Browse Articles

Impact of expression of metabolic genes on patient (pts) outcomes in metastatic colorectal cancer (mCRC): Data from CALGB/SWOG 80405 (Alliance).

224 Background: Metabolic pathways are reprogrammed during CRC development, leading to increased glycolysis, glutaminolysis, and fatty acid synthesis. Understanding the impact of metabolic reprogramming on treatment outcomes is paramount. Hence, we investigated whether the tumor gene expression of 4 selected major metabolic genes ( PKM, SLC2A1 , SLC16A1 , and CAV1 ) could affect treatment response in pts enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of gene expression (high [H], medium [M] and low [L]). Logrank P -values provide a non-parametric unadjusted assessment of differences. Likelihood ratio tests (LRT) were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ECOG, tumor side, number of metastatic sites, KRAS , CMS, and treatment. Results: PKM gene expression was associated with cet treatment outcomes with PKM- low tumors showing significantly longer PFS and OS (median PFS: 14.3 vs 9.8 vs 8.1 months, L vs M vs H, P < 0.0001, LRT P = 0.011; median OS: 45.9 vs 31.2 vs 20.9 months, P < 0.0001, LRT P = 0.12). Low SLC2A1 was also associated with longer OS in cet-treated pts (32.4 vs 35.8 vs 25.2 months, P = 0.02, LRT P < 0.0001). Similar results were observed in bev-treated pts where low SLC2A1 expressing tumors had longer OS (37.4 vs 26.1 vs 29 months, P = 0.037, LRT P = 0.069) and a non-significant trend for longer PFS (13.1 vs 11 vs 9.5 months, P = 0.076). CAV1 low gene expression was associated with longer OS in cet-treated pts (37.4 vs 34 vs 21.5 months, P = 0.0048, LRT P = 0.013), while no significant associations were found in bev-treated (interaction LRT P = 0.0009). No significant results were observed for SLC16A1 . Conclusions: The intratumoral expression of metabolic genes was prognostic and predictive in mCRC pts treated with first-line therapy. GLUT1 (encoded by SLC2A1 ) and PKM2 (encoded by PKM ) promote aerobic glycolysis of cancer cells, known as Warburg effect, supporting rapid cell proliferation and survival. CAV1 has been shown to be involved in mitochondrial bioenergetics and fatty acid metabolism and to play either a tumor suppressor or oncogenic role depending on the cancer type and stage. Lower expression of SLC2A1 and PKM was associated with improved survival and increased benefit from cet treatment in our cohort. Low CAV1 expression was also associated with increase survival suggesting a cancer-promoting role in mCRC. Our results suggest that targeting cancer cell metabolism through novel inhibitors of the aforementioned pathways may be a promising therapeutic strategy.

Ultra‐Fast Moisture Sensor for Respiratory Cycle Monitoring and Non‐Contact Sensing Applications

Abstract As human‐machine interface hardware advances, better sensors are required to detect signals from different stimuli. Among numerous technologies, humidity sensors are critical for applications across different sectors, including environmental monitoring, food production, agriculture, and healthcare. Current humidity sensors rely on materials that absorb moisture, which can take some time to equilibrate with the surrounding environment, thus slowing their temporal response and limiting their applications. Here, this challenge is tackled by combining a nanogap electrode (NGE) architecture with chicked egg‐derived albumen as the moisture‐absorbing component. The sensors offer inexpensive manufacturing, high responsivity, ultra‐fast response, and selectivity to humidity within a relative humidity range of 10–70% RH. Specifically, the egg albumen‐based sensor showed negligible response to relevant interfering species and remained specific to water moisture with a room‐temperature responsivity of 1.15 × 10 4 . The nm‐short interelectrode distance (circa 20 nm) of the NGE architecture enables fast temporal response, with rise/fall times of 10/28 ms, respectively, making the devices the fastest humidity sensors reported to date based on a biomaterial. By leveraging these features, non‐contact moisture sensing and real‐time respiratory cycle monitoring suitable for diagnosing chronic diseases such as sleep apnea, asthma, and pulmonary disease are demonstrated.

UGT1A1 mutation rates in a minority-rich comprehensive cancer center: A retrospective pharmacogenomic study.

294 Background: Irinotecan is a widely used and effective treatment for various gastrointestinal malignancies. Its toxic metabolite, SN-38, is inactivated by UDP glucuronosyltransferase-1A1 (UGT1A1). However, variability in individual clearance of irinotecan and SN-38 can cause unpredictable toxicities. Mutations in the UGT1A1 gene reduces enzyme activity, resulting in dose-limiting neutropenia and diarrhea, hospitalizations, treatment delays, and dose reductions. The best characterized germline variant is a polymorphism in the UGT1A1*28 allele, but data in underrepresented groups remains particularly lacking. Methods: We conducted a retrospective cohort study of patients who were treated at our minority-rich academic medical center. A total of 63 patients with gastrointestinal malignancies were tested for the UGT1A1*28 polymorphism. Data for irinotecan treatment course, related toxicities, and dose reductions was available for 41 patients. Analysis was performed using Fisher’s exact test, one-way ANOVA, and Welch’s two-sample test. Results: 73% (n = 46) of patients were identified with the UGT1A1*28 polymorphism, including 63% (n = 29) with heterozygous genotype and 36.9% (n = 17) with homozygous genotype. There were significantly more patients of UGT1A1*28 polymorphisms carriers in the African American and Hispanic population as compared to the white population (p = 0.001, 0.01 respectively). The polymorphism frequency was 0.66 in the African American group [95% CI (0.49 – 0.81)], 0.48 in the Hispanic group [95% CI (0.34 – 0.62)], and 0.06 in the white group [95% CI (0.001 – 0.30)]. The frequency was significantly lower in the white population when compared to all other races (p-value = 0.0002), to African American (p- value < 0.001), and to Hispanic (p-value = 0.003) populations. There were higher rates of overall toxicities of any grade in the heterozygotes (76%) and homozygotes (64%) when compared to the wild-type group (56%). 55% (n = 6) of the homozygous and 48% (n = 10) of the heterozygous patients developed G1-G4 neutropenia, as compared to the 22% (n = 2) of the wild-type patients. Conclusions: Ethnic differences are known to exist in UGT1A1*28 polymorphism, with the prevalence being significantly higher in African and Caucasian populations. Historical data based on large-scale genotyping report allele frequencies of 0.42 in African/African American, 0.37 in Hispanic American, and 0.29 in Europeans. Our local population has a higher rate overall in both the African American and Hispanic populations with significantly higher rates than the white population. Patients with the UGT1A1*28 polymorphism experienced more toxicities and neutropenia of any grade. UGT1A1 genotyping is not routinely performed in patients initiating irinotecan treatment, however it may prove to be beneficial in certain demographics with higher rates of UGT1A1*28 polymorphisms.

Q-TWiST analysis of pembrolizumab plus trastuzumab and chemotherapy for patients with metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the KEYNOTE-811 trial.

354 Background: In the phase 3 KEYNOTE-811 trial (NCT03615326), first-line pembrolizumab plus trastuzumab and chemotherapy (pembrolizumab group) statistically significantly improved PFS and OS versus placebo plus trastuzumab and chemotherapy (placebo group), with manageable safety, in patients with metastatic HER2-positive G/GEJ adenocarcinoma, while maintaining HRQoL, specifically in patients with PD-L1 combined positive score (CPS) ≥1 tumors. The objective of this analysis was to assess quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) for patients treated in the KEYNOTE-811 trial. Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 adverse events (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for patients with PD-L1 CPS ≥1 tumors. The data cutoff date was March 20, 2024. Results: At the maximum follow-up of 63 months, patients in the pembrolizumab group had a 2.36-month (95% CI, −0.24 to 4.56) longer restricted mean time in TOX (6.98 vs 4.63 months), a 3.40-month (95% CI, −0.44 to 7.45) longer restricted mean time in TWiST (12.03 vs 8.62 months), and a 1.45-month (95% CI, −5.84 to 3.09) shorter restricted mean time in REL (8.87 vs 10.32 months) versus the placebo group. For the restricted mean Q-TWIST at month 63, based on the US mapping algorithm, the difference between the pembrolizumab and placebo groups favored the pembrolizumab group by 3.90 months (95% CI, 1.30 to 6.72), representing a 16.57% relative Q-TWiST gain. Based on the standardized base case utility weights, the difference also favored the pembrolizumab group by 3.86 months (95% CI, 1.47 to 6.67), representing a 16.38% relative Q-TWiST gain. Conclusions: Pembrolizumab plus trastuzumab and chemotherapy produced a clearly clinically important improvement in quality-adjusted survival time based on Q-TWiST analyses compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated metastatic HER2-positive G/GEJ adenocarcinoma with PD-L1 CPS ≥1. Clinical trial information: NCT03615326 .

Disparities in incidence and mortality of colorectal cancer in Appalachian Kentucky.

33 Background: Since the late 1990s, both the incidence and mortality of invasive colorectal cancer (CRC) have decreased across the United States, including in Kentucky. Despite this, CRC incidence and mortality are above national average in Kentucky. Over the last two decades, a disparity in CRC incidence and mortality has emerged between Appalachian Kentucky (AK), a distinct eastern region, and Non-Appalachian Kentucky (NAK). This disparity is attributed to differences in social and structural determinants of health (SSDH) between these populations. Methods: Age-adjusted CRC incidence and mortality rates (2016-2020) for both Kentucky and the U.S. were obtained from the National Cancer Institute’s public database. Data from the Kentucky Cancer Registry were used to compare CRC incidence and mortality rates in AK and NAK counties from 1994-2021. Incidence rate ratio analyses across discrete time periods demonstrated statistical differences between these regions. Results: Compared to national data (2016-2020), Kentucky's CRC age-adjusted incidence and mortality rates were significantly higher: 45.9 vs. 36.5/100,000, 25.8%, for incidence, and 16.2 vs. 13.1/100,000, 23.7%, for mortality (both p<0.0001). From 1995-2003 incidence and 1994-2003 mortality of CRC, were higher in NAK, these rates eventually decreased and equalized between NAK and AK. By 2010-2015 both incidence and mortality rates were higher in AK, 55.8 vs 48/100,000, 16.3%, (p=<0.0001) and 20.1 vs 15.8/100,000, 27.2%, (p=<0.0001) respectively. The most recent data (2016-2021) shows that these significant disparities persist, with AK’s incidence and mortality 51.8 vs 44.1/100,000, 17.5% (p=<0.0001) and mortality 19.0 vs 15.1/100,000, 25.8% (p=<0.0001) higher, respectively. Conclusions: While CRC rates have decreased nationwide and in Kentucky, a pronounced gap in both incidence and mortality has developed between Appalachian and Non-Appalachian Kentucky. Appalachian counties—which are more rural and impoverished—face greater barriers to accessing preventive healthcare, contributing to this disparity. Additionally, AK has higher rates of obesity, poverty, smoking, and lower educational attainment and screening rates . Recent public health efforts, such as promoting stool-based screening and increasing preventive care discussions, aim to reduce these disparities. However, delays in CRC screenings during the COVID-19 pandemic— resulting in approximately 1.7 million missed colonoscopies nationally— may have skewed the most recent data, necessitating further analysis in the coming years.

Perovskite‐Based Smart Eyeglasses as Noncontact Human–Computer Interaction

AbstractMore than 70% of human information comes from vision. The eye is one of the most attractive sensing sites to collect biological parameters. However, it is urgent to develop a cost‐effective and easy‐to‐use approach to monitor eyeball information in a minimally invasive way instead of current smart contact lenses or camera‐based eyeglasses. Here, the biomimetic mineralization strategy is developed to prepare large‐grained perovskite film on the glass with prepared ITO electrodes, which displays the on–off ratio close to 300 times at 500 Lux light intensity, and the responsiveness reaches 22.09 A W−1. The smart eyeglasses composed of perovskite‐based photodetectors can directly convert the visual stimuli from the reflective light of eyeballs into electrical signals in all light circumstances. After scaling up the pretraining data and the model size, the smart eyeglasses achieve the noncontact monitoring of the eyeball movement with the recognition angle of 5°, which can be used to unobtrusively drive the model car with great freedom. The smart eyeglasses based on the perovskite photodetectors provide cost‐effective approaches for monitoring eyeball movements, which will show great potential in the applications of man‐machine control, augmented reality, individual healthcare, etc.

WW vs TME in patients with rectal cancer with a complete or near-complete response to TNT: Pooled analysis of CAO/ARO/AIO-12 and OPRA trials.

21 Background: Patients with locally advanced rectal cancer (LARC) and a clinical complete response (cCR) or near-complete response (nCR) to total neoadjuvant therapy (TNT) can be offered watch-and-wait (WW) with the intention of achieving organ preservation. However, one third of patients on WW develop tumor regrowth and require total mesorectal excision (TME). Assessing the safety of WW in patients with a cCR or nCR is challenging due to the difficulty of finding an adequate control group. Here we compare the survival outcomes of patients with LARC treated with TNT and either mandatory TME or selective WW stratified by tumor response. Methods: This is a pooled analysis of two multicenter, phase II trials (CAO/ARO/AIO-12 [CAO] and OPRA) that randomized patients with stage II/III rectal cancer to either induction or consolidation TNT. All patients in the CAO trial underwent TME within 6 weeks of TNT. Pathologic tumor regression grade (TRG) was categorized as complete (TRG 4), intermediate (TRG 2,3) or poor (TRG 0,1). Patients in the OPRA trial were restaged by endoscopy and MRI 8±4 weeks after end of TNT. Clinical response was graded as cCR, nCR, or incomplete clinical response (iCR). Patients with a cCR or nCR were offered WW; patients with an iCR were recommended for TME. Survival curves were estimated using the Kaplan-Meier method and the log-rank test. Results: The study included 628 patients ( n =304 CAO; n =324 OPRA). Median follow-up was 3.6 (IQR 1.13) and 5.1 (IQR 2.2) years. Patients in the CAO trial were more likely to have cT3/4 and cN positive disease while patients in the OPRA trial had tumors closer to the anal verge. Compliance with TNT and rates of grade 3+ adverse events were similar between studies. A total of 144 (47%) patients in the OPRA trial achieved long term organ preservation. We found no differences in survival between trials. In addition, we found no differences in DFS between studies for patients with an excellent (TRG4 87% [95% CI, 79-97%], cCR 87% [95% CI, 81-93%]) or intermediate (TRG2-3 69% [95% CI, 62-76%], nCR 71% [95% CI, 68-80%]) response. Conclusions: This pooled analysis demonstrated that almost half of LARC patients treated with TNT can achieve organ preservation and that a selective WW strategy yields similar survival outcomes compared to mandatory TME. In addition, we found no differences in survival based on paired clinical and pathologic tumor response grades following TNT. This data provides further evidence supporting the safety of WW for patients with LARC and a cCR or nCR to TNT. Three-year survival outcomes in the CAO/ARO/AIO-12 and OPRA trials. CAO/ARO/AIO-12(95% CI) OPRA(95% CI) P 3y DFS 73 (71–81)% 76 (68–78)% 0.3 3y DRFS 82 (78–87)% 82 (78–87)% 0.7 3y LRFS 95 (92–98)% 95 (92–97)% 0.4 3y OS 92 (89–95)% 94 (89–95)% 0.5 DFS: disease-free survival, DRFS: distant recurrence-free survival, LRFS: local recurrence-free survival, OS: overall survival.

Interim analysis of feasibility, safety, and tumor control in two first-in-human trials of a novel alpha-emitting radionuclide for pancreatic adenocarcinoma.

741 Background: This study aims to report the initial feasibility, safety, and tumor response of delivering Diffusing Alpha-Emitter Radiation Therapy (Alpha DaRT) to the pancreas. This innovative approach involves the interstitial implantation of a novel alpha-emitting radiation source via endoscopic ultrasound (EUS) for the treatment of pancreatic cancer. Methods: The study enrolled patients treated with Alpha DaRT to the pancreas across two protocols (PANC and ALL). The primary objective was to assess the safety of Alpha DaRT delivery to the target lesion via EUS, while the secondary objective was to evaluate initial tumor response using the Response Evaluation Criteria in Solid Tumors version 1.1 at 1 and 3 months post-Alpha DaRT source insertion. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. The PANC protocol included patients with biopsy-proven adenocarcinoma, either unresectable, recurrent, or metastatic, who were unfit for standard treatment. The ALL protocol allowed for any malignancy with a targetable lesion and permitted concurrent systemic therapy. For this analysis, only patients from the ALL protocol with pancreatic adenocarcinoma treated to the primary tumor were included. Pre-procedure planning involved CT simulation and EUS, and EUS-guided Alpha DaRT placement was confirmed by CT. The median follow-up time was 91 days. Results: A total of 12 patients (9 male, 3 female) median age 73 (range: 59-85) were enrolled (4 in PANC, 8 in ALL). Four patients had localized, unresectable disease and eight had metastatic disease. Three patients had a history of prior radiotherapy. Successful placement of Alpha DaRT sources into the targetable pancreatic lesions was achieved in all cases (100%), as confirmed by post-treatment imaging. Grade 1-2 acute toxicities included fever in 2 of 12 patients (16.7%), fatigue/weakness in 2 of 12 patients (16.7%) and abdominal or back pain in 3 of 12 patients (25.0%). One patient was hospitalized for obstructive jaundice (Grade 3) possibly secondary to inflammation seven days post-implantation requiring percutaneous transhepatic cholangiography; all hepatic laboratory values returned back to normal post procedure. All adverse events resolved. No long-term toxicities ( > 3 months) have been seen to date. Tumor response data were available for 8 of 12 patients. Local control was 100% for all evaluable patients. Of these, 6 (75.0%) exhibited stable disease, while 2 (25.0%) showed a partial response ( > 30% tumor reduction). One patient had a complete metabolic response on PET-CT at both the primary pancreatic lesion and liver metastasis. Conclusions: Alpha DaRT delivered via endoscopy is feasible with a favorable safety profile and demonstrates promising tumor responses. Ongoing longer follow-up and larger studies are required to validate these findings. Clinical trial information: NCT05781555 and NCT05657743 .

The presenting symptoms of patients with appendiceal malignant tumors.

824 Background: Timely detection of appendiceal malignant tumors is a clinical priority because of the propensity for this malignancy to metastasize to the peritoneal cavity. Up to one in every 2 patients with this rare tumor type will present with distant metastatic disease, owing to there being no standardized screening tests for early detection of primary appendiceal cancers. Case reports have pointed to broad/non-specific symptoms of patients diagnosed with appendiceal malignant tumors, yet information is needed from large cohorts to support prompt/accurate clinical diagnoses. Methods: We analyzed data from patients with a pathologically-confirmed first primary appendiceal malignant tumor (AC) who prospectively enrolled in the nation-wide Genetics of Appendix Cancer [GAP] clinical cohort study (Clinicaltrials.gov, NCT05734430) between November 2022 and May 2024. The primary outcome was presenting symptoms that led to AC diagnosis. Symptom effects and interactions with diagnosis age/year, sex, body mass index (BMI), and tumor histology, were quantified with negative binomial regression models and presented as incidence rate ratios (IRRs) and 95% confidence intervals. Results: Of the 352 patients included in our analyses (median [IQR] age, 51.0 [42-59] yr), 77.6% were female and 96.6% had an adenocarcinoma histology. Seventy-seven percent of patients (n=270) reported one or more presenting symptoms, of whom 55.2% (n=149) experienced these symptoms for 3+ months prior to diagnosis. On average, patients reported 3 symptoms (mean: 2.9, SD 3.0). The most prevalent symptoms among males and females were abdominal pain (57.1%), bloating/distension (32.1%), pelvic pain (18.5%), and abdominal/pelvic mass (18.2%). Overall, patients with early-onset AC [age<50] more commonly presented with symptoms versus cases with late-onset AC (82.9% vs 71.7%, p =0.01). This finding persisted in adjusted models—the number of symptoms was highest among younger patients, rapidly decreased and plateaued around age 50 (IRR 0.97, 95%CI 0.95-0.99, p =0.002), and slowly increased again with older age (IRR 1.03, 95%CI 1.00-1.05, p =0.037). Patient sex was also significantly associated with symptom number, as males had a lower rate of symptoms versus females (IRR 0.63, 95%CI 0.48-0.83, p =0.001). In contrast, histology (IRR 1.03, 95%CI 0.53-2.02), diagnosis year (IRR 1.01, 95%CI 0.99-1.04, p =0.35) and BMI (IRR 1.01, 95%CI 0.99-1.02) were not associated with symptom number in adjusted models. Conclusions: In a large nation-wide cohort, three of every 4 patients were symptomatic prior to primary AC diagnosis. Compared to the rapid time course of acute appendicitis, over 40% of this population presented with symptoms for 3+ months prior to AC diagnosis. The higher symptom burden among young patients and females supports the need for clinical providers to keep occult appendiceal tumors in the differential diagnosis of patients presenting in this manner.

Immunotherapy outcomes in dMMR/MSI-H and/or TMB-H metastatic colorectal cancer (CRC) with peritoneal metastases (PM).

163 Background: CRC with PM has a poor prognosis and limited treatment options. Immunotherapy has shown promise in improving outcomes for patients with microsatellite instability-high (MSI-H), mismatch repair-deficient (dMMR), and high tumor mutational burden (TMB-H) tumors. However the peritoneal niche has a unique microenvironment, which can influence the effectiveness of immune check point inhibitors (ICIs). We assessed the impact of ICI on progression-free survival (PFS) and overall survival (OS) in CRC patients (pts) and PM, considering key clinical and molecular characteristics. Methods: A retrospective review aiming to identify CRC pts with MSI-H/dMMR and PM treated with immunotherapy between 2015 and 2023 was performed. Data collected included pt demographics, tumor characteristics, and treatment details. Responses were evaluated using RECIST v1.1 criteria. Results: 37 pts were included, 9 (24%) had Lynch syndrome. The median age of diagnosis was 61 years and most pts were females (65%). Most pts had MSI-H/dMMR tumors, while one pt was treated based on ultra-hypermutated phenotype (TMB 202) and POLE mutation. Among those with available TMB data, the median TMB was 52 mutations/Mb (0-202). Common mutations were PMS2 (51%), MLH1 (38%), MSH6 (16.2%), and MSH2 (16.2%). Right-sided tumors were in 54%, mucinous histology in 62%, and ascites in 54%. Pts received a median of 11 cycles of ICI (2-52). Pembrolizumab was the most frequently used ICI (78%), while Nivolumab was used either alone (11%) or in combination with Ipilimumab (11%). Median PFS in our cohort was 7.8 months and median OS was 29.9 months. The disease control rate (DCR) was 81%, with an objective response rate (ORR) of 51.3% (9 complete responses, 12 partial responses). At the time of data collection, 30% of pts were off systemic therapy and 5-FU-based chemotherapy combined with a biologic agent was the most common subsequent treatment in 32% who had PD. Univariate analysis showed no significant differences in PFS or OS based on tumor sidedness, isolated PM, liver metastases, mucinous vs. non mucinous histology or BRAF / RAS status (WT vs mutant). Malignant ascites was associated with worse OS(HR 0.3; p= 0.03). Conclusions: Treatment with ICIs in pts with MSI-H/dMMR and/or TMB-H CRC and PM improved disease control in CRC pts with PM, however, as compared to historical controls for patients with MSI-H/d-MMR disease treated with ICI, this group showed less favorable outcomes. Malignant ascites was associated with poorer overall survival. Further research of the immune response and tumor microenvironment in the peritoneal cavity is warranted.

Phase II study of cabozantinib and nivolumab in refractory metastatic microsatellite stable (MSS) colorectal cancer (CRC).

229 Background: Current data suggest that combining tyrosine kinase inhibitors with immune checkpoint inhibitors may be a promising treatment strategy in patients with metastatic MSS CRC. This prospective, open-label, single-arm, phase II study (NCT04963283) evaluated the efficacy of cabozantinib in combination with nivolumab in patients with metastatic refractory MSS CRC. Methods: Patients with metastatic/unresectable MSS CRC who were refractory to chemotherapy in the 3 rd line setting and beyond were eligible. Patients were treated with cabozantinib 40 mg orally daily and nivolumab 480 mg IV every 28 days. Tumor assessments were obtained every 8 weeks for the first 16 weeks, and then every 12 weeks thereafter. Response was assessed via RECIST v1.1. The primary endpoint was 16-week disease control rate (16-wk DCR); secondary endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS), safety and tolerability, and correlative studies (to be presented at a future date). Results: Between June 2021 and January 2024, 49 pts were enrolled; 63% were male; median age 55 [50-64]. Median prior treatment regimens were 4 [2-14]. Most patients (84%) had not received prior trifluridine/tipiracil; only 1 patient had received prior regorafenib. The 16-wk DCR was 40% (19/47) (95% CI 0.264 – 0.557). The 16-wk ORR was 8.5% (4/47) (95% CI 0.024 – 0.204). mPFS was 3.4 months (95% CI 1.8-5.0) and mOS was 10.9 months (95% CI 4.7-13.8). Thirty nine percent of patients experienced a serious adverse event (SAE), with 4% Gr 1, 37% Gr 2, 35% Gr 3 and 4% Gr 4; there were no Gr 5 treatment related adverse events. The most common AEs were diarrhea (53%), fatigue (43%), hypothyroidism (31%), weight loss (29%), nausea (29%), and hypertension (27%). Two patients remain on study at time of abstract submission. Conclusions: The combination of cabozantinib and nivolumabwas well tolerated and provided modest benefit in a population of patients with metastatic, chemotherapy refractory, MSS CRC. Clinical trial information: NCT04963283 .

Multi-target stool DNA test adherence among average-risk 45- to 49-year-old patients from 2017-2023.

102 Background: Colorectal cancer (CRC) is the third most common cancer in the United States and the second most common cause of cancer-related mortality. In 2021, the US Preventive Services Task Force (USPSTF) lowered the age of initial CRC screening from 50 to 45 years of age for average risk individuals. At that time, only 20% of adults aged 45-49 years were up-to-date with CRC screening. With its at-home use, accessibility, and patient navigation, the multi-target stool DNA test (mt-sDNA) could help support screening uptake in this population. Here, we analyzed national claims data to investigate mt-sDNA adherence rates among average-risk adults aged 45-50 years. Methods: Using a national claims database of over 165 million individuals linked with Exact Sciences Laboratories data, mt-sDNA orders for AA patients were retrospectively identified from 2017 to 2023. Average CRC risk individuals aged ≥45 years, and new to mt-sDNA, were included in this analysis. Primary outcome of interest was adherence, defined as mt-sDNA kit return rate within 365-days from shipment. Test return time was examined as the secondary outcome. Demographics were age, sex, ordering provider, residential geography, payor, and outreach preference. Covariates on adherence were examined using logistic regression. Results: A total of 607,388 mt-sDNA orders were prescribed during the study period, with an overall 365-day return rate of 65.4%. Average time to test return was 30.4 days. Women outnumbered men in the cohort (58.6%), and most mt-sDNA orders were prescribed by primary care providers (59.4%). The majority of individuals preferred ‘Digital SMS’ communication (62%), and nearly 90% of the cohort was Commercially insured (87.6%). Among those in the cohort participants’ self-reported race/ethnicity was: White (37.3%), Hispanic or Latino (10.1%), Black or African American (8.8%), unknown (8.8%), Asian or pacific islander (4.6%), and other (3.7%). Adherences for the four identified races/ethnicities were all near, or above 60%. Men demonstrated higher adherence than women (66.7% vs 64.5%; p<0.0001). Time to test return was shortest in men (28.9 days) and African American persons (28.5 days). Tests ordered by gastroenterologists yielded the quickest adherence times amongst providers (26 days). After controlling for race, gender, payor class, setting (urban/rural classification), and preferred language, digital outreach and provider type were significantly associated with increased mt-sDNA adherence. Conclusions: This large, national analysis reports a substantially higher rate of adherence among individuals ages 45-49 with the mt-sDNA test than the current nationally reported rates. At-home testing, along with standard and preference-based navigation may have contributed to high mt-sDNA completion rates. More research is warranted to explore screening behaviors and the benefits of screening within this younger population.

Effectiveness of the Colorectal Cancer Alliance's digital screening quiz and navigation model for promoting CRC screening.

97 Background: Evaluating the effectiveness of a Colorectal Cancer screening navigation model delivered in a digital platform offered by a patient advocacy organization. Designed as a digital screening quiz tool and live navigation to promote CRC screening, the Colorectal Cancer Alliance’s Screening Quiz is a risk stratification tool that connects respondents to live certified cancer care navigators delivering evidence-based interventions to increase CRC screening, education and patient and family support. The framework utilizes small and mass media, one-on-one education and patient navigation services to help address and reduce barriers to care. Research on these critical interventions shows that on-time screening for CRC leads to better outcomes. Methods: The Screening Quiz has been promoted through social sharing, community outreach, and media, including influencer campaigns to increase outreach to at-risk communities. Questions assess personal and family history, hereditary syndromes, and demographics to provide a CRC screening recommendation based on current USPSTF guidelines. Respondents overdue for screening are triaged to the Alliance’s patient navigation team. This interaction includes phone calls and emails for symptomatic individuals/high risk for CRC, telephone and email for average-risk uninsured, and emails for average-risk insured. At-risk individuals are connected to resources, such as financial assistance, free at-home screening tests, and colonoscopy scheduling services. Results: July 2022 to July 2024, the Screening Quiz provided over 50,000 screening recommendations. The median age of respondents was 46; 32% of respondents were between the ages of 45 to 64. Of the respondents, 29% were male and 71% were female. Most were White (79.2%), but nearly half of those who opted into navigation identified as BIPOC, including 16.7% Black/AA, 6.6% Asian, and 2.1% AI/AN. Additionally, 8.4% of respondents identified as ethnically Hispanic/Latino with another race. Most respondents were symptomatic (66.6%) but 6.5% were asymptomatic high-risk. These two groups represented 88% of 1,869 respondents triaged to patient navigation. Conclusions: The digital Screening Quiz, combined with live navigation, represents a promising approach for increasing CRC screening rates and addressing care gaps compared to traditional methods. The Alliance’s ability to engage at-risk communities through its national network of volunteers and partners, combined with evidence-based interventions, positions it well to continue closing screening gaps. Going forward, the Alliance aims to leverage its relationships with healthcare providers and community organizations further to expand the reach of its CRC screening efforts.

Statistical Perspectives and Meta-Analytic Approaches in Surrogate End Point Evaluation for Chronic Lymphocytic Leukemia

Real-world biomarker testing patterns, first line treatment and drivers of treatment choice in patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma in the United States and Europe.

353 Background: For first line (1L) treatment (tx) in HER2- gastric/gastroesophageal junction (G/GEJ) adenocarcinoma (AC), clinical guidelines recommended platinum-fluoropyrimidine (PF) chemotherapy (CT) in patients (pts) with a PD-L1 combined positive score (CPS) <5 and PF CT in combination with immunotherapy (IO) for CPS ≥5. There is little contemporary evidence into IO tx uptake in the real world. This real world study examined biomarker testing, 1L tx characteristics, and reasons for 1L tx choice in pts with HER2- G/GEJ AC to identify unmet needs and opportunities for optimal clinical practice. Methods: Data were derived from the Adelphi G/GEJ Cancer Disease Specific Programme: a systematic approach involving multi-national, multi-faceted data sources including cross-sectional surveys capturing data from physicians and their consulting pts. Physicians reported pt demographics, clinical characteristics, tx received and reasons for tx decisions, via chart review. Data were collected across US and Europe (EU: France, Germany, Spain, the UK) between Oct 2022 to Apr 2023. All pts were alive at data collection and analyses were descriptive. Results: Overall, 243 treating physicians (US n=60/EU n=183) provided data on 642 HER2- pts (US n=83/EU n=559) receiving 1L tx at data collection. For pts from US/EU, median age was 66/67 years, 84%/79% had an ECOG of 0-1 and 52%/75% had metastatic disease at data collection. In the US/EU, 87%/80% of pts were tested for PD-L1 status respectively, of which 63%/69% had a known CPS. For US/EU, 67%/45% of pts (n=30/n=139) had a CPS ≥5. Differences in biomarker testing rates were observed in US v EU pts respectively for MSI/dMMR (66% v 58%), NTRK-gene fusion (31% v 4%) and FGFR2 (27% v 3%). Of US/EU physicians, 70%/85% (n=60/n=183), reported the main reason for conducting biomarker testing was ‘to inform tx decisions’. Cost related concern (50%/39%) and time constraints (23%/15%) were the main perceived barriers to testing. Among pts with PD-L1 CPS <5, 27% of US pts and 2% of EU pts received IO + CT; in pts with CPS ≥5, 63% of US pts and 76% of EU pts received IO + CT. Whilst progression free survival/overall survival benefit were the most common reasons selected by physicians for 1L tx choice across the US/EU (75%/74% and 60%/61%), differences across regions were reported for tx choice based on maintaining and improving pt’s QoL (4%/28%) and pt’s performance status (2%/24%). Conclusions: PD-L1 testing was not performed by 19% of physicians and approximately one third of pts with CPS ≥5 across the US/EU were not receiving IO + CT in 1L. As informing 1L tx choice was a key driver for biomarker testing, there may be scope for improvement in 1L tx by increasing testing rates. Further studies are needed to address barriers to biomarker testing and uptake of IO in pts who can benefit from 1L IO tx.

Design of Fluorinated Peptides as Biotransformed Urinalysis Biomarkers for Non‐Invasive Diagnosis and Treatment of Liver Injury through Enzyme Directed Kinetics

Abstract Urinalysis, as a non‐invasive and efficient diagnostic method, is very important but faces great challenges due to the complex compositions of urine and limited naturally occurring biomarkers for diseases. Herein, by leveraging the intrinsic absence of endogenous fluorinated interference, a strategy with the enzymatically activated assembly of synthetic fluorinated peptide for cholestatic liver injury (CLI) diagnosis and treatment through 19 F nuclear magnetic resonance (NMR) urinalysis and efficient drug retention is developed. Specifically, alkaline phosphatase (ALP), overexpressed in the liver of CLI mice, triggers the assembly of fluorinated peptide, thus, directing the traffic and dynamic distribution of the synthetic biomarkers after administration, whereas CLI mice display much slower clearance of peptides through urine as compared with healthy counterparts. As such, it enables to transform pathophysiological information into exogenous signals via noninvasive urinary monitoring. Moreover, as a proof‐of‐concept, by grafting different functional groups to peptides, the theranostic platforms can be established to provide a new paradigm for the design of multifunctional peptides.

BXQ-350, a novel sphingolipid metabolism modulator, in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal cancer (mCRC) patients: A phase 1b/2 randomized study.

TPS320 Background: Ceramides and sphingosine-1-phosphate (S1P) are key bioactive signaling molecules. Ceramides are proapoptotic and mitigate chemoresistance. Conversely, S1P promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies in colorectal cancer patients have shown high levels of ceramides are associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism could be a promising therapeutic approach. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies (NCT02859857). BXQ-350 was safe and well-tolerated (no DLT, no MTD). Also, 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 and beyond (PR, SD). Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 7 years suggesting potential long-term benefit. Furthermore, there were signs that BXQ-350 may alleviate symptoms of CIPN as 4 out of 10 patients with chronic CIPN at time of enrollment experienced an improvement of their symptoms. Methods: BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab in newly diagnosed mCRC patients (NCT05322590) to assess the efficacy and safety of BXQ-350. Design of the Phase 1b (open label study): 1) A safety dose escalation part to establish the RP2D: patients will initially receive 1.8 mg/kg BXQ-350 in combination with mFOLFOX7 and Bevacizumab. If safe (no MTD), dose of BXQ-350 will be increased to 2.4 mg/kg and 9 additional patients will be entered at this dose level. If safe, then this dose will be the RP2D and 21 additional patients will be enrolled, completing a 30 patient expansion cohort 2) Efficacy will then be evaluated for all patients entered at the RP2D. Primary objectives of the Phase 1b are to assess safety, identify RP2D, and assess preliminary efficacy of BXQ-350 in this combination. A secondary objective is to determine if BXQ-350 decreases CIPN. Enrollment in the expansion cohort of 30 patients is nearly complete, with 26 patients enrolled as of September 2024. Clinical trial information: NCT05322590 .

Updated analysis of a phase 2 study of fruquintinib plus trifluridine/tipiracil (TAS-102) as third-line treatment in patients with metastatic colorectal adenocarcinoma.

145 Background: Fruquintinib and TAS-102 are two standard therapies for patients (pts) with previous-treated mCRC worldwide. The study aimed to evaluate the efficacy and safety of fruquintinib plus TAS-102 as third-line treatment for mCRC. We previously reported that fruquintinib plus TAS-102 was well tolerated with encouraging clinical activity in pretreated mCRC. Here, we reported the updated results at the data cutoff of Sep 3, 2024. Methods: In this open-label, single-arm, multi-center, phase 2 trial (NCT05004831), pts with mCRC who had failed at least two prior standard treatment regimens were enrolled. Eligible pts received fruquintinib (4mg, qd, d1-21) and TAS-102 (35mg/m 2 , bid, d1-5, 8-12) orally every 4 weeks until disease progression or unacceptable toxicity. Primary endpoint was PFS (per RECIST v1.1). Secondary endpoints were OS, ORR, DCR and safety (per NCI-CTCAE v5.0). Results: From Mar 2022 to Aug 2023, 50 eligible pts were enrolled. Median age was 60 years (range 39-76) and 58.0% were male. 82% pts were of left-sided colon and rectal cancer, 42.0% pts were RAS mutant, 58.0% had liver metastasis and 18.0% had peritoneal metastasis. Prior treatments and proportion were standard chemotherapy 100%, anti-VEGF 88.0% and anti-EGFR 26.0%. As of Sep 3, 2024, ORR was 10.9% (95%Cl: 3.6-23.6) and DCR was 73.9% (95%Cl: 58.9-85.7). The median PFS was 6.33 months (m) (95% CI: 4.20-8.62). The 6-m, 9-m and 12-m PFS rates were 53.0% (95% CI: 40.2-70.0), 28.3% (95% CI: 17.4-45.9) and 23.1% (95% CI: 13.2-40.5), respectively. At a median follow-up of 17.6m, median OS was 18.4m (95% CI: 12.0-NA). The 6-m, 9-m and 12-m OS rates were 87.0% (95% CI: 77.8-97.3), 66.9% (95% CI: 54.0-82.9) and 64.3% (95% CI: 51.1-80.8), respectively. Median PFS was comparable in liver metastasis (LM) and non-LM pts (6.33m [95%CI: 4.13-8.62] vs. 6.46m [95%CI: 3.74-NA], P =0.54). Similar results were observed in peritoneal metastasis (PM) and non-PM pts (6.07m [95%CI: 3.74-NA] vs. 6.33m [95%CI: 4.20-8.27], P =0.95). None of RAS gene mutation, prior treatment lines ≥ 3, age ≥ 65 years, metastatic sites ≥ 2, peritoneal metastasis and right-sidedness were identified as factors significantly associated with PFS or OS (by univariable Cox proportional-hazards model). The most common treatment-related adverse events (TRAEs) of any grade and grade ≥ 3 were mainly hematological toxicities. TRAEs (any grade, grade ≥ 3) in ≥ 50% of pts including neutrophil count decreased (80.0%, 54.0%), white blood cell count decreased (70.0%, 26.0%), anemia (58.0%, 20.0%) and proteinuria (50.0%, 4%). No treatment-related deaths were observed. Conclusions: The updated analysis demonstrated encouraging survival benefits of fruquintinib plus TAS-102 as third-line treatment in patients with mCRC with acceptable toxicities. This regimen could be an alternative therapeutic approach for these patients. Clinical trial information: NCT05004831 .

Impact of homologous recombination deficiency on survival and chemotherapy response in small bowel adenocarcinoma.

800 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, and its genomic profile is distinct from that of gastric and colorectal cancers. However, the role of homologous recombination repair (HRR) gene mutations in SBA remains unexplored. This study aims to investigate the clinical significance of HRR gene mutations in SBA. Methods: We retrospectively analyzed data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) utilization portal, in accordance with its policy. Between June 2019 and February 2024, patients with SBA who underwent comprehensive genomic profiling (Foundation One CDx, Foundation One Liquid, OncoGuide NCC Oncopanel, Guardant 360 CDx, and GenMineTOP) were included. The frequency of HRR variants ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, RAD51, ATRX, ARID1A, BAP1, CDK12, MRE11, NBN, PTEN, FANCA, FANCC ) was analyzed. Homologous recombination deficiency (HRD) was defined as the presence of one or more alterations in HRR variants. Clinicopathological features, treatment outcomes, and survival were compared between HRD-positive and HRD-negative groups. Results: A total of 628 cases were analyzed, with a median age of 65 years, including 238 males and 390 females. The primary tumor sites were the duodenum in 332 cases and the jejunum in 296 cases. HRD was observed in 165 cases (26.5%) overall. The incidence of microsatellite instability-high (MSI-H) was significantly higher in the HRD-positive group compared to the HRD-negative group (15% vs. 1.1%, P < 0.001). Similarly, the median tumor mutational burden (TMB) values were significantly higher in the HRD-positive group compared to the HRD-negative group (5 Mut/Mb vs. 3.8 Mut/Mb, P < 0.001). The median overall survival (OS) was similar between HRD-positive and HRD-negative groups (1,243 days vs. 1,055 days, P = 0.22). However, in duodenal primary cases, the median OS was significantly longer in the HRD-positive group compared to the HRD-negative group (1,243 days vs. 702 days, P = 0.025). No significant difference in median OS was observed between HRD-positive and HRD-negative groups in jejunal primary cases (1,145 days vs. not reached, P = 0.51). The overall response rate (ORR) to platinum-based chemotherapy in first-line treatment was significantly higher in the HRD-positive group compared to the HRD-negative group in duodenal primary cases (34% vs. 18%, P < 0.05). Conversely, there was no significant difference in ORR between HRD-positive and HRD-negative groups in jejunal primary cases (23% vs. 20%, P = 0.70). Conclusions: Duodenal primary SBA with HRD showed better response rates to platinum-based chemotherapy and had a more favorable prognosis compared to non-HRD cases. In duodenal cancer, which typically has a worse prognosis than jejunal cancer, HRD may represent a novel prognostic and predictive marker for treatment efficacy.

The value and indications for surgery in pancreatic cancer with synchronous liver metastases.

714 Background: Over half of pancreatic cancer patients present with advanced disease and distant metastases, primarily in the liver, at initial diagnosis. Although systemic combination therapies have improved outcomes, the role of surgery remains contentious. This study seeks to pinpoint prognostic factors for patients with synchronous liver metastatic pancreatic cancer (sPDACLM) who receive effective treatments, and to identify patients likely to benefit from surgery. Methods: This is a retrospective cohort study. Included patients received first-line chemotherapy (AG/mFOLFIRINOX), with efficacy assessed every 4-6 cycles through imaging and biochemical evaluations. Imaging assessments were conducted according to RECIST 1.1 criteria, while biochemical evaluation focused on the reduction of CA19-9 (calculating cutoff values). Patients with good responses were considered for curative surgery, while those with minor responses decided between surgical treatment or continued maintenance therapy after being fully informed. Results: From May 2017 to February 2024, a total of 48 patients with sPDACLM who met the inclusion criteria were recruited for this study. The prognosis of patients with resectable or borderline resectable primary tumors was significantly superior to unresectable cases (18 months vs 11 months, p = 0.0011). Multivariate analysis revealed independent favorable prognostic factors: surgery (HR 0.22; p = 0.026), partial response (PR) per RECIST 1.1 criteria (HR 0.09, p = 0.040), and tumor marker reduction >85% (HR 27.99; p = 0.005). Achieving conversion effectiveness, as defined by imaging and biochemical criteria, was associated with a significantly improved prognosis compared to cases where conversion was ineffective (28 months vs. 12 months, p = 0.0086). Notably, effective surgery patients had a median survival of 49 months and a 5-year survival rate of 33%. Conversely, for patients who did not respond to systemic therapy, surgery did not confer any significant impact on overall survival; however, the corresponding survival curve indicated a trend towards shorter survival compared to those who did not undergo surgery. Conclusions: Patients with sPDACLM fulfill both imaging and biochemical criteria, exhibit improved prognoses; additionally, surgery has been shown to significantly prolong their median overall survival times. Research indicates that accurate screening for cases suitable for conversion surgery can significantly improve the survival rates of sPDACLM. Overall survival time and survival rates in patients with synchronous liver metastatic pancreatic cancer undergoing conversion therapy. OS 1-year survival rate 2-year survival rate 3-year survival rate 5-year survival rate Effective group Surgery 49 months 100% 88% 66% 33% Non-surgery 18 months 80% 20% - - Non-effective group Surgery 11 months 33% - - - Non-surgery 12 months 36% - - - OS, overall survival time.