Neoadjuvant Durvalumab Plus Chemo Improves pCR Vs Chemo Alone in Gastric and GEJ Cancers

The addition of durvalumab (Imfinzi) to standard neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) significantly improved pathologic complete response (pCR) over neoadjuvant chemotherapy alone in patients with resectable, early-stage and locally advanced gastric and gastroesophageal junction (GEJ) cancers, meeting a key secondary end point of the phase 3 MATTERHORN trial (NCT04592913).¹

Additional data from the planned interim analysis showed that the toxicity profile of durvalumab plus neoadjuvant FLOT was consistent with what has previously been reported with the regimen. Notably, addition of durvalumab to chemotherapy did not reduce the number of patients who were able to receive surgery.

As planned, the trial will continue to evaluate event-free survival and overall survival. Study investigators and patients remain blinded.

“Patients with resectable gastric and GEJ cancers urgently need better treatment options, because today, 1 in 4 patients still progress within 1 year even after surgery with curative intent,” Josep Tabernero, MD, PhD, head of the Medical Oncology Department at Vall d’Hebron University Hospital, stated in a press release. “These results demonstrate an increase in pCR after adding durvalumab treatment to FLOT chemotherapy and surgery. This is an encouraging early sign that this regimen may deliver long-term clinical benefit for these patients, as pCR has been correlated with both [EFS and OS] in multiple settings.”

Gastric and GEJ cancers represent the fifth most common type of cancer, and the fourth leading cause of cancer-related deaths on a global scale.² The standard treatment for these diseases in Western countries comprises neoadjuvant/adjuvant FLOT with surgery. Despite progress made in the treatment paradigm, recurrence rates continue to be high, and survival is poor. It is known that chemotherapy can encourage antitumor immunity. Investigators hypothesized that the addition of an immune checkpoint inhibitor to chemotherapy can boost efficacy.

In the multicenter, randomized, double-blind, global, phase 3 trial enrolled patients with histologically confirmed, stage II or higher, resectable gastric or GEJ cancer who were at least 18 years of age and who had not received prior treatment. To be eligible, patients were required to have an ECOG performance status of 0 or 1 and acceptable organ and marrow function. They also needed to have an available tumor sample.

Patients could not have previously received immune-mediated therapy, nor could they have peritoneal dissemination or distant metastasis. Additional exclusion criteria included having adenosquamous or squamous cell carcinoma or gastrointestinal stromal tumor; receiving concurrent chemotherapy, investigational agent, biologic, or hormonal therapy; or a contraindication to any of the study drugs.

Study participants were randomly assigned to receive neoadjuvant durvalumab at 1500 mg on day 1 plus fluorouracil at 2600 mg/m² plus leucovorin at 200 mg/m², oxaliplatin at 85 mg/m², and docetaxel at 50 mg/m² on days 1 and 15 every 4 weeks for 2 cycles (arm A) vs placebo and FLOT (arm B). Patients then underwent surgery and received adjuvant treatment with durvalumab (arm A) or placebo (arm B) on day 1 plus FLOT on days 1 and 15 every 4 weeks for 2 cycles followed by single-agent durvalumab on day 1 every 4 weeks for 10 cycles.

The primary end point of the trial is EFS for arm A vs arm B, and secondary end points include OS, pCR, safety, and tolerability.

“These early results from MATTERHORN support harnessing the immune system together with chemotherapy and surgery as a new treatment approach to improve outcomes for patients with earlier stages of gastric and GEJ cancers,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in the press release. “These findings reinforce our focus on delivering novel [durvalumab]-based treatments that have the potential to redefine care for patients with gastrointestinal cancers.”

Data from the trial will be shared with health authorities and presented at a future conference.

References

1. Imfinzi (durvalumab) plus chemotherapy significantly improved pathologic complete response in gastric and gastroesophageal junction cancers in MATTERHORN phase III trial. News release. AstraZeneca. June 2, 2023. Accessed June 7, 2023. https://www.astrazeneca-us.com/media/press-releases/2023/imfinzi-durvalumab-plus-chemotherapy-significantly-improved-pathologic-complete-response-in-gastric-and-gastroesophageal-junction-cancers-in-matterhorn-phase-iii-trial-06022023.html
2. Janjigian YY, Van Cutsem E, Muro K, et al. MATTERHORN: efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—a randomized, double-blind, placebo-controlled, phase 3 study. J Clin Oncol. 2021;39(suppl 15):TPS4151. doi:10.1200/JCO.2021.39.15_suppl.TPS4151