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editorial
. 2024 Mar 21;3:100035. doi: 10.1016/j.esmogo.2023.100035

A wind of change in upper gastrointestinal cancers: updates from ESMO 2023

A Cammarota 1, AR Siebenhüner 2,3, MA Maqueda 4, T Fleitas-Kanonnikoff 5,6, H van Laarhoven 7, C de la Fouchardière 8, R Obermannova 9,10, M Moehler 11, EC Smyth 12
PMCID: PMC12836638  PMID: 41648747

Introduction

Biomarker-selected strategies, including immune checkpoint inhibitors (ICIs), have marked a paradigm change in the treatment of advanced gastric and gastroesophageal junction adenocarcinoma (GEA), showing improved survival over standard chemotherapy.1, 2, 3, 4, 5, 6, 7, 8

Treatment of locally advanced operable disease still relies on chemotherapy with or without radiotherapy for all-comers with rather disappointing outcomes, increasing the interest in moving targeted approaches forward in the perioperative setting.9,10

In this editorial, we will discuss the results of the studies in GEA presented at the European Society for Medical Oncology (ESMO) 2023, helping put these in perspective of current knowledge and ongoing studies.

Perioperative studies

The phase III KEYNOTE 585 tested perioperative fluorouracil plus cisplatin (FP) (n = 804) or fluorouracil, leucovorin, oxaliplatin plus docetaxel (FLOT) (n = 203) with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody, or placebo followed by pembrolizumab/placebo for 11 cycles.11 In this study the chemotherapy regimen choice was mostly non-FLOT and the study used a complex statistical method to assess the co-primary endpoints of pathological complete response (pCR), event-free survival (EFS), and overall survival (OS). In the third interim analysis, pCR was significantly improved with pembrolizumab both in the FP [Δ10.9%, 95% confidence interval (CI) 7.5% to 14.8%, P < 0.00001] and FP plus FLOT (Δ10.6%, 95% CI 7.4% to 14.0%, P < 0.0001) cohorts. Despite not reaching the boundaries for statistical significance required for a change in practice, in the FP cohort EFS was longer with pembrolizumab [44.4 versus 25.3 months, hazard ratio (HR) 0.81, 95% CI 0.67-0.99, P = 0.0198]. OS was similar (60.7 versus 58.0 months, HR 0.90, 95% CI 0.73-1.12) between arms. Final survival data, including EFS/OS in the FLOT cohort, are awaited.

Similarly, the phase III MATTERHORN enrolled 948 patients to receive perioperative FLOT with or without durvalumab, an anti-programmed death-ligand 1 (PD-L1) antibody, followed by maintenance with durvalumab for 10 cycles.12 Durvalumab plus FLOT reached the secondary objective and improved pCR [Δ12%, odds ratio (OR) 3.08, P < 0.00001], major pathological response (MPR) (OR 2.19, P < 0.00001), and tumour down-staging (pT0, 21% versus 10%; pN0, 47% versus 33%) while access to surgery, R0 rates, and safety were similar. The study continues until EFS, the primary endpoint, is mature. In both KEYNOTE 585 and MATTERHORN, all ICI-related endpoints were better, as expected, in patients with high PD-L1-expressing tumours.

Although not yet ready for clinical use, these studies highlight the feasibility of adding biological agents to polychemotherapy, without safety concerns or negative effects on surgical outcomes. The substantial improvement in pCR rates with ICIs also suggests increased activity of such strategies. It remains to be elucidated whether the lack of survival advantage in KEYNOTE 585 is attributable to the backbone chemotherapy or other factors. High tumour burden (cN2 or cT4) may have impacted outcomes. Diagnostic laparoscopy before inclusion was not mandatory in KEYNOTE 585, which implies that patients with difficult-to-cure peritoneal carcinomatosis may have been included. Within the next year, MATTERHORN should report on EFS and we will understand whether adding an ICI to perioperative chemotherapy will yield a new treatment approach for all-comers or whether it will be back to the drawing board for biomarker-selected trials.

Long-term outcomes from the Chinese phase III RESOLVE trial showed that perioperative SOX significantly improved both 5-year disease-free survival (53.2% versus 45.8%, HR 0.79, 95% CI 0.63-0.98, P = 0.034) and OS (60.0% versus 52.1%, HR 0.79, 95% CI 0.62-1.00, P = 0.049) compared to adjuvant SOX, suggesting a role for perioperative treatment in Asian patients, particularly with more locally advanced disease (cT4aN+ or cT4bNany).13 S1 was non-inferior in terms of OS compared to 5-fluorouracil (5-FU) and, based on data from the metastatic setting, may be better tolerated. The results of this trial mean that perioperative, rather than adjuvant chemotherapy, may become a standard of care in Asia for locally advanced gastric cancer.

The phase III, stepped-wedged cluster randomized SANO trial showed non-inferiority of active surveillance versus planned surgery (OS: HR 1.14, 95% CI 0.74-1.78, P = 0.55) in clinical complete responders (CCR, n = 274) after neoadjuvant chemoradiotherapy (CRT).14 The inclusion of mixed histology (squamous cell and adenocarcinoma), non-randomized patients (n = 35), and cross-over between surveillance and surgery arms (n = 41) leave the study inconclusive, particularly for adenocarcinoma, which has renowned different biology and poorer response to CRT. Also, unreported outcomes from non-CCR patients, who had undergone surgery outside of the study, impair the external validity of this trial. More comprehensive data are needed to understand whether non-operative management could become an option, sparing long-term quality-of life (QoL) issues.

Metastatic setting

The results of the global phase III KEYNOTE 811 trial have changed practice in the treatment of human epidermal growth factor receptor-2 (HER2)-positive advanced GEA.15 By incorporating pembrolizumab into the standard first-line trastuzumab–chemotherapy, KEYNOTE 811 met one of its dual primary endpoints, progression-free survival (PFS) (10.0 versus 8.1 months, HR 0.73, 95% CI 0.61-0.87) surpassing trastuzumab–chemotherapy and placebo. Patients receiving pembrolizumab also had a greater objective response rate (ORR) of 73% (95% CI 68.0% to 77.0%) versus 60% (95% CI 55.0% to 65.0%). At this data cut-off, OS with pembrolizumab plus trastuzumab–chemotherapy failed to meet the criteria for superiority over the comparator arm in the all-comer population (HR 0.84, 95% CI 0.70-1.01). However, a subgroup analysis showed a clinically meaningful benefit (20 versus 15.7 months, HR 0.81, 95% CI 0.67-0.98) in the PD-L1-positive (by combined positive score ≥ 1, 85% of the entire population) subgroup. While final OS is pending, these data supported the update of the ESMO Gastric Cancer Living Guidelines and the combination has been approved by regulatory authorities.16

Aligned with other first-line combinations of ICIs plus chemotherapy, the phase III RATIONALE 305 study reported its final results.17 Patients diagnosed with advanced, HER2-negative GEA were randomised to receive front-line chemotherapy with or without tislelizumab, a humanised immunoglobulin G4 anti-PD-1 monoclonal antibody. PD-L1 tumour area positivity (TAP) score was ≥5% in 55% of the population. A meaningful OS advantage was observed only for patients with PD-L1 TAP ≥ 5% (16.4 versus 12.8 months, HR 0.71, 95% CI 0.58-0.86, P = 0.0056), providing consistent evidence for the benefit of PD-1 inhibition in immune-sensitive GEA with higher levels of PD-L1 expression.

Furthermore, while upfront ICI for microsatellite instable (MSI) colorectal cancer is well established, no front-line prospective trial has been conducted specifically for metastatic MSI-H GEA.18 The phase II Japanese ‘No limit’ study evaluated the efficacy and safety of the anti-PD-1 nivolumab plus low-dose ipilimumab (1mg/kg), an anti-cytotoxic T-lymphocyte associated protein 4 antibody, as first-line therapy for patients with MSI-H advanced gastric cancer.19 Of 935 cases screened, 29 MSI patients were enrolled (positivity rate = 5.6%). The primary aim, ORR, measured by blinded independent central review, was 62.1% (95% CI 42.3% to 79.3%), including 10.3% complete responses. With a median follow-up of 9.0 months (range 4.0-18.0 months), mPFS was 13.8 months (95% CI 13.7 months to not reached) and 73% (95% CI 52% to 86%) of patients were progression free at 12 months. In keeping with the subgroup analyses from Checkmate 649, 12-month OS rates reached 80% (95% CI 57% to 91%).20 Adverse events (AEs) were the main reason for treatment discontinuation (44.8%) without new safety signals. Mature data on survival are required, but this evidence could set the scene for a much-needed registration trial of a chemotherapy-free approach in this subgroup.

The French phase III GASTFOX study demonstrated the superiority of first-line mFLOT/TFOX (docetaxel 50 mg/m2 + oxaliplatin 85 mg/m2 + 5-FU continuous 2400 mg/m2 in 46 h, q2w) versus FOLFOX for patients with HER2-negative, locally advanced unresectable or metastatic GEA.21 With 506 patients enrolled, the study met its primary endpoint, PFS in the intention-to-treat population (restricted mean survival time at 12 months of follow-up: 7.5 versus 6.6 months, P = 0.007). OS (HR 0.82, P = 0.048) and ORR (66.0 versus 56.7%, P = 0.038) also significantly favoured mFLOT/TFOX. Although treatment-related AEs occurred more frequently with the triplet, patients on mFLOT/TFOX experienced delayed QoL deterioration. Subgroup analyses suggested that young (<65 years), fit [Eastern Cooperative Oncology Group (ECOG) performance status 0] patients and diffuse subtype may derive greater benefit from the triplet, placing mFLOT/TFOX as a potential first-line therapeutic option for a population with no actionable biomarkers.

Updated results were presented from the phase I trials GLOW and SPOTLIGHT, evaluating the addition of zolbetuximab to first-line platinum doublet chemotherapy in patients with HER2-negative advanced GEA with Claudin 18.2 expression.22,23 Zolbetuximab, a monoclonal antibody targeting Claudin 18.2, continued to demonstrate consistent and statistically significant improvements in PFS (GLOW: HR 0.68, P = 0.0004; SPOTLIGHT: HR 0.73, P = 0.0022) and OS (GLOW: HR 0.77, P = 0.0079; SPOTLIGHT: HR 0.78, P = 0.0067) compared to placebo, with no additional safety concerns or deterioration in health-related QoL.24

Conclusions

The data presented at ESMO 2023 showcased a boost in treatment options for GEA patients. ICIs plus chemotherapy appeared to be safe and active, particularly in PD-L1 highly expressing tumours, with pending survival results for perioperative use. Upfront pembrolizumab plus trastuzumab–chemotherapy set a new standard for HER2-positive PD-L1 combined positive score ≥ 1 advanced GEA, as timely implemented in the ESMO Gastric Cancer Living Guidelines. Dual checkpoint blockade (PD-1/anti-cytotoxic T-lymphocyte associated protein 4) proved a robust ORR benefit in patients with MSI-H advanced disease, holding promise for chemotherapy-free regimens for this rare subgroup. Targeting Claudin 18.2 was validated as effective, and mFLOT offered a new regimen for fit patients without actionable biomarkers. Improving outcomes of patients with upper gastrointestinal cancers remains an utmost priority that ongoing studies with novel generations of ICIs and targeted agents would hopefully unravel.

Acknowledgments

Funding

None declared.

Disclosure

ARS advisory boards and consulting honoraria from AMGEN, AAA, Bayer, BMS, IPSEN, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, and Servier, and travel grants from IPSEN and ROCHE. MAM consulting/advisory role with Merck Sharp & Dohme, Bristol Myers Squibb, Eli Lilly, and Servier; and travel accommodations from Eli Lilly. HvL (all payments are made to their institution) consultant or advisory role for AstraZeneca, BeiGene, BMS, and MSD and Amphera, Daiichi-Sankyo, Dragonfly, Eli Lilly, Nordic Pharma, and Servier; research funding, medication supply, or both from Incyte, Merck, Roche, and Servier and from Bayer, BMS, Celgene, Janssen, Eli Lilly, Nordic Pharma, and Philips; and speaker roles for Astellas, Benecke, Daiichi-Sankyo, JAAP, Medtalks, Novartis, and Travel Congress Management. CdlF consultant/advisor for Amgen, Astellas Pharma, Bristol Myers Squibb, Eisai, Eli Lilly and Company, Daichi-Sankyo, IPSEN, MSD Oncology, Pierre Fabre, Roche/Genentech and Servier; research funding by MSD, Natera, Pierre Fabre and Servier; travel/accommodation expenses by Amgen, MSD Oncology, Pierre Fabre, Roche and Servier. RO personal fees from BMS, Servier, Merck, Merck KGaA and a research grant from Roche (institutional). MM honoraria from Amgen, Roche/Genentech, Merck Serono, MSD Oncology, Bristol Myers Squibb, AstraZeneca/MedImmune, Servier, Pierre Fabre, Sanofi; consulting or Advisory Role for Bayer, MSD, Merck Serono, Amgen, Taiho Pharmaceutical, Pfizer, Roche, Lilly, Servier, BeiGene, BMS, AstraZeneca; research funding from Amgen (Inst), Leap Therapeutics (Inst), Merck Serono (Inst), AstraZeneca (Inst), MSD (Inst); Travel, Accommodations, Expenses support by Amgen, Merck Serono, Roche, Bayer, ASCO, German Cancer Society, MSD, ESMO, BeiGene, Hong Xiao; employment: Bristol Myers Squibb/Celgene; stock and other ownership interests: Bristol Myers Squibb/Celgene. ECS grants and personal fees from BMS and AstraZeneca; personal fees from Amgen, Daiichi-Sankyo, Merck, Viracta, Astellas, Novartis, Pfizer, Zymeworks, and BeiGene; personal fees and non-financial support from Mirati; Chair of the EORTC Gastric Cancer Taskforce 2021-2024; and has been a UK and Ireland Oesophagogastric Cancer Group trustee since 2022. ECS is supported by the NIHR Biomedical Research Centre at Oxford. All other authors have declared no conflicts of interest.

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