CROSS Regimen Research Articles

Safety assessment of the world’s first novel cocktail of two monoclonal antibodies in WHO category-III animal-bite patients

ABSTRACT Background: Rabies, a zoonotic disease, poses a significant global public health challenge, and post-exposure prophylaxis (PEP) is crucial for prevention. Monoclonal antibodies (mAbs) have emerged as a promising alternative to rabies immunoglobulins due to their high efficacy and standardized manufacturing process. Materials and Methods: A prospective, open-label post-marketing surveillance study was conducted with patients of WHO category-III suspected rabid animal bites. TwinRab™, a novel cocktail of docaravimab and miromavimab, was administered at a dosage of 40 IU/kg in and around the wound, along with the anti-rabies vaccine, which was administered intradermal as per Thai Red Cross regimen. Results: In this study, 200 subjects received TwinRab™ with a 100% completion rate. Three (1.5%) patients showed solicited local AEs, and two (1%) patients showed solicited systemic AEs, which were resolved after appropriate treatment intervention. The overall tolerability assessment showed positive ratings from doctors (94%) and patients (74%). Conclusion: The post-marketing surveillance study demonstrated the safety of TwinRab™ in patients who experienced category-III suspected rabid animal bites, thereby supporting its potential as an alternative option for PEP in the management of animal bite for the prevention of rabies.

780. NEOADJUVANT IMMUNOTHERAPY COMBINED WITH CHEMORADIOTHERAPY VS NEOADJUVANT CHEMORADIOTHERAPY FOR LOCALLY ADVANCED ESOPHAGEAL CARCINOMA (CSTAGEII-III): A MULTI-CENTER PROSPECTIVE RANDOMIZED CLINICAL TRIAL (ICROSS)

Abstract Background The role of neoadjuvant immunotherapy combined with chemoradiation in the treatment of esophageal cancer is not yet fully understood. This study aims to compare the efficacy and safety of neoadjuvant immunotherapy combined with chemoradiation versus traditional neoadjuvant chemoradiation in treating locally advanced esophageal squamous cell carcinoma (stages cII-III). Methods This prospective randomized controlled trial included histologically confirmed patients with potentially resectable esophageal squamous cell carcinoma (stages cII-cIII). Patients were randomly assigned to two groups: the treatment group (Arm A) received BGB-A317 (200mg IV) combined with the CROSS regimen of chemotherapy and radiation, while the control group (Arm B) received only the CROSS chemotherapy and radiation regimen. All patients underwent surgery followed by a five-year follow-up. The primary endpoints included pathological complete response rate (pCR), tumor regression grades, and lymph node clearance. Results The study enrolled 67 patients (52 males, 15 females) aged between 18-75 years. Tumor locations were as follows: upper segment in 16 cases, middle segment in 45 cases, and lower segment in 6 cases. A total of 64 patients were included in the analysis. There were no significant differences between the two groups in terms of pCR rates (Arm A 41.4% vs. Arm B 30.8%, p=0.414), tumor regression grades, Surgical time (221.09 ± 37.54 minutes vs. 227.05 ± 50.28 minutes, p=0.593), Estimated blood loss (182.73 ± 337.41 ml vs. 90.47 ± 66.36 ml, p=0.109), and postoperative hospital stay (9.31 ± 4.12 days vs. 8.42 ± 1.16 days, p=0.555). However, the treatment group had significantly more lymph nodes retrieved during surgery compared to the control group (26.86 ± 7.96 vs. 20.85 ± 9.68, p=0.020). The safety profiles were similar between the groups with no significant adverse events observed. Conclusion For patients with locally advanced esophageal squamous cell carcinoma, neoadjuvant immunotherapy combined with chemoradiation is comparable in efficacy and safety to neoadjuvant chemoradiation alone and may facilitate more effective lymph node clearance. Although these preliminary results are encouraging, further long-term follow-up and larger-scale studies are needed to validate these clinical findings once the study is complete.

Accuracy of detecting residual disease after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (preSINO trial): A prospective multicenter diagnostic cohort study in Asia.

196 Background: The benefit of standard esophagectomy in patients with clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) is disputable and the alternative of active surveillance should be studied. PreSANO study demonstrated that clinical response evaluations (CREs) are accurate to detect residual tumor after nCRT in patients with mainly adenocarcinoma, however, its applicability to esophageal squamous cell carcinoma (ESCC) is unknown. The preSINO trial (NCT03937362) aimed to assess the accuracy of CREs based on bite-on-bite biopsy, endoscopic ultrasonography with fine needle aspiration (EUS-FNA) of suspected lymph nodes, PET-CT in patients with ESCC, and to provide a basis for organ-sparing strategy of ESCC in Asia. Methods: Patients were eligible when they were planned for nCRT (CROSS regimen) followed by standard surgery. Patients received the first CRE (bite-on-bite biopsies) 4-6 weeks after completion of nCRT. Patients with locoregional residual tumor and without distant metastases underwent immediate surgery. In patients with a cCR at CRE-1, a second CRE (CRE-2) was done 10-12 weeks after completion of nCRT using PET-CT, bite-on-bite biopsies and EUS-FNA of suspicious lymph nodes. All patients underwent surgery irrespective of the outcome of CRE-2, in the absence of distant metastases. Circulating tumor DNA (ctDNA) analyses based on tumor-informed assay were performed at baseline and CREs for exploratory analysis. Primary endpoint was the accuracy of CREs for detecting TRG3-4 or TRG1-2 with ypN+ residual tumor. A false-negative rate (FNR) of 19.5% was considered acceptable according to the study protocol. Results: From Aug 20, 2019, to Jan 15, 2023, 309 patients were included of whom 250 patients underwent nCRT plus surgery. Eighteen of 133 patients with TRG3-4 or TRG1-2 with ypN+ residual tumor were not detected by bite-on-bite biopsies and EUS-FNA (FNR: 13.5%). Sensitivity, specificity, negative predictive value and positive predictive value of detecting any residual tumor were 82%, 93%, 69% and 97%, respectively. PET-CT detected interval distant metastases in 13 (5%) of 268 patients prior to surgery. Postoperative distant recurrence rate among patients with ctDNA-positive and ctDNA-negative during CREs were 15.1% (11/73) and 3.3% (2/59), respectively. Conclusions: Bite-on-bite biopsies and EUS-FNA for lymph nodes were accurate for detecting locoregional residual disease after nCRT in patients with ESCC. Post-nCRT ctDNA-positive during CREs may indicate an increased risk of long-term distant metastasis, potentially serving as a diagnostic tool to identify patients who would benefit from postponement of surgery and additional systemic therapy. The long-term follow-up results of this trial will further answer this question. Clinical trial information: NCT03937362 .

Comparison of the treatment outcomes of different neoadjuvant chemoradiotherapy regimens for resectable locally advanced esophageal cancer

BackgroundNeoadjuvant chemoradiotherapy (nCRT) followed by radical esophagectomy is the standard treatment for locally advanced esophageal squamous cell cancer (LA-ESCC). However, various nCRT regimens have been used, and their comparative efficacy and safety remain unclear. MethodsPatients with histologically confirmed LA-ESCC who underwent nCRT followed by radical esophagectomy between January 2016 and February 2022 were enrolled in this study. Of note, 3 different nCRT regimens were retrospectively compared: conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP) (Conv-FP), hypofractionated RT + FP (Hypo-FP), and regimens from the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial (CROSS). The overall survival (OS), pathologic complete response (pCR), toxicity, and treatment compliance rates were analyzed. ResultsAmong the 600 patients, 225 received Conv-FP, 255 received Hypo-FP, and 120 received the CROSS regimen. The OS rates at 1 year were 78.7%, 83.9%, and 88.1% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). The pCR rates were 30.6%, 33.9%, and 35.0%, respectively (P = .653). The overall incidence of grade 3 toxicities was 10.2%. Hematologic and nonhematologic toxicities of grade ≥ 3 were observed in 8.4% and 11.4%, 0% and 7.6%, and 5.5% and 0.8% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P = .002 and P = .030). Weight loss of > 5% was observed in 44.0%, 51.4%, and 32.5% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). In the multivariate analysis, clinical T stage (P = .004), N stage (P = .012), FP chemotherapy regimen (P = .013), surgical resection (P < .001), hematologic toxicity (P = .001), and weight loss (P = .004) were significantly associated with poor OS. ConclusionThe choice of nCRT regimen did not significantly affect the pCR rates in patients with LA-ESCC. However, the CROSS regimen demonstrated better OS and lower toxicity, suggesting that it may be the optimal treatment option among the groups.

A propensity score-matched comparison of neoadjuvant chemoradiotherapy with cisplatin-5FU and carboplatin-paclitaxel in locally advanced esophageal squamous cell carcinoma: A Turkish oncology group study.

Neoadjuvant treatment is the standard treatment in locally advanced ESCC. However, the optimal chemotherapy regimen is not known. This is a retrospective observational cohort study conducted with propensity score matching. Patients with resectable ESCC from 13 tertiary centers from Türkiye were screened between January 2011 and December 2021. We comparedthe efficacy and safety of neoadjuvant chemoradiotherapy with the CF and the CROSS regimens in patients with ESCC. Three hundred and sixty-two patients were screened. Patients who received induction chemotherapy (n = 72) and CROSS-ineligible (n = 31) were excluded. Two hundred and fifty nine patients received neoadjuvant chemoradiotherapy. After propensity score matching (n = 97 in both groups), the mPFS was 18.4 months (95% CI, 9.3-27.4) and 25.7 months (95% CI, 15.6-35.7; p = 0.974), and the mOS was 35.2 months (95% CI, 18.9-51.5) and 39.6 months (95% CI 20.1-59.2; p = 0.534), in the CF and the CROSS groups, respectively. There was no difference between subgroups regarding PFS and OS. Compared with the CF group, the CROSS group had a higher incidence of neutropenia (34.0% vs. 62.9%, p < 0.001) and anemia (54.6% vs. 75.3%, p = 0.003) in all grades. On the other hand, there was no significant difference in grade 3-4 anemia, grade 3-4 neutropenia, and febrile neutropenia between groups. There were more dose reductions and dose delays in the CROSS group than in the CF group (11.3% vs. 3.1%, p = 0.026 and 34.0% vs. 17.5%, p = 0.009, respectively). The resection rate was 52.6% in the CF-RT and 35.1% in the CROSS groups (p = 0.014). Favorable PFS and pCR rates and a comparable OS were obtained with the CROSS regimen over the CF regimen as neoadjuvant chemoradiotherapy in patients with ESCC.

Temporal Trends in Survival Outcomes for Patients with Esophageal Cancer Following Neoadjuvant Chemoradiotherapy: A 14-Year Analysis.

The prognosis for patients with esophageal cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery has shown improvement in recent years. We sought to identify the critical factors contributing to enhanced survival outcomes. We retrospectively examined 427 patients with esophageal cancer treated with nCRT and esophagectomy across two periods: P1 (from 1 January 2004 to 31 December 2011) and P2 (from 1 January 2012 to 31 December 2017). The introduction of the CROSS regimen and total meso-esophagectomy in P2 prompted an evaluation of their effects on perioperative outcomes and overall survival (OS). During P2, the occurrence of recurrent laryngeal nerve palsy increased significantly from 3.9 to 16.8% (p < 0.001), while pneumonia and in-hospital mortality rates remained unchanged. The median OS improved from 19.2 to 29.2 months (p < 0.001) between P1 and P2. Multivariable analysis identified higher nodal yields and the achievement of major response as favorable prognostic factors. Conversely, an involved circumferential resection margin (CRM), an advanced ypN stage, and pneumonia were independently associated with poor outcomes. Patients treated during P2 had a lower prevalence of involved CRM (10% vs. 25.1%, p < 0.001), a higher rate of major response (52.7% vs. 34.8%, p < 0.01), and a greater nodal yield (27.8 vs. 10.9, p < 0.001). The clinical outcomes following nCRT and surgery have improved significantly over time. This progress can be attributed to multiple factors, with the primary drivers being the refinement of nCRT protocols and the application of radical surgery.

Neoadjuvant immuno-chemo-radiotherapy in operable esophageal and gastroesophageal junction adenocarcinoma with carboplatin, paclitaxel plus radiotherapy and avelumab (anti-PDL1 antibody): Neo-CREATE trial.

4086 Background: Neoadjuvant CROSS regimen followed by adjuvant nivolumab or perioperative FLOT are current standards of care for patients with curable esophageal/ gastroesophageal (GEJ) junction adenocarcinoma. We hypothesized that adding avelumab to neoadjuvant chemo-radiation (CRT-A) before surgery can further improve outcomes. Methods: Patients with cT1-3 and N0/N1 M0 esophageal or GEJ adenocarcinomas eligible for curative surgery received weekly carboplatin and paclitaxel concurrently with radiotherapy (41.4 Gy in 23 fractions) and bi-weekly avelumab (5 doses). The trial had a run-in phase of 10 patients to evaluate feasibility and safety and a planned futility analysis after 15 patients have undergone surgery. The primary endpoint was pathological complete response (pCR) (Mandard criteria) by central pathology review, secondary endpoints were major histological response and survival outcomes. Using an A’hern single stage design for efficacy forty-seven patients were required to rule out a lower limit of a 20% pCR rate (p0) and to demonstrate an increase to a 40% pCR rate (p1), with 90% power and significance level α=0.05. Tissue, blood, and stool samples were collected for corelative analysis. Results: 48 patients were enrolled between Sept 2019 to Oct 2022 across seven Australian sites. Median age 65 [44-81], 95% were male (n=45), with majority of cancers being esophageal/GEJ type I (n = 35), with GEJ type II (n = 13). Forty-seven (97%) patients completed CRT -A and 46 (95%) had surgery. CRT-A was well tolerated, with two patients having &gt; grade 2 adverse event of interest in the form of myocarditis attributed to avelumab. Notable toxicities included grade 2-4 myocarditis (4%), anastomotic leak (4%), infection (6%) and diarrhoea (6%). In 44 evaluable patients, pCR was 23%. MHR was 58.3% (95% CI, 43.3%-72.1%), complete or near complete response (Tumor Regression Grade 1-2) was 31%. Overall, 1-yr disease free survival was 83.8% and OS was 91.2%. 1-yr disease free survival was 91.7% for patients with MHR vs 73.3% without MHR, p=0.20. Conclusions: Combining avelumab with neoadjuvant CRT is feasible in patients with acceptable tolerability in locally advanced esophageal/ GEJ adenocarcinoma. Avelumab with CRT is active however observed pCR rate does not represent a signal of substantial improvement compared to historical controls. Exploratory analysis suggests improved outcomes in patients with optimal tumour regression after neoadjuvant CRT-A. Exploratory biomarker work to corelate with outcomes is underway. Clinical trial information: ACTRN12619000288123.

Abstract CT208: High tumor monocyte content predicts long-term survival for patients with operable oesophageal cancer treated with neoadjuvant immunochemotherapy in the LUD2015-005 trial

Abstract Background: Combined immune checkpoint inhibitors (ICI) with chemotherapy in advanced oesophageal cancer (OC) has shown survival benefit in phase III studies, resulting in ICI’s recent approval to treat advanced OC. The role of ICI in peri-operative OC is debated, and large clinical studies are ongoing. Patients’ response to immunochemotherapy is highly variable and it is unclear what underlies this heterogeneity. To address this challenge, 38 advanced and 35 operable OC patients were enrolled to receive ICI in the LUD2015-005 trial (NCT02735239). Methods: We investigated the clinical and biological effects of adding the anti-PD-L1 ICI durvalumab to peri-operative chemotherapy or chemoradiotherapy (CRT) in a phase II multicentre study (LUD2015-005 trial). Operable OC patients received ICI for four weeks, followed by combination treatment with ICI + chemotherapy (oxaliplatin and capecitabine or fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT)), or ICI + CRT (CROSS regimen). Patients could also receive ICI for up to 6 months after surgery. Tissue samples were collected at baseline, after four weeks ICI-only, and on the day of surgery. Further to assessing synergy of ICI with standard peri-operative treatment for OC, our trial design enables an in-depth analysis of molecular features of response, and to dissect the impact of ICI alone on the tumor microenvironment. Single cell and bulk transcriptomic data were generated and used to perform RNA deconvolution to estimate tumor cell composition. Results: The treatment was well-tolerated and two-year survival was 80% and 73.3% with ICI + chemotherapy and ICI + CRT, respectively. Survival was superior to that of propensity score matched patients receiving standard of care (p = 0.047). Tumor cell composition analysis revealed that neither total T-cell numbers nor a specific T-cell functional phenotype was associated with outcome, but high tumor monocyte content (TMC) at baseline was highly predictive of overall survival (p = 0.003). Moreover, a 13-gene core monocyte gene signature was sufficient to predict overall survival (p = 0.022) and major pathological response (mPR, Mandard 1-2, p = 0.009). Patients with mPR at resection showed enrichment of interferon and IL15 signalling at the four-week ICI-only timepoint (p &amp;lt; 0.001). Single cell trajectory interference combined with immune response enrichment analysis also show that high interferon and IL15 signalling drive monocytes to differentiate into M1 macrophages and dendritic cells. Conclusion: Similar to our previous finding in immunochemotherapy treated advanced OC patients (Carroll et al. Cancer Cell 2023), TMC is a highly predictive biomarker of long-term survival for operable OC patients treated with neoadjuvant immunochemotherapy, highlighting the importance of tumor monocytes and their differentiation potential in OC patients’ response to ICI. Citation Format: Hannah S. Fuchs, Sabrina A. James, Thomas M. Carroll, Phil F. Xie, Joseph A. Chadwick, Duncan Parkes, Simon R. Lord, Lucinda Griffiths, Tim Underwood, Ioannis Karydis, Russell T. Petty, Benjamin Schuster-Böckler, Richard P. Owen, Mark R. Middleton, Xin Lu. High tumor monocyte content predicts long-term survival for patients with operable oesophageal cancer treated with neoadjuvant immunochemotherapy in the LUD2015-005 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT208.

OGC O06 Long term outcomes of immune checkpoint inhibition in oesophageal cancer

Abstract Background Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors (ICIs) to conventional chemotherapy for patients with gastro-oesophageal cancer. Large scale studies of chemo-immunotherapy prior to and after surgery are under way. We studied the clinical and biological effects of adding the PD-L1 inhibitor durvalumab (D) to peri-operative chemotherapy or chemoradiotherapy in a multi-centre phase II trial and used multiple phenotyping approaches to identify features associated with benefit. Methods Patients suitable for surgery were given D for 4 weeks, then one of Oxaliplatin and Capecitabine (CapOx), fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT), or chemoradiotherapy (CXRT, CROSS regimen) were given with D before surgery, and D was continued for up to 12 further infusions postoperatively. Toxicity, response, and survival were recorded until death, for 3 years or until June 2022 when the study ended. Comparisons were made with propensity score matched patients treated over the same period in the one of the participating sites. Tumour phenotyping was with single cell and bulk sequencing approaches. Results 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. Treatment side effects were as expected. Only 2 out of 35 patients did not have surgery, due to progressive disease on D-CXRT. Two (5.7%) and 6 (17.1%) patients had complete or partial pre-op responses (RECIST) and 3 (8.6%) had progression prior to surgery. Tumour regression at surgery (Mandard 1-3) occurred in 24/33 pts. 2-year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. After propensity score matching, there was a survival advantage after addition of ICI (p=0.047). In selected patients we also demonstrate molecular features associated with response. Conclusions Adding D to standard neo-adjuvant regimens for gastro-oesophageal cancer is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2-year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. There was a survival advantage from the addition of ICI when compared to a matched cohort of patients treated in one of the study centres over the same period. Specific pre-treatment tumour phenotypes were associated with durable cure.

Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial

The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative radiotherapy with carboplatin plus paclitaxel [CROSS regimen]) with optimum contemporaneous perioperative chemotherapy regimens (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine [a modified MAGIC regimen] before 2018 and fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT] subsequently). Neo-AEGIS (CTRIAL-IE 10-14) was an open-label, randomised, phase 3 trial done at 24 centres in Europe. Patients aged 18 years or older with clinical tumour stage T2-3, nodal stage N0-3, and M0 adenocarcinoma of the oesophagus and oesophagogastric junction were randomly assigned to perioperative chemotherapy (three preoperative and three postoperative 3-week cycles of intravenous 50 mg/m2 epirubicin on day 1 plus intravenous 60 mg/m2 cisplatin or intravenous 130 mg/m2 oxaliplatin on day 1 plus continuous infusion of 200 mg/m2 fluorouracil daily or oral 625 mg/m2 capecitabine twice daily up to 2018, with four preoperative and four postoperative 2-week cycles of 2600 mg/m2 fluorouracil, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, and 50 mg/m2 docetaxel intravenously on day 1 as an option from 2018) or trimodality therapy (41·4 Gy in 23 fractions on days 1-5, 8-12, 15-19, 22-26, and 29-31 with intravenous area under the curve 2 mg/mL per min carboplatin plus intravenous 50 mg/m2 paclitaxel on days 1, 8, 15, 22, and 29). The primary endpoint was overall survival, assessed in all randomly assigned patients who received at least one dose of study drug, regardless of which study drug they received, by intention to treat. Secondary endpoints were disease-free survival, site of treatment failure, operative complications, toxicity, pathological response (complete [ypT0N0] and major [tumour regression grade 1 and 2]), margin-free resection (R0), and health-related quality of life. Toxicity and safety data were analysed in the safety population, defined as patients who took at least one dose of study drug, according to treatment actually received. The initial power calculation was based on superiority of trimodality therapy (n=366 patients); it was adjusted after FLOT became an option to a non-inferiority design with a margin of 5% for perioperative chemotherapy (n=540). This study is registered with ClinicalTrials.gov, NCT01726452. Between Jan 24, 2013, and Dec 23, 2020, 377 patients were randomly assigned, of whom 362 were included in the intention-to treat population (327 [90%] male and 360 [99%] White): 184 in the perioperative chemotherapy group and 178 in the trimodality therapy group. The trial closed prematurely in December, 2020, after the second interim futility analysis (143 deaths), on the basis of similar survival metrics and the impact of the COVID-19 pandemic. At a median follow-up of 38·8 months (IQR 16·3-55·1), median overall survival was 48·0 months (95% CI 33·6-64·8) in the perioperative chemotherapy group and 49·2 months (34·8-74·4) in the trimodality therapy group (3-year overall survival 55% [95% CI 47-62] vs 57% [49-64]; hazard ratio 1·03 [95% CI 0·77-1·38]; log-rank p=0·82). Median disease-free survival was 32·4 months (95% CI 22·8-64·8) in the perioperative chemotherapy group and 24·0 months (18·0-40·8) in the trimodality therapy group [hazard ratio 0·89 [95% CI 0·68-1·17]; log-rank p=0·41). The pattern of recurrence, locoregional or systemic, was not significantly different (odds ratio 1·35 [95% CI 0·63-2·91], p=0·44). Pathological complete response (odds ratio 0·33 [95% CI 0·14-0·81], p=0·012), major pathological response (0·21 [0·12-0·38], p<0·0001), and R0 rates (0·21 [0·08-0·53], p=0·0003) favoured trimodality therapy. The most common grade 3-4 adverse event was neutropenia (49 [27%] of 183 patients in the perioperative chemotherapy group vs 11 [6%] of 178 patients in the trimodality therapy group), followed by diarrhoea (20 [11%] vs none), and pulmonary embolism (ten [5%] vs nine [5%]). One (1%) patient in the perioperative chemotherapy group and three (2%) patients in the trimodality therapy group died from serious adverse events, two (one in each group) of which were possibly related to treatment. No differences were seen in operative mortality (five [3%] deaths in the perioperative chemotherapy group vs four [2%] in the trimodality therapy group), major morbidity, or in global health status at 1 and 3 years. Although underpowered and incomplete, Neo-AEGIS provides the largest comprehensive randomised dataset for patients with adenocarcinoma of the oesophagus and oesophagogastric junction treated with perioperative chemotherapy (predominantly the modified MAGIC regimen), and CROSS trimodality therapy, and reports similar 3-year survival and no major differences in operative and health-related quality of life outcomes. We suggest that these data support continued clinical equipoise. Health Research Board, Cancer Research UK, Irish Cancer Society, Oesophageal Cancer Fund, and French National Cancer Institute.

183. NEOADJUVANT CAMRELIZUMAB PLUS CHEMOTHERAPY (NICE) VERSUS CROSS REGIMENS IN OESOPHAGEAL SQUAMOUS CELL CARCINOMA, A PROPENSITY-SCORE MATCHED ANALYSIS

Abstract Background The CROSS regimen represents standard neoadjuvant management for oesophageal squamous cell carcinoma (ESCC) for the last decade, while the utility of Camrelizumab plus chemotherapy (NICE) is increasingly gaining attention. In the absence of published Randomized Controlled Trials, there remains a paucity of robust information on comparison of these two modalities. This study aims to compare the treatment response and short-term outcomes of NICE followed by oesophagectomy with that after CROSS-induced chemoradiotherapy, in treatment for ESCC. Methods A total of 234 patients staged as clinical II-IV, 117 in each arm, was enrolled in this study after propensity-score match. The primary outcomes were tumor response and survival. Secondary outcomes were toxicity and postoperative complications. Pathological response of tumor was evaluated by Chirieac tumor regression grade (TRG) and major pathological response (MPR) as well as responders were defined as TRG1–2 N0. Complications were defined as per the Esophageal Complications Consensus Group (ECCG) criteria and severity per Clavien-Dindo. Survival was evaluated by Kaplan–Meier method using Breslow test, and freedom from recurrence with the competing risk of death estimated per Fine-Gray method. Results After matching, R0 resection (93.2% vs 94.9%, P = 0.784), pCR (ypT0N0) (25.6% vs 30.8%, P = 0.468), MPR (46.2% vs 47.0%, P = 0.896) rates and TRG1/2 grades (P = 0.331) were comparable between CROSS and NICE regimens. However, NICE was associated with more lymph nodes yield (P &amp;lt; 0.001) and higher risk of anastomotic leak (type2/3) (P = 0.030)(Fig. 1A-C). The 1-year overall survival was 86.6% and 93.5% for CROSS and NICE (P = 0.088) with comparable recurrence risk (21% vs 21%, P = 0.520) (Fig. 1D/E). Patients with pCR or responders showed similar K-M curves, but in nonresponder subgroup analysis, NICE regimen demonstrated superior survival benefit than CROSS (P = 0.035) (Fig. 1F-H). Conclusion In this matched study, NICE is safe and feasible for ESCC with comparable perioperative outcomes compared to CROSS. Moreover, NICE regimen shows superior survival benefit in nonresponder group than CROSS, suggesting its more powerful systemic treatment effects. However, Prospective RCT studies are needed to further verify these findings.

Facing adenocarcinoma of distal esophagus and esophagogastric junction: a CROSS versus FLOT propensity score-matched analysis of oncological outcomes in a high-volume institution.

Multimodality treatments are the gold standard for advanced resectable gastroesophageal cancer. Neoadjuvant CROSS and perioperative FLOT regimens are adopted for distal esophageal and esophagogastric junction adenocarcinoma (DE/EGJ AC). At present, none of the approaches is clearly superior in the context of a curative-intent multimodal treatment. We analyzed consecutive patients treated with CROSS or FLOT and surgery for DE/EGJ AC between August 2017 and October 2021. Propensity score matching was performed to balance baseline characteristics of patients. The primary endpoint was disease-free survival. Secondary endpoints included overall survival, 90-day morbidity/mortality rates, pathological complete response, margin-negative resection, and pattern of recurrence. Of the 111 patients included, 84 were correctly matched after PSM, 42 in each group. The 2-year DFS rate was 54.2% versus 64.1% in the CROSS and FLOT group, respectively (p = 0.182). Patients in the CROSS group showed a lower number of harvested LN when compared to the FLOT group (29.5 versus 39.0 respectively, p = 0.005). A higher rate of distal nodal recurrence was found in the CROSS group (23.8% versus 4.8%, p = 0.026). Although not significant, the CROSS group showed a trend toward higher rate of isolated distant recurrence (33.3% versus 21.4% respectively, p = 0.328), together with a higher rate of early recurrence (23.8% versus 9.5% respectively, p = 0.062). FLOT and CROSS regimens for DE/EGJ AC offer similar DFS and OS, together with comparable morbidity/mortality rates. CROSS regimen was associated with a higher distant nodal recurrence rate. Results of ongoing randomized clinical trials are awaited.

Long-term outcomes from adding durvalumab to neoadjuvant treatment of operable gastroesophageal cancers: Results from a multicenter study LUD2015-005.

398 Background: Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors to conventional chemotherapy for patients with gastroesophageal cancer (GEC). Large scale studies of chemoimmunotherapy prior to and after surgery are under way. We sought to characterise the effects of the PDL1 inhibitor durvalumab (D) with standard neo-adjuvant chemo(radio)therapy regimens in an open label phase I/II study in patients (pts) with operable GEC (LUD2015-005, NCT02735239, EudraCT 2015-005298-19). Methods: In pts identified as suitable for potentially curative surgery we gave D (750mg q2w) alongside their standard treatment. Pts had D only at first then Oxaliplatin and Capecitabine (CapOx) q3w or fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT) starting with the third cycle of D. Chemotherapy and further D were given for 6 (CapOx) or 8 (FLOT) weeks before pts had surgery and for up to 12 further infusions of D after operation. Patients on FLOT could also have more chemotherapy. Pts suitable for chemoradiotherapy (CXRT, CROSS regimen) were offered two cycles of D before starting their treatment, and were able to have up to 12 further cycles after recovering from surgery. Participants were followed for toxicity, response and survival from the time of study enrolment until death, for 3 years or until June 2022 when the study ended. Results: 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. All were evaluable for safety and efficacy. Treatment side effects were as expected for the agents used with diarrhoea, nausea and fatigue the most commonly reported and no new safety signals. 156 of 160 planned pre-op D doses were given. Only 2 out of 35 patients did not have surgery, both due to progressive disease on D-CXRT. 23 of the 33 patients having surgery had post-operative treatment. Amongst 33 evaluable pts 2 (5.7%) and 6 (17.1%) had complete or partial pre-op responses (RECIST) and 3 (8.6%) progression prior to surgery. Tumor regression at surgery (Mandard 1-3) occurred in 24/33 pts. Median recurrence free survival was 25.4 months (mo) (D-CapOx), 32.0 mo (D-FLOT) and not reached (D-CXRT). 2 year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. Conclusions: Adding D to standard neo-adjuvant regimens for GEC is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2 year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. Clinical trial information: NCT02735239 .

Neo-AEGIS (Neoadjuvant Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Final primary outcome analysis.

295 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) remains controversial, specifically whether multimodal therapy or perioperative chemotherapy is superior. Neo-AEGIS was designed as the first randomized clinical trial (RCT) to directly compare the multimodal CROSS regimen (carboplatin/paclitaxel, 41.4Gy radiation therapy) with a modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) regimen (pre-2018) and more latterly the FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin) regimen. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5% for peri-operative chemotherapy. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 34.2 (0.43-111.8) months, there were 186 deaths, 91 CROSS and 95 MAGIC/FLOT arm, with 3-year estimated survival probability of 57% (95% CI 49,64) and 55% (95% CI 47,62), respectively [(HR 1.03 (95%CI. 0.77-1.38))]. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy in the primary outcome of overall survival, notwithstanding greater proxy markers of local tumor response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in clinical decision making in modern practice. Clinical trial information: NCT01726452 . [Table: see text]

Reproducibility of the CROSS Trial Results in the Multimodal Treatment of Esophageal Cancer in Daily Practice: A Single Center Retrospective Observational Study.

Treatment of nonmetastatic esophageal cancer with curative intention remains a major challenge. Neoadjuvant radiochemotherapy followed by surgery, as described in the CROSS trial in 2012, has been established as a standard of care. With this retrospective observational study, we aimed to analyze the results of the CROSS regimen in daily practice over the last 10 years at the St. Clara Hospital, a Swiss center for esophageal surgery. To determine the clinical outcome in our daily practice, the medical records of all patients with potentially curable localized esophageal cancer (T1N1 or T2-3N0-1 M0) treated with radiochemotherapy in neoadjuvant intention according to the CROSS regimen were reviewed. The primary endpoint was overall survival. Furthermore, an overall survival analysis of the subgroups of patients who exactly met the inclusion criteria of the CROSS trial with respect to age and weight loss before therapy was performed. The Kaplan-Meier method was used to estimate survival and compared by the log-rank test. From January 2012 to January 2022, 91 patients with T1N1 or T2-3N0-1M0 esophageal cancer underwent neoadjuvant radiochemotherapy according to the CROSS regimen. The median age was 70 years (range 31-86 years), and 26 (29%) patients were over 75 years of age. Weight loss of more than 10% was observed in 23 (25%) patients. 77 (85%) patients underwent esophagectomy, and complete resection (R0) was obtained in 73 (95%) of them. The median overall survival was 41 months, compared to 49.4 months in the CROSS trial. The overall survival rate at 12 months was 85% and at 24 months, it was 68%, very similar to the CROSS trial results. 51% of the patients fully met the inclusion criteria of the CROSS trial with respect to age and pretherapeutic weight loss. Their overall survival rate at 12 months was 94% at St. Clara Hospital versus 82% in the CROSS trial (p=0.04), and at 24 months, 81% versus 67% (p=0.05). Overall, in a center specialized for the multimodal treatment of nonmetastatic esophageal cancer, the results of the CROSS trial seem to be well reproducible in daily practice.

Prognostic and predictive biomarkers for response to neoadjuvant chemoradiation in esophageal adenocarcinoma

BackgroundEsophageal adenocarcinoma is a lethal disease. For locally advanced patients, neoadjuvant chemoradiotherapy followed by surgery is the standard of care. Risk stratification relies heavily on clinicopathologic features, particularly pathologic response, which is inadequate, therefore establishing the need for new and reliable biomarkers for risk stratification.MethodsThirty four patients with locally advanced esophageal adenocarcinoma were analyzed, of which 21 received a CROSS regimen with carboplatin, paclitaxel, and radiation. Capture-based targeted sequencing was performed on the paired baseline and post-treatment samples. Differentially mutated gene analysis between responders and non-responders of treatment was performed to determine predictors of response. A univariate Cox proportional hazard regression was used to examine associations between gene mutation status and overall survival.ResultsA 3-gene signature, based on mutations in EPHA5, BCL6, and ERBB2, was identified that robustly predicts response to the CROSS regimen. For this model, sensitivity was 84.6% and specificity was 100%. Independently, a 9 gene signature was created using APC, MAP3K6, ETS1, CSF3R, PDGFRB, GATA2, ARID1A, PML, and FGF6, which significantly stratifies patients into risk categories, prognosticating for improved relapse-free (p = 4.73E-03) and overall survival (p = 3.325E-06). The sensitivity for this model was 73.33% and the specificity was 94.74%.ConclusionWe have identified a 3-gene signature (EPHA5, BCL6, and ERBB2) that is predictive of response to neoadjuvant chemoradiotherapy and a separate prognostic 9-gene classifier that predicts survival outcomes. These panels provide significant potential for personalized management of locally advanced esophageal cancer.

187. ADENOCARCINOMA OF DISTAL ESOPHAGUS AND ESOPHAGO-GASTRIC JUNCTION: CROSS VERSUS FLOT PROPENSITY SCORE MATCHING ANALYSIS OF SURVIVAL IN A SINGLE-CENTER INSTITUTION

Abstract Multimodal treatments are the gold standard for advanced resectable gastroesophageal cancer. The exclusive neoadjuvant, chemoradiation-based CROSS regimen and the perioperative chemotherapy-based FLOT regimen are commonly adopted for adenocarcinoma of distal esophagus and esophago-gastric junction (EGJ). At present, there is no clear evidence of the superiority of either of these two approaches on survival. An intention-to-treat analysis was performed on a cohort of consecutive patients who underwent neoadjuvant CROSS or FLOT regimen and subsequently confirmed to curative-intent surgery for adenocarcinoma of distal oesophagus and EGJ between August 2017 and October 2021. Propensity Score Matching (PSM) was performed in order to balance baseline characteristics of patients undergoing CROSS and FLOT neoadjuvant regimen. The primary endpoint was Overall Survival (OS). Secondary endpoints included Disease-Free Survival (DFS), 90-day morbidity rate, margin status, incidence and pattern of recurrence. Subgroup analyses were performed according to the specific neoadjuvant regimen adopted. Of the 111 patients included, 84 were correctly matched after PSM, 42 in each group. CROSS and FLOT patients showed similar 1-year OS rate (85.3% and 85.4% respectively, p = 0.189) and 1-year DFS rate (73.3% and 81.3% respectively, p = 0.267). When compared to FLOT patients, CROSS patients reported lower but not significant rates of post-operative severe complications (4.8% vs 11.9%, p = 0.433) and negative margins of resection (95.2% vs 97.6%, p = 1.000). In the CROSS group, 89% of recurrences occurred outside the radiation field. In FLOT group, 69% of patients completed all the 8 expected perioperative cycles. FLOT and CROSS offer similar OS and DFS, together with comparable 90-day morbidity/mortality rates and pathological findings. Both regimens are affected by specific limitations that have to be kept in mind during treatment assessment. The results of ongoing Randomized Controlled Trials are urgently awaited.

361. EARLY RECURRENCE PATTERNS AFTER ESOPHAGECTOMY FOR ESOPHAGEAL CANCER IN PATIENTS UNDERGOING CROSS NEOADJUVANT THERAPY

Abstract Chemoradiotherapy (CROSS regimen) has been regarded as standard preoperative treatment for patients with locally advanced esophageal cancer, but some patients still developed early recurrence after such intensive therapy. The present study aimed to determine the factors associated with early recurrence for patients with ESCC treated by CROSS therapy within 6 months. Patients were identified from single institution from 2019 to 2021. All patients with locally advanced ESCC who underwent CROSS regimen NCRT and following R0 esophagectomy were reviewed. Total 115 patients were included. 19 patients (16.52%) recurred within 6 months post-surgery. 8 patients (6.96%) had local-regional recurrence with most common location was cervical lymphnodes; 11 patients (9.56%) had distant recurrence and most often occured in lung. In univariate analysis: BMI before CROSS (p = 0.03), tumor size regression (p = 0.03), ypN≧1 (p = 0.002) and neck metastases (p = 0.01) were significantly associated with local-regional recurrence. In multivariate analysis: ypN≧1 (HR = 9.08, p = 0.05) was only independent covariate. For distant recurrence, tumor size regression (p = 0.02), ypN≧1 (p &amp;lt; 0.0001) and TRG3/4 (p = 0.01) were risk factors in univariate analysis, ypN≧1 (HR = 15.60, p = 0.01) was also independent covariate in multivariate analysis. For patients after CROSS neoadjuvant therapy, if there are still positive lymph nodes in clinical evaluation, M staging should be performed more carefully to avoid ineffective surgery with early postoperative distant recurrence.

377. NEOADJUVANT CARBOPLATIN/PACLITAXEL VERSUS 5-FLUOROURACIL/CISPLATIN IN COMBINATION WITH RADIOTHERAPY FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A MULTICENTER COMPARATIVE STUDY

Abstract Treatment options for esophageal cancer (EC) have rapidly expanded from surgery alone to multimodal approaches comprising surgery, chemotherapy or radiotherapy. High-quality evidence from clinical trials indicated that both carboplatin/paclitaxel (CROSS) and cisplatin/5-fluorouracil (PF) regimens are significantly effective at improving survival. However, the most beneficial neoadjuvant chemoradiotherapy (nCRT) combination for esophageal squamous cell carcinoma (ESCC) in Asia still remains uncertain. In this study we compared neoadjuvant CROSS versus PF regimen in combination with 41.4-50.4Gy of radiotherapy. Patients with ESCC were enrolled from three asian medical centers and stratified according to their nCRT regimen, i.e., CROSS+41.4-45Gy (CROSS) versus PF + 45Gy (PF4500) versus PF + 50.4Gy (PF5040). Propensity score analyses with stratification by inverse probability of treatment weighting (IPTW) was applied for nine baseline variables: gender, age, Charlson’s comorbidity index, clinical T and N stages, clinical stage, tumor length, tumor level and year of nCRT. Primary and secondary endpoints included overall survival (OS) and treatment-related complications. Compared to CROSS, patients who received PF regimens were expected to achieve comparable OS albeit more treatment-related complications. Before IPTW, 334 patients were included (CROSS, n = 124 versus PF4500, n = 105 versus PF5040, n = 105). The lowest chemotherapy completion rate was observed in the PF5040 group (76.2% versus 89.4% in CROSS and 92% in the PF4500 group). Compared with CROSS, both PF groups showed more severe weight loss during nCRT and a higher frequency of post-esophagectomy anastomotic leaks. PF5040 had the significantly highest pCR rate (45.3%). CROSS conferred a significant OS benefit over PF4500 (hazard ratio [HR] =1.30, 95% CI = 1.05-1.62) and similar survival compared with PF5040 (HR = 1.17, 95% CI = 0.94-1.45). The same trends were found upon analysing recurrence free survival. (Figure). Prior investigations reporting on the safety and efficacy of CROSS are mainly conducted in western populations, generally consisting adenocarcinoma, limiting the generalisability of these findings to Asian patients with ESCC. In our study, the CROSS regimen conferred a significant survival benefit over PF4500 and similar survival figures compared with PF5040. Considering the lower incidences of severe weight loss and post-esophagectomy anastomotic leaks, CROSS represents a safe and effective neoadjuvant treatment in Asian patients with ESCC.

266. EXTENSION OF FDG-PET-BASED RADIOMIC MODELS ON IDENTIFICATION OF PATIENTS WITH RESIDUAL ESOPHAGEAL CANCER AFTER NEOADJUVANT CHEMORADIOTHERAPY

Abstract For esophageal cancer patients, detection of residual tumor after neoadjuvant chemoradiotherapy (nCRT) is important for guiding treatment decisions regarding standard esophagectomy or active surveillance. Prediction models incorporating clinical variables and FDG-PET quantitative radiomic features have been previously developed in a single-center setting (‘development cohort’, Beukinga et al. 2018) to identify patients with residual tumor after nCRT. The aim was to improve generalizability by redeveloping the models (i.e. ‘model extension’) using a multicenter prospectively acquired cohort. The development cohort was combined with a patient cohort collected from a prospective multicenter study in four Dutch institutes. Patients underwent nCRT according to the CROSS regimen followed by esophagectomy 6–14 weeks after nCRT between 2013–2019. Outcome was tumor regression grade (TRG) 1–2 (0–10% tumor) vs TRG 3–4 (&amp;gt;10% tumor). FDG-PET/CT was performed 6–12 weeks after nCRT. Post-treatment FDG-PET-radiomic features were calculated from gross tumor volumes. Features were standardized per scanner. A bootstrapped least absolute shrinkage and selection (LASSO) model using clinical variables and radiomic features was developed and a model incorporating clinical variables was developed for reference. Some 262 patients were included. Median age was 65 years (IQR 60–70), 158 of 262 were male (82%) and outcomes were 129/262 TRG 1–2 (49%) and 133/262 TRG 3–4 (51%). The extended LASSO model included seven radiomic features and the clinical variables cT stage and histology (internally validated AUC, 0.59). At a probability threshold to obtain 90% sensitivity for detection of TRG 3–4 (benchmark with bite-on-bite biopsies + fine-needle aspiration of suspected lymph nodes), specificity was 36% and accuracy 63%. A LASSO clinical reference model (including cT, sex, histology) achieved an internally validated AUC of 0.58 (Fig. 1). The extended internally validated LASSO model incorporating post-treatment radiomic features and clinical variables yielded moderate discriminative ability. The improvement in predictive performance with this model compared with a model using only clinical variables was marginal. The application of radiomics to post-treatment FDG-PET/CT scans is of no help in decision-making in individual patients regarding the choice for active surveillance after nCRT.