tbuckley/cabot-search huggingface dataset:
Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).
Authors: Kian-Huat Lim, Kristen Renee Spencer, Rachael A Safyan, Vincent J. Picozzi, Anna M. Varghese, Despina Siolas, Kimberly Perez, Sheena Clift, Louis J. Denis, Vijeta Bhambhani, Stacey Hill, Jonathan A. Pachter, Philippe Pultar, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2024)

4140 Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]
Prognostic value of circulating tumor DNA testing in surgically resected pancreatic cancer.
Authors: Madeline Rose Miceli, Dalia Littman, Lena Masri, Daniel Jacob Becker, Paul Eliezer Oberstein
Journal: Journal of Clinical Oncology (2024)

4134 Background: The majority of patients with pancreatic cancer who undergo curative intent resection have recurrence, but optimal surveillance is unknown. Circulating tumor DNA (ctDNA) tests, custom-designed multiplex-PCR tumor assays unique to each patient’s tumor, may assist in monitoring for recurrence. Methods: We performed a single center retrospective review of patients with surgically resected pancreatic cancer who had at least 1 ctDNA test performed post-operatively between 8/1/21 and 11/13/23 with Natera Inc.’s Signatera assay. Primary outcomes were documented radiographic progression and death. Results: 74 patients were identified, of whom 36 were positive for ctDNA at any point during the study (median follow up from surgery 19.1 months) while 38 remained negative for ctDNA (15.3 months). There was no difference in age (≥ or &lt; 70), sex, or race. Positive ctDNA at any time point was associated with advanced stage disease (p=0.013), positive resection margins (p=0.008), and having received neoadjuvant therapy (p=0.005). Those with any positive ctDNA were more likely to have radiographic progression (p&lt;0.0001) or death (p=0.0005) by the end of the study. These differences remained when the population was examined in subgroups of first post-operative ctDNA positive, first ctDNA negative but at least one subsequent ctDNA positive, and all ctDNA negative. In Cox proportional hazard models, both any positive ctDNA test and positive first ctDNA test (first ctDNA limited to ≤120 days post-op) were associated with higher risk of radiographic progression and/or death compared to never testing positive for ctDNA and negative first ctDNA test, respectively (HR 12.6 (3.0-51.9), p=0.0005; HR 5.6 (1.4-22.8), p=0.02). Conclusions: Positive ctDNA tests, both in the immediate post-operative and subsequent settings, are associated with higher risk of radiographic progression or death in patients with resected pancreatic cancer. These data suggest that ctDNA testing provides independent, meaningful prognostic information superior to traditional pathologic risk factors and CA19-9 testing alone. These findings have implications for future clinical study design and decisions about surveillance and treatment. [Table: see text]
Early-onset appendiceal adenocarcinoma (EOAA): 10-year experience from a single center.
Authors: Rushabh Gujarathi, Erika Belmont, Christopher Rodman, Varun Vivek Bansal, Namrata Setia, Lindsay Alpert, John Hart, Mecker Moller, Oliver S. Eng, Grace Lee, Janet Chin, Manik A. Amin, Blase N. Polite, Chih-Yi Liao, Kiran Turaga, Ardaman Shergill
Journal: Journal of Clinical Oncology (2024)

4178 Background: The incidence of early-onset (age &lt;50) gastrointestinal cancers, including early onset Appendiceal Adenocarcinoma (EOAA) is on the rise, however reported data on etiology, treatment, and outcomes is scarce. Here we present outcomes for EOAA patients treated at a single high-volume center. Methods: Records of patients (pts) with EOAA were reviewed. Clinicopathological and genomic data were abstracted. Pts aged 18 - 49 years at diagnosis with Appendiceal Adenocarcinoma (AA) seen at UCMC between 2013 - 2023 were included. The primary outcome of Overall survival (OS) was analyzed using univariable Cox proportional hazards regression analysis. Results: 116/492 (23.6%) appendix cancer pts seen at UCMC had early-onset disease. 45 pts met eligibility (Table). 10/20 (50%) pts with localized disease had recurrence after hemicolectomy (median recurrence free survival = 41.6 months; 95% CI, 34.3 – NR; follow-up = 46.42 months). 22/44 (50%) pts had mucinous AA, 21 (47.7%) goblet cell AA, and 1 (2.33%) had poorly differentiated AA. In 35 pts with metastatic/recurrent disease, mOS was 35.93 months (95% CI, 28.4 – NR). Lymphovascular (LVI) or perineural invasion (PNI) (HR, 6.41; 95% CI, 2.10 – 19.59, p = 0.001), lymph nodes metastasis (HR, 13.11; 95% CI, 3.53 – 48.68; p &lt; 0.001), and grade 3 disease (vs. grade 1; HR, 5.28; 95% CI, 1.43 – 19.51, p = 0.01) were prognostic for worse OS in univariable analysis. Cytoreductive surgery (CRS), irrespective of completeness, was associated with improved OS (HR = 0.21; 95% CI, 0.09 – 0.53; p &lt; 0.001). Next Generation Sequencing results were available in 20 cases: KRAS (n = 10, 50%), TP53(n = 7, 35%), GNAS (n = 6, 30%), SMAD4 (n = 4, 20%), and MYC (n = 3, 15%) were frequently altered. Alterations with potential therapeutic targets were seen in 12/20 (60%) cases. 10 pts had germline testing with 2 (20%) pathogenic alterations detected: SDHA(H447Mfs*23) and CHEK2 (T367Mfs*15). The pt with CHEK2 mutation had AA as the only malignancy, was the youngest (age 26.17) and passed away 17.26 months after diagnosis. Conclusions: A considerable number of patients with AA may have early-onset disease. A median OS of about 3 years in this young and vulnerable patient population is alarming. As in late-onset disease, EOAA is often incidentally diagnosed. LVI or PNI may be associated with poorer outcomes and deserve additional consideration for risk stratification. Many patients have targetable genomic alterations and should be included in clinical trials where current enrollment is often unsatisfactory for AA. Germline mutation testing in patients with EOAA should be widely implemented. [Table: see text]
FG-M108 plus nab-paclitaxel and gemcitabine (AG) as first-line (1L) treatment for patients with Claudin-18.2 (CLDN18.2) positive locally advanced unresectable or metastatic pancreatic cancer (PC): Preliminary results from the phase 1b study.
Authors: Zhaoyu Jin, Yanqiao Zhang, Funan Liu, Shu Zhang, Jifang Gong, Miao Zhang, Xinjun Liang, Junye Wang, Yun Li, Xiaochun Yang, Yaping Yang, Lin Shen
Journal: Journal of Clinical Oncology (2024)

4142 Background: PC is one of the most lethal cancers with limited treatment options and poor outcomes. The CLDN18.2 antigen is frequently expressed in malignant gastrointestinal cancers including pancreatic cancer. FG-M108 is a human monoclonal antibody specifically targeting CLDN18.2 with optimal affinity and enhanced antibody-dependent cellular cytotoxicity. Methods: A multi-center phase 1b study of FG-M108 (NCT04894825) is ongoing, with one cohort evaluating the safety, tolerability, preliminary efficacy, pharmacokinetics, and immunogenicity of FG-M108 plus AG in patients with locally advanced unresectable or metastatic PC. Only patients with positive CLDN18.2 expression (IHC 1+/2+/3+≥10%) were eligible. This cohort of patients received FG-M108 (intravenous, 300 mg/m 2 day 1) plus gemcitabine (intravenous, 1000 mg/m 2 , days 1 and 8) and nab-paclitaxel (intravenous, 125 mg/m 2 , days 1 and8) every 3 weeks until disease progression, unacceptable toxicity, or discontinuation. The primary safety endpoint was the incidence of adverse events (AEs) and the secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS). Responses were assessed by RECIST 1.1 every 6 weeks. AEs were graded using CTCAE v5.0. Results: As of January 15, 2024, 31 patients received 300 mg/m 2 FG-M108 plus chemotherapy. The most common FG-M108 related AEs were nausea (43.5%), emesis (30.4%), neutropenia (21.7%), and anemia (21.7%). The most common grade ≥3 AEs of any cause were neutropenia (26.1%). FG-M108–related serious AEs occurred in 29.0% of patients. No FG-M108–related grade 4 or 5 AEs and no treatment-related deaths were reported. Median PFS and median OS have not been reached yet. Of the 14 patients who received tumor evaluation at least once, ORR was 50.0% (7/14) and DCR was 100% (14/14). Conclusions: FG-M108 plus AG showed excellent safety profile and promising clinical efficacy as 1L treatment for patients with CLDN18.2+ locally advanced unresectable or metastatic PC. The safety and efficacy, especially PFS and OS, of FG-M108 plus AG treatment will be further evaluated. Clinical trial information: NCT04894825 .
Penpulimab combined with anlotinib and nab-paclitaxel plus gemcitabine (PAAG) as first-line treatment for metastatic pancreatic cancer: A prospective, multicenter, single-arm, phase 2 study.
Authors: Juan Du, Fan Tong, Hui-zi Sha, Yi Sun, Yahui Zhu, Liang Qi, Xiaoqin Li, Wei Li, Yan Yang, Zeqing Li, Caihua Xu, Jiayao Ni, Qing Gu, Xing Zhang, Chan Zhu, Xiaoxuan Wang, Baorui Liu
Journal: Journal of Clinical Oncology (2024)

4135 Background: Chemotherapy currently serves as the cornerstone for treating metastatic pancreatic cancer (mPC). Nevertheless, the survival of patients with mPC remains poor. Besides, the efficacy of single-agent immune checkpoint inhibitors or antiangiogenesis in the treatment of mPC is not satisfying. Therefore, it is important to explore combination therapy options for patients with mPC. This trial was conducted to evaluate the effectiveness and safety of penpulimab combined with anlotinib and nab-paclitaxel plus gemcitabine (PAAG) for mPC. Methods: This was a prospective, multicenter, single-arm phase II trial. Eligible pts were those who aged over 18 years, histologically or cytologically confirmed PC, have not received treatment before and radiographically showed distant metastases and measurable lesions. Patients received penpulimab (200mg, IV, D1) and Anlotinib (12mg, P.O, QD, D1-14), in addition to nab-paclitaxel (125mg/m 2 , I.V, D1,8) and gemcitabine (1.0g/m 2 , I.V, D1,8), administered over a 21-day treatment cycle. The primary endpoint was objective response rate (ORR) and disease control rate (DCR). Secondary end points included Progression-free Survival (PFS), overall survival (OS) and safety. Immune microenvironmental features of baseline were analyzed as exploratory results (NCT05493995). Results: 66 pts were enrolled and received PAAG therapy, and the last follow-up time was December 31, 2023. All pts were eligible for response evaluation. The ORR was recorded at 50% (33/66) (95% CI, 37.4%-62.6%), with 33 pts achieving partial response. The DCR was 95.5% (63/66) (95% CI, 87.3%-99.1%). With median follow-up duration of 12.8 months, median PFS was 8.8 months (95% CI, 8.1–11.3) and median OS was 13.7 months (95% CI, 12.4-not reached). The most common TRAEs were anaemia, leukocytopenia, fatigue and rash. Grade 3 TRAEs were reported in 36.4% pts (24/66). In exploratory analysis, higher T cell recruiting score and lower baseline serum CA72-4 level were detected in PR pts compared with SD/PD pts. Furthermore, the B cell, NK CD56dim cell and Th9 cell scores were up-regulated in PFS-long pts. Conclusions: PAAG regimen as first-line treatment was demonstrated to be tolerable, with promising anti-tumor activity in mPC. The identified biomolecular markers revealed potential to guide precision treatment of PAAG for mPC. Clinical trial information: NCT05493995 .
Multi-region exome sequencing to determine the origin of esophageal spindle-cell squamous cell carcinoma.
Authors: Yulu Wang, Li Han, Boyi Li, Yuchen Han
Journal: Journal of Clinical Oncology (2024)

4072 Background: Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of carcinomatous and sarcomatous components. However, the genomic origin and gene signature of ESS remain unclear. Methods: A total of 24 patients diagnosed with ESS were enrolled from Shanghai Chest Hospital and underwent either radical resection (23/24) or endoscopic submucosal dissection (1/24). Laser-capture microdissection was employed to isolate cancerous and sarcomatous components from tumor and lymph node metastatic tissues. The cancerous components were subsequently microdissected based on morphology. Whole exome sequencing (WES) was conducted on both tumor tissues and paired white cell samples to analyze genomic profiles. Results: The tumor tissue samples of carcinomatous and sarcomatous components showed high mutational commonality. With the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden, paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. It showed a significant association of CDC27, LRP2, APC, and SNAPC4 mutations with poor prognosis in ESS patients. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. Conclusions: In conclusion, our results regarding to the mutation characteristics of microdissected samples substantiate the monoclonal origin of both the carcinomatous and sarcomatous components of ESS.
The safety and efficacy of ivonescimab in combination with chemotherapy as first-line treatment for advanced biliary tract cancer.
Authors: Jieer Ying, Yanru Xie, Qi Xu, Jingjing Li, Cong Luo, Lei Zhang, Yonghui Wang, Li Chen, Jianhui Huang, Wenting Li, Yu Xia
Journal: Journal of Clinical Oncology (2024)

4095 Background: Despite that PD-1/L1 inhibitors combined with chemotherapy have been approved as first-line(1L) treatment for advanced biliary tract cancer (BTC), the overall survival benefit remains limited, particularly for patients with gallbladder cancer. Ivonescimab, a tetrameric bispecific antibody targeting PD-1 and VEGF, has the potential to produce complementary and synergistic anti-tumor effects through both pathways. This study aimed to evaluate the safety and efficacy of ivonescimab in combination with chemotherapy in advanced BTC. Methods: This was an open-label, multi-center phase II study in patients with unresectable locally advanced and metastatic BTC. Ivonescimab was administered every 3 weeks for up to 8 cycles, along with gemcitabine and cis-platinum. After that, ivonescimab monotherapy was given until disease progression or unacceptable toxicity. The primary endpoints were safety and objective response rate (ORR) by RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate (DCR), time-to-response (TTR), progression-free survival (PFS), and overall survival (OS). Results: As of Nov 26, 2023, a total of 22 pts with advanced BTC were enrolled in the study. The median age was 65.0 years (range, 47-75), 81.8% of patients had ECOG of 1. All patients had initially unresectable disease status, 54.5% of patients had intrahepatic cholangiocarcinoma, 4.5% of patients had extrahepatic cholangiocarcinoma and 40.9% of patients had gallbladder cancer at baseline. The median follow-up time was 10.7 months, and the median exposure time of ivonescimab was 7.2 months. A total of 86.4% (19/22) of patients experienced at least one grade 3 or higher treatment-related adverse event (TRAE), but none led to discontinuation treatment or death. The most common grade 3/4 TRAEs with a frequency of at least 10% included white blood cell count decreased (50.0%), neutrophil count decreased (50.0%), anemia (40.9%), platelet count decreased (22.7%), and hypertension (13.6%). The ORR by investigator assessment was 63.6% (14/22) regardless of PD-L1 status, with an ORR of 77.8% (7/9) for gallbladder cancer patients specifically. The DCR was 100% (22/22). The median PFS was 8.5 months (95% CI, 6.8-9.9), with a 6-month PFS rate of 84.2% (95% CI, 58.7-94.6). The median OS was 16.8 months (95% CI, 9.8- NE), with a 9-month OS rate of 81.8% (95% CI, 58.5-92.8). Conclusions: Ivonescimab combined with chemotherapy as 1L treatment demonstrated promising efficacy in pts with advanced BTC. Further trials to validate the efficacy and safety are warranted. Clinical trial information: NCT05214482 .
Somatic mismatch repair deficiency in pancreas cancer (PC): Immune checkpoint blockade (ICB) outcomes and exploratory genomic analyses.
Authors: Catherine A O'Connor, Emily Harrold, Yun-Te Lin, Henry S. Walch, Andrea Gazzo, Sarah R. Kane, Fergus Keane, Joshua David Schoenfeld, Drew Moss, Sarah Phillips Suehnholz, Debyani Chakravarty, Fiyinfolu Balogun, Anna M. Varghese, Kenneth H. Yu, David Paul Kelsen, Alicia Latham, Britta Weigelt, Wungki Park, Zsofia Kinga Stadler, Eileen M. O'Reilly
Journal: Journal of Clinical Oncology (2024)

4144 Background: Microsatellite instability (MSI-H) occurs in the setting of Lynch syndrome (LS), which is caused by germline pathogenic variants (gPV) in mismatch repair (MMR) genes. The incidence and implications of somatic MMR variants without LS gPV in PC is unknown. We present a large cohort of patients (pts) with somatic only MMR variants and PC, and outline clinico-genomic descriptors, MSI-H prevalence, MMR methylation status, and response to ICB, comparing these features with a LS PC cohort. We also present microsatellite status (MS) orthogonal testing strategies. Methods: Institutional databases queried to identify pts with somatic MMR variants or LS gPVs and PC consented to matched tumor-normal NGS from 2012-2023. Clinico-genomic data abstracted from medical record. MiMSI used to assess MS stable (MSS) and indeterminate (MSI-I) PC. MMR status determined by immunohistochemistry (IHC). Composite MSI-H adjudicated as loss of MMR protein expression by IHC or MSI-H interpretation by MSISensor or MiMSI. Zygosity status assessed with FACETs. Exploratory mutational signature analysis performed on tumor mutation burden-high (TMB-H &gt; 10) tumors with deconstructSigs. MMR methylation analyses underway. Results: N=55/4,626 (1.2%) pts with PC and MMR variant: N=23 somatic MMR variant only (Somatic Cohort) and N=32 LS Cohort. In Somatic Cohort, 10 (43%) MSI-H cases; 6 reclassified as MSI-H by MiMSI (N=2 MSI-I; N=4 MSS). Zygosity status: 11 (48%) biallelic, 11 (48%) monoallelic, 1 (4%) indeterminate. Of 11 monoallelic cases, 3 MSI-H. N=7/14 (50%) evaluable pts had dominant MSI-H mutational signatures. In LS Cohort, 17 (59%) MSI-H cases; 5 reclassified as MSI-H by MiMSI (N=4 MSI-I; N=1 MSS). Zygosity status (N=27 evaluable): 9 (33%) biallelic, 15 (56%) monoallelic, 3 (11%) indeterminate. Of 15 monoallelic cases, 4 MSI-H. N=7/15 (44%) evaluable pts had dominant MSI-H signatures. N=20 pts received ICB (N= 14 LS; N= 6 Somatic Cohort). Median ICB duration: 27.7 months (95% confidence interval (CI) 11.5, -). Overall response rate: 50% in both cohorts; similar duration of response. Conclusions: MSI-H arises due to somatic and germline oncogenesis at similar rates in ~1% of PC. MMR methylation analyses may provide further insight into the mechanisms of MSI-H. Orthogonal MS testing key to inform accurate MS status. MiMSI valuable in classifying low-cellularity specimens. Pts with MSI-H PC treated with ICB derive durable benefit, irrespective of germline or somatic etiology. [Table: see text]