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BackgroundZolbetuximab plus first-line EOX (epirubicin, oxaliplatin, capecitabine; ZOL/EOX) significantly prolonged progression-free survival and overall survival in the FAST trial vs EOX alone. We report the patient-reported outcomes (PROs) of FAST in patients with advanced gastroesophageal adenocarcinoma.MethodsPatients were randomized to ZOL/EOX or EOX alone. Patients could receive ≤ 8 EOX cycles and remained on zolbetuximab until disease progression. PROs were collected using the EORTC QLQ-C30 and QLQ-STO22 before drug administration at day 1/cycle 1, day 1/cycle 5, end of EOX treatment, and q12w thereafter until disease progression. Time to deterioration (TTD), defined as the first meaningful worsening from baseline, in the individual QLQ-C30/QLQ-STO22 scores was analyzed. Longitudinal changes in scores from baseline were analyzed using a mixed-effects model for repeated measures (MMRM).ResultsThe per protocol population included 143 (ZOL/EOX: 69; EOX: 74) patients. Baseline QLQ-C30 and STO22 scores were comparable between arms and denoted intermediate-to-high quality of life (QoL), intermediate-to-low global health status (GHS) and low symptom burden. Descriptive analyses showed no differences between arms until end of EOX but maintenance therapy with zolbetuximab was associated with better QoL and less symptom burden thereafter. TTD for most scores favored ZOL/EOX over EOX and reached statistical significance for GHS (p = 0.008). MMRM results support TTD findings; no statistically significant differences were observed between arms in any score except for nausea and vomiting (p = 0.0181 favoring EOX).ConclusionsZOL/EOX allowed patients to maintain good QoL and low symptom burden for longer than EOX alone.

In resectable gastric and gastroesophageal junction cancer, adding durvalumab to perioperative chemotherapy improved event-free survival and pathological complete response, with no major increase in high-grade adverse events.

Background: No clinical trial has directly compared nab-paclitaxel/gemcitabine (nab-P/G) with FOLFIRINOX (fluorouracil/leucovorin/oxaliplatin/irinotecan) in metastatic or advanced pancreatic cancer (mPC or aPC). We conducted a systematic review of real-world studies comparing these regimens in the first-line setting. Methods: Embase and MEDLINE databases through 22 January 2019, and Gastrointestinal Cancers Symposium 2019 abstracts were searched for real-world, retrospective studies comparing first-line nab-P/G versus FOLFIRINOX in mPC or aPC that met specific parameters. Studies with radiotherapy were excluded. Study quality was assessed using the Newcastle–Ottawa Scale. Results: Of 818 records initially identified, 35 were duplicates and 749 did not meet the eligibility criteria, mostly because they were either not comparative (n = 356) or not first line (n = 245). The remaining 34 studies (21 mPC; 13 aPC) assessed >6915 patients who received nab-P/G or FOLFIRINOX. In the studies identified, the median overall survival (OS) reached 14.4 and 15.9 months with nab-P/G and FOLFIRINOX, respectively, and median progression-free survival reached 8.5 and 11.7 months, respectively. Safety data were reported in 14 studies (2205 patients), including 8 single-institutional studies. In most single-institutional studies that reported safety data, rates were higher with FOLFIRINOX versus nab-P/G for grade 3/4 neutropenia (five of six studies) and febrile neutropenia (all three studies), while rates of grade 3/4 peripheral neuropathy were higher with nab-P/G in four of seven studies. Conclusions: Although FOLFIRINOX was associated with slightly longer median OS in more studies, the differences, when available, were not statistically significant. Therefore, a randomized, controlled trial is warranted. Toxicity profile differences represent key considerations for treatment decisions.

Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1, intravenous cisplatin 60 mg/m2 on day 1, and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally (two doses of 625 mg/m2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10–23] of 128 patients vs eight [6%; 3–11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3–4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. None.

Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Merck KGaA.

Background Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. Methods This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. Discussion If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. Trial registration The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014–002665-30.

Background The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40–50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60–70% of tumors of diffuse type, compared to only 20–30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since pts. with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. Methods This is a multicenter, randomized, controlled, open-label study including a total of 200 pts. with localized and locally advanced diffuse or mixed type (Laurens’s classification) adenocarcinoma of the stomach and Type II/III GEJ. All enrolled pts. will have received 3–6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m 2 ; Oxaliplatin 85 mg/m 2 ; Leucovorin 200 mg/m 2 ; 5-FU 2600 mg/m 2 , q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (control arm) or surgery + intraoperative HIPEC (cisplatin 75 mg/m 2 solution administered at a temperature of 42 °C for 90 min) and postoperative FLOT (experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, rate of pts. with peritoneal relapse at 2 and 3 years, perioperative morbidity/mortality and quality of life. The trial starts with a safety run-in phase. After 20 pts. had curatively intended resection in Arm B, an interim safety analysis is performed. Recruitment has already started and first patient in was on January 18th, 2021. Discussion If the PREVENT concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, pts. with gastric cancer and no peritoneal involvement will not be treated with HIPEC during surgery. Trial registration The study is registered on June 25th, 2020 under ClinicalTrials.gov Identifier: NCT04447352 ; EudraCT: 2017-003832-35 .

Background Despite obvious advances over the last decades, locally advanced adenocarcinomas of the gastroesophageal junction (GEJ) still carry a dismal prognosis with overall 5-year survival rates of less than 50% even when using modern optimized treatment protocols such as perioperative chemotherapy based on the FLOT regimen or radiochemotherapy. Therefore the question remains whether neoadjuvant chemotherapy or neoadjuvant radiochemotherapy is eliciting the best results in patients with GEJ cancer. Hence, an adequately powered multicentre trial comparing both therapeutic strategies is clearly warranted. Methods The RACE trial is a an investigator initiated multicenter, prospective, randomized, stratified phase III clinical trial and seeks to investigate the role of preoperative induction chemotherapy (2 cycles of FLOT: 5-FU, leucovorin, oxaliplatin, docetaxel) with subsequent preoperative radiochemotherapy (oxaliplatin weekly, 5-FU plus concurrent fractioned radiotherapy to a dose of 45 Gy) compared to preoperative chemotherapy alone (4 cycles of FLOT), both followed by resection and postoperative completion of chemotherapy (4 cycles of FLOT), in the treatment of locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction. Patients with cT3–4, any N, M0 or cT2 N+, M0 adenocarcinoma of the GEJ are eligible for inclusion. The RACE trial aims to enrol 340 patients to be allocated to both treatment arms in a 1:1 ratio stratified by tumour site. The primary endpoint of the trial is progression-free survival assessed with follow-up of maximum 60 months. Secondary endpoints include overall survival, R0 resection rate, number of harvested lymph nodes, site of tumour relapse, perioperative morbidity and mortality, safety and toxicity and quality of life. Discussion The RACE trial compares induction chemotherapy with FLOT followed by preoperative oxaliplatin and 5-Fluorouracil-based chemoradiation versus preoperative chemotherapy with FLOT alone, both followed by surgery and postoperative completion of FLOT chemotherapy in the treatment of locally advanced, non-metastatic adenocarcinoma of the GEJ. The trial aims to show superiority of the combined chemotherapy/radiochemotherapy treatment, assessed by progression-free survival, over perioperative chemotherapy alone. Trial registration ClinicalTrials.gov ; NCT04375605 ; Registered 4th May 2020;

BackgroundRamucirumab is a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor-2. Second-line ramucirumab, in conjunction with paclitaxel (ramucirumab 8 mg/kg or placebo in combination with 80 mg/m2 paclitaxel), has been shown to be effective and safe in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in RAINBOW, a global phase III randomized clinical trial. We conducted an exploratory exposure–response analysis of efficacy and safety of ramucirumab in East Asian patients from the RAINBOW trial.MethodsUsing sparse pharmacokinetic samples collected in the RAINBOW trial, a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss) using a nonlinear mixed-effect modeling approach. Kaplan–Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (Cmin,ss) and efficacy relationship by overall survival and progression-free survival. Exposure-safety relationships were assessed descriptively.ResultsTwo hundred and twenty-two East Asian patients were included in this exposure–response analysis. Higher ramucirumab Cmin,ss was associated with longer overall survival (p = 0.0115) and progression-free survival (p = 0.0179) in this patient cohort. Patients with higher ramucirumab Cmin,ss (≥56.87 ng/ml median) had higher incidences of grade ≥3 leukopenia and neutropenia, but not febrile neutropenia or hypertension.ConclusionsThis exploratory analysis suggests a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in East Asian patients from RAINBOW, consistent with the overall exposure–response analysis from this trial. A regimen with a higher dosage of ramucirumab warrants further consideration for East Asian patients with gastric/GEJ cancer.

Background Paclitaxel in combination with ramucirumab is the standard of care second-line therapy in gastro-esophageal adenocarcinoma (GEA). As the number of taxane pretreated patients in the perioperative or first-line setting is increasing, it is unknown whether these patients benefit from re-applying a taxane in using the combination of paclitaxel and ramucirumab. Furthermore, the rates of neurotoxicity with first-line FOLFOX or FLOT range from 30%–70%, making second-line taxane‐containing therapy less suitable to a meaningful portion of patients. This patient group is likely to benefit from a taxane-free second-line chemotherapy regimen, such as FOLFIRI and ramucirumab (FOLFIRI-Ram). Therefore, the RAMIRIS phase III trial evaluates the effects of the regimen of FOLFIRI-Ram in the second-line treatment after a taxane-based chemotherapy in patients with advanced GEA. Methods The RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B). The Phase II is already closed with 111 enrolled patients. In the phase III, 318 taxane-pretreated patients with advanced GEA will be recruited and randomized 1:1 to FOLFIRI (5-FU 2400 mg/m 2 over 46 h i.v., irinotecan 180 mg/m 2 i.v.; 5-FU 400 mg/m 2 bolus; leucovorin 400 mg/m 2 i.v.; on day 1 and 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm A) or paclitaxel 80 mg/m 2 (days 1, 8, 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm B). The primary endpoints are overall survival (OS) and objective overall response rate (ORR). Secondary endpoints are progression-free survival (PFS), disease control rate and safety and quality of life as assessed by EORTC-QLQ-C30 questionnaire. Discussion The already completed RAMIRIS phase II demonstrated feasibility and efficacy of FOLFIRI-Ram. Especially docetaxel-pretreated patients seemed to markedly benefit from FOLFIRI-Ram, with favorable response- and PFS rates and lower toxicity. This offers a rationale for the phase III trial. If the RAMIRIS III trial transfers and confirms the results, they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA. Trial registration NCT03081143 Date of registration: 13.11.2015