Citations

e23317 Background: mCRC poses significant challenges, particularly in patients (pts) who progress after multiple lines of therapy. Limited effective treatment options are available in the advanced chemotherapy-refractory setting. The FRESCO-2 trial demonstrated that Fruq, a selective VEGFR inhibitor, provides meaningful overall survival (OS) benefit in pts with refractory mCRC. However, there is limited real-world evidence regarding Fruq's efficacy in patients treated after approved third-line therapies. Methods: This retrospective, multi-site cohort study evaluated outcomes in 33 mCRC pts who received Fruq following treatment with Rego and/or TAS-102 with or without bevacizumab. Patients were stratified into two groups: Fruq as a second late-line therapy, after either Rego or TAS-102, (27 patients) and as a third late-line therapy, after both Rego and TAS-102, (6 patients). Overall survival (OS) was calculated from Fruq initiation to death, while time to treatment discontinuation (TTD) was defined as the duration from Fruq initiation to cessation for any reason, including death. Survival analysis was performed using the Kaplan-Meier method to estimate median survival, and the comparison between groups were done using the log-rank test. Results: Among the 33 pts, the median age was 58 years (range: 35–84), with 57.6% being male. Hepatic metastases were present in 78.8%, and 60.6% had left-sided primary tumors. RAS mutations were observed in 63.6%, and 97% were BRAF wild-type. Median OS was significantly longer in pts who received Fruq as a second late-line therapy (7.2 months) compared to those receiving it as a third late-line therapy (4.0 months) (p = 0.039). Median TTD was similar between groups (2.4 vs. 2.8 months, p = 0.916). Conclusions: This real-world analysis highlights the clinical benefit of Fruquintinib in mCRC patients following treatment with Regorafenib and/or TAS-102. The data suggest flexibility in treatment choices, with Fruquintinib showing improved OS when used earlier in the treatment sequence. These findings underscore the importance of exploring optimal sequencing strategies and evaluating Fruquintinib as a potential option before other approved agents in the refractory setting. Clinical outcomes with fruquintinib as second vs. third late-line therapy. Fruq as Second Late-Line Fruq as Third Late-Line p-value Median OS 7.2 months 4 months 0.039 Median TTD 2.4 months 2.8 months 0.916 OS: Overall Survival; TTD: Time to Treatment discontinuation.

e15527 Background: Fruquintinib, regorafenib, and trifluridine-tipiracil (TAS-102) alone or in combination with bevacizumab (bev) are approved for use in treatment of metastatic colorectal cancer (mCRC) following progression on or intolerance to fluoropyrimidine-based therapy with irinotecan, oxaliplatin, and targeted agents if indicated. All three medications have established overall survival (OS) benefit when used third line or later; however, there is a paucity of literature and guideline recommendations regarding optimal sequencing of these agents. The aim of this study was to investigate OS in patients (pts) with mCRC based on the sequencing of these three “late-line” treatments. Methods: This retrospective, multi-site cohort study evaluated OS in pts with mCRC who received fruquintinib possibly sequenced with regorafenib and/or TAS-102 +/- bev between 11/01/2023 and 11/19/2024. Pts prescribed fruquintinib (N = 64) were identified utilizing SlicerDicer within EPIC. Pts were excluded from final analysis for incomplete information, non-mCRC diagnosis, or failure to initiate fruquintinib (N = 21). OS was defined as the time from initiation of first late-line therapy to death from any cause. Cox regression models were utilized for multivariable adjustment. P-values were calculated using Chi-Square for categorical variables and Kruskal-Wallis for continuous variables. Results: Forty-three pts were included in the final analysis. The median age at initiation of first late-line therapy was 56 years old. Most pts had left-sided primary tumors (60.5%) and liver metastases (79.1%). RAS and BRAF V600E mutations occurred in 65.1% and 4.7% of pts, respectively, and 83.7% of pts had received prior bev therapy. All pts were pMMR/MSI-S. TAS-102 +/- bev was the most common first late-line agent utilized (72.1%), and fruquintinib the most common second late-line agent (73%). Regorafenib was prescribed in only 12 pts (27.9%) and used primarily as a second or third late-line option. OS was not statistically different based on initial late-line therapy chosen (median OS 19.2 months for TAS-102 +/- bev and not estimable for fruquintinib and regorafenib, p = 0.058). This result was maintained on multivariate analysis after adjusting for age, liver metastases, and RAS mutation status. However, fruquintinib sequenced after TAS-102 +/- bev demonstrated improved OS (median 20.5 months) compared to fruquintinib as first or last late-line therapy (median not estimable vs. 15.8 months, p = 0.049). Conclusions: Fruquintinib sequenced after TAS-102 +/- bev may confer an OS advantage in the treatment of mCRC. However, prospective studies evaluating sequencing strategies representative of standard prescribing patterns are still needed to firmly establish optimal sequencing of fruquintinib, regorafenib, and TAS-102-based therapy.

Abstract Background Optimal treatment for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma remains unclear due to limited head-to-head comparisons among chemotherapy and chemoradiation regimens. This network meta-analysis aimed to determine the relative efficacy of available multimodality treatment regimens in these patients. Methods MEDLINE, EMBASE, Scopus, Web of Science, and CENTRAL were searched till September 20, 2024. Phase 3 randomized trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ adenocarcinoma were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Frequentist network meta-analysis was conducted to compare hazard ratios (HRs) and 95% confidence intervals (CIs). Results Fifteen trials (8072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P-score 91%), achieving significant improvements compared to surgery alone (HR 0.48, 95% CI, 0.38-0.60) and nCROSS (neoadjuvant paclitaxel, carboplatin, and radiotherapy) (0.67, 0.56-0.81). For OS, nPLF + nCRT(EP) (neoadjuvant cisplatin, leucovorin, and fluorouracil for induction, followed by etoposide, cisplatin, and radiotherapy) (P-score 90%) and pFLOT (P-score 87%) were the top regimens. pFLOT significantly outperformed surgery alone (0.57, 0.45-0.72) and nCROSS (0.73, 0.60-0.89). Based on the limited data available, adding neoadjuvant chemoradiation to pFLOT provided no additional OS (1.14, 0.76-1.72) or DFS (1.22, 0.83-1.82) benefit. Similarly, adding pembrolizumab to perioperative chemotherapy (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT (DFS: 1.10, 0.71-1.69; OS: 1.09, 0.69-1.72). Conclusions pFLOT demonstrated superior efficacy in resectable gastric/GEJ adenocarcinoma, outperforming surgery alone, nCROSS, and alternative perioperative regimens. The additive role of immunotherapy requires further investigation to optimize patient selection and outcomes.

PURPOSE Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various malignancies. However, the high cost of these therapies limits access for much of the global population. This systematic review aims to evaluate the efficacy of low-dose ICIs compared with standard doses in different malignancies, addressing financial and access barriers in global cancer care. METHODS We conducted a systematic review of studies comparing the efficacy of low-dose versus standard-dose ICI regimens in advanced solid tumors. A comprehensive search was performed across multiple electronic databases, including retrospective and prospective studies. Excluded were animal studies, editorials, conference papers, book chapters, and other immunotherapy modalities. Outcomes assessed included overall survival (OS), progression-free survival, and objective response rate. Results were summarized descriptively due to study heterogeneity. RESULTS From 1,010 screened articles, four studies with 435 Asian patients were included, covering a variety of solid tumors. All included studies were with a low quality of evidence and a high risk of bias due to retrospective design. Two studies used weight-based dosing (pembrolizumab <2 mg/kg and nivolumab <2.15 mg/kg), showing similar OS to standard dosing in non–small cell lung cancer (NSCLC) and renal cell carcinoma, respectively. Flat dose regimens in two studies (nivolumab 20 mg or 100 mg once every 3 weeks and pembrolizumab 100 mg once every 3 weeks) also demonstrated comparable OS in NSCLC. CONCLUSION Low-dose ICIs may offer equivalent clinical benefits to standard dosing, potentially reducing costs and expanding access in developing countries. Although awaiting more representative randomized clinical trials, weight-based ICI regimens could be a viable alternative in low- and middle-income countries.

Abstract Biliary tract cancer (BTC) remains among the most challenging malignancies with a poor prognosis and limited treatment options, particularly in pretreated patients. As most patients experience disease progression after first-line treatment, effective second-line and subsequent treatments are required. Although the addition of modified FOLFOX (fluorouracil, leucovorin, and oxaliplatin) to active symptom control improved the overall survival of patients with progressing advanced BTC despite gemcitabine plus cisplatin treatment, its efficacy was modest. Moreover, most clinical trials demonstrated modest efficacy of molecular-targeted agents for molecularly unselected pretreated advanced BTC. Patients with advanced BTC carry a relatively high druggable genetic alteration rate and have shown promising responses to molecular-matched therapies targeting gene alterations such as FGFR2 fusions/rearrangements, IDH1 mutation, and HER2 overexpression/amplification. Additionally, tumor-agnostic approaches, including BRAF V600E, NTRK fusion, and RET fusion, have expanded the treatment options for some patients. Immune checkpoint inhibitors have shown limited efficacy as mono- or combination therapy in patients with pretreated advanced BTC. Therefore, developmental efforts have shifted to immune checkpoint inhibitor and other combinations such as vascular endothelial growth factor receptor inhibitors or radiation. In addition to refining combination strategies to enhance the therapeutic potential of immune checkpoint inhibitor, future research should focus on elucidating the tumor microenvironment. This review delineates the evolution of systemic therapies in patients with pretreated advanced BTC. By examining past developments and recent advances through prospective trials, it highlights novel approaches that may improve outcomes in this challenging disease.

In a retrospective study of patients with Lynch syndrome vs non‐Lynch syndrome and microsatellite instability high colorectal cancer, there were no observed differences with immune checkpoint inhibitors toward progression‐free survival or overall survival. Univariate analysis of Stage IV patients showed BRAF V600E mutations were associated with decreased survival.

243 Background: HER2-amplified aCRC is associated with poor prognosis despite new anti-HER2 regimens. Insight on biomarkers that predict response to these therapies is limited. This study aims to evaluate whether baseline alterations in oncogenic drivers along the HER2 pathway predict response to anti-HER2 therapy in HER2-amplified aCRC. Methods: In this international multi-center study involving Mayo Clinic, Duke Cancer Institute and National Cancer Center Hospital East (Japan), we collected baseline genomic alterations from tissue or blood samples using next-generation sequencing (NGS) prior to anti-HER2 therapy initiation. We defined PIK3CA, RAS, RAF, MAP2K, and MET as oncogenic drivers of resistance within the HER2 pathway. Overall survival (OS) was evaluated with the Kaplan-Meier method and a log-rank test was used to compare median OS (mOS) between pts with and without alterations in the above genes. A chi-square test (significance level 0.05) was performed to compare overall response rate (ORR) and disease control rate (DCR). Results: We identified 39 pts with HER2-amplified aCRC and baseline NGS. Median age was 57 (range 30-77), 54% were male. Baseline alterations in HER2 pathway oncogenic drivers were identified in 17 pts (43.5%). 18 (46%) received monoclonal antibodies (mAbs) plus tyrosine kinase inhibitors, 12 (30%) received dual mAbs and 7 (18%) received trastuzumab deruxtecan. The mOS was 41.9 months (mos) (95%CI 23.7-60.1) for other alterations vs 24.2 mos (95%CI 14.1-34.3) in pts with HER2 pathway alterations (p = 0.1). ORR was 47% vs 41% (p = 0.7) and DCR 82% vs 73% (p = 0.4), for pts with HER2 pathway alterations and without HER2 pathway alterations, respectively. 4 pts receiving trastuzumab/tucatinib had complete response, none of which had HER2 pathway alterations. Conclusions: Pts with baseline alterations in oncogenic drivers of the HER2 pathway had clinically worse outcomes compared to pts without such alterations despite receiving HER2-targeted therapy, though results lacked statistical significance. Larger studies are needed to confirm the lack of benefit from anti-HER2 therapy in this subgroup.

820 Background: The number of FDA-approved anticancer drugs have increased in recent years with a more use of surrogate endpoints. However, it is unclear whether the same trend applies to GI cancers. Therefore, we aimed to evaluate the trend in FDA-approved GI cancer drugs over the past two decades and the associated clinical benefit. Methods: The FDA’s online database was searched for drugs approved for GI cancers from 2006 until 2024. Primary and secondary endpoints along with trial characteristics were extracted. ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) was assessed by two blinded investigators with a third resolving disagreements. We divided the study into period A (01/2006-12/2014) and period B (01/2015-08/2024). Results: Since 2006, FDA approved 62 regimens for GI cancer based on 70 trials, mostly (n= 45;72.6%) in period B. Most trials (n=44) were phase III with only 26 phase II: 22 single arm, and 4 randomized. All the 22 single-arm phase II trials were approved in period B with two randomized phase II trials approved in each period. Approvals based on phase III trials dropped by 33.5% (from n=15 to n=29) between the two periods. Half (n=34) of the approvals were based on overall survival (OS) benefit, while the use of objective response rate (ORR) as an endpoint has increased from 11.8% (n=2) in period A to 45.3% (n=24) in period B. Quality of life (QoL) was assessed only in 27% of the studies and found benefit only in 22.7%. The mean gain in OS was similar across both periods; 2.3 months [1.2-4.7]. Out of the 19 accelerated approvals, 17 were in period B, of which 23% (4/17) were based on secondary endpoint, 18% (3/17) were withdrawn, and 59% (10/17) received full approval. Substantial clinical benefit (ESMO score 4-5) was seen in 11.8% of the trials in period A and 19.6% in period B, with 17.4% overall from 2006-2024. Conclusions: Despite rising FDA approvals for GI cancer drugs since 2006, only 17.4% demonstrated substantial clinical benefit based on ESMO-MCBS. Recent approvals rely more on single-arm phase II studies and ORR, often without OS or QoL benefit. These trends underscore the need for more rigorous clinical trials that prioritize meaningful endpoint to ensure that new therapies provide real clinical value to the patient.