to tissue-based testing in pts diagnosed with CUP. Clinical trial information: NCT04750109 . [Table: see text]
Therapeutic implications of phosphoproteomics in molecular cancer diagnostics.
Authors: Annika Schneider, Julia Woortman, Cecilia Bang Jensen, Amirhossein Sakhteman, Maria-Veronica Teleanu, Peter Horak, Simon Kreutzfeldt, Barbara Hutter, Jennifer Huellein, Moritz Resch, Christoph Stange, Chien-Yun Lee, Olaf Witt, David T.W. Jones, Daniel Hübschmann, Stefan M. Pfister, Wilko Weichert, Matthew The, Stefan Froehling, Bernhard Kuster
Journal: Journal of Clinical Oncology (2024)

3068 Background: Precision oncology approaches employing genomics-guided targeted therapies for individual patients have provided significant survival benefits in several cancer types. However, varying response rates in solid malignancies, many patients without actionable genomic lesions, and increasing evidence that non-genomic mechanisms may play an important role in tumors indicate that genomics alone is often insufficient to inform and guide the clinical care of patients. Since most targeted anti-cancer drugs inhibit the activity of protein kinases, measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is poised to enhance molecular stratification. Methods: We established a clinical (phospho)proteomic workflow for integration into the molecular tumor board (MTB) workflow of the Germany-wide INFORM (for children with relapsed cancers) and MASTER (for young adults with refractory cancers and patients with rare tumors) registry studies and profiled &gt; 1000 tumor tissue specimen from patients enrolled in the DKFZ/NCT/DKTK MASTER study or the INFORM registry trial. To assess the aberrant activity of druggable signaling pathways, we developed a new tumor pathway activity (TUPAC) scoring methodology using expression data of &gt; 8,000 proteins and &gt; 20,000 phospho-sites per patient in a heterogeneous pan-cancer cohort. TUPAC scores integrate protein expression and phosphopeptide abundance data at several levels to detect aberrant signaling pathway activities of several interdependent oncogenic signaling pathways within one tumor specimen. Results: We show for the first time that comprehensive (phospho)proteome profiling is feasible and informative in a real-world prospective precision oncology setting. Discussion of (phospho)proteomic data of &gt; 500 prospective patients in weekly MTB meetings revealed that adding a (phospho)proteomic layer can supply critical information for personalized therapies that is not discernible from genomic and transcriptomic data. In an independent value evaluation (329 target recommendations in 104 patients), the phosphoproteome layer was decisive in 22% of all recommended targets. Based on anecdotal cases with available clinical follow-up, we provide evidence that (phospho)proteome profiling carries important diagnostic value by detecting actionable tumor-driving kinase signaling in patients without actionable genomic lesions or by functionalizing genomic variants of unknown significance. Conclusions: Measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is feasible and adds complementary, therapy-relevant information in a real-world prospective precision oncology setting.
MyTACTIC: Activity of targeted therapy in patients (pts) with advanced solid tumors harboring specific biomarkers.
Authors: Lee S. Schwartzberg, David R. Spigel, Ari VanderWalde, Richard Michael Zuniga, Jason Hong, Tania Szado, Bongin Yoo, Luke Passler, Yong Wang, Walter C. Darbonne, Davey Daniel
Journal: Journal of Clinical Oncology (2024)

3100 Background: MyTACTIC (NCT04632992) is a tumor-agnostic, non-randomized, open-label phase II basket trial evaluating the activity of targeted therapies, alone or in combination, in pts with advanced solid tumors carrying potentially actionable molecular alterations. We report pt outcomes across all arms of the MyTACTIC trial. Methods: Eligible pts were ≥18 years old, had an ECOG PS ≤2, and measurable or evaluable lesions per RECIST v1.1 with one or more of these actionable oncogenic biomarkers: ROS1, PIK3CA, ALK, AKT, PTEN, TMB, MSI/dMMR, ERBB2,and RET. Alterations were identified prior to enrolment using local testing, typically by next-generation sequencing. Pts who had previously received the study drug or had symptomatic or active CNS metastases were excluded. Prior targeted therapy other than trial agents was allowed. Pts were assigned to 1 of 15 treatment arms to receive single-agent or combined targeted therapy according to positive biomarker results. The primary outcome was investigator-assessed confirmed objective response rate (cORR). Safety was assessed in all treated pts. Results: At data cut-off (Jan 12, 2024), 252 pts were enrolled into one of 14 arms; no pts were enrolled into arm A (entrectinib in ROS1fusion-positive tumors). Overall, pts had a median age of 65 years (range 34–90) and 93% of them had an ECOG PS ≤1. Median follow-up was 8.3 months (range 0.7–32.0). Responses were observed across 7 arms, with a cORR ranging from 11.5% to 66.7% (Table); no responses were seen in arms G, H, J, K, and L. Further efficacy outcomes including progression-free survival, duration of response, and disease control rate will be reported for each arm. The safety profile of each drug or drug combination was as expected based on prior reports. Conclusions: Targeted therapies yielded responses across tumor types in most treatment arms; testing for actionable molecular alterations is warranted for pts with limited treatment options. Clinical trial information: NCT04632992 . [Table: see text]
Phase II dose optimization with EZH2/EZH1 inhibitor tulmimetostat in patients (pts) with advanced solid tumors or hematologic malignancies.
Authors: Ana Oaknin, Kalyan Banda, Charles Drescher, Vincent Ribrag, Hedy L. Kindler, Harriet S. Walter, Alok Tewari, Elvire Pons-Tostivint, Nehal J. Lakhani, R. Donald Harvey, Ryan J. Sullivan, Pier Luigi Zinzani, Antonio Gonzalez Martin, Lauriane Eberst, Luis Manso Sánchez, Anjali Thakur, Lennart Kann, Archana Reddy, Nicola Faulhaber, Linda Duska
Journal: Journal of Clinical Oncology (2024)

3097 Background: Phase I dose-finding recommended a Phase II dose of 350 mg for the investigational oral, next-generation, dual EZH2/EZH1 inhibitor tulmimetostat (1), with preliminary Phase II results previously reported (2). To find an optimal dose, design of the ongoing Phase II part was later updated under the FDA’s dose-optimization paradigm (NCT04104776). Here we report updated preliminary findings including dose expansions. Methods: Phase II is evaluating tulmimetostat ≤350 mg once daily (QD) in 28-day cycles in 6 disease-based cohorts. The dose-optimization design randomizes further pts with ovarian clear cell carcinoma (OCCC; M2)/endometrial carcinoma (EC; M3) to 200/300 mg tulmimetostat QD. Primary endpoint is objective response rate (complete response [CR]/partial response [PR]); secondary objectives include pharmacokinetics/pharmacodynamics and safety. Results: As of Oct 15, 2023, 117 pts received ≥1 dose (safety set); 111 had ≥1 post-baseline tumor assessment or discontinued prior to it (efficacy set). Median time since diagnosis was 2.8 years (0–19.6); 86.3% of pts had ≥2 prior lines of therapy. At cut-off, best responses of ≥1 CR/PR were seen in 5 cohorts (Table). 74.4% had dose modifications due to treatment-emergent adverse events (TEAEs), 41.9% had ≥1 serious TEAE, and 9.4% discontinued therapy due to TEAEs. Most frequent TEAEs (≥35% of pts; any grade/Grade ≥3) considered possibly related to treatment were diarrhea (49.6%/10.3%), thrombocytopenia (48.7%/24.8%), anemia (39.3%/16.2%), and nausea (35.9%/2.6%). Phase I/II data showed a direct correlation between increasing doses (50–375 mg) or exposure (area under the curve 0–24 hours or maximum concentration) and larger changes in gene expression, which plateau at higher doses (≥225–≤375 mg). Conclusions: The evolving Phase II data, including early data from lower doses, continue to show signs of antitumor activity/disease stabilization. The safety profile is consistent with EZH2 inhibition. These preliminary findings in heavily pretreated pts with multiple tumor types and evolving dose-optimization data support ongoing investigation of tulmimetostat. 1. Lakhani et al. ASCO 2021. 2. Drescher et al. ASCO 2023. Clinical trial information: NCT04104776 . [Table: see text]
Development of a serum miRNA panel for detection of early stage non-small cell lung cancer.
Authors: Echo Xinyu Zhang, Chang Su, Songhua Cai, Jiahao Qu, Xiaotong Guo, Yuan Cao, Mengjing Cao
Journal: Journal of Clinical Oncology (2024)

3058 Background: Lung cancer remains the leading cause of cancer deaths, largely due to late-stage diagnosis. Early detection significantly improves survival rates, but current methods like chest X-rays and low-dose CT (LDCT) scans face limitations in sensitivity and specificity. MicroRNAs (miRNAs) are small non-coding RNAs whose dysregulation has been widely observed in different stages of cancer. Evidence suggests that circulating miRNAs could be promising biomarkers for early diagnosis of lung cancer. In this study, we developed and validated a 15-miRNA panel as a blood-based minimally invasive test for early detection of non-small cell lung cancer (NSCLC) using the proprietary multiplex quantitative real-time PCR (qPCR). Methods: 332 serum samples (182 Stage I&amp;II NSCLC, 150 healthy controls) were divided into training (n=266) and validation (n=66) cohorts. Differentially expressed serum miRNAs were screened with Miseq sequencing followed by qPCR validation. The multi-miR panel was developed with a logistic regression model and validated using an independent cohort. Receiver operating characteristic curves were constructed to evaluate the diagnostic accuracy of the panel. A stem-loop quadruplex qPCR assay was invented for concurrent detection of 4 miRs in a single reaction. Results: 15 differentially expressed miRNAs were selected for logistic model construction based on their Ct values (Ct&lt;35) and high diagnostic accuracy of stage I&amp;II NSCLC (AUC&gt;0.7). The 15-miRNA panel model achieved 88.4% sensitivity, 81.7% specificity (AUC = 0.912) in the training cohort (Table), and was validated with 94.4% sensitivity, 73.3% specificity (AUC = 0.892) in the validation cohort. Quantification of 15 miRs and 1 internal control was performed in 4 reactions tubes via quadruplex qPCR assay. Conclusions: The serum 15-miR panel developed and validated in this retrospective study exhibited robust performance for detection of early stage NSCLC. The panel demonstrates potential diagnostic applications and clinical utility to be implemented together with LDCT in current lung cancer screening program as a blood biomarker to reduce false positive results. In addition, the proposed stem-loop quadruplex qPCR system offers an efficient and promising approach for miRNA profiling in future clinical applications. [Table: see text]