In patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma, perioperative treatment with the checkpoint inhibitor durvalumab in combination with standard chemotherapy significantly reduced the risk of recurrence or death by 29% in the phase III MATTERHORN trial. The findings, which experts agree may represent a new standard of care in this cancer, were reported during the Plenary Session of the 2025 ASCO Annual Meeting by Yelena Y. Janjigian, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York.1 The findings were published concurrently in The New England Journal of Medicine.2
“We demonstrated an early and sustained separation in the event-free survival curve, with a hazard ratio of 0.71, which is statistically and clinically meaningful.”— YELENA Y. JANJIGIAN, MD
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“We demonstrated an early and sustained separation in the event-free survival curve, with a hazard ratio of 0.71, which is statistically and clinically meaningful. The event-free survival benefit was seen across prespecified subgroups, and we did not see any new safety signals. Therefore, this will change practice for our patients, which is exciting to see,” Dr. Janjigian said at a press briefing during the meeting.
At a median follow-up of about 31 months, the median event-free survival was not reached with durvalumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), as compared with 32.8 months with placebo plus FLOT (hazard ratio [HR] = 0.71; P < .001). In the arm given durvalumab plus FLOT, the 18- and 24-month event-free survival rates were 73% and 67%, respectively, as compared with 64% and 59% in the control arm. The benefit was consistent across subsets, with most hazard ratios being concordant with that of the primary endpoint.
Pamela Kunz, MD, FASCO
ASCO expert Pamela Kunz, MD, FASCO, Director of the Center for Gastrointestinal Cancers at the Smilow Cancer Hospital and Yale Cancer Center, New Haven, Connecticut, shared these comments at a press briefing: “MATTERHORN shows that the addition of durvalumab to FLOT prolongs event-free survival in localized gastric and GEJ cancers, and this is going to change the standard of care for this patient population. The study enrolled globally, across multiple regions, indicating this is a feasible treatment to implement across the world.”
Understanding the Trial Design
Dr. Janjigian emphasized there is a need for a new approach in localized, nonmetastatic gastric or GEJ cancer. “We know that immunotherapy works for stage IV disease. We’ve been using anti–PD-1 agents for years now in the advanced setting, but it has not been proven to help patients in early-stage cancer. MATTERHORN was designed to address this,” she said.
The global, double-blind, placebo-controlled trial enrolled patients with stage II to IVA gastric or gastroesophageal junction adenocarcinoma without evidence of metastases and no prior treatment. They were randomly assigned to receive durvalumab plus FLOT or FLOT alone, as follows:
Experimental arm: Neoadjuvant therapy with two cycles of durvalumab plus FLOT, followed by surgery, followed by adjuvant therapy with two cycles of durvalumab plus FLOT and then 10 additional adjuvant cycles of durvalumab for up to 1 year.
Control arm: Neoadjuvant FLOT, followed by two cycles of FLOT and then 10 cycles of placebo for up to 1 year.
In terms of patient characteristics, Dr. Janjigian pointed out that although this was a global trial, there were few (19%) patients enrolled from Asia (where gastric cancer is more common). Two-thirds of the cancers were gastric, about one-quarter were T4 tumors, most (90%) were PD-L1–positive, and 5% were microsatellite-instable (MSI-high). Commenting on the typical patient in the study, she said: “They were not ‘well-behaving’ cancers. A lot of these tumors were invading through the serosa, and 70% of patients had positive lymph nodes.”
The primary endpoint was event-free survival, defined as the time from randomization to an event (ie, recurrence) or death. Along with overall survival and pathologic complete response, a key secondary endpoint was disease-free survival, which was the time to disease recurrence or death in participants achieving R0 resections.
Secondary Endpoints
At a median follow-up of almost 3 years, the median overall survival was not reached in the durvalumab-plus-FLOT arm and was 47.2 months with placebo plus FLOT alone (HR = 0.7; P = .025). The 18- and 24-month overall survival rates were 81% and 76%, respectively, in the durvalumab-plus-FLOT arm and 77% and 70%, respectively, in the placebo-plus-FLOT arm. Pathologic complete responses were achieved by 19% of patients receiving durvalumab plus FLOT vs 7% of those receiving placebo plus FLOT, for a 12% absolute different (odds ratio = 3.08; P < .001).
Median disease-free survival—an endpoint for patients achieving R0 resections—was not reached in the durvalumab-plus-FLOT arm and was 39.8 months in the placebo-plus-FLOT arm (HR = 0.70; 95% confidence interval = 0.53–0.93). The 18- and 24-month disease-free survival rates were 79% and 75%, respectively, for durvalumab plus FLOT vs 73% and 66%, respectively, for placebo plus FLOT.
Rates of Treatment, Completion of Surgery
Dr. Janjigian emphasized that the addition of durvalumab did not seem to compromise the receipt of standard FLOT. At least 95% of patients in both arms received their assigned neoadjuvant treatment. Surgery was attempted by approximately 90% in both arms and completed by 87% in the durvalumab-plus-FLOT arm and 84% in the control arm, with R0 resections achieved by 92% of both arms. Any adjuvant therapy was given to 77% and 74% of patients, respectively.
A total of 52% percent of patients in both arms completed adjuvant therapy with durvalumab or placebo; 61% and 64%, respectively, completed adjuvant therapy with FLOT—a figure Dr. Janjigian considered “actually pretty good for this cohort of patients.” At data cutoff, 68% of patients in the durvalumab-plus-FLOT arm and 59% of patients in the placebo-plus-FLOT arm were actively in follow-up. In terms of the number of neoadjuvant and adjuvant cycles of durvalumab and FLOT, she noted that treatment delivery was similar in both arms.
Safety Profile
Adverse effects possibly related to treatment were observed in 95% of each treatment arm, including those of grade 3 or 4 in 60% receiving durvalumab plus FLOT and 59% receiving placebo plus FLOT. Adverse events led to discontinuation of any study treatment in 30% and 23%, respectively. Immune-related adverse events of any grade were observed in 23% of the durvalumab-plus-FLOT arm and 7% of the placebo-plus-FLOT arm and were grade 3 or 4 in 7% and 4%, respectively. Surgery was delayed or not performed in three patients in each arm.
DISCLOSURE: Dr. Janjigian reported financial relationships with AbbVie, AmerisourceBergen, Arcus Biosciences, AskGene Pharma, Astellas Pharma, AstraZeneca, Axis Medical Education, Basilea Pharmaceutical, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clinical Care Options, Daiichi Sankyo, eChinaHealth, Ed Med Resources (OncInfo), Eisai, Geneos, Genzyme, Giants of Cancer Care, GlaxoSmithKline, Guardant Health, HC Wainwright & Co, HMP Education, Imedex, Imugene, Inspirna, Jazz Pharmaceuticals, Lilly, Lynx Health, Master Clinician Alliance, Merck, Merck Serono, Mersana, Michael J. Hennessy Associates, Paradigm, PeerView, Pfizer, Physicians’ Education Resource, Research to Practice, Seagen, Silverback Therapeutics, Suzhou Liangyihui Network Technology, Talem Health, TotalCME, WebMD, and Zymeworks. Dr. Kunz has received institutional research funding from RayzeBio and Novartis.
REFERENCES
1. Janjigian Y, Al-Batran SE, Wainberg Z, et al: Event-free survival in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer. 2025 ASCO Annual Meeting. Abstract LBA5. Presented June 1, 2025.
2. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med. June 1, 2025 (early release online).
EXPERT POINT OF VIEW
“The MATTERHORN trial moves the field forward and establishes perioperative durvalumab plus FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel] as the new standard for patients with locally advanced gastric and gastroesophageal junction cancers,” said the invited discussant of the MATTERHORN trial, Samuel J. Klempner, MD, FASCO, a gastrointestinal medical oncologist at the Massachusetts General Hospital Cancer Center and Associate Professor at Harvard Medical School, Boston.
Samuel J. Klempner, MD, FASCO
Dr. Klempner began by reminding listeners at the Plenary Session of the significance of this malignancy. Gastric or gastroesophageal junction cancer represents the fifth leading cause of cancer-related deaths, he said, and outside of a few countries with routine screening, most patients present with at least regional node-positive disease. Cure [5-year overall survival] rates have hovered around 50% for patients with stage III disease, indicating the cancer’s propensity for occult micrometastatic spread. Finally, the field has not yet been able to translate biomarkers from the metastatic setting to nonmetastatic disease or incorporate response-adaptive strategies such as circulating tumor DNA into routine management. “Improving outcomes remains a significant unmet need,” he observed.
A perioperative three-drug regimen such as FLOT, with surgery, is a well-established global standard of care for these patients “and is a stable and modern control arm,” Dr. Klempner noted. FLOT was established as the benchmark by the phase III FLOT4-AIO trial, where FLOT achieved a median disease-free survival of 30 months (hazard ratio [HR] = 0.75; P = .0036) and overall survival of 50 months (HR = 0.77; P = .012).1 MATTERHORN evaluated the benefit of adding durvalumab, demonstrating that median event-free survival was not reached with this approach and was 32.8 months with FLOT plus placebo (control arm). In KEYNOTE-585,2 which was overall a negative trial, the exploratory FLOT cohort demonstrated a median event-free survival with FLOT plus placebo similar to MATTERHORN at 30.9 months, supporting the performance of the MATTERHORN control arm, he said.
‘Survival Curve Features We Like to See’
“The bottom line is that MATTERHORN is a positive trial and durvalumab plus FLOT—and I stake the claim for calling this ‘D-FLOT’—will become our new standard,” Dr. Klempner said. “The separation of the curves begins as early as 3 months and is maintained throughout. The 8% increase in the landmark 24-month event-free survival timepoint is clinically relevant. The lower bound of the 95% confidence interval is a 1-year difference in favor of durvalumab. These results are all survival curve features we like to see.”
Clinical Implications
“Now, with D-FLOT set to become our standard, an immediate clinical question is whether we should offer this to all operable patients,” Dr. Klempner commented. “My takeaway about these data is that PD-L1 is probably not an adequate biomarker for selecting patients for D-FLOT. Although PD-L1–positive patients may have a greater magnitude of benefit, I will plan to discuss and offer D-FLOT across the MATTERHORN subgroups, though the rare microsatellite instability–high patients may have additional options.”
With MATTERHORN establishing a new standard, we can now turn our attention to the future and seek to increasingly incorporate biomarker-selected strategies and perhaps begin to explore organ-sparing approaches in some patient populations.
DISCLOSURE: Dr. Klempner has served as a consultant or advisor to Merck, Amgen, Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Eisai, Elevation Oncology, Gilead Sciences, I-Mab, Merck, Novartis, Boehringer Ingelheim, and Taiho Oncology; has received institutional research support from Arcus Biosciences, I-Mab, AstraZeneca, Mersana, Parabilis Medicines, The Gastric Cancer Foundation, Debbie’s Dream Foundation, The Degregorio Foundation, SU2C-AACR, NIH/NCI, and the Korean Ministry of Health; and has served as a member (uncompensated) on the NCCN Guidelines panel for gastric and esophageal cancers.
REFERENCES
1. Al-Batran, SE, Homann N, Pauligk C, et al: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): A randomised, phase 2/3 trial. Lancet 393:1948-1957, 2019.
2. Shitara K, Rha SY, Wyrwicz LS, et al: Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): An interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet 25:212-224, 2024.
