bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.
Authors: Jackman David Michael , Jegede Opeyemi , Zauderer Marjorie Glass , Mitchell Edith P. , Zwiebel James , Gray Robert James , Li Shuli , McShane Lisa , Rubinstein Lawrence , Patton David R , Williams Paul M. , Hamilton Stanley R. , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith
Published: June 2021

3087

Background: The NCI-MATCH trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on genetic alterations identified in tumor biopsies. Neurofibromatosis 2 (NF2)-inactivated tumors demonstrate increased sensitivity to FAK inhibition in preclinical models. Arm U evaluated the FAK inhibitor defactinib in pts with NF2 altered tumors. Methods: Patients found to harbor an inactivating NF2 mutation on NGS were assigned to the ARM U substudy MATCH. Defactinib 400 mg was given by mouth twice daily until progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and 6-month PFS. Results: Of 5,548 cases with sufficient tissue for genomic analysis, 51 pts were found to have NF2 alterations (< 1% of the total analyzed). While NF2 alterations are known to occur more commonly in meningiomas and mesotheliomas, alterations were also detected in an array of other tumor types, including renal cell carcinomas and ovarian cancers. Thirty-five pts were ultimately enrolled; 33 patients were started on therapy, with 2 of those determined to be ineligible for outcome analysis. All pts had received at least one prior therapy, with 52% (16/31) having received 3 or more prior lines of therapy. Median follow-up was 35.9 months. ORR [90% CI] was 3% (1/31, [0.16, 14.86]), with the one partial response in a pt with choroid meningioma. Of the twelve pts whose best response was stable disease (39%, 12/31), 8 demonstrated some degree of tumor shrinkage (Table) with a disease control rate of 42% (13/31). Median PFS was 1.9 months for the 31 eligible pts who received study treatment, with median PFS of 9.3 months for the 9 patients who had a best response of stable disease or better. Six pts achieved a PFS of greater than 5.5 months. Among all treated pts (n=33), the most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%). There were no grade 4 or 5 toxicities; 27% of pts had grade 3 toxicities. No correlation could be made between clinical outcomes and tumor histology or specific NF2 genotype. Conclusions: Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss. Clinical trial information: NCT04439331. [Table: see text]
A phase I study of a TGF-β receptor I kinase inhibitor YL-13027 in patients with advanced solid tumors.
Authors: Li Jin , Liu Tianshu , Bao Hanying , Xu Zusheng , Shu Yang , Zheng Binghua
Published: June 2021

3098

Background: Transforming growth factor beta (TGF-β) is upregulated in the majority of tumors, promoting tumor cell proliferation, differentiation, and, modulation of the tumor microenvironment. YL-13027, a small molecule inhibitor of type 1 receptor of TGF-β, is a potent highly selective oral agent that downregulates TGFbR1-dependent pathways in tumor cells. YL-13027 dosed into tumor bearing animals drives tumor growth inhibition and interruption of metastasis. In this first-in-human phase1 study, we characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YL-13027 in patients with advanced solid tumors. Methods: YL-13027 tablets were administered orally, twice daily under fasted conditions for 28 days, for at least two 28 day cycles until disease progression, unacceptable toxicity or withdrawal from the study. Starting with an initial dose of 60 mg, dose escalation in a 3+3 design, and pre-determined PK assessments were applied. Adverse events (AEs) were graded by NCI-CTCAE v5.0. PK analysis was performed using a non-compartmental method. Efficacy was evaluated according to RECIST1.1. Results: As of January 18th 2021, thirteen patients were enrolled sequentially to Cohort-1 (60 mg, n = 2), Cohort-2 (120 mg, n = 1), Cohort-3 (180 mg, n = 3), Cohort-4 (240 mg, n = 4) and Cohort-5 (300 mg, n = 3), having gastrointestinal (n = 9), esophageal (n = 1), gallbladder (n = 1), lung (n = 1) and breast (n = 1) carcinomas. These patients had prior systemic antitumor standard therapies, including multi-line chemotherapy, radiation therapy, molecular targeted therapy, immunotherapy, or surgery. Twelve patients completed the cycle 1 safety observation period, with no cardiovascular toxicities or other DLTs observed. The MTD was not reached. Twelve patients experienced AEs possibly related to YL-13027. The most frequent related TEAEs (all grades/grade ≥3) were gamma-glutamyltransferase increased (38.5%/7.7%), haemoglobin decreased (38.5%/0%), blood alkaline phosphatase increased (23.1%/7.7%), aspartate aminotransferase increased (23.1%/0%) and blood phosphorus decreased (23.1%/0%). A maximum YL-13027 plasma concentration was reached within 2h post dose, and the mean elimination half-life was 4.2h in the steady state. Six subjects were evaluable for efficacy. One triple-negative breast cancer (TNBC) subject (Cohort-4) acquired a Partial Response (38.8% reduction of the target lesion), with the response exceeding 4 cycles, and YL-13027 treatment is continuing. The TNBC patient’s tumor profile indicated genomic mutations of EGFL7p.Q256H(13.50%), TP53p.E51*(10.90%) and NF1p.L21V(8.70%) from the initial tumor specimen at diagnosis. Conclusions: YL-13027 is well tolerated and further clinical investigation is warranted. Clinical trial information: NCT03869632.
A phase Ib trial of ERK inhibition with ulixertinib combined with palbociclib in patients (Pts) with advanced solid tumors.
Authors: Raybould Alison L. , Burgess Brian , Urban Clarissa , Naim Rashid , Lee Michael Sangmin , McRee Autumn Jackson
Published: June 2021

3103

Background: Activating KRAS mutations are the most frequently detected aberrant oncogenes in pancreatic adenocarcinoma. Combination strategies to target the downstream RAF-MEK-ERK effector pathway are a rational approach. Preclinical data with ERK and CDK4/6 inhibition in both pancreatic cancer cell lines and xenografts demonstrates synergistic cell death and tumor growth suppression. Ulixertinib (BVD-523) is an oral small molecule inhibitor of ERK1/2. This phase 1b study evaluated the safety, pharmacokinetics, and early clinical efficacy of ulixertinib when combined with the oral CDK4/6 inhibitor palbociclib in pts with advanced solid tumors. Methods: Using a 3+3 design, pts received ulixertinib at a starting dose of 300mg (range 300-600mg) twice daily continuously with palbociclib at a starting dose of 75mg (range 75-125mg) on D1-21 out of a 28 day cycle. The primary objective was to establish the maximum tolerated dose (MTD) of the combination. Secondary objectives included characterizing safety and estimating progression free survival (PFS). Dose limiting toxicities (DLTs) were evaluated during the first cycle of treatment. Adverse events were graded by CTCAE v4.03. Response was evaluated after 2 cycles (8 weeks) by RECIST 1.1 criteria. Results: 26 pts were enrolled (13 colorectal, 9 pancreas, 2 melanoma, 1 cholangiocarcinoma, 1 GIST); 16 were evaluable for response. The MTD of the combination was ulixertinib 450mg BID and palbociclib 125mg daily. DLTs included grade 3 fatigue, grade 3 acute kidney injury and grade 3 hyponatremia (Table). Due to toxicity in cohort 3, the protocol was amended to include two additional cohorts (2A and 2B) with a reduced dose of ulixertinib and increasing doses of palbociclib. The most common treatment-related adverse events (TRAEs) (all grades) were fatigue (70%), rash (62%) and nausea (54%). The most common laboratory TRAEs were decreased lymphocyte count (77%), decreased WBC count (73%) and anemia (65%). Grade 3 TRAEs were decreased WBC count, decreased lymphocyte count, anemia and fatigue. No grade 4/5 TRAEs were reported. Three pts demonstrated stable disease (SD). For this heavily pre-treated pt population, PFS was 2.05 months (95% CI 1.87, not determined). PK analysis for ulixertinib and palbociclib was linear and consistent with previously reported data; no drug-drug interactions were observed. Conclusions: The MTD of this phase Ib study of advanced solid tumor pts was ulixertinib 450mg BID combined with palbociclib 125 mg daily. At this dosing, 2 pts demonstrated SD, one with pancreatic cancer and one with cholangiocarcinoma. An expansion cohort of metastatic pancreatic cancer pts is ongoing. Clinical trial information: NCT03454035. [Table: see text]
Inhibition of histone lysine demethylases with TACH101, a first-in-class pan-inhibitor of KDM4.
Authors: Chandhasin Chandtip , Yoo Sanghee , Del Rosario Joselyn , Chen Young K , Stafford Jeffrey , Perabo Frank , Clarke Michael F.
Published: June 2021

3105

Background: The KDM4 family of histone lysine demethylases consists of four main isoforms (KDM4A, B, C, D), all of which have been identified as key oncogenic drivers. They function as epigenetic regulators and control transitions between transcriptionally silent and active chromatin states via removal of methyl marks on histone H3K9 and histone H3K36. KDM4 isoforms play an important role in the epigenetic dysregulation in various cancers and is linked to more aggressive disease and poorer clinical outcomes. Functional redundancy and cross-activity have been observed across KDM4 family members, thus, selective inhibition of one isoform appears to not be effective. TACH101 is a novel, first-in-class pan inhibitor of KDM4 that simultaneously targets multiple isoforms of KDM4. Here we present data that show TACH101 has promising pre-clinical and pharmacologic properties as a cancer therapeutic. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell-proliferation assays in multiple cancer cell lines, apoptotic and cell cycle analyses, and efficacy studies in various xenograft tumor models and patient-derived organoid models. Results: In vitro, TACH101 was broadly effective in killing 67% (200 out of 300) of cancer cell lines screened. TACH101 demonstrated potent increase of H3K36me3 levels (EC50 < 0.001 mM, HTRF) in KYSE-150 cell line engineered to overexpress KDM4C and potent anti-proliferative activity in multiple cell lines in OncoPanel. TACH101 treatment increased cancer cell population in S-phase in multiple cancer cell lines indicating cell-cycle arrest. TACH101 induced apoptosis in human colorectal (HT-29), esophageal (KYSE-150), and triple negative breast cancer (MDA-MB-231) cell lines with EC50s ranging from 0.033-0.092 µM. In vivo, TACH101 triggered effective tumor control in xenograft models including colorectal, esophageal, gastric, breast, and lymphoma with tumor growth inhibition of up to 100%. Further evaluation using a panel of patient-derived colorectal models and patient-derived organoids showed a strong correlation of TACH101 sensitivity with MSI-H status (IC50 ranges 1-150 nM). TACH101 also reduced tumorigenic potential by 4.4-fold as determined by FACS analysis using sorted CD44High EpCAM+ population in Limiting Dilution Assays in vivo, suggesting that reduction of cancer stem cells by TACH101 may be effective in therapy-resistant settings. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Extensive preclinical work on TACH101 KDM4 inhibitor shows compelling data and broad applicability as a potential anti-cancer agent. Further evaluation is ongoing to advance the molecule into clinical trials.
Institutional experience with nab-sirolimus in patients with malignancies harboring TSC1 or TSC2 mutations.
Authors: Dickson Mark Andrew , Ravi Vinod , Ganjoo Kristen N. , Iyer Gopa
Published: June 2021

3111

Background: TSC1/ TSC2 genes are tumor suppressors in the mTOR pathway; mutated at low frequency across tumor types (̃1–2%). Retrospective analyses of patients (pts) with mTOR pathway mutations treated with everolimus did not show improved outcomes vs the wild type (Voss et al. Clin Cancer Res 2019. PMID 30327302). In NCT02201212, pts with TSC1/TSC2 mutations treated with everolimus had a 7% (2/30) response rate. In the AMPECT study, pts with advanced PEComa treated with a novel mTOR inhibitor (mTORi), nab-sirolimus ( nab-S, ABI-009), the subset of pts with TSC1/TSC2 mutations had a response rate of 64% (9/14) (Wagner et al. CTOS 2020. #3463014). In a xenograft model, nab-S showed significantly higher tumor accumulation, target suppression (pS6) and antitumor activity vs everolimus or sirolimus (Hou et al. AACR 2019. #348). In an expanded access program (NCT03817515), pts with advanced tumors bearing TSC1/ TSC2 mutations were treated with nab-S and outcomes in pts with malignancies other than PEComa are reported herein. Methods: Eligible pts (ECOG 0–2) received nab-S 100 mg/m2 IV, once weekly for 2 of every 3 weeks at 3 US sites between 7/2019 and 11/2020. Results: 7 pts with TSC1/ TSC2 mutations have been consecutively enrolled and are reported here. 6/7 pts had multiple prior therapies including 2 pts previously progressing on an mTORi. 4/7 pts had partial response (PR), all in mTORi naïve pts. 2/7 pts had stable disease (SD). In 2 pts previously treated with an mTORi, 1 had SD and 1 came off treatment after 1 cycle (CA125 ↑) with no follow-up scan. Treatment-related serious adverse events (SAEs; hyperglycemia and infection) and dose reduction were reported in 1 pt with metastatic angiosarcoma; SAEs resolved and the pt continued Rx. No other SAE or dose limiting event was reported Conclusions: Patients with various malignancies bearing TSC1 or TSC2 mutations, most with progression on multiple prior therapies, showed evidence of response and manageable toxicities during treatment with nab-S. A basket trial of nab-S in malignancies with TSC1/ TSC2 mutations is planned. Clinical trial information: NCT03817515. [Table: see text]
The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models.
Authors: Franovic Aleksandra , Miller Nichol , Severson Paul , Kanouni Toufike , Timple Noelito , Jiang Ping , Murphy Eric , Martin Eric
Published: June 2021

3116

Background: Oncogenic BRAF gene alterations, leading to aberrantly activated BRAF monomers (Class I mutations) or dimers (Class II and Class III mutations), are observed in approximately 6% of all human cancers. First-generation BRAF inhibitors targeting Class I BRAF mutants, including dabrafenib, encorafenib, and vemurafenib, provide significant clinical benefit to patients with BRAF V600 mutation-driven melanoma and select solid tumors as monotherapies or in combination with other targeted therapies. The currently approved BRAF inhibitors have not, however, proven to be effective in patients with Class II or III BRAF alterations which account for a large proportion (34%) of BRAF mutations. KIN-2787 is an orally available, potent and selective small molecule pan-RAF inhibitor specifically designed to inhibit Class II and III BRAF dimers, in addition to Class I mutants. Methods: The efficacy and tolerability of the pan-RAF inhibitor, KIN-2787, was evaluated in vitro and in vivo in Class I, II, and III BRAF mutation-driven human cancer models. Results: In biochemical assays, KIN-2787 showed low nanomolar to picomolar potency against RAF1, BRAF, and ARAF (IC50 0.06-3.46 nM) with minimal activity towards non-RAF kinases. In cell-based assays, KIN-2787 inhibited RAF activity, as measured by inhibition of downstream ERK phosphorylation (pERK), across multiple BRAF mutant cancer cell lines. Class II and III BRAF mutant cell lines were the most responsive when treated with KIN-2787 (IC50 < 50 nM); 19- and 7-fold more sensitive compared to cells harboring wild-type BRAF, respectively. Dose-dependent inhibition of A-375 (Class I), BxPC-3 (Class II), and WM3629 (Class III) BRAF mutant human xenograft tumor growth was attained with daily KIN-2787 treatment and was well-tolerated. A trend towards greater tumor responses was observed with twice daily (BID) compared to once daily (QD) dosing of KIN-2787; however, the two dosing regimens led to similar tumor growth inhibition (TGI) and regressions (mean TGI up to 101-118%; p ≤0.0001) at equivalent total daily doses. Furthermore, KIN-2787 led to a significant in vivo pharmacodynamic response using either regimen, however, prolonged target coverage, as measured by pERK, was achieved with BID dosing. The impact of KIN-2787 treatment on additional biomarkers, including transcriptional changes and MAPK pathway modulation in cell-based models and patient-derived samples, will be presented at the meeting. Conclusions: KIN-2787 is a next-generation pan-RAF inhibitor with pronounced in vitro and in vivo activity against human cancers driven by Class II and III BRAF mutations. A phase 1 dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 monotherapy in patients with advanced or metastatic solid tumors harboring BRAF gene alterations, including Class II and III mutations, is expected to initiate in 2021.
Patients with advanced solid cancers treated with ERK inhibitors exhibit pseudo-progession in lymphatic nodes.
Authors: Abo-Zahrah Reem , Karp Daniel D. , Adat Abha , Yap Timothy A. , Fu Siqing , Rodon Ahnert Jordi , Piha-Paul Sarina Anne Anne , Tsimberidou Apostolia Maria , Naing Aung , Subbiah Vivek , Dumbrava Ecaterina Elena , Overman Michael J. , Patel Sapna Pradyuman , Amaria Rodabe Navroze , Westin Shannon Neville , Meric-Bernstam Funda , Janku Filip
Published: June 2021

3138

Background: ERK1/2 signaling is often overactivated in cancer, especially in patients with molecular alterations activating the MAPK pathway. MAPK pathway inhibition can result in the increase of CD8+ and CD4+ T-cells and decreased expression of immunosuppressive cytokines. Methods: This is a retrospective study of 52 patients with advanced solid cancers and oncogenic alterations in the MAPK pathway, who were treated in phase I/II clinical trials with five different single agent ERK1/2 inhibitors at MD Anderson Cancer Center. We reviewed serial PET and/or CT imaging obtained before therapy, on therapy, and after therapy completion. We evaluated dynamic changes in the lymphatic nodes (LN) in the context of overall response per RECIST 1.1 and other outcomes. Results: Of the 52 patients, 19 (37%) patients were evaluated with serial PET/CT and 33 (63%) with serial CT imaging only. Of the 19 patients evaluated with PET/CT, 12 (63%) demonstrated increased FDG uptake in LN compared to pre-treatment imaging (LN enlargement, n = 9; no LN enlargement, n = 3) discrepant from the known target and non-target lesions. These 12 patients were on therapy with ERK inhibitors (11 at doses > recommended phase 2 dose [RP2D]) for a median of 3.6 months (range, 1.8-12 months) with a best response per RECIST 1.1. as follows: partial response, n = 1; stable disease (SD), n = 10; progressive disease (PD), n = 1. Of interest, in 6 of those 12 patients, FDG uptake in LN decreased or resolved after treatment discontinuation. Further, one patient had a biopsy of an emerged LN, which showed lymphocytic infiltrate without tumor cells. Of the 33 patients evaluated with CT only, 5 (15%) demonstrated increased size of LN discrepant from the known target and non-target lesions compared to pre-treatment imaging. These 5 patients were on therapy with ERK inhibitors (all at doses < RP2D) for a median of 1.4 months (range, 1.1-3.5 months) with a best response per RECIST 1.1. as follows: SD, n = 2; PD, n = 3. Of interest, in 2 of those 5 patients, size of LN decreased or resolved after treatment discontinuation. In addition, one patient had a biopsy of an emerged LN, which showed lymphoid aggerates without tumor cells. Conclusions: Our data suggest that treatment with ERK inhibitors can result in activation of the lymphatic nodes, which can manifest as pseudo-progression. This can lead to an inconclusive assessment of their therapeutic benefit and further suggests exploration of the potential synergistic effects with immune therapy.
Early-onset stage II/III colorectal adenocarcinoma in the IDEA database: Treatment adherence, toxicities, and outcomes from adjuvant fluoropyrimidine and oxaliplatin.
Authors: Fontana Elisa , Meyers Jeffrey P. , Sobrero Alberto F. , Iveson Timothy , Shields Anthony Frank , Taieb Julien , Yoshino Takayuki , Souglakos Ioannis , Smyth Elizabeth Catherine , Lordick Florian , Moehler Markus H. , Harkin Andrea , Labianca Roberto , Meyerhardt Jeffrey A. , Andre Thierry , Yamanaka Takeharu , Boukovinas Ioannis , Grothey Axel , Ben-Aharon Irit , Shi Qian ,   Adolescent and Young Adult Gastrointestinal Cancer Task Force EORTC
Published: June 2021

3517

Background: Incidence of early-onset colorectal cancer (eoCRC, age < 50) is steadily increasing. Decisions on adjuvant treatment (adjTx) regimen and duration should consider tx adherence, toxicity (tox) and expected outcomes in a population with life-expectancy longer than late onset CRC (loCRC, age ≥ 50). Methods: Individual patient data from stage II/III patients (pts) from 6 randomised trials in the IDEA database were used to compare characteristics, tx adherence, and adverse events of eoCRC to loCRC. To reduce the confounder of non-cancer-related deaths due to age/co-morbidities, time-to-recurrence (TTR) and cancer-specific survival (CSS) were compared by stratified Gay k-sample test. 5-year cancer-specific mortality (CSM) rate were estimated by adjusted cumulative incidence function. 3-year relapse-free survival (RFS) rate were compared by stratified and adjusted COX models. Results: Out of 16,349 pts included, 1564 (9.6%) were eoCRC. Compared to loCRC, eoCRC had lower percent of male pts (51% vs 57%, p < 0.01) better performance status (PS0 86% vs 80%, p < 0.01), similar T stage distribution (% T1-3/T4: 76/24 vs 77/23, p = 0.97), higher rate of N2 disease (24% vs 22%, p < 0.01), more likely to complete pre-planned duration of adjTx (83.2% vs 78.2%, p < 0.01) and received a higher tx intensity especially with 6 month tx (mean oxaliplatin dose intensity 75% vs 72%, p < 0.01; capecitabine 85% vs 78%, p < 0.01; 5FU 85% vs 82% p < 0.01). Gastrointestinal tox was more common in eoCRC (any grade nausea 58% vs 45%, p < 0.01; any grade vomiting 22% vs 16%, p < 0.01); haematological tox was more frequent in loCRC (62% vs, 69%, p = < 0.01); any grade neuropathy rate was similar (75%). Significant interaction was found between age and T stage for TTR (p = 0.04). Clinical outcome estimates and comparisons are shown in Table. Notably, high risk stage III (T4/N2) eoCRC had significantly lower 3-y RFS rate (54% vs 64%, HRadj 0.74, p < 0.01). Conclusions: eoCRC have better tx adherence than loCRC, as expected. While in high risk stage II and low risk stage III, cancer-specific outcomes are not different, in high risk stage III young age is negatively prognostic and associated with significantly higher relapse rate and risk of CRC death; this is despite a higher administered adjTx-intensity, suggesting a more aggressive disease biology. Clinical trial information: NCT00749450 (SCOT); NCT00646607 (TOSCA); NCT01150045 (CALGB/SWOG 80702); NCT00958737 (IDEA France) [Table: see text]
Association between cancer stem cell marker ALDH1 and clinical and morphological factors of colorectal cancer prognosis.
Authors: Dzhenkova Elena A. , Novikova Inna A. , Kit Oleg I. , Zlatnik Elena Yu. , Ulianova Elena P. , Sitkovskaya Anastasia O. , Shulgina Oksana G. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kolesnikov Vladimir E. , Aleksandrovich Maksim K. , Dashkov Andrey V. , Poluektov Sergey I. , Kaymakchi Dmitry O. , Mirzoyan Ellada A. , Pavlov Vladislav K. , Vereshchak Maksim A. , Katelnitskaya Oksana V. , Savchenko Dmitriy A. , Tolmakh Roman E.
Published: June 2021

3522

Background: Cancer stem cells (CSCs) capable of self-sustaining and multipotent differentiation are considered among the most important factors limiting treatment effectiveness. ALDH1 is a marker of colorectal cancer (CRC) CSCs; it is involved in cell differentiation and proliferation, determines resistance to alkylating chemotherapeutic agents, and also induces epithelial-mesenchymal transition (EMT), which increases the invasive and metastatic potential of tumors. The purpose of the study was to assess the association between the expression of the ALDH1 CSC marker in tissues of CRC of different stages and clinical and morphological factors of the disease prognosis. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. Tissues of surgically removed tumors were studied with IHC analysis using mouse monoclonal anti-ALDH1 antibodies (clone B-5, Santa Cruz Biotechnology) diluted 1:1800 and the Reveal Polyvalent HRP-DAB Detection System. The percentage of cells positively stained for ALDH1 among all tumor cells was assessed. Statistical analysis was performed using the STATISTICA 13.0 program (StatSoftInc., USA). Results: Positive ALDH1+ expression was registered in 52.5% of all patients, negative expression – in 47.5%. Statistically significant association was observed between the ALDH1 expression and the CRC stage, since the ALDH1+ expression increased from stage II to stage IV (p = 0.003). The ALDH1 expression was statistically significantly associated with the depth of tumor invasion (p = 0.018) and the presence of distant metastases (p < 0.001). No significant relationship was observed between the ALDH1 expression and regional lymph node metastasis (p = 0.788). Statistically significant association was registered between the ALDH1 expression and the tumor grade (p < 0.001), perineural invasion (p = 0.010) and lymphocytic infiltration (p < 0.001). No significant relationship was observed between the tumor histological structure (p = 0.979), lymphovascular invasion (p = 0.772) and ALDH1 expression. Tumor site was not statistically significantly associated with ALDH1 expression (p = 0.349). Conclusions: The study demonstrated statistically significant association between the ALDH1 expression and clinical and morphological characteristics of CRC, determining invasive and metastatic potential of the tumor, and ALDH1 may be an independent prognostic factor and a new therapeutic target for the regulation of the progression process.
Profiling plasma angiogenesis factors after use of biologics in metastatic colorectal cancer (mCRC): Update results from GI-SCREEN CRC Ukit study.
Authors: Sunakawa Yu , Yuki Satoshi , Shiozawa Manabu , Masuishi Toshiki , Nishina Tomohiro , Yasui Hisateru , Ohta Takashi , Takahashi Naoki , Satake Hironaga , Kanazawa Akiyoshi , Goto Masahiro , Bando Hideaki , Taniguchi Hiroya , Okugawa Yoshinaga , Yamazaki Kentaro , Ebi Hiromichi , Abe Yukiko , Nomura Shogo , Asano Chiharu , Yoshino Takayuki
Published: June 2021

3529

Background: No predictive biomarkers have been validated to determine which patients (pts) with metastatic colorectal cancer (mCRC) benefit the most from angiogenesis inhibitors. Recent studies suggest that plasma angiogenesis factors and their dynamics may have some prognostic or predictive value. Methods: In this prospective longitudinal study, serial plasma sample collections were done at the time points of pre- and post-treatments in mCRC pts receiving biologics in either first- or second-line chemotherapy (chemo). Comprehensive measurements of 17 factors were performed by the multiplex assay with Luminex technology. Statistical analyses were conducted by using the Brunner-Munzel and Jonckheere-Terpstra test. Results: From Sep 2017 to Dec 2020, 789 plasma samples were collected from 498 enrolled pts [first-line chemo plus bevacizumab (BEV, n=102), first-line chemo plus anti-EGFR antibody (aEGFR, n=100), second-line chemo plus BEV (n=100), second-line FOLFIRI plus ramucirumab (RAM, n=99), second-line FOLFIRI plus aflibercept (AFL, n=85) and other treatment (n=7)]. 789 samples were evaluable for this analysis. In the analysis of first-line, level of VEGF-D was significantly higher in both post-BEV and post-aEGFR comparing with pre-first-line [pre-first-line; 264 pg/ml, post-first-line BEV; 354 pg/ml (p<0.001), post-first-line aEGFR; 380.5 pg/ml (p<0.001)], while PlGF was significantly higher only in post-BEV [pre-first-line; 6.7 pg/ml, post-first-line BEV; 23.4 pg/ml (p<0.001), post-first-line EGFR; 7.4 pg/ml (p=0.650)]. These dynamics were also observed in pts with paired samples (Table). In pts with paired samples who received second-line treatment, level of VEGF-A was significantly decreased in post-BEV, while it significantly increased in post-RAM and AFL. A significant elevation of VEGF-D level was observed in only post-RAM. PlGF level significantly increased in post all second-line angiogenesis inhibitors. In the distribution analysis of angiogenesis factors, there were no or weak correlations between VEGF-D and PlGF at the time points of all post-treatments (r = 0.09-0.26). Conclusions: Plasma levels of VEGF-D, VEGF-A and PlGF were independently changed by angiogenesis inhibitors as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting better biologics by measuring baseline angiogenesis-related factors in first- and second-line chemo. Clinical trial information: UMIN000028616. [Table: see text]
Resectability, conversion and resections rates, and outcomes in RAS&BRAF wildtype (wt), RAS mutant (mt) and BRAFmt metastatic colorectal cancer (mCRC) subgroups in the prospective Finnish RAXO-study.
Authors: Osterlund Pia J. , Osterlund Emerik , Uutela Aki , Halonen Päivi , Kallio Raija S. , Ålgars Annika , Salminen Tapio , Lamminmäki Annamarja , Soveri Leena-Maija , Ristamäki Raija , Lehtomäki Kaisa I , Stedt Hanna , Heervä Eetu , Nordin Arno , Ovissi Ali , Sundström Jari , Nieminen Lasse , Mäkinen Markus J , Ristimäki Ari , Isoniemi Helena ,   The RAXO study group
Published: June 2021

3532

Background: Outcomes of metastasectomy varies with RAS and BRAF-status, but the effect on resectability, conversion and resection rates has not been extensively studied. Methods: The prospective Finnish RAXO study (NCT01531621) included 1086 patients 2011-2018 (Osterlund et al TLRHE 2021, Isoniemi et al BJS 2021) of which 906 were included in this secondary endpoint analysis. Excluded had missing KRAS/ NRAS/ BRAF-V600E test, were untreatable or had an atypical BRAF mutation. We studied repeated centralized resectability assessment, conversion and resectability rates in mCRC, and overall survival (OS) after resection and/or local ablative therapy (LAT) and systemic therapy. Results: Included were 289 RAS& BRAFwt, 529 RASmt (overrepresented) and 88 BRAFmt, with median age 65.8/66.1/66.9 years. Demographics per RAS& BRAFwt, RASmt and BRAFmt showed significant differences in male proportion (68/61/39%), ECOG PS 2-3 groups (16/14/25%), primary tumour location (right colon 16/30/69%, left colon 47/34/17%, rectum 38/36/14%), but not for Charlson comorbidity index, BMI, resection of primary, synchronous presentation or adjuvant therapy (Bonferroni corrected Chi-square). Metastatic profile was different for liver (78/74/61% per RAS& BRAFwt, RASmt and BRAFmt), lung (24/35/28%) and peritoneal (15/15/32%) metastases, but not for lymph nodes or other sites, nor for number of metastatic sites (1 in 53/54/52%). Upfront resectability rates were different with 32/29/15% for RAS& BRAFwt, RASmt and BRAFmt, respectively, as were conversion rates with 16/13/7%, and resection/LAT rates with 45/37/17%, respectively. Kaplan-Meier median OS estimate in R0/1/2-resected and/or LAT group (n = 342) was 83/69/30 months for RAS& BRAFwt, RASmt and BRAFmt groups, respectively and 5-year OS-rates 67/60/24%, with Cox HR ref/1.53 (95% CI 1.04-2.25)/3.11 (1.49-6.49). In the “systemic therapy only” (n = 564) OS was 29/21/15 months and 5-year OS-rates 11/6/2% respectively, with HR ref/1.43 (1.15-1.76)/2.34 (1.73-3.17). Resection/LAT patients had improved OS over “systemic therapy only” patients in all subgroups, HR 5.74 (3.90-8.44)/5.06 (3.92-6.55)/2.89 (1.43-5.86). Conclusions: There were significant differences in resectability, conversion and resection/LAT rates according to RAS& BRAFwt, RASmt and BRAFmt status. OS was also significantly longer for RAS& BRAFwt versus either mutant. Resected/LAT had better OS than “systemic therapy alone” patients in all subgroups. Clinical trial information: NCT01531621.
Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, RAS wild type colorectal cancer: OGSG 1602, survival update data.
Authors: Noura Shingo , Kato Takeshi , Terazawa Tetsuji , Goto Masahiro , Ohta Katsuya , Satake Hironaga , Kagawa Yoshinori , Kawakami Hisato , Hasegawa Hiroko , Yanagihara Kazuhiro , Shingai Tatsushi , Nakata Ken , Kotaka Masahito , Hiraki Masayuki , Konishi Ken , Nakae Shiro , Sakai Daisuke , Kurokawa Yukinori , Shimokawa Toshio , Satoh Taroh ,   Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
Published: June 2021

3558

Background: We previously reported the result of the phase II OGSG1602 study in which single agent of panitumumab (Pmab) demonstrated 76.5% and 50% of disease control rate (DCR), primary endpoint, and response rate (RR), respectively, in chemotherapy-naïve frail or elderly patietns (pts) with wild-type (wt) RAS unresectable colorectal cancer (CRC). Here, we reports the survival analysis including overall survival (OS) and progression free survival (PFS) in terms of sidedness and early tumor shrinkage (ETS). Methods: Thirty-six pts aged ≥76 years, or ≥65 considered unsuitable for intensive chemotherapy were enrolled and received Pmab 6 mg/kg intravenously every 2 weeks. Primary tumors located in the cecum to transverse colon were coded as right-sided tumors (RST), while tumors located from the splenic flexure to rectum were considered left-sided tumors (LST). Early tumor shrinkage (ETS) was determined as tumor reduction of 20% at week 8 compared to baseline. Results: Of total of 36 enrolled pts, 34 pts were included in the efficacy analysis, with pts with LST vs. RST being 26 vs. 8 cases, while pts who achieved ETS (ETS+) vs. those who did not achieve ETS (ETS-) being 15 vs. 19 cases. Among the evaluable 34 pts, the median PFS (mPFS) and median OS (mOS) were 6.0 months (95% Confidence Interval [CI]: 5.4-10.0) and 17.5 months (95%CI, 13.8-24.3), respectively, with the median follow-up of 17.0 months. For PFS, there were no significant differences between pts with LST vs. RST [6.6 months (95%CI, 5.4-11.5) vs. 4.9 months (95%CI, 1.9-NA), p = 0.120] but between pts with ETS+ vs. ETS- [10.4 months (95%CI, 7.4-NA) vs. months (95%CI, 2.1-7.9), p = 0.001]. Furthermore, OS was significantly different either in pts with LST vs. RST [19.3 months (95%CI, 14.2-NA) vs. 12.3 (95%CI, 9.9-NA), p = 0.043] or in pts with ETS+ vs. ETS- [ months (n = 15, 95%CI, 19.6-NA) vs. 10.1 months (n = 19, 95%CI, 6.8-21.8), p < 0.001]. Conclusions: Pmab monotherapy showed the favolable OS in the frail or elderly pts with RAS wt, unresectable CRC. Our data also confirmed the prognostic value of sidedness as well as predictive value of ETS in this setting. Clinical trial information: UMIN000024528. [Table: see text]
Efficacy and safety of vactosertib and pembrolizumab combination in patients with previously treated microsatellite stable metastatic colorectal cancer.
Authors: Kim Tae Won , Lee Keun Wook , Ahn Joong Bae , Lee Jin , Ryu Jiyeon , Oh Bitna , Ock Chan-Young , Hwang Sunjin , Hahm Ki Baik , Kim Seong-Jin , Park Young Suk
Published: June 2021

3573

Background: Microsatellite stable metastatic colorectal cancer (MSS mCRC) represents a high unmet need since there are currently no approved immunotherapy options. Since the inhibition of the transforming growth factor-β (TGF-β) pathway is known to contribute to the enhancement of immunotherapy efficacy, here, we report the results of vactosertib, a potent and selective TGF-β receptor I kinase inhibitor, combined with pembrolizumab in patients with MSS mCRC. Methods: In this phase 2, open label trial, patients have received vactosertib (300 mg BID, 5 days on / 2 days off) and pembrolizumab (200 mg, every 3 weeks) until confirmed progressive disease (PD), unacceptable toxicity or consent withdrawal. Patients with histologically confirmed mCRC who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan were enrolled. Eligible patients were ≥19 years old, had ECOG status ≤1, and had no prior exposure to immunotherapy. The objectives were to evaluate the safety and efficacy (objective response rate (ORR) per RECIST v1.1). Results: Thirty-three patients with MSS mCRC were enrolled. Median age was 60 (range 33-72), 55% were male, median number of previous lines of chemotherapy was 3 (range 1-7), and 82% were consensus molecular subtype (CMS) 4. The ORR was 15.2% including 5 partial responses (PRs), 7 stable diseases, and 17 PDs as best overall responses; 12 patients remain on treatment. Among 5 patients with PR, 3 patients had confirmed PR and median duration of response was not reached yet. As of 04 Jan 2021, the most common treatment related adverse events (AEs) were increased amylase (21.2%), pruritus (21.2%), rash (21.2%), and increased lipase (18.2%). There were 3 treatment-related SAEs reported; drug induced pneumonitis (3%), nausea (3%), and vomiting (3%). Conclusions: The combination treatment with vactosertib and pembrolizumab showed favorable safety profile with promising efficacy in patients with MSS mCRC. Updated data including pharmacodynamic markers will be presented at the meeting. Clinical trial information: NCT03724851.
The prognostic impact of RAS and TP53 mutation according to primary tumor location in colorectal liver metastases.
Authors: Cha Yongjun , Kim Bun , Roh Seung Jae , Choi Moon Ki , Lee Dong Woon , Han Sung-Sik , Kim Seong Hoon , Park Sang-Jae , Baek Ji Yeon , Park Sung Chan , Chang Hee Jin , Oh Jae Hwan
Published: June 2021

3582

Background: Somatic gene mutations have been suggested to impact survival following resection of colorectal liver metastases (CRLM). However, most studies included a selected population with known mutation data and did not employ homogeneous methods. This study aimed to determine the prognostic impact of somatic gene mutations and microsatellite instability (MSI) in CRLM using a standardized protocol and assess their survival effects according to primary tumor location. Methods: A total of 568 patients who underwent resection of CRLM during 2001-2014 were identified from a prospectively maintained registry of the National Cancer Center. MassARRAY based mutation profiling of cancer-related genes ( KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, PTEN, APC, TP53)/MSI analysis was made in primary tumors from 538 (94.7%)/526 (92.6%) patients. Results: Primary tumor locations were: right colon for 51 (9.0%); transverse colon for 42 (7.4%); left colon for 238 (34.5%); rectum for 279 (49.1%) patients. Right sided tumors were associated shorter overall survival (OS) after liver resection compared to left colon primary tumors (5-year OS, 31.4% vs. 54.0% [ P = 0.011]). Mutation frequencies were: 45.9% for RAS ; 2.4% for BRAF ; 8.4% for PIK3CA ; 0.2% for PTEN ; 0.4% for MET ; 12.1% for APC ; 24.3% for TP53. RAS (5-year OS, 40.8% vs. 55.7% [ P = 0.001], PIK3CA (5-year OS, 31.1% vs. 50.5% [ P = 0.027]), and TP53 mutation (5-year OS, 42.7% vs. 50.8% [ P = 0.035]) were associated with worse OS after liver resection. On multivariable analyses, RAS (hazard rato [HR] 1.27; P = 0.033) and TP53 mutation (HR 1.35; P = 0.014) were significantly associated with poor OS after adjustment for covariates. Co-mutation in RAS/ TP53 (12.4%) was associated with the worst oncologic outcome (HR 1.81; P <.001). Notably, while the negative prognostic impact of RAS mutation did not differ significantly according to primary tumor location, the adverse effect of TP53 mutation was limited to rectal cancer (interaction P = 0.002). In this study, MSI-high (2.3%) was not associated with survival. Conclusions: Both RAS and TP53 mutation are associated with worse survival following CRLM resection. In contrast to RAS mutation, the negative prognostic impact of TP53 mutation appears to be limited to CRLM from the rectal origin.
Young-onset colorectal cancer treatment side effects: Infertility, sexual dysfunction, and quality-of-life outcomes.
Authors: Porter Laura Diane , Yarden Ronit , Newcomer Kim Lynn , Fathi Negeen ,   N2Y Advisory Board
Published: June 2021

3587

Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. Young-onset colorectal cancer refers to individuals diagnosed under the age of 50. In recent years, the incidence has increased by 2.2% annually in individuals younger than 50 years and 1% in individuals 50-64, in contrast to a 3.3% decrease in adults 65 years and older. Young-onset (YO) CRC patients and survivors face unique clinical challenges with fertility and sexual dysfunctions, but this risk is not well quantified. There is limited data and public discussion on the long-term effects of colorectal cancer treatments on fertility and sexual dysfunction and the long-term impact on the quality of life. Methods: To explore the unique challenges and unmet needs of the young-adult patient population, a cross-sectional study was conducted. Colorectal cancer patients and survivors (N = 884) diagnosed between the ages of 20 to 50 years old (median age 42 ± 7.0) completed an online questionnaire based on established instruments EORTC-QOL-30, EORTC-CR-29, and EORTC-SHC-22. Results: Thirty-one percent of respondents stated that a medical professional spoke to them about fertility preservation at the time of diagnosis and during treatment. Only 31% were referred to a reproductive endocrinologist, even though 37% of women and 16% of men reported that treatment left them infertile or sterile. Among survey respondents, 12% of women had an egg retrieval procedure, and 36% of men had their sperm preserved prior to the start of treatment. Fifty-three percent of women reported treatment led to premature menopause. Sixty-five percent of respondents suffer from some level of sexual dysfunction due to treatment. In patients who received radiation therapy, women were 12% less likely than men to have discussed sexual side effects with the provider before treatment. Patients who have an ostomy reported more severe sexual dysfunction (17.8%). Rectal cancer patients were 2.5 times more likely than those with colon cancer to report severe dysfunction after their treatment. More than 25% of the respondents said they would have considered alternative treatment if they would have known the risks of sexual dysfunction. Conclusions: Our survey demonstrates inadequate communications between patients and providers about the irreversible fertility and sexual effects of colorectal cancer treatments. Younger patients and survivors face unique long-term challenges and require further information about fertility preservation options and emotional support regarding their sexuality post-treatment. Other studies are needed to assess the physical and psychological side effects endured by young-onset CRC patients and survivors.
Young-onset colorectal: Emotional and psychosocial effects on patients, survivors, and caregivers.
Authors: Porter Laura Diane , Yarden Ronit , Newcomer Kim Lynn ,   N2Y Advisory Board
Published: June 2021

3592

Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. Young-onset colorectal cancer refers to individuals diagnosed under the age of 50. In recent years, the incidence has increased by 2.2% annually in individuals younger than 50 years, and 1% in individuals 50-64, in contrast to a 3.3% decrease in adults 65 years and older. The Colorectal Cancer Alliance launched the Never Too Young Survey and the Caregiver Survey to assess and better understand the unmet needs of the young-onset population and their caregivers. Methods: A cross-sectional study, conducted in the form of an online survey, was launched to better understand the experiences around YO-CRC patients and caregivers. YO-CRC patients and survivors (N = 885) and caregivers (N = 204) completed an online questionnaire that was based on established instruments including PROMIS, EORTC-QOL-30, and EORTC-CR-29. The final survey instrument and study plan were reviewed and approved by the Aspire Inc. Institutional Review Board. Results: Nearly 75% of patients/survivors shared that they have been concerned about their mental health, and 64% responded that they have needed help for their depression. Further, 67% of caregivers surveyed responded that they were also concerned about their mental health, and 68% responded that they needed help with their depression. Seventy-one percent of caregivers often felt sadness, and 30% indicated that they had lost hope. Emotional exhaustion was reported by 77% of caregivers, whether they were providing round-the-clock care or caregiving from a distance. The effect was more pronounced in the patient/survivor cohort, with 95% indicating that emotional exhaustion impacted their lives. As a result, 71% of caregivers and 29% of patients/survivors indicated that they had withdrawn from other people. These results indicate the emotional toll that colorectal cancer has on patients/survivors and caregivers and their need for further resources. Conclusions: The Colorectal Cancer Alliance is committed to meeting these needs and providing resources that support patients, survivors and caregivers. Information and services may assist the caregiver in helping the patient make decisions, including shifting roles and routines in response to changing demands of YO-CRC. Further studies should investigate psychological well-being and support strategies.