The addition of the PD-L1–targeting monoclonal antibody durvalumab to conventional perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) resulted in a statistically significant and clinically meaningful improvement in overall survival, with benefit seen regardless of PD-L1 status, based on the final report of this outcome from the global phase III MATTERHORN trial of resectable gastric and gastroesophageal junction adenocarcinomas. Presented at the European Society for Medical Oncology (ESMO) Congress 2025 by Josep Tabernero, MD, PhD, of Vall d’Hebron Institute of Oncology, Barcelona, this analysis also showed improved event-free survival irrespective of the extent of pathologic response or node involvement.¹

The [final] overall survival results…strongly support perioperative durvalumab plus chemotherapy with FLOT as a new global standard of care for patients with localized gastric and gastroesophageal junction resectable adenocarcinomas.

— JOSEP TABERNERO, MD, PhD

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Earlier reports from the trial revealed a significant improvement in event-free survival, as well as higher rates of pathologic complete response, with FLOT plus durvalumab vs placebo.^2,3 An interim overall survival analysis furthermore indicated a trend toward improvement.²

“The [final] overall survival results…strongly support perioperative durvalumab plus chemotherapy with FLOT as a new global standard of care for patients with localized gastric and gastroesophageal junction resectable adenocarcinomas,” commented Dr. Tabernero.

Study Details

Patients with resectable stage II to IVA gastric or gastroesophageal junction adenocarcinoma were eligible for enrollment. Additional eligibility criteria included the absence of metastatic disease, no prior therapy, and an Eastern Cooperative Oncology Group performance status score of 0 or 1.

A total of 948 patients were randomly assigned in a 1:1 ratio to receive four doses of FLOT plus two doses of either durvalumab or placebo preoperatively. After surgery, they received these regimens again, followed by 10 doses of durvalumab or placebo as maintenance. The population was stratified by geographic region (Asia vs other regions), clinical lymph node status (positive vs negative), and PD-L1 expression (tumor area positivity < 1% vs ≥ 1%).

Event-free survival was evaluated as the primary endpoint. Key secondary endpoints included overall survival and pathologic complete response, the latter assessed by central review according to the modified Ryan criteria.

Three separate analyses were conducted within the MATTERHORN trial. The first assessed pathologic complete response after all patients had either undergone surgery or were deemed ineligible. The second was an interim analysis evaluating event-free survival, triggered at 41% maturity; overall survival was assessed at 34% maturity, with a minimal alpha-spend of 0.01%. The present analysis represents the final overall survival evaluation, conducted using the remaining alpha of 4.99%.

Overall Survival

With a median follow-up of 43 months, Dr. Tabernero reported that the final overall survival analysis “met the statistical hypothesis,” showing a statistically significant and clinically meaningful improvement with FLOT plus durvalumab vs placebo in the intention-to-treat population (hazard ratio [HR] = 0.78, 95% confidence interval [CI] = 0.63–0.96; stratified log-rank P = .021). Although medians were not reached in either arm, according to Dr. Tabernero, the curves separated after 13 months and continued to diverge over time. At 36 months, a 6.7% absolute improvement was observed, from 61.9% with placebo to 68.6% with durvalumab.

Subgroup analyses revealed a consistent overall survival benefit with durvalumab across most key populations. Dr. Tabernero emphasized, however, that the number of patients with clinical lymph node–negative status was much lowerthan those who were lymph node–positive, and that histologic subtype assessment was done locally rather than centrally, with 23% of patients having an indeterminate status.

An overall survival improvement was observed with durvalumab regardless of PD-L1 status. Dr. Tabernero noted that it was “interesting to see the hazard ratios are the same [for both the < 1% and ≥ 1% tumor area positivity groups: 0.79; 95% CI = 0.41–1.50 and 0.63–0.99, respectively].” He also said the survival curves for these populations begin to diverge around the 13-month mark, consistent with the findings in the overall population.

Pathologic Outcomes and Event-Free Survival

Pathologic response was assessed centrally in 757 patients who completed surgery and had samples evaluable by modified Ryan scoring. Among this population, 16.5% achieved a pathologic complete response, 25.8% achieved a major pathologic response, and 87.1% demonstrated any pathologic response. A total of 811 patients who completed surgery and had evaluable samples underwent locally assessed nodal staging, of whom 51.5% were node-negative and 48.5% were node-positive.

Dr. Tabernero reported improved event-free survival with FLOT plus durvalumab vs placebo among patients who showed any pathologic response. The hazard ratios in those with pathologic complete response, major pathologic response, and any pathologic response were 0.29 (95% CI = 0.08–0.96), 0.32 (95% CI = 0.15–0.68), and 0.60 (95% CI = 0.46–0.79), respectively.

Durvalumab vs placebo resulted in a higher rate of pathologic node-negative status (58.2% vs 44.8%). Event-free survival also improved with durvalumab regardless of nodal status, according to Dr. Tabernero, with a hazard ratio of 0.74 (95% CI = 0.46–1.18) in patients with node-negative disease and 0.77 (95% CI = 0.58–1.02) in their node-positive counterparts.

Dr. Tabernero shared these concluding comments: “The addition of durvalumab to conventional perioperative chemotherapy with FLOT demonstrated a statistically significant, but more importantly, a clinically meaningful improvement in overall survival in the intention-to-treat population. Also important, the overall survival improvement was seen in the same magnitude regardless of PD-L1 status. Any degree of pathologic response was associated with improved event-free survival in patients receiving durvalumab plus FLOT. Event-free survival was also improved regardless of pathologic nodal status.”

DISCLOSURE: Dr. Tabernero has served as a scientific consultant for Accent Therapeutics, Alentis Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Carina Biotech, Cartography Biosciences, Chugai, Daiichi Sankyo, F. Hoffmann–La Roche, Genentech, Johnson & Johnson/Janssen, Lilly, Marengo Therapeutics, Menarini, Merus, MSD, Novartis, Ono Pharma USA, Peptomyc, Pfizer, Pierre Fabre, Quantro Therapeutics, Scandion Oncology, Scorpion Therapeutics, Servier, Sotio Biotech, Syntelios AG, Taiho, Takeda Oncology, and Tolremo Therapeutics; and owns stock in Alentis Therapeutics, Oniria Therapeutics, 1TRIALSP, and Pangaea Oncology.

REFERENCES

1. Tabernero J, Al-Batran SE, Wainberg ZA, et al: Final overall survival and the association of pathological outcomes with event-free survival in MATTERHORN: A randomised, phase III study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric/gastroesophageal junction adenocarcinoma. ESMO Congress 2025. Abstract LBA81. Presented October 17, 2025.
2. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med 393:217-230, 2025.
3. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: Pathological complete response to 5-fluorouracil, leucovorin, oxaliplatin and docetaxel with or without durvalumab in resectable gastric and gastroesophageal junction cancer: Subgroup analysis by region from the phase 3, randomized, double-blind MATTERHORN study. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract LBA246. Presented January 18, 2024.

Expert Point of View

In commenting on the results of the final overall survival and pathologic correlates analyses of the phase III MATTERHORN trial, invited discussant Sylvie Lorenzen, MD, PhD, of Rechts der Isar Hospital, Technical University of Munich, asked whether the findings signal it may be time to change practice in locally advanced gastroesophageal cancer. She began by framing the key questions that should guide our evaluation of perioperative therapy: Is it safe and tolerable? Does it allow surgery to proceed without delay? Does it improve R0 resection rates? Does it affect downstaging? Does it increase pathologic response rates? And, “of course,” does it delay recurrence, improve survival, and benefit all patients?

Sylvie Lorenzen, MD, PhD

The FLOT4 trial results, Dr. Lorenzen noted, established the European Society for Medical Oncology (ESMO) Guidelines’ recommendation for perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy. Highlighting earlier findings from MATTERHORN, which demonstrated a significant improvement in event-free survival and trend toward improved overall survival,¹ she called durvalumab plus FLOT “the new standard,” although guideline updates are still awaited.

Contextualizing Outcomes

Dr. Lorenzen explained that patients who achieve a pathologic response have been found to experience lower recurrence rates and prolonged overall survival, and MATTERHORN provides the “largest and clearest” data set to date as to whether this is prognostic in the context of immunotherapy. The addition of durvalumab to FLOT increased pathologic response and improved nodal clearance, she noted, and these effects were linked to improved event-free survival in the overall population.

Raising the question of whether the event-free survival benefit would ultimately translate into improved overall survival, Dr. Lorenzen noted that “the shape of the curves [from the interim overall survival analysis] already looked very positive.” Now, with longer follow-up, more events, and higher maturity, the endpoint reached statistical significance, which she noted “is important for our patients.”

She compared the findings with other trials, noting that “in the context of [KEYNOTE-585, RESOLVE, and PRODIGY], it looks like the magnitude of effect increases with longer follow-up. This is confirmed now also with MATTERHORN, showing a significant increase in overall survival, although the hazard ratios look similar.”

Looking back on nearly 2 decades of progress in perioperative treatment, Dr. Lorenzen drew attention to the MAGIC trial, in which the 24-month overall survival rate with surgery alone was approximately 41%.² With modern regimens like durvalumab plus FLOT, that rate has risen to 75.5%—an additional 34.5% improvement.

Implementation Considerations

Dr. Lorenzen agreed with the notion of Klempner et al at the 2025 ASCO Annual Meeting that durvalumab plus FLOT is “the right therapy for everyone,” noting that the present final overall survival analysis confirmed the effect to be independent of PD-L1 expression. Nevertheless, she cautioned, “we should pay attention to subgroups like female, node-negative, and diffuse type, as they seem not to have the same benefit as the others; however, these numbers are small, and the confidence intervals are wide.”

“MATTERHORN…is answering all the [abovementioned] questions satisfactorily,” Dr. Lorenzen concluded. She emphasized the need to adapt in the era of immunotherapy: “We have to think about novel immune-related pathologic response criteria.” She furthermore described the overall survival results as “positive and relevant around all subgroups” and expressed optimism that the phase III DANTE trial will confirm these data, while cautioning that implementation guidelines are still pending.

DISCLOSURE: Dr. Lorenzen has received personal honoraria from Amgen, Astellas, AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, Falk Foundation, Merck, MSD, Novartis, Roche, Servier, and Takeda; and has received research support from Lilly and Amgen.

REFERENCES

1. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med 393:217-230, 2025.
2. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006.