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The role of immunotherapy for real-world patients with HER2-negative advanced gastric cancer between 2011-2023.
404 Background: Although the appearance of immunotherapy has apparently brought benefits for all patients (pts) with advanced gastric cancer (AGC), the magnitude of the benefit in real-world pts with HER2-negative AGC has not been fully investigated. Methods: We conducted a retrospective study on pts with HER2-negative AGC who received first-line platinum-based chemotherapy between 2011 and 2023. We evaluated the clinical outcomes across different periods of immunotherapy approval in Japan: Group A (pre-immunotherapy approval): 2011-2017, Group B (approved for third-line treatment or later): 2018-2021, and Group C (approved for first-line treatment): 2022-2023. Results: A total of 949 pts were enrolled (A: n = 477; B: n = 344; C: n = 128). Patient's characteristics were comparable except for the proportion of those with age ≥75 years (P = 0.002), prior gastrectomy (P = 0.03), and liver metastases (P < 0.001). The median overall survival (OS) was 16.2, 15.2, and 21.3 months in group A, B, and C, respectively, with no significant difference between groups (log-rank P = 0.50). Pts who had received first-line immunotherapy plus chemotherapy (n = 173) showed significantly improved OS compared with pts without having received any immunotherapy-containing treatment at 2011-2017 (n = 382) (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.61-0.99; P = 0.04). In the multivariate analysis, the use of immunotherapy at first-line treatment was not significantly associated with worse OS, whereas the use of immunotherapy at any lines was prognostic (HR, 0.54; 95% CI, 0.41-0.71; P < 0.0001). The proportion of pts who had received any second-line treatment was comparable among groups: 76%, 80%, and 71%, respectively. Conclusions: Our study suggests that the immunotherapy might partially have an impact on the survival improvement of real-world pts with HER2-negative AGC, which calls for the need for appropriate treatment strategies, including other agents.
Updated survival results of ZL-IRIAN: Irinotecan plus anlotinib or in combination with penpulimab as second-line treatment of metastatic colorectal cancer.
167 Background: The irinotecan based chemotherapy in combination with bevacizumab had become the standard second-line treatment for metastatic colorectal cancer (mCRC), but the efficacy was limited. Anlotinib, an oral anti-angiogenic tyrosine kinase inhibitor, had initially shown promising clinical effects when combined with chemotherapy in the first-line treatment of mCRC. Whether anlotinib could bring clinical benefit in the second line treatment warrants further exploration. The PD-1 antibody might have partial effects when combined with anti-angiogenic agents with or without chemotherapy in first- and third-line treatment for proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC. Our study was to explore the rationality of anlotinib plus chemotherapy or further combined with a novel anti-PD-1 IgG1 antibody—penpulimab in the second line treatment of mCRC. Methods: This study was an open label, non-randomized, multi-cohorts, phase II prospective clinical trial that included pts with pMMR/MSS mCRC who were eligible for the second-line systemic treatment. Two cohorts were established as follows: Cohort A consisted of anlotinib(10mg daily, d1-10, q2w) + irinotecan (180mg/m d6, q2w) (n = 23); Cohort B consisted of anlotinib (8mg daily, d1-10, q2w)+irinotecan (180mg/m d6, q2w) + penpulimab (200mg, d6, q2w) (n = 23). The primary endpoint was ORR. Secondary endpoints included progress free survival (PFS), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. The ORR was reported at 2024 ASCO, and PFS and OS have been updated in this report. Results: At the cutoff date on August 2024, a total of 23 Pts were enrolled in A cohort, and 23 pts were enrolled B cohort but 21 pts received at least one dose of treatment. The median PFS was 7.87 months (95% CI 5.52-10.22) in A cohort, compared to 7.4 months (95% CI 3.17-11.63) in B cohort, p=0.141. The 6-month, 12-month and 18-month PFS rates in A cohort and B cohort were 69.3% vs 80.7%, 27.5% vs 40.3% and 5.5% vs 22.4%, respectively. The median OS of A cohort was 21.73 months (95% CI 9.43-34.03), compared to 19.17 months (95% CI 11.44-26.90 months) in B cohort, p=0.987. The 12-month and 24-month OS rates in A cohort and B cohort were 64.7% vs 73.1% and 20.2% vs 54.8%, respectively. Safety profile indicated that 65.2% (15/23) and 66.7% (14/21) experienced grade≥3 adverse events in A cohort and B cohort, respectively. Common grade ≥ 3 adverse reactions (≥ 20%) mainly include hypertension (4.35% vs 14.29%), diarrhea (13.04% vs 9.52%), neutrophilopenia (39.13% vs 33.33%), and leukopenia (26.09% vs 9.52%). Conclusions: There was no statistically significant difference in overall efficacy between the two cohorts, but the long-term PFS and OS rates were higher in group B cohort, indicating that immunotherapy may bring long-term survival benefits to certain patients. Clinical trial information: NCT05229003 .
Missense mutations of the ephrin receptor EPHA1 associated with Alzheimer’s disease disrupt receptor signaling functions
<i>TP53</i> Y220C mutations in pancreatic ductal adenocarcinoma (PDAC): A genomic landscape study.
761 Background: A novel targeted therapy designed to restore wild-type function to the p53 Y220C mutant protein has demonstrated promising activity in an early-phase trial (NCT04585750). While the TP53 Y220C mutation is found in < 1% of all solid malignancies, its prevalence is enriched in certain cancers including PDAC. Here we report results of comprehensive genomic profiling (CGP) in a cohort of patients with advanced PDAC, with a focus on TP53 Y220C mutations. Methods: A total of 27,377 cases of clinically advanced PDAC underwent hybrid capture-based CGP to assess all classes of genomic alterations (GAs). Cases were sequenced to a mean coverage depth of 650X. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were determined using sequencing data; PD-L1 expression was measured by immunohistochemistry (Dako 22C3, tumor proportion score [TPS]). Results: TP53 Y220C alterations were identified in 488 (1.8%) PDAC patients (Y220C+). In comparison to PDAC patients lacking the TP53 Y220C alteration (Y220C-), Y220C+ patients were of similar age, but were more likely to be female (52.9% vs 46.8%; p = 0.0008) and harbor KRAS mutations (96.7% vs 92.7%; p = 0.007). Meanwhile, alterations in ATM were more frequent in the Y220C- group (4.0% vs 1.4%; p = 0.0008). Frequencies of other GAs were similar between Y220C+ and Y220C- groups, including alterations in the homologous recombination defect-associated genes BRCA1/2 and RAD21 , as well as ERBB2 , BRAF , MTAP and PIK3CA . MSI-high status and elevated TMB (≥ 10 mutations/Mb) were extremely uncommon in both groups. PD-L1 expression was similar in the Y220C+ and Y220C- groups, with positive PD-L1 expression (TPS ≥ 1) observed in 31.5% and 34.9% of patients, respectively. Conclusions: The potentially targetable TP53 Y220C mutation was identified in close to 2% of clinically advanced PDAC cases. Those with TP53 Y220C mutations were more likely to be female and harbor KRAS mutations, and less likely to harbor ATM mutations. However, TP53 Y220C mutations were not associated with other distinct genomic characteristics. These findings are consistent with previous reports of interactions between TP53 and KRAS alterations in PDAC. Given the emergence of drugs aimed at restoring p53 function in cases with the Y220C mutation, further study of this alteration in PDAC is warranted. Age, number of genomic alterations (GA) per tumor, and alteration frequency of select commonly altered genes based on TP53 Y220C status. TP53 Y220C+ (n = 488) TP53 Y220C- (n = 26,889) P Value Median Age, years (range) 66 (36-89+) 66 (21-89+) NS GA/tumor 5.2 5.0 NS KRAS 96.7% 92.7% 0.007 CDKN2A 60.1% 56.6% NS CDKN2B 28.6% 29.5% NS MTAP 24.4% 23.8% NS ARID1A 7.8% 8.7% NS ATM 1.4% 4.0% 0.0008 BRCA2 2.3% 3.1% NS NS = non-significant.
Patient-centered adverse event reporting in clinical trials: A novel approach using ECOG-ACRIN E2211.
658 Background: The Common Terminology Criteria for Adverse Events (CTCAE) classifies adverse events (AEs) in clinical trials but traditionally limits the analysis to a single occurrence per patient and grade 3-4 AEs, overlooking frequent and lower grade AEs. We propose a new approach of AE reporting that captures both the safety profile and patient experience. Methods: We analyzed related AEs collected in the ECOG-ACRIN E2211 [Phase II capecitabine + temozolomide (Arm A) vs. temozolomide (Arm B) in advanced pancreatic neuroendocrine neoplasms] by CTCAE v4.0 and limited to hematologic and gastrointestinal (GI) categories for this exploratory analysis. We calculated AE burden, defined as the average occurrence of AE per patient experiencing the AE, measured by total occurrence of AEs, and divided by number of patients who developed the AE. We then compared burden of grade 3-4 AEs vs. grades 1-4 AEs. Sex differences were evaluated using t-tests. Results: For hematologic AEs, 72 patients reported 426 occurrences across grades 1-4 and 24 patients reported 39 occurrences for grades 3-4, resulting in AE burdens of 5.9 (grades 1-4) versus 1.6 (grades 3-4). For GI AEs, 108 patients reported 997 grade 1-4 events, and 13 patients reported 22 grade 3-4 events, resulting in AE burdens of 9.23 versus 1.69, respectively. Sex differences in AE burden are tabulated below (Table). For example, in Arm B, anemia burden was 4.8 (males) vs 2.7 (females) [p=0.068] for grades 1-4 and 0 (males) vs 1 (females) for grades 3 and 4. Conclusions: This AE reporting approach, accounting for the burden across grade 1-4, offers a different and more patient-centered assessment of AEs in clinical trials and may help better identify sex-based differences. Burden of AEs by treatment arm and sex distribution. Burden of Related AEs Categories of AEs Arm A (N=65) Arm B (N=68) Grade 1-Grade 4 Grade 3-Grade 4 Grade 1-Grade 4 Grade 3-Grade 4 Male Female p-value Male Female p-value Male Female p-value Male Female p-value Hematologic Anemia 2.9 3 0.937 0 0 4.8 2.7 0.068 0 1* Neutropenia 1.7 2.2 0.686 1 1* 1.2 2.3 0.064 1 1.1 0.356 Thrombocytopenia 4.3 2.6 0.241 1* 1.2 3.6 3.3 0.781 1 1 ** Gastrointestinal Abdominal pain 2.5 2.2 0.835 0 0 3.1 3 0.955 0 1* Constipation 4.1 3.2 0.515 1* 0 4.9 3.3 0.169 0 0 Diarrhea 1.8 3.6 0.158 0 0 2.6 2.5 0.940 1.25 1 0.390 Nausea 4.2 4.9 0.619 0 0 4.4 4.2 0.893 1 1** ** Vomiting 2.2 1.9 0.703 0 0 1.8 2.8 0.241 1 1 ** *Only 1 patient in each group **No variance within each group.
KEYMAKER-U06: Phase 1/2 umbrella platform study of TROP2 antibody-drug conjugate sacituzumab tirumotecan plus pembrolizumab plus chemotherapy (substudy 06C) and sacituzumab tirumotecan plus paclitaxel (substudy 06D) in gastroesophageal adenocarcinoma.
TPS511 Background: Treatment options for patients with gastroesophageal adenocarcinoma (GEA) are limited and prognosis is poor. KEYMAKER-U06 is a multicenter, open-label, phase 1/2, umbrella platform study designed to evaluate investigational agents with or without pembrolizumab and/or chemotherapy for GEA. Substudy 06C (NCT06469944) will be conducted to evaluate sacituzumab tirumotecan(TROP2 antibody-drug conjugate; formerly MK-2870/SKB264) plus pembrolizumab plus investigator’s choice of chemotherapy as first-line therapy for patients with advanced or metastatic GEA. Substudy 06D (NCT06445972) will be conducted to evaluate sacituzumab tirumotecan plus paclitaxel as second-line therapy for patients with advanced or metastatic GEA. Methods: In both substudies, patients aged ≥18 years with confirmed advanced or metastatic HER2-negative GEA (gastric, gastroesophageal junction, or esophageal adenocarcinoma), measurable disease per RECIST v1.1 by investigator review and verified by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status score of 0 or 1 are eligible; patients in substudy 06C should be treatment naive and patients in substudy 06D should have disease progression on or after 1 prior therapy. Both substudies will have a safety lead-in phase of ≤10 patients to determine the recommended phase 2 dose of sacituzumab tirumotecan when used in combination with pembrolizumab plus chemotherapy (substudy 06C) or paclitaxel (substudy 06D). In the safety lead-in phase, patients will receive sacituzumab tirumotecan 3 mg/kg or 4 mg/kg IV per a Bayesian optimal interval design. In the efficacy phase of substudy 06C, ≅120 patients (including 10 patients in safety lead-in) will be allocated or randomly assigned to receive pembrolizumab 400 mg IV every 6 weeks plus investigator’s choice of chemotherapy (arm 1) or sacituzumab tirumotecan IV on days 1, 15, and 29 of each 6-week cycle plus pembrolizumab plus investigator’s choice of chemotherapy (arm 2). In the efficacy phase of substudy 06D, ≅80 patients (including 10 patients in safety lead-in) will be allocated or randomly assigned to receive ramucirumab 8 mg/kg IV on days 1 and 15 of each 4-week cycle plus paclitaxel 80 mg/m 2 IV on days 1, 8, and 15 of each 4-week cycle (arm 1) or sacituzumab tirumotecan IV on days 1, 15, and 29 of each 6-week cycle plus paclitaxel (arm 2). Primary outcomes for both substudies are safety and tolerability for the safety lead-in and ORR per RECIST v1.1. by BICR for the efficacy phase (calculated based on pooled data from safety lead-in and efficacy phase); secondary outcomes include DOR and PFS per RECIST v1.1 by BICR, OS, safety, and tolerability. Enrollment is ongoing in both substudies. Clinical trial information: NCT06469944 ; NCT06445972 .
Increasing RAS mutation result availability in newly diagnosed patients with metastatic colorectal cancer by their first outpatient medical oncology clinic visit at a large safety net hospital.
110 Background: Rat sarcoma virus mutation testing (RASmt) is critical in guiding systemic therapy selection for patients with metastatic colorectal cancer (mCRC) in the first-line setting. Missing results at the initial medical oncology visit can negatively impact patient outcomes by delaying treatment or leading to inappropriate treatment selection. This quality improvement (QI) project aims to increase the percentage of patients with newly diagnosed mCRC with RASmt results available by their first outpatient medical oncology appointment at a large safety net hospital to 20% over an 8-month period. Methods: A multidisciplinary team of key stakeholders including clinicians, a pathologist, and administrators was assembled to determine factors associated with failure to obtain RASmt. A baseline analysis of all patients referred to the gastrointestinal (GI) oncology clinic from June 2022 to April 2023, with manual review of electronic medical records by investigators, showed that only 6% (3/46) of newly diagnosed patients with mCRC had RASmt results available by their first GI oncology appointment. Two Plan-Do-Study-Act (PDSA) cycles were conducted to assess interventions that were implemented based on process mapping and reasons for unavailable test results. To increase the percentage of patients with RASmt results available, starting December 2023, patients initially diagnosed with mCRC as inpatients who were being followed by the oncology consult service had RASmt ordered on the tissue biopsy prior to discharge (PDSA1). Starting April 2024, the medical directorfor outpatient GI oncology clinics ordered RASmt for all patients with mCRC referred to the clinic at the point of referral (PDSA2) . New patient referrals were reviewed through July 3, 2024. Results: At baseline, the most common reason for unavailable RASmt results was the lack of test orders, with 70% (32/46) of new patients with mCRC not having RASmt ordered prior to their first appointment. Once RASmt was ordered, the average time for results was 13 days. After the first intervention, 4% (1/23) of patients with mCRC had RASmt results available at their first appointment. After the second intervention, 42% (5/12) of patients had RASmt results available. Additionally, median time from diagnosis of mCRC to first appointment decreased from 23 days at baseline to 17 days during PDSA1 to 12 days during PDSA2. Conclusions: By ordering RASmt at the point of referral, the percentage of patients who had RASmt available at their first appointment markedly increased from 6% to 42%. This QI initiative additionally demonstrates the importance of multidisciplinary teams to enhance patient care efficiency at a large safety net hospital. Further efforts are ongoing to increase RASmt availability beyond 42% with a focus on reducing the turnaround time of the test.
Unveiling ADAMTS12: A key driver of bladder cancer progression via COL3A1-Mediated activation of the FAK/PI3K/AKT signaling pathway
The effect of TU-100 on hepatocarcinogenesis and colorectal liver metastasis in MASH model.
577 Background: TU-100 is most commonly used herbal medicine in clinical setting. We have already reported that TU-100 suppressed dysbiosis (J Med Invest, 2013), bacterial translocation (Surg Today, 2017) and hepatic fibrosis (Surgery, 2016). This time we investigate the effect of TU-100 on hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in MASH model. Methods: 1: Effect on HCC: Seven-week-old Tsumura Suzuki obese diabetes mice, a model that shows the spontaneous onset of MASH and HCC, were used. They were divided into a TU-100 treated group and a control group. Mice were sacrificed at 24 and 48 weeks to evaluate hepatic steatosis, fibrosis, carcinogenesis, cytokine expression, and microbiome abundance. 2: Effect on CRLM: Six-week-old male C57BL/6J mice were used. They were divided into the western diet (WD) group and the WD+TU-100 group. MC38 colon cancer cells were injected into the spleen at 16 weeks, and mice were killed at 2 weeks after injection to evaluate hepatic steatosis, fibrosis and mRNA expression in the liver. Results: 1: Effect on HCC: At 24 weeks, the TU-100 group showed significantly lower expression of IL6, IL1B, and ACTA2 mRNA in the liver (P<0.05). At 48 weeks, the TU-100 group showed a lower rate of MASH than the control group (28% vs 72%; P=0.1). Tumor diameter was significantly smaller in the TU-100 group compared with that in the control group (P<0.05). Regarding the intestinal microbiome, the genera Blautia and Ruminococcus were increased in the TU-100 group (P<0.05), whereas Dorea and Erysipelotrichaceae were decreased in the TU-100 group (P<0.05). 2: Effect on CRLM: Steatosis of the WD+TU-100 group was significantly suppressed compared with the WD group (p<0.05). The WD+TU-100 group showed significantly smaller tumor diameter than the WD group (p<0.05). In the WD+TU-100 group, expression of SAA1 and TIMP1 mRNA in the liver was significantly lower than in the WD group (p<0.05). Conclusions: TU-100 regulates the intestinal microbiome and may suppress hepatic steatosis and subsequent hepatocarcinogenesis in the MASH model. Furthermore, TU-100 may have effect on CRLM via suppression of SAA1/TIMP1.
A real-world study of treatment patterns among patients (pts) with metastatic colorectal cancer (mCRC) receiving third-line (3L) or fourth-line (4L) treatment in the US.
64 Background: There are limited real-world data describing 3L and 4L treatments for pts with mCRC. However, the landscape is evolving with new options becoming available, including fruquintinib, a highly selective oral inhibitor of all 3 VEGF receptors, approved by the US FDA in November 2023. This study aimed to understand pt characteristics and real-world treatment patterns in 3L and 4L to characterize the standard of care, adherence to guidelines, and identify unmet needs among pts with mCRC in the US, prior to recent changes in the landscape. Methods: A retrospective study of adults with mCRC who had received ≥3L of therapy between 1/1/2018 and 3/31/2023 in the US-based Flatiron electronic health records database. In two cohorts, defined by initiating 3L and 4L systemic treatment, pt demographics, clinical characteristics, and treatment by line of therapy were summarized. Results: Overall, 5401 pts were included in the 3L cohort and 2868 pts in the 4L cohort: median age at baseline was 63 and 62 years (yrs), 56% and 56% were male, 43% and 43% had a KRAS variant, and 46% and 49% had liver metastasis, respectively. 96% of pts in the 3L cohort received standard chemotherapy (CT) +/- targeted therapy as 1L treatment (55% CT + anti-vascular endothelial growth factor [VEGF] therapy; 34% CT only; 7% CT + anti-epidermal growth factor receptor [EGFR] therapy). In 2L, 87% of pts had standard CT-containing regimens (53% CT + anti-VEGF therapy; 19% CT alone; 15% CT + anti-EGFR therapy). A similar treatment history was observed for the 4L cohort. Commonly used 3L regimens in the 3L cohort were trifluridine/tipiracil (TAS-102; 11%), regorafenib (rego; 10%), and standard CT-containing regimens (54%; including: 12% FOLFIRI + bevacizumab [bev], 7% FOLFOX + bev, 4% FOLFIRI, 3% FOLFOX, and 15% standard CT + anti-EGFR therapy). Approximately 47% (n=2513) of pts did not receive subsequent treatments after 3L. In the 4L cohort, use of TAS-102 (16%) and rego (15%) increased slightly in 4L, accompanied with a moderate decrease in CT-containing regimens (42%; including 6% FOLFOX + bev, 5% FOLFIRI + bev, 3% FOLFOX, 3% FOLFIRI, and 12% standard CT + anti-EGFR therapy). Approximately 4% of pts in the 3L and 4L cohorts received TAS-102 + bev in 3L and 4L, respectively. Pts receiving standard CT-containing regimens were slightly younger (<65 yrs: 3L 57%, 4L 58%) and had better Eastern Cooperative Oncology Group performance status (ECOG PS; 0-1: 3L 77%, 4L 77%) vs pts receiving TAS-102 (<65 yrs: 3L 54%, 4L 58%; ECOG PS 0-1: 3L 70%, 4L 68%) or rego (<65 yrs: 3L 50%, 4L 53%; ECOG PS 0-1: 3L 68%, 4L 70%). Conclusions: Characterization of treatment patterns in US pts from 1/2018 to 3/2023 showed that standard CT +/- targeted therapy was used frequently in 3L and 4L, demonstrating an unmet need for additional therapies. Approval of novel treatments, such as fruquintinib, may help to address this need.
Differential gut microbiota profiles among normal colorectal mucosa, adenomatous and hyperplastic polyps in healthy volunteers: ColoMAR-1 study.
271 Background: Increasing evidence indicates that the interaction between intestinal microbiota and host cells plays an important role in colorectal cancer oncogenesis through immune, inflammatory and/or metabolic alterations. However, there are no clear evidence in the very early adenoma-carcinoma sequence at which microbiota species influences future steps to colorectal carcinoma. This study aims do find a point in the adenoma-carcinoma sequence ad witch microbiota species suggest the risk of a future tumor to develop less invasive forms of early diagnosis. Methods: In this cross-sectional study, healthy volunteers above 45 years old were selected to participate. Exclusion criteria includes previous colonoscopy performed in the last 5 years. Stool sample were collected before a colonoscopy with biopsy. Samples of normal mucosa were systematically obtained, and all polyps found were removed. In fecal samples, microbiota species were identified using GoodGut test: Bacteroides fragilis, Subdoligranulm variabile, Ruminococcus, Roseburia, Coprococcus , eubacteria, Faecalibacterium prausnitzii and Gemella morbillorum . Number of genomic copies/μL were analyzed using the Wilcoxon test. Results: From February to June 2024, 29 healthy volunteers between 45 and 69 years were recruited. 62% were female. Adenomatous polyps or hyperplastic polyps were found in 9 volunteers. No case of colorectal cancer was found. For species S. variabile, Ruminococcus, Roseburia, Coprococcus and F. prausnitzii , higher counts were found in stool samples from volunteers with adenomatous or hyperplastic polyps than in those from volunteer with a normal colonoscopy, both in the total count and after correction for bacterial load (p<0.001). For B. fragilis , bacterial count was higher in samples from volunteers with adenomatous polyps, but not in the samples from people with hyperplastic polyps compared with those samples from volunteers with a normal colonoscopy. G. morbillorum counts were not related to any type of polyps. None of this counts met the laboratory-designated threshold related to colorectal cancer. Conclusions: The presence of B. fragilis could be related to the differential risk of malignancy of adenomatous compared to hyperplastic polyps. Bacterial count for each sample and specie. Bacteria specie* Normal mucosa Adenoma Hyperplastic B. fragilis 22.13 22.3 20.42 S.variable 6.06 7.29 7.53 Ruminococcus, Roseburia, Coprococcus 6.08 7.29 7.47 F. prausnitzii 4.7 6.28 7.09 G.morbillorum 20.91 20.54 20.84 *Number of genomic copies/μL.
Real-world use of supportive medications to prevent and manage key adverse events during first-line (1L) treatment of metastatic pancreatic adenocarcinoma (mPDAC) with FOLFIRINOX (FFX), FFX without 5FU bolus, and gemcitabine+nab-paclitaxel (GnP).
695 Background: 1L treatment of mPDAC with FFX or GnP typically requires supportive care to alleviate toxic effects. Two of the most common adverse events are neutropenia, which may be treated with granulocyte colony-stimulating factor (G-CSF), and diarrhea, often treated with atropine and/or loperamide. Medications may be administered as prophylaxis (PPx) or to manage symptoms as they occur. Other methods to improve tolerability include modifying regimens with lower doses or omitted components, such as removing the 5FU bolus from FFX (FFXnb). This study examines PPx vs non-PPx G-CSF, atropine, and loperamide during 1L treatment with FFX, FFXnb, and GnP. Methods: This retrospective observational study utilized Optum Market Clarity claims + EHR linked data. Inclusion criteria were: adult patients (pts) diagnosed with mPDAC between January 1, 2015 and May 31, 2023; initiated treatment (index date) with 1L FFX, FFXnb, or GnP -14 to +90 days from diagnosis; no evidence of other cancers in 6 months pre-index continuous enrollment; at least one EHR record post-index. G-CSF PPx was defined as administration/fill within 7 days of the start of a treatment, inclusive. PPx with atropine or loperamide was defined as administration/fill the day before or day of a treatment; all other use was categorized “non-PPx”. Pts may appear in both PPx and non-PPx categories. Results: Rates of overall use, PPx, and non-PPx for each medication of interest are shown (Table). The overall G-CSF use rate was >3.5 times higher for FFX and FFXnb vs GnP. While ≥70% of FFX/FFXnb pts received PPx, non-PPx still occurred in more than 1 in 8 pts. One-fifth of FFX and FFXnb pts received atropine at any time, vs. just 6% of GnP pts. Atropine PPx was less common than non-PPx for FFX/FFXnb and was rare in GnP pts. Similar to the other medications, loperamide was observed more for FFX and FFXnb vs. GnP, but was the least common of the medications, used by <10% of pts in any regimen. PPx and non-PPx use were similar. Use of the three medications was similar between FFX and FFXnb. Conclusions: In a RW cohort of 1L mPDAC pts, G-CSF and antidiarrheal use was more common in FFX and FFXnb than GnP pts. Most FFX and FFXnb pts received PPx G-CSF, reflecting clinician efforts to manage the high risk of neutropenia with these regimens. Non-PPx G-CSF still occurred in 14–18% of pts. FFXnb had similar rates of concomitant medications as FFX, indicating that removing the 5FU bolus may have minor impact on the need for some supportive medications. Concomitant medication use. Medication 1L FFX(n=511) 1L FFXnb(n=583) 1L GnP(n=958) G-CSF % treated overall 77% 71% 20% % PPx 76% 70% 17% % non-PPx 18% 14% 9% Atropine % treated overall 20% 20% 6% % PPx 11% 9% 2% % non-PPx 15% 16% 5% Loperamide % treated overall 7% 9% 3% % PPx 4% 5% 1% % non-PPx 4% 6% 2%
The C-terminal α-helix is crucial for the activity of the bacterial ABC transporter BmrA
The prognostic value of HER2 gene dosage and heterogeneity at a single-cell resolution in gastroesophageal adenocarcinoma.
473 Background: HER2 gene dosage (i.e. level of amplification) and heterogeneity are key prognostic variables for HER2+ gastroesophageal adenocarcinoma (GEA), yet no standardized approach to test these in routine clinical use exists. Here we modify the analytical pipeline for HER2 FISH to quantitatively estimate these prognostic variables and correlate them with clinical outcomes. Methods: Patients with metastatic HER2+ GEA who received trastuzumab-based therapy between 2011-2024 at Dana-Farber Cancer Institute and had available pre-treatment tissue for FISH analysis were included. HER2 FISH was conducted in a CLIA approved clinical pathology laboratory. Standard HER2/CEP17 ratio (an average of 50 cells) and individual cell HER2/CEP17 ratio were calculated. Kaplan-Meier method was used to estimate progression free (PFS) on trastuzumab-based therapy and overall survival (OS). Survival outcomes were adjusted for age, gender, tumor site, grade, prior resection, number of metastatic sites, and HER2 IHC using cox proportional hazard regression models. Results: A total of 77 patients were included. Median age was 60 years, 88% were male, and 92% had HER2 3+ tumors. Individual cells with HER2/CEP17 ratio ≥ 2.0 were defined as amplified (same cutoff as current bulk standard) and those with HER2/CEP17 ratio ≥ 4.95 (population median) were labeled highly HER2 amplified providing objective metrics to assess heterogeneity and gene dosage. Using these metrics we defined three subgroups: 1. Heterogenous (Het, n = 15): <75% cells HER2+; 2. Homogenous, low gene dosage (HL, n = 30): >75% cells HER2+, <50% cells with high HER2 amplification; 3. Homogenous, high gene dosage (HH, n = 32): >75% cells HER2+, >50% cells with high HER2 amplification. Cutoffs for both metrics were determined using data distribution patterns. The subgroups were prognostically relevant and PFS and OS were significantly lower for heterogenous tumors and numerically lower for homogenous tumors with low gene dosage after multivariable adjustment (Table). Conclusions: HER2 gene dosage and heterogeneity significantly impact outcomes in HER2+ GEA. More importantly by deconvoluting clinical HER2 FISH data at single cell level, we demonstrate an objective metric with prognostic value that could be adopted for routine clinical use and for patient stratification. Further insights into differing biology of these molecular subtypes are needed. Outcomes of patients by HER2 heterogeneity and gene dosage. Hazards ratio (HR) and p values are adjusted using multivariable cox proportional hazard regression model. PFS OS Patients, No. Median, mo HR (95%CI) P Value Median, mo HR (95%CI) P Value HH 32 16.2 1 16.4 1 HL 30 12.1 1.70 (0.79-3.66) 0.173 15.7 1.71 (0.93-3.14) 0.085 Het 15 6.7 3.12 (1.35-7.2) 0.008 12.4 2.72 (1.28-5.75) 0.009
First-in-human, phase 1a, dose escalation study of BGB-B167, a CEA x 4-1BB bispecific antibody, as monotherapy or combined with tislelizumab (anti-PD-1), in patients with selected advanced or metastatic solid tumors.
123 Background: BGB-B167 is potentially a first-in-class IgG-based bispecific antibody that targets CEA, a tumor-associated antigen overexpressed in many cancers, and 4-1BB, a key T-cell co-stimulatory receptor expressed on activated CD4+/CD8+ T lymphocytes. Preclinical data suggest BGB-B167 binds to these target proteins with high specificity/affinity, inducing T-cell activation and antitumor activity, with potential for mitigating strong AEs, eg CRS and hepatoxicity. We present results of a first-in-human, phase 1a, open-label, multicenter trial of BGB-B167 given as monotherapy (Part A [A]) or with tislelizumab (TIS) (Part B [B]) (NCT05494762). Methods: Eligibility: ≥18 y with unresectable/metastatic CRC, CEA+ GC or CEA+ NSCLC previously treated with standard systemic therapy or for whom treatment is unavailable; pts with CRC and known MSI-H/dMMR status must have received prior ICI, if available. Primary objectives: safety/tolerability; MTD and RP2D for BGB-B167 ± TIS; key secondary objective: antitumor activity (RECIST v1.1). Results: As of July 7, 2024, 54 pts were enrolled (31 in A, 23 in B) with BGB-B167 dose ranges of 5–1200 mg IV QW assessed in A and 50–600 mg IV QW in B. In A and B, respectively, 29/31 (93.5%) and 18/23 (78.3%) had CRC, 2/31 (6.5%) and 3/23 (13%) had GC, 0/31 (0%) and 2/23 (8.7%) had NSCLC; 19/31 (61.3%) and 18/23 (78.3%) had liver metastases; 20/31 (64.5%) and 14/23 (60.9%) received ≥3 lines of prior therapy. TEAEs occurred in all pts (Table). Most common treatment-related TEAEs were nausea (4/31; 12.9%) and fatigue (3/31; 9.7%) in A and pruritus (5/23; 21.7%) and diarrhea (4/23; 17.4%) in B; there were no treatment-related TEAEs indicative of hepatotoxicity or CRS. There was a single DLT (gr 3 SJS) in a pt who received 600 mg BGB-B167 + TIS (resolved after treatment discontinuation). MTD was not reached. 3 pts (1 with CRC [A]; 1 with CRC and 1 with GC [B]) had confirmed PRs. DoR was ≥5.6 mo for the pt in A and ≥5.6 mo and ≥6.9 mo for the pts in B; all remained on treatment with ongoing responses as of the data cutoff date. DCR (95% CI) was 33.3% (17.3–52.8) in A and 40.9% (20.7–63.6) in B. Serum exposure of BGB-B167 increased dose dependently from 150 to 1200 mg. Conclusions: Overall, BGB-B167 ± TIS was well tolerated and has demonstrated limited antitumor activity in pts with advanced/metastatic CEA+ solid tumors. Clinical trial information: NCT05494762 . Safety. Part ABGB-B167 monotherapy(N=31) Part BBGB-B167 + TIS(N=23) Any TEAE 31 (100.0) 23 (100.0) Any treatment-related TEAE 17 (54.8) 15 (65.2) Gr ≥3 4 (12.9) 1 (4.3) Serious 0 (0) 2 (8.7) Leading to death 0 (0) 0 (0) Leading to treatment discontinuation 0 (0) 1 (4.3) Any imAE 2 (6.5) 5 (21.7) IRRs 4 (12.9) 6 (26.1) Patients with multiple adverse events (AEs) are counted once. All AEs are listed as n (%). imAE, immune-mediated AE; IRR, infusion-related reaction; TEAE, treatment-emergent AE.
Molecular characteristics and prognostic impact of <i>GNAS</i> mutations in colorectal cancer: An international collaborative study between United States and Japan.
48 Background: GNAS (Guanine nucleotide-binding protein, alpha stimulating) encodes the alpha subunit of the stimulatory G protein, and gain of function mutations in this gene have been previously identified, especially those located at the R201 codon. Although GNAS R201C/H has been associated with mucinous histology and poor response to chemotherapy in appendiceal cancer, the impact of GNAS mutations in colorectal cancer (CRC) remains unclear. Methods: We conducted a comparative, integrative analysis of GNAS mutations in CRC using two cohorts: MD Anderson Cancer Center (MDA) across all stages (N=5,249) and the GALAXY study involving only resectable disease (UMIN000039205, N=2,599). We assessed the correlation between GNAS pathogenic mutations and microsatellite stability, CRC sidedness, co-mutations, and survival outcomes. The Chi-squared test was used for categorical variables, and the log-rank test for overall survival (OS) and disease-free survival (DFS). Results: In the MDA and GALAXY cohorts, GNAS mutations were identified in 107 (2.0%) and 61 (2.4%) patients, respectively. Prevalence of GNAS mutations was higher in right sided tumors (MDA: 3.8% vs. 1.3%, GALAXY: 6.2% vs 2.8%, p<0.01 for both cohorts) and microsatellite instability-high (MSI-H) tumors (MDA: 6.5% vs. 1.8%, GALAXY: 16.5% vs. 1.4%, p<0.01 for both cohorts). There was not an association of GNAS mutations with stage in either cohort. GNAS was significantly enriched for co-mutation with KRAS in the MDA cohort (OR=3.26, P<0.01), similar to prior observations in appendix cancer, but was not significantly associated with KRAS mutations in the GALAXY cohort (OR=1.35, P=0.3). GNAS mutations were mutually exclusive with TP53 in both cohorts (MDA: OR=0.58, P=0.026; GALAXY: OR=0.21, P<0.01). With regards to survival, in the MDA cohort, GNAS mutant tumors had a trend towards worse OS in the overall population (20 mo vs. 33 mo, HR=1.27, 95% CI=0.61-1, P=0.085). The survival impact of GNAS mutations was greatest in metastatic patients (Stage IV: 19 mo vs. 38 mo, HR=1.49, 95% CI=0.47-0.94, P=0.021 vs. Stage I-III: HR=1.35, 95% CI=0.46-1.2, P=0.22). The GALAXY cohort showed no significant association between GNAS mutations and DFS (HR=1.05, 95% CI=0.6-1.8, P=0.9). In both cohorts, GNAS mutations had a worse prognosis in left-sided CRC (MDA: HR for OS = 1.45, P = 0.091; GALAXY: HR for DFS=2.15, P=0.09) with no significant effect observed in right-sided CRC (MDA: HR for OS=0.91, P=0.68; GALAXY: HR for DFS=0.65, P=0.3). Conclusions: Our findings highlighted the intricate role of GNAS mutations in CRC, demonstrating its higher prevalence in MSI-H and right-sided colon, significant association with KRAS mutations, and divergent prognostic impacts based on tumor sidedness. Further research is needed to elucidate the mechanisms behind the worsened survival in left-sided GNAS- mutated CRC.
Management of patients with locally advanced rectal cancer in the total neoadjuvant therapy (TNT) era: Experience from Argentina.
85 Background: In the last years a paradigm shift has changed the way we manage non metastatic rectal cancer. The varied options within TNT have gradually been adapted in our country. This study aims to depict the strategies implemented. Methods: A prospective and retrospective observational study was performed from 2020 to 2024 including stage II-III rectal cancer patients treated at three centers in Buenos Aires, Argentina. Data was extracted from medical records. Results: 68 patients were included in the analysis. Median age was 59 years (IQR 48–71). 72% were male. 88% (60) had stage III disease, and 12% (8) stage II. Geriatric assessment was performed in 7 of 19 patients aged over 70 (5 frail). All patients were staged with high resolution MRI and discussed in multidisciplinary tumor board. Mismatch repair was assessed in 72%(49) of patients, only one had MLH1 deficiency. 79%(54) patients received TNT: 22%(12) short course vs 78%(42) long course radiotherapy; 24%(13) induction vs 76%(41) consolidation chemotherapy. Preferred chemotherapy regimen was CAPOX both in induction and consolidation chemotherapy (69.7% and 63.4%, respectively) Despite small numbers non significant differences in risk factors were found between TNT vs non TNT groups (Table). We registered 13 Grade 3-4 toxicity events: 3 in induction chemotherapy, 7 in consolidation and 3 in radiotherapy. Clinical complete response was achieved in 25.9% of TNT (11 consolidation, 3 induction) and 7.1%(1) of non-TNT (p=0.25). Watch and Wait was employed in 9 patients in TNT and 1 in non TNT group. 40 patients underwent surgery in the TNT and 11 in the non-TNT group; complete pathological response was reached in 17.5% (7) and 9% (1), respectively. Overall relapse rate was 19.14% (13): 2.94% (2) local and 16.2% (11) systemic. (TNT: 1.85%(1) local vs 18.5%(10) metastatic; nonTNT: 7.14%(1) both local and metastatic) p=0.4. At a median follow-up of 20 months (IQR 15–32 months), 2-year progression-free survival (PFS) rate was 87% (95% CI: 38–98%) in the non-TNT group and 78% (95% CI: 61–88%) in the TNT group. Conclusions: This study highlights the feasibility of worldwide adoption of TNT. We describe the preferred regimens and results of TNT in three high volume centers in Argentina. Long course radiotherapy and consolidation treatment with CAPOX are the predominant strategies. Non operative management is routinely offered to complete responders. Our efficacy results are comparable with published literature. Comprehensive geriatric assessment is recommended but still partially applied. In line with recent findings MMR testing has been widely adopted as an initial workup parameter. TNT %(n=54) non-TNT %(n=14) p T4 disease 26 (14) 21 (3) 0.99 N2 37 (20) 29 (4) 0.75 EMVI positivity 49 (26) 18 (3) 0.16 Circumferential resection margin <1 mm 29.6 (16) 28.57 (4) 0.23 Low-lying tumors 33 (18) 43 (6) 0.54
New insights in uranium bioremediation by cytochromes of the bacterium Geotalea uraniireducens
Relationship between PD-L1 expression and the number of biopsy specimens in advanced gastric cancer.
481 Background: Programmed cell death ligand 1 (PD-L1) expression shows spatial heterogeneity in gastric cancer. Compared with single biopsies, multiple biopsies may provide reliable PD-L1 expression results. However, the optimal number of biopsy specimens remains unclear. This study aimed to assess the relationship between PD-L1 expression and the number of biopsy specimens in advanced gastric cancer. Methods: We retrospectively analyzed patients with advanced gastric cancer who received first-line chemotherapy at a single institution between December 2021 and June 2024. Those in whom PD-L1 expression was evaluated using tumor-containing biopsy specimens were included. PD-L1 expression was measured using the Dako PD-L1 IHC 28-8 pharmDx assay. PD-L1 positivity was defined as a combined positive score of ≥5. The association between PD-L1 positivity and the number of biopsy specimens was tested using the chi-square or Fisher’s exact test. Results: Of the 183 patients screened, 110 were included. The patient characteristics were as follows: median age, 71 (range: 34–87) years; sex (male/female), 75/35; primary site (gastric/gastroesophageal junction), 102/8; and histological type (diffuse/intestinal/other), 59/34/17. The PD-L1 positivity prevalence was 71.8%. In 97 patients, human epidermal growth factor receptor 2 (HER2) expression was detected in the same specimens as PD-L1, with a HER2-positive rate of 14.4%. The mean numbers of biopsy and tumor-containing biopsy specimens were 5.14 (range: 2–10) and 4.25 (range: 1–10), respectively. The PD-L1 positivity prevalence was significantly higher when the number of biopsy specimens was ≥5 compared with ≤4 (77.5% vs 56.7%, P =0.03; Table). The same trend was observed according to the histological type (diffuse type, 75.0% vs. 46.7%, P =0.04; intestinal type, 79.2% vs. 60.0%, P =0.39). In HER2-negative cases, PD-L1 positivity was significantly more prevalent when the number of biopsy specimens was ≥5 compared with ≤4 (83.6% vs 54.5%, P =0.006; Table). However, there was no such difference in HER2-positive cases (54.4% vs 66.7%, P =1). Conclusions: The data suggest that collecting at least five biopsy specimens increases the likelihood of identifying PD-L1 positivity in advanced gastric cancer, particularly in HER2-negative cases. This approach may improve PD-L1 evaluation accuracy and lead to better treatment decisions. Relationship between the number of biopsy specimens and PD-L1 positivity. Number of biopsy specimens PD-L1 positivity (%) PD-L1 negativity (%) P value Overall 0.03 ≥5 77.5 22.5 ≤4 56.7 43.3 HER2-negative 0.006 ≥5 83.6 16.4 ≤4 54.5 45.5
Phase 1/2 study of FOG-001, a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer, hepatocellular carcinoma, and other locally advanced or metastatic solid tumors.
TPS322 Background: Wnt/B-catenin pathway activation, which is frequently present in most colorectal cancers and a variety of other solid tumors, is associated with poor prognosis and resistance to immunotherapy. FOG-001 is a Helicon peptide that competitively inhibits the interaction between β-catenin and the T-cell factor (TCF) family of transcription factors. Experiments in patient-derived-xenograft (PDX) models of colorectal cancer (CRC) and hepatocellular carcinoma (HCC) have demonstrated that FOG-001 can inhibit tumor growth and promote tumor regression when administered as monotherapy or in combination with immune checkpoint inhibitors or standard of care therapies, including bevacizumab and 5-FU. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Part 1) and dose-expansion (Part 2) study evaluates the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor effects of FOG-001 as monotherapy and in combination with other anti-cancer therapies. Eligible patients must have received at least one prior systemic anti-cancer therapy and either progressed on, not responded to, or be unfit for available therapies. In Part 1, FOG-001 is administered intravenously, either weekly or every other week, at escalating dose levels evaluated sequentially in a standard 3+3 design as monotherapy in patients with: (1a) microsatellite stable (MSS) CRC or any solid tumor with a documented Wnt/b-catenin pathway activating mutation (WPAM) and (1c) HCC with WPAM. Part 1b will evaluate PD effects in cohorts of approximately six patients with MSS CRC. Upon selection of the preliminary recommended Phase 2 dose from Part 1a for weekly dosing, combination dose escalation (1d) evaluates the safety/tolerability, PK and anti-tumor effects of FOG-001 in CRC patients combined with FOLFOX+bevacizumab, anti-PD-1/PD-L1 (also includes other solid tumors with known WPAM), or trifluridine/tipiracil+bevacizumab. Part 2 dose expansion evaluates FOG-001 monotherapy in MSS CRC, HCC, and other solid tumors with documented WPAM. Combination dose expansion evaluates the combinations initially evaluated in Part 1d. Primary endpoints are safety/tolerability and preliminary anti-tumor effects (objective response rate). Secondary endpoints are PK, PD, and other anti-tumor responses (e.g., best objective response, duration of response, and progression free survival). Enrollment in Parts 1 and 2 is ongoing in the USA. Clinical trial information: NCT05919264 .