3 days ago
Durvalumab Plus FLOT Improves Early Upper-GI Cancer
Adding the immune checkpoint inhibitor durvalumab (Imfinzi) to the standard chemotherapy regimen of fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) improved event-free survival (EFS) in patients with resectable, early–stage adenocarcinoma of the upper-gastrointestinal (GI) tract.
Experts say these interim results, which were presented by Yelena Janjigian, MD, at the American Society of Clinical Oncology (ASCO) 2025 annual meeting in Chicago, make the case for a new standard for treating these cancers.
The phase 3 MATTERHORN study 'supports the global adoption of perioperative durvalumab plus FLOT for patients with localized gastric and gastroesophageal junction adenocarcinoma,' said Janjigian of the Memorial Sloan Kettering Cancer Center in New York City at the plenary session of the meeting. The study was published simultaneously in The New England Journal of Medicine .
The goal of the study is to address the low cure rates for early-stage gastroesophageal cancer, which remain below 50% with most recurrences occurring within 2 years after surgery, said Janjigian, who is also an author of the new paper.
MATTERHORN enrolled 948 people with stage II, III and IVA resectable gastric cancer and gastroesophageal junction cancer, randomizing them to two regimens: Durvalumab 1500 mg plus FLOT before surgery, followed by two cycles of durvalumab 1500 mg every 4 weeks plus FLOT, and then 10 cycles of durvalumab 1500 mg every 4 weeks; or placebo plus FLOT before surgery, and then two cycles of placebo plus FLOT followed by 10 cycles of placebo.
Applying Immunotherapy in Early-Stage Disease
'We know that immunotherapy works for stage IV disease in an advanced setting,' Janjigian said at a press conference before the plenary session. 'In metastatic disease, we've been using anti-PD-1 agents for years, but they have not been proven to help patients with early-stage cancer.'
In MATTERHORN, patients in the durvalumab group had a 29% relative risk reduction in 2-year EFS, which was the primary endpoint. That risk reduction was 67.4% for the treatment group vs 58.5% for the placebo group ( P <.001), Janjigian said at the plenary session. Because the results are interim, the median EFS with durvalumab was not reached, which means that more than half of the patients in the durvalumab plus FLOT group had not had a cancer recurrence at 2 years. The median EFS for the placebo group was 32.8 months.
Among secondary endpoints, 2-year overall survival was 75.7% in the durvalumab group vs 70.4% in the placebo group, a 22% advantage for the former, Janjigian said, but that has not yet reached statistical significance in the interim analysis.
The median overall survival rate has not yet been reached because there have not been enough deaths in that group to calculate it, Janjigian told Medscape Medical News . In the placebo group, 2-year overall survival was 47.2 months.
'Survival data will continue to be followed and will be updated,' she said.
'There was a consistent event-free survival benefit with the addition of durvalumab across all subgroups, including patients aged 65 or older, patients enrolled in Asia, and patients with anti-PDL-1 and PDL-1- negative and gastroesophageal junction tumors,' Janjigian said at the plenary session. About 19% of the study participants were in Asia, 53% in Europe, 19% in South America, and 9% in North America.
'All hazard ratio estimates for the subgroups were < 1, reinforcing the consistency and robustness of the treatment effect,' Janjigian said.
Safety outcomes were similar in both the durvalumab and placebo groups, Janjigian said. 'Grade 3 and 4 treatment-related adverse events occurred in 60% of patients in the durvalumab arm and 59% in the placebo arm,' she said. Grade 3 or 4 immune-mediated adverse events occurred more frequently in patients in the durvalumab group, she added: 7% vs 4%.
The addition of durvalumab did not interfere with the delivery of FLOT in the perioperative setting, and, in the adjuvant phase, 52% of patients in the durvalumab group completed 1 year of therapy, as did 51% of patients in the placebo group, she said.
A New Standard?
'To put it simply, the MATTERHORN trial moves the field forward and establishes perioperative durvalumab plus FLOT as the new standard for this patient population,' Samuel Klempner, MD, director of Gastroesophageal Medical Oncology and associate professor at Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, said in comments as the discussant at the plenary session.
'While overall survival is immature, I'm very optimistic that MATTERHORN will show a statistical improvement in overall survival based on the shape of the curves, the strong statistical design, and observations from other phase 3 perioperative gastric trials like RESOLVE and PRODIGY, where longer follow-up improved the hazard ratio and enhanced the significance of the P value,' Klempner said.
The RESOLVE trial confirmed the survival advantage of perioperative-S-1 and oxaliplatin (SOX) and adjuvant-SOX compared with the standard adjuvant-postoperative capecitabine-and-oxaliplatin regimen in gastric or gastroesophageal junction cancer. The PRODIGY trial found that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 followed by surgery and adjuvant S-1 chemotherapy improved progression-free survival over surgery followed by adjuvant S-1 for patients with resectable locally advanced gastric cancer.
The MATTERHORN population 'looks like patients in the clinic,' and the similarity in patient dispositions between the study groups was important, said Klempner.
'To me, this says that academic and community oncologists and our surgical colleagues can feel confident that adding durvalumab to FLOT does not impact our ability to complete neoadjuvant FLOT, get to surgery, achieve our zero resection, or complete adjuvant therapy,' he said. 'I also want to stake the claim for D-FLOT as the name for this new standard regimen,' he added to loud applause in the session.
'This is a pivotal trial in upper GI cancer patients in a space that's really been taking center stage in recent years with many recent advances,' Pamela Kunz MD, PhD, director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center in New Haven, Connecticut, said at a press conference before the presentation. 'This is going to change the standard of care for this patient population.'
She added that physicians must carefully select patients for durvalumab plus FLOT treatment.
'Can all patients tolerate a four-drug treatment?' Kunz asked. 'The study demonstrated it was reasonably well tolerated, but in terms of the patients in front of us, we need to think about them.'
This study was funded by AstraZeneca. Janjigian reported disclosed financial relationships with AbbVie, AmerisourceBergen, Arcus Biosciences, Ask-Gene Pharma, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Clinical Care Options, Daiichi Sankyo, eChinaHealth, ED MedResources, EISAI, Eli Lilly and Co., Genentech, Geneos Therapeutics, GlaxoSmithKline, Guardant Health, H.C. Wainwright & Co., Imedex, Imugene, Inspirna, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Pfizer, Sanofi Genzyme, Seagen, Silverback Therapeutics, Transcenta, and Zymeworks.
Klempner reported relationships with Nuvalent, Merck Serano, Amgen, Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo UCB Japan, Eisai, Elevation Oncology, Gilead Sciences, I-Mab, Merck, Novartis, SERVIER, Taiho Oncology, Arcus Biosciences, Leap Therapeutics, and Mersana.
Disclosures for Kunz were not available at press time.
