Dataset Information

Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study.

ABSTRACT:

Background

PLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients.

Patients and methods

Patients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with disease control or response to 18 weeks of platinum-based first-line chemotherapy were randomised to active surveillance or maintenance durvalumab. The primary endpoint was progression-free survival (PFS). Safety was assessed in all patients who had commenced surveillance visits or received at least one dose of durvalumab. Exploratory survival analyses according to PD-L1 Combined Positive Score (CPS) and immune (biomarker-positive) or angiogenesis dominant (biomarker-negative) tumour microenvironment (TME) phenotypes were conducted.

Results

Between March 2015 and April 2020, 205 patients were randomised to surveillance (n = 100) and durvalumab (n = 105). No significant differences were seen in PFS [hazard ratio (HR) 0.84, P = 0.13] and overall survival (OS; HR 0.98, P = 0.45) between surveillance and durvalumab. Five patients randomised to durvalumab demonstrated incremental radiological responses compared with none with surveillance. Treatment-related adverse events occurred in 77 (76.2%) durvalumab-assigned patients. A favourable effect in OS with durvalumab over surveillance in CPS ≥5 and immune biomarker-positive patients was observed compared with CPS <5 and biomarker-negative subgroups, respectively: CPS ≥5 versus <5: HR 0.63, 95% confidence interval (CI) 0.32-1.22 versus HR 0.93, 95% CI 0.44-1.96; biomarker-positive versus negative: HR 0.60, 95% CI 0.29-1.23 versus HR 0.84, 95% CI 0.42-1.65.

Conclusion

Maintenance durvalumab does not improve PFS in patients with OG adenocarcinoma who respond to first-line chemotherapy but induced incremental radiological responses in a subset of patients. TME characterisation could refine patient selection for anti-PD-L1 therapy above PD-L1 CPS alone.

SUBMITTER: Fong C

PROVIDER: S-EPMC11298822 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study.

Fong C C Patel B B Peckitt C C Bourmpaki E E Satchwell L L Cromarty S S Kidd S S von Loga K K Uhlik M M Begum R R Rana T T Waddell T T Darby S S Bradshaw A A Roques T T Morgan C C Rees C C Herbertson R R Das P P Thompson C C Hewish M M Petty R R Thistlethwaite F F Rao S S Starling N N Chau I I Cunningham D D

ESMO open 20240713 7

<h4>Background</h4>PLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients.<h4>Patients and methods</h4>Patients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with dis ...[more]

PMID: 39002179

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Project description:Background18-Fluorodeoxyglucose-PET (18F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice. Only 40%-50% of the patients respond metabolically to therapy. As metabolic non-response is known to be associated with a dismal prognosis, metabolic non-responders are increasingly treated with alternative neoadjuvant chemotherapies or chemoradiation in order to improve their clinical outcome. We plan to investigate whether PET can be used as response assessment during radiochemotherapy given as salvage treatment in early metabolic non-responders to standard chemotherapy.Methods/designThe HICON trial is a prospective, non-randomized, explorative imaging study evaluating the value of PET as a predictor of histopathological response in metabolic non-responders. Patients with resectable AEG type I and II according to Siewerts classification, staged cT3/4 and/or cN+ and cM0 by endoscopic ultrasound, spiral CT or MRI and FDG-PET are eligible. Tumors must be potentially R0 resectable and must have a sufficient FDG-baseline uptake. Only metabolic non-responders, showing a < 35% decrease of SUV two weeks after the start of neoadjuvant chemotherapy are eligible for the study and are taken to intensified taxane-based RCT (chemoradiotherapy (45 Gy) before surgery. 18FDG-PET scans will be performed before ( = Baseline) and after 14 days of standard neoadjuvant therapy as well as after the first cycle of salvage docetaxel/cisplatin chemotherapy (PET 1) and at the end of radiochemotherapy (PET2). Tracer uptake will be assessed semiquantitatively using standardized uptake values (SUV). The percentage difference ΔSUV = 100 (SUV Baseline - SUV PET1)/SUV Baseline will be calculated and assessed as an early predictor of histopathological response. In a secondary analysis, the association between the difference SUV PET1 - SUV PET2 and histopathological response will be evaluated.DiscussionThe aim of this study is to investigate the potential of sequential 18FDG-PET in predicting histopathological response in AEG tumors to salvage neoadjuvant radiochemotherapy in patients who do not show metabolic response to standard neoadjuvant chemotherapy.

Project description: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.

Project description:BackgroundFirst-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.MethodsIn this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.FindingsFrom March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.InterpretationNivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.FundingBristol Myers Squibb, in collaboration with Ono Pharmaceutical.

Project description:IntroductionThere is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial.Methods and analysisThis multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m2) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma.Ethics and disseminationThe protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.Drug supplyAstraZeneca.Protocol versionCTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021.Trial registration numberClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.

Dataset Information

Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study.

Background

Patients and methods

Results

Conclusion

Publications

Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study.

Similar Datasets

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