BACKGROUND:PLATFORM is an adaptive phase II trial assessing maintenance therapies in advanced oesophagogastric adenocarcinoma (OGA). We evaluated maintenance capecitabine in patients with disease control after first-line chemotherapy. METHODS:HER2-negative patients with advanced OGA who had response or stable disease after 18 weeks of first-line chemotherapy were randomised (1:1) to surveillance or capecitabine. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. RESULTS:Between May 2015 and May 2024, 266 patients were randomised (129 surveillance, 137 capecitabine). Median follow up was 70.7 months. Capecitabine significantly improved PFS (HR 0.69; 95% CI 0.54-0.89; p = 0.002), with median PFS of 5.0 vs 2.8 months. One-year PFS rates were 19.9% vs 6.8%; and two-year rates 8.1% vs 4.3%. No OS difference was observed (median OS: 10.5 vs 10.0 months; HR 0.87; 95% CI 0.67-1.12; p = 0.143). One and two-year OS rates were similar (1-year: 44.1% vs 45.7%; 2-year: 18.8% vs 16.8%). Grade ≥3 adverse events were more frequent with capecitabine (46% vs 29%), with 21% experiencing grade 3 treatment related events. DISCUSSION:Maintenance capecitabine significantly prolonged PFS compared to surveillance, meeting the primary endpoint and supporting its use to extend disease control in advanced OGA.

PLATFORM is an adaptive phase II study assessing maintenance therapies in advanced esophagogastric adenocarcinoma (OGA). We evaluated the role of capecitabine plus a vascular endothelial growth factor receptor 2 inhibitor ramucirumab (cape-ram) in these patients. Human epidermal growth factor receptor 2 (HER2)-negative patients with advanced OGA with stable or responding disease after 18 weeks of induction platinum-based chemotherapy were randomly assigned 1:1 to surveillance or cape-ram. The primary end point was progression-free survival (PFS), and key secondary end points were overall survival (OS) and safety. Recruitment to the cape-ram arm closed prematurely because of industry support withdrawal. A one-sided log-rank test with a 2.5% significance level was considered significant. Between April 2019 and November 2022, 25 surveillance and 22 cape-ram patients were contemporaneously randomly assigned. Median follow-up was 24.4 months. Compared with surveillance, cape-ram significantly prolonged PFS (hazard ratio [HR], 0.33 [95% CI, 0.17 to 0.63], P < .001; median PFS: 2.5 months with surveillance versus 5.5 months with cape-ram; 6-month PFS rate: 4% [95% CI, 0.3% to 17.0%] v 42.9% [95% CI, 21.9% to 62.3%], respectively) and OS (HR, 0.51 [95% CI, 0.26 to 1.00], P = .023; median OS: 7.1 months with surveillance v 14.4 months with cape-ram; median OS from start of induction chemotherapy was 12.1 months v 19.5 months, respectively). Of 10 cape-ram patients with measurable disease, 1 had an incremental partial response. Grade ≥3 adverse events (AEs) were seen in 32% surveillance and 57% cape-ram patients. Six cape-ram patients had grade 3 treatment-related AEs, and no new safety signals were identified. Maintenance cape-ram after induction chemotherapy for patients with HER2-negative OGA significantly improved survival compared with surveillance. To our knowledge, this is the first randomized maintenance study demonstrating survival benefit and provides support for maintenance treatment.

3521 Background: People living with HIV (PLHIV) usually have more advanced cancer at diagnosis and a higher cancer-related mortality, posing a significant burden on health care. However, clinical studies often exclude cancer patients with HIV, thereby limiting access to therapies for this patient population. PLHIV have a 25- to 35-fold higher chance of being diagnosed with SCAC than individuals who are HIV negative. We therefore evaluated safety and efficacy of retifanlimab in PLHIV with SCAC. Methods: The study designs for POD1UM-202 (NCT03597295) and POD1UM-303/InterAACT-2 (NCT04472429) have previously been described. Both trials permitted PLHIV to enroll if CD4+ count was ≥200/μL with an undetectable viral load per standard of care assay, and who did not experience any HIV-related opportunistic infection for ≥4 weeks prior to study enrollment. Patients continued to receive antiretroviral therapy (ART/HAART) without interruption or dose reduction. HIV viral load and CD4+ cell count was assessed every 8 weeks during the studies and could be reduced to every 6 months during safety and disease follow-up. Results: Patient and disease characteristics were similar among PLHIV and the overall study populations. Among the 20 patients with HIV enrolled in these SCAC trials, median age was 58 years, 70% (n = 14) were male, and 80% (n = 16) were White. Forty-five percent (n = 9) of patients received retifanlimab and 30% (n = 6) received retifanlimab with platinum-based chemotherapy, whereas the remaining 5 patients were assigned to placebo plus chemotherapy. During these studies, no patient experienced a sustained drop in CD4+ T-cell counts or increase in HIV viral load of clinical significance. No treatment-emergent opportunistic infections were recorded. Immune-related adverse events (irAEs) and grade ≥3 irAEs were consistent with the non-HIV population. Objective response rates were 22% (2/9) with retifanlimab in second-line and 67% (4/6) with retifanlimab and chemotherapy in first-line (previously untreated). Patient-reported outcomes showed no negative impact and based on Quality-of-Life Questionnaire for Anal Cancer, good scores for bowel function, sexual, and symptom domains were maintained. Retifanlimab pharmacokinetics was independent of HIV status and not impacted by the HAART required for ongoing HIV management. Conclusions: Among PLHIV and advanced SCAC who received treatment, retifanlimab showed significant clinical activity with efficacy qualitatively similar to patients without HIV and no excess toxicity or reduced HIV control. The analysis indicates that retifanlimab is generally safe for PLHIV and SCAC and also supports inclusion of HIV-positive patients in other immunotherapy trials. The favorable outcomes in PLHIV are encouraging because infection with HIV is among the most important risk factors for SCAC. Clinical trial information: NCT03597295 and NCT04472429 .

384 Background: Advanced oesophago-gastric cancers have showcased varied responses to immunotherapy based on biomarkers such as tumour mutational burden, microsatellite instability, and PD-L1 expression. However, these markers may not fully capture tumour heterogeneity and evolutionary dynamics. Hence, understanding the intricate relationship between immune selection, specifically immune dN/dS,1 and tumour evolution is vital for devising personalized therapeutic strategies. Methods: In our phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182), patients received maintenance durvalumab post first-line chemotherapy. A survival advantage was not seen with maintenance durvalumab compared to surveillance and exploratory analysis of PD-L1 expression was not associated with improved survival outcomes.2 However, a subset of patients treated with durvalumab experienced durable responses and some experienced incremental radiological responses. A pilot substudy on a selected cohort (n=24) of these patients was designed to explore the potential of immunogenomics evolutionary-based metrics, notably dN/dS, as predictive biomarkers. DNA and RNA from FFPE baseline tumour samples underwent analysis, examining genomic factors including tumour mutational burden, indel signatures, PDL1 status, and immune evasion mechanisms. Furthermore, the evolutionary metric, immune dN/dS, which has implications in tumour immunoediting and its response to immunotherapies, was scrutinized. Results: A dominant indel mutational signature emerged from the analysis. The majority of patients displayed a significantly higher number of indel variants, compared to non-synonymous and synonymous single-nucleotide variants. A recurring observation was dN/dS values consistently above 1, indicating positive selection for non-synonymous somatic variants. Additionally, hypermutation in driver genes, notably TP53 and XIRP2, was detected. One patient, with a unique dN/dS < 1, showcased survival beyond four years without liver metastases. Immune dN/dS > 1 and no evidence of liver metastases displayed the best prognosis after treatment in contrast with those that have immune dN/dS < 1 with or without liver metastases. Conclusions: Immune dN/dS emerges as a promising tool to decode tumour evolutionary mechanisms, providing profound insights into the dynamics of tumour evolution in advanced HER2 negative oesophago-gastric cancer patients receiving durvalumab immunotherapy. This pilot study underscores the potential of this novel immunogenomic approach in improving patient stratification and tailoring therapeutic strategies in cancer immunotherapy. 1. Zapata et al, Nature Genetics, 2023. 2. Fong et al, J Clin Oncol, 2021. Clinical trial information: NCT02678182 .

Gastric and oesophageal (OG) cancers are the leading causes of cancer mortality worldwide. In OG cancers, recent studies have showed that PDL1 immune checkpoint inhibitors (ICI) in combination with chemotherapy improves patient survival. However, our understanding of the tumour immune microenvironment in OG cancers remains limited. In this study, we interrogate multiplex immunofluorescence (mIF) images taken from patients with advanced Oesophagogastric Adenocarcinoma (OGA) who received first-line fluoropyrimidine and platinum-based chemotherapy in the PLATFORM trial (NCT02678182) to predict the efficacy of the treatment and to explore the biological basis of patients responding to maintenance durvalumab (PDL1 inhibitor). Our proposed Artificial Intelligence (AI) based marker successfully identified responder from non-responder (p < 0.05) as well as those who could potentially benefit from ICI with statistical significance (p < 0.05) for both progression free and overall survival. Our findings suggest that T cells that express FOXP3 seem to heavily influence the patient treatment response and survival outcome. We also observed that higher levels of CD8+PD1+ cells are consistently linked to poor prognosis for both OS and PFS, regardless of ICI.

446 Background: ICONIC evaluated 4+4 cycles of FLOT-A (2-weekly standard FLOT with 10mg/kg of the anti-PDL1 antibody avelumab) for perioperative treatment of early-stage OGA. We report R0 resection rates, pathologic complete response rates (pCR), pathologic tumour regression grades (TRG) according to Mandard classification and progression free survival (PFS) data in the modified intention to treat population (mITT), and translational analyses. Methods: ICONIC is a single-arm phase II trial of FLOT-A in patients (pts) with ≥cT2-4 or N+ OGA. The pCR rate in surgical specimens was the primary endpoint. Response evaluation according to Mandard, R0 rates and PFS were among secondary endpoints. PD-L1 expression was assessed according to the combined positive score (CPS) with the 22C3 pharmDx kit. Results: The trial closed early after the pCR rate was 15% (95% CI: 49%-83%) once 34 pts in the mITT population (defined as pts who had 1-4 cycles FLOT-A and surgery) as the pre-specified aim to demonstrate a pCR rate of 25% in 40 pts was unlikely to be met. Baseline characteristics of the mITT population were: median age 64y, 79% male, 79% OG junction, 6% oesophageal, 15% stomach, 65% poorly differentiated, 79% T3/4, 59% N+. 91% of pts received all 4 pre-operative cycles and 97% of pts achieved R0 resections. PDL1 CPS ≥1 and CPS ≥5 were nevertheless associated with increased TRG3 and decreased TRG4/5 rates. 3/34 pts (9%) had hypermutated/MMRd tumours and after their exclusion, the association of higher CPS with better TRG3 and decreased TRG4/5 remained. With a median follow up duration of 15.8 months the 12-month PFS was 93.1% (95% CI: 75.1%-98.2%) which is promising compared to historic results with peri-operative FLOT. Conclusions: Although FLOT-A failed to increase pCR rates to 25%, there is a trend towards higher TRG3 and lower TRG4/5 in pts with PDL1 CPS≥1 and CPS≥5 and promising PFS indicate activity of immunotherapy in combination with FLOT chemotherapy. Translational and biomarker analyses by exome- and RNA-sequencing, and multiplex immune cell staining are ongoing and will be reported. Clinical trial information: NCT03399071 . [Table: see text]

Upper gastrointestinal cancer encompasses tumour types – pancreatic, liver, biliary tract and oesophago-gastric cancers – that are associated with high mortality rates. Although mortality rates are high, with pancreatic cancer remaining the most aggressive and little progress made, treatment paradigms for both early-stage and advanced disease have evolved, most associated with an incremental benefit. Single-modality treatment was once the standard of care; however, practice now integrates multidisciplinary and multimodality treatment approaches including chemotherapy, radiotherapy, surgery and, more recently, immunotherapy and targeted therapy. The era of precision medicine has provided a gateway for novel targeted therapy and it continues to be part of the wider approach for personalizing gastrointestinal cancer treatment to improve patient outcomes.

419 Background: A predictive biomarker for resistance to trastuzumab in HER2 positive oesophago-gastric cancer would refine patient selection. Our preclinical studies suggest that patients with HIGH baseline plasma miR-148a-3p levels will experience shorter Overall Survival (OS), Progression Free Survival (PFS), and worse Progression Free Rates (PFR) than those with LOW plasma miR-148a-3p levels. Methods: This sub-study is a prospective biomarker analysis of baseline plasma samples for HER2 positive advanced oesophago-gastric cancer patients registered within Arm B1 of the Phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182). All HER2 positive patients assessable for clinical response and miR signatures were included. Copies of miR-148a-3p and miR-16 per ml of plasma were quantified using Digital Droplet Polymerase Chain Reaction (ddPCR). OS as primary endpoint for miR-148a-3p LOW (≤median) versus HIGH (>median) was analysed using Kaplan-Meier curves and Cox model regression. Secondary endpoints were PFS and PFR. OS and PFS are from start of 1st line therapy; PFR are from start of maintenance trastuzumab. Sensitivity analysis normalised miR-148a-3p to miR-16. Results: Of 63 patients with analysable lab samples and available survival data, normalisation was possible for 41 patients. Median follow-up was 38 months. There was no statistically significant relationship between OS and miR-148-3p copies/μl of ddPCR reaction LOW versus HIGH (n= 62, Hazard Ratio (HR) 0.98, p=0.933), PFS (n=62, HR 1.08, p=0.759) or PFR (n=31, Odds Radio (OR) 0.67, p=0.577). Normalised miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in PFR at 3 months (n=23, OR=0.11, p=0.027) but no difference in OS or PFS. A model adjusting for primary tumour site, metastatic disease and number of sites demonstrated a statistically significant difference in PFR at 3 months (aOR=0.03, p=0.029). Conclusions: Patients with HIGH NmiR-148-3p have 0.03 times the odds of being progression-free at 3 months than patients with LOW NmiR-148a-3p in this population, when adjusted for key factors. Limitations include small sample size and normalisation. Clinical trial information: NCT02678182 . [Table: see text]

Background: The utility of molecular residual disease (MRD) detection by circulating tumor (ct)DNA in early-stage (pT2+ or N+, M0) esophagogastric adenocarcinoma treated with peri-operative systemic therapy has not been assessed in prospective trials. Methods: This exploratory analysis of the phase 2 ICONIC trial (NCT03399071), assessed whether ctDNA can predict recurrence and determine the efficacy of 4xFLOT+avelumab (FLOT-A) before and after surgery. Exome sequencing of pre-treatment biopsies was successful in 24/26 patients (pts) (92.3%) who had received FLOT-A and had undergone surgery at the time of analysis. All pts had R0 resections. Tumor-informed ctDNA assays (SignateraTM) were designed for these 24 pts and 220 serial plasma samples were analyzed. Pathologic response was assessed using Mandard tumor regression grading (TRG1 complete, 2 excellent, 3 good, 4 poor and 5 no response). The median follow-up was 17.0m from surgery. Progression free survival (PFS) was calculated from surgery to radiological recurrence or death. Results: ctDNA was detected in 23/24 pts (95.8%) prior to treatment. PFS was significantly shorter for pts with a mean number of tumor DNA molecules per ml plasma in the middle & highest tertile (p=0.049, HR=8.33, 95% CI: 1.01-1083, Firth Correction for Cox regression). 6 pts remained ctDNA-positive post neoadjuvant chemotherapy (NAC). None of these pts had a TRG1/2, 3 (50.0%) had TRG3 and 3 (50%) TRG4/5 in the resection specimen. Of 18 ctDNA-negative pts 5 (27.8%) had TRG1/2, 10 (55.6%) TRG3 and 3 (16.7%) TRG4/5. Post-surgery and prior to adjuvant therapy, 6/24 pts were ctDNA-positive. ctDNA positivity at this time point was associated with significantly shorter median PFS (12.9m) compared to ctDNA-negative status (PFS not reached, p<0.0001, HR=27, 95%CI: 3.0-241). Nodal status and Mandard TRG are routinely used as clinical predictors. Only the former was significantly associated with poor median PFS (pN+: 13.5m, pN-: not reached, p=0.027, HR=11, 95%CI: 1.3-98). Of 6 pts who remained ctDNA positive post-operatively, none achieved ctDNA clearance despite adjuvant FLOT-A. The median lead-time from ctDNA positivity after surgery to recurrence was 11.4 months. Conclusions: Post-NAC/pre-surgical ctDNA positivity correlated with worse pathological response. Persistent ctDNA after NAC & surgery was a stronger predictor of recurrence than nodal status or TRG in the resection specimen. Post-operative adjuvant therapy failed to clear ctDNA in any of the pts who were ctDNA positive after surgery, indicating that administering more of the same treatment is ineffective. This provides an opportunity to test new adjuvant therapies in pts who remain ctDNA positive after surgery. Whether post-operative therapy can be omitted in pts who are ctDNA negative after surgery should be assessed in future trials. Citation Format: Marco Gerlinger, Anderley Gordon, Louise J. Barber, Georgios Laliotis, Avani Athauda, Benjamin Challoner, Andrew Woolston, Sonia Mansukhani, Matt Dunstan, Nikoletta Petrou, Komel Khabra, Retchel Lazaro-Alcausi, Richard Crux, Victoria Borja, Ruwaida Begum, Isma Rana, Charuta Palsuledesai, Meenakshi Malhotra, Minetta Liu, Adham Jurdi, Shruti Sharma, Sheela Rao, Sacheen Kumar, David Cunningham, Ian Chau, Naureen Starling, M Asif Chaudry. Circulating tumor DNA for recurrence prediction and efficacy analysis in the ICONIC trial of peri-operative FLOT and avelumab (PD-L1) in localized esophago-gastric adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5591.

BackgroundThis study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.MethodsA high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in trastuzumab-treated HER2-positive NCI-N87 and HER2-negative FLO-1 oesophago-gastric cancer cell lines. NanoString nCounter® miR analysis was performed in NCI-N87, FLO-1, and MAGIC trial (ISRCTN93793971) formalin-fixed paraffin-embedded (FFPE) oesophago-gastric cancer patient samples. MiR-148a-3p copies in plasma samples were quantified using digital droplet polymerase chain reaction (ddPCR) from HER2-positive oesophago-gastric cancer patients treated with standard-of-care trastuzumab-based therapy within the FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. The primary endpoints were overall survival (OS) for plasma miR-148a-3p HIGH (>median) versus LOW (≤median). The secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFRs) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p).ResultsThe inhibition of miR-148a-3p reduced NCI-N87 relative cell viability (<0.6) and expression was high (>242) in NCI-N87 and HER2-positive MAGIC trial patients (n=5). Normalised-miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in 3-month PFRs (n=23; OR, 0.11 [0.02–0.78]; p=0.027; aOR, 0.03 [0.001–0.71], p=0.029) but no difference in OS or PFS. There was no statistically significant relationship between miR-148-3p LOW versus HIGH for OS (PLATFORM, n=62; hazard ratio [HR], 0.98 [0.57–1.66]; p=0.933; FOrMAT, n=8; HR, 0.54 [0.13–2.31]; p=0.322), PFS (n=62; HR, 1.08 [0.65–1.81]; p=0.759; FOrMAT, n=8; HR, 1.26 [0.31–5.07]; p=0.714), or PFRs (PLATFORM, n=31; odds ratio [OR], 0.67 [0.2–2.8]; p=0.577).ConclusionNormalised miR-148a-3p may be a relevant biomarker for trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.

Despite recent advances in the systemic treatment of gastroesophageal cancers, prognosis remains poor.Comprehensive molecular analyses have characterized the genomic landscape of gastroesophageal cancer that has established therapeutic targets such as human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR) and programmed death ligand 1 (PD-L1).The aberrant fibroblast growth factor receptor 2 (FGFR2) pathway is attractive for targetable therapy with FGFR inhibition based on preclinical data showing a pivotal role in the progression of gastric cancer (GC).FGFR2 amplification is the most common FGFR2 gene aberration in gastroesophageal cancer, and most associated with diffuse GC, which is often linked to poorer prognostic outcomes.There has been considerable progress with drug development focused on FGFR inhibition.At present, there is no approved FGFR inhibitor for FGFR2 positive gastroesophageal cancer.A selective FGFR2b monoclonal antibody bemarituzumab is currently being investigated in the first phase III randomized trial for patients with first line advanced GC, which may change the treatment paradigm for FGFR2b positive GC.The role of FGFR signalling, specifically FGFR2, is less established in oesophageal squamous cell cancer (ESCC) with a paucity of evidence for clinical benefit in these patients.Precision medicine is part of the wider approach in gastrointestinal cancers; however, it can be challenging due to heterogeneity and here circulating tumour DNA (ctDNA) for patient selection may have future clinical utility.In our review, we outline the FGFR pathway and focus on the developments and challenges of targeting FGFR2 driven gastroesophageal cancers.

Oesophago–gastric adenocarcinoma remains a leading cause of cancer-related morbidity and mortality worldwide. Although there has been an enormous progress in the multimodality management of resectable oesophago–gastric adenocarcinoma, most patients still develop a recurrent disease that eventually becomes resistant to systemic therapy. Currently, there is no global consensus on the optimal multimodality approach and there are variations in accepted standards of care, ranging from preoperative chemoradiation to perioperative chemotherapy and, more recently, adjuvant immune checkpoint inhibitors. Ongoing clinical trials are aimed to directly compare multimodal treatment options as well as the additional benefit of targeted therapies and immunotherapies. Furthermore, our understanding of the molecular and genetic features of oesophago–gastric cancer has improved significantly over the last decade and these data may help inform the best approach for the individual patient, utilising biomarker selection and precision medicine.