Durvalumab Regimen Extends EFS in Resectable Gastric/GEJ Adenocarcinoma

“The [EFS] benefit was seen across prespecified [subgroup] cohorts. We did not see any new safety signals. [Therefore], this will change practice for our patients, which is exciting to see,” according to lead study author Yelena Y. Janjigian, MD.

An improvement in event-free survival (EFS) occurred in patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma who received perioperative durvaluab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), according to data from the phase 3 MATTERHORN trial presented in a press briefing at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Findings showed that at a median follow-up of 31.6 months (range, 0.0-48.1) for the durvalumab arm (n = 474) and 31.4 months (range, 0.0-48.1) for the placebo arm (n = 474), durvalumab plus FLOT generated a median EFS that was not reached (NR; 95% CI, 40.7-NR) compared with 32.8 months (95% CI, 27.9-NR) for placebo plus FLOT (HR, 0.71; 95% CI, 0.58-0.86; P < .001). In the durvalumab arm, the 18- and 24-month EFS rates were 73% and 67%, respectively. These respective rates were 64% and 59% in the placebo arm.

“The [EFS] benefit was seen across prespecified [subgroup] cohorts. We did not see any new safety signals. [Therefore], this will change practice for our patients, which is exciting to see,” lead study author Yelena Y. Janjigian, MD, said in the press briefing.

Janjigian is chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York.

Scaling the MATTERHORN

Investigators of the global, double-blind, placebo-controlled trial enrolled patients with stage II to IVa gastric/GEJ adenocarcinoma who had no evidence of metastases and received no prior therapy. Patients also needed to have an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to the durvalumab or placebo arm. Neoadjuvant therapy lasted 2 cycles, comprising durvalumab at 1500 mg once every 4 weeks plus FLOT or placebo plus FLOT. Following surgery, patients received 2 additional cycles of durvalumab at 1500 mg once every 4 weeks plus FLOT, or placebo plus FLOT. Patients then received durvalumab at 1500 mg once every 4 weeks or placebo as monotherapy for 10 additional adjuvant cycles.

Key stratification factors included region (Asia vs non-Asia), clinical stage (N+ vs N–), and PD-L1 status (tumor area positivity [TAP] <1% vs TAP ≥1%).

EFS served as the trial’s primary end point. Overall survival (OS), pathological complete response (pCR) rate, and disease-free survival (DFS) were key secondary end points.

All patients in the durvalumab arm received any neoadjuvant treatment compared with 99% of patients in the placebo arm. Neoadjuvant treatment with durvalumab or placebo was completed in 97% and 95% of patients, respectively. The respective rates of patients who completed neoadjuvant FLOT were 96% and 95%.

Surgery was attempted in 91% of patients in the durvalumab arm vs 90% of those in the placebo arm. Surgery was completed in 87% and 84% of patients, respectively. The rates of R0 resection were 92% in both arms. Any adjuvant therapy was given to 77% of patients in the durvalumab group vs 74% of patients in the placebo group. Fifty-two percent of patients in both arms completed adjuvant durvalumab or placebo; 61% and 64%, respectively, completed adjuvant FLOT. At the data cutoff, 68% of patients in the durvalumab arm and 59% of patients in the placebo arm were actively in follow-up.

At baseline, the median age was 62 years (range, 26-84) in the durvalumab arm vs 63 years (range, 28-83) in the placebo arm. The majority of patients in both groups were male (durvalumab, 69%; placebo, 75%), from regions outside of Asia (81%; 81%), had an ECOG performance status of 0 (71%; 77%), had gastric tumors (68%; 67%), had non-T4 disease (75%; 75%), had node-positive disease (69%; 70%), had a PD-L1 TAP of at least 1% (90%; 90%), had an intestinal histology (52%; 50%), and did not have microsatellite instability–high disease (64%; 65%).

Secondary End Points and Safety

The median OS was NR (95% CI, NR-NR) in the durvalumab arm vs 47.2 months (95% CI, 45.1-NR) in the placebo arm (HR, 0.78; 95% CI, 0.62-0.97; P = .025; threshold for statistical significance, P < .0001). The 18- and 24-month OS rates were 81% and 76%, respectively, in the durvalumab arm. These respective rates were 77% and 70% in the placebo arm. The median follow-up for OS was 34.6 months (range, 3.5-48.6) in the durvalumab group vs 34.6 months (range, 0.0-48.1) in the placebo group.

Patients in the durvalumab arm achieved a pCR rate of 19% (95% CI, 15.75%-23.04%) compared with 7% (95% CI, 5.02%-9.88%) for those in the placebo arm, translating to a 12% difference (OR, 3.08; 2.03-4.67; P < .001).

The median DFS was NR (95% CI, NR-NR) in the durvalumab arm vs 39.8 months (95% CI, 38.7-NR) in the placebo arm (HR, 0.70; 95% CI, 0.53-0.93). The 18- and 24-month DFS rates were 79% and 75%, respectively, for durvalumab plus FLOT vs 73% and 66%, respectively, for placebo plus FLOT.

Patients in both arms received a median of 2.0 neoadjuvant cycles of durvalumab/placebo and FLOT. They received a median of 12.0 adjuvant cycles of durvalumab/placebo and a median of 2.0 adjuvant cycles of FLOT. All patients received at least 1 neoadjuvant cycle of durvalumab/placebo plus FLOT. Exactly 2 cycles of neoadjuvant durvalumab and FLOT were each given to 97% of patients in the experimental arm; these rates were both 96% in the control arm.

In the experimental arm, at least 1 cycle of adjuvant durvalumab and FLOT was given to 76% and 75% of patients, respectively. The rates of patients who received at least 2 cycles of each were 73% and 67%, respectively. Seventy-two percent of patients received at least 3 cycles of adjuvant durvalumab, and 52% received 12 cycles. In the control arm, at least 1 cycle of adjuvant placebo and FLOT was given to 74% of patients each. Seventy-two percent received at least 2 placebo cycles, and 68% completed 2 adjuvant FLOT cycles. Seventy-one percent of patients completed at least 3 cycles of adjuvant placebo, and 51% completed the full 12-cycle adjuvant placebo course.

Regarding safety, any-grade adverse effects (AEs) occurred in 99% of patients in both arms. The rates of AEs possibly related to study treatment were both 95%. The rates of grade 3/4 AEs were 72% for the durvalumab arm vs 71% for the placebo arm. Grade 3/4 AEs possibly related to treatment occurred at rates of 60% and 59%, respectively. The rates of serious AEs were 48% for the durvalumab arm vs 44% for the placebo arm.

AEs led to treatment discontinuation of any study treatment in 30% of patients in the experimental arm vs 23% of patients in the control arm. Ten percent of patients discontinued durvalumab due to AEs, whereas 6% discontinued placebo. FLOT was discontinued due to AEs in 25% and 20% of patients, respectively.

AEs led to death in 5% of patients in the durvalumab arm vs 4% of patients in the placebo arm. These AEs were deemed possibly related to durvalumab or placebo in 1% and less than 1% of patients, respectively. AEs leading to death that were possibly related to FLOT occurred at respective rates of 1% and less than 1%.

Any-grade immune-mediated AEs (irAEs) were reported in 23% of patients in the durvalumab group vs 7% of patients in the placebo arm. The rates of grade 3/4 irAEs were 7% and 4%, respectively.

Surgery was not performed due to AEs in 1% of patients in the experimental arm vs less than 1% of patients in the control arm. The rates of AEs leading to a delay in surgery were 2% and 3%, respectively.

Reference

Janjigian Y, Al-Batran S-E, Wainberg Z, et al. Event-free survival (EFS) in MATTERHORN: a randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 2025;43(suppl 17):LBA5. doi:10.1200/JCO.2025.43.17_suppl.LBA5