Neoadjuvant Durvalumab Plus Chemo Boosts pCR Vs Chemo Alone in Gastric/GEJ Cancers Regardless of Region

Yelena Janjigian, MD

Durvalumab (Imfinzi) plus standard neoadjuvant chemotherapy comprised of 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) led to improved pathologic complete responses (pCRs) over chemotherapy alone in patients with resectable early-stage and locally advanced gastric and gastroesophageal junction (GEJ) cancers irrespective of region, according to data from a subgroup analysis of the phase 3 MATTERHORN trial (NCT04592913).¹

Prior findings from an interim analysis showed that durvalumab plus FLOT (n = 474) elicited a pCR rate of 19% by central review vs 7% with placebo plus FLOT (n = 474; Δ12%; OR, 3.08; 95% CI, 2.03-4.67; P < .00001), meeting a secondary end point of the trial.² The durvalumab regimen also improved combined complete and near-complete pathological response vs placebo plus FLOT, at 27% and 14%, respectively (Δ12%; OR, 2.19; 95% CI, 1.58-3.04; P < .00001).

Data presented at the 2024 Gastrointestinal Cancers Symposium demonstrated a consistent pCR improvement with the addition of durvalumab to FLOT vs FLOT alone when broken down by region.¹ The pCR rate among those in Asia who received durvalumab plus FLOT (n = 90) was 19% vs 6% with placebo plus FLOT (n = 90; Δ13%; OR, 3.96; 95% CI, 1.39-11.26). Those in the non-Asia group who received durvalumab/FLOT (n = 384) experienced a pCR rate of 19% vs 8% for those given placebo/FLOT (n = 384; Δ12%; OR, 2.92; 95% CI, 1.85-4.61).

When the non-Asia subgroup was broken down further into country, those in Europe (n = 506) who received durvalumab plus FLOT (n = 256) achieved a pCR rate of 18% vs 8% with placebo plus FLOT (n = 250; Δ10%; OR, 2.45; 95% CI, 1.42-4.24). Within the North America subgroup (n = 82), durvalumab plus FLOT (n = 42) led to a pCR rate of 29% vs 8% with placebo plus FLOT (n = 40; Δ21%; OR, 4.93; 95% CI, 1.27-19.10). In the South America subgroup (n = 180), the pCRs achieved with durvalumab/FLOT (n = 86) and placebo/FLOT (n = 94), were 17% and 5%, respectively (Δ12%; OR, 3.76; 95% CI, 1.30-10.84).

“MATTERHORN is the first global phase 3 study that successfully randomly assigned patients to receive perioperative FLOT globally in gastric and gastroesophageal adenocarcinoma [with] placebo [or] durvalumab, and we demonstrated that the addition of durvalumab to perioperative FLOT showed consistent improvement in pCR vs placebo across the globe,” Yelena Janjigian, MD, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, said in a presentation during the meeting. “We [also] saw benefit in microsatellite instability–high (MSI-H) and non–MSI-H subgroups.”

For patients with operable gastric or GEJ cancer, perioperative treatment with FLOT is the standard of care based on findings from the phase 2/3 FLOT-4 trial (NCT01216644); however, global data on this chemotherapy regimen are limited, Janjigian noted. For those with metastatic disease, standard treatment generally consists of PD-1 blockade paired with chemotherapy, she added.

Breaking down MATTERHORN’s Enrollment Criteria

The global, double-blind, placebo-controlled MATTERHORN study enrolled patients from Asia, Europe, North America, and South America who had stage II, III, and IVA gastric or GEJ adenocarcinoma and an ECOG performance status of 0 or 1. Patients could not have evidence of metastasis, nor could they have received prior treatment.

Participants (n = 948) were randomly assigned 1:1 to the durvalumab or placebo arm. Two doses of preoperative placebo or durvalumab 1500 mg were administered on day 1 plus 4 doses of FLOT, which comprised 2600 mg/m² of 5-FU, 85 mg/m² of oxaliplatin, 50 mg/m² of docetaxel, and 200 mg/m² of leucovorin, and was given on days 1 and 15 every 2 weeks for 4 cycles. Patients then underwent surgery and received 2 doses of durvalumab or placebo plus 4 doses of FLOT, followed by durvalumab or placebo monotherapy given on day 1 every 4 weeks for 10 further cycles. “They received up to 1 year of total adjuvant therapy,” Janjigian noted.

Stratification occurred by geographic region (Asia vs non-Asia), clinical lymph node status (positive vs negative), and PD-L1 status (tumor area positivity [TAP] < 1% vs TAP ≥ 1%). The trial’s primary end point is event-free survival (EFS), and key secondary end points include pCR by central review and modified Ryan criteria and overall survival.

“This was truly a global study and the first of its kind to be able to deliver FLOT to the Asian continent,” Janjigian noted. Nineteen percent of patients were treated in Asia and 19% in South America. “The predominant patient population were in Europe [53%,] where FLOT is the most used and common regimen,” she added. Nine percent of patients received treatment in North America.

Baseline characteristics were generally well balanced across the durvalumab and placebo treatment arms, Janjigian said. The median age was 62 years (range, 26-84) compared with 63 years (range, 28-83), and most patients were male (69% vs 75%) and had an ECOG performance status of 0 (71% vs 77%), respectively. More than half of patients had gastric cancer (68% vs 67%), and the remainder had GEJ cancer (32% vs 33%). Most patients had T3 disease (65% vs 68%), positive clinical lymph nodes (69% vs 70%), and non–MSI-H disease (92% vs 93%). Moreover, patients in the durvalumab vs placebo arms had intestinal histology (37% vs 35%), diffuse histology (22% vs 18%), or an unspecified adenocarcinoma or other (41% vs 47%).

In the durvalumab arm, 10% of patients had a PD-L1 TAP of less than 1%, 90% had a TAP of 1% or higher, 50% had a TAP of less than 5%, 50% had a TAP of 5% or higher, 78% had a TAP of less than 10%, and 22% had a TAP of 10% or higher; these rates were 10%, 90%, 49%, 51%, 79%, and 21%, respectively, in the placebo arm.

Examining Further Findings

“Across the exploratory analysis for the subgroups, you can see the OR favor the addition of durvalumab essentially across all subgroups,” Janjigian said. “The MSI-H subgroup is very rare, so there’s a very wide confidence interval. Also, there were very few patients with a TAP of less than 1% expression, so also a very wide range.”

At the time of the data cutoff, 45% of patients in the durvalumab/FLOT arm and 43% of those in the placebo/FLOT arm were still receiving treatment.

“When it comes to exposure, we did quite well with FLOT in this global study, suggesting that FLOT is feasible as a global treatment,” she noted. “Ninety-seven percent of patients received all preoperative FLOT and 63% of patients received adjuvant FLOT in completion.”

She added that they also broke it down further by PD-L1 expression and found that the delivery of FLOT was “feasible and quite good.” When looking at pathologic staging of patients who underwent surgery, 52% and 36% of patients in the respective durvalumab and placebo arms had node-negative status. She added that there was also a higher percentage of patients who achieved T0 with durvalumab/FLOT vs placebo/FLOT, at 23% and 11%, respectively, “as suggested by the higher pCR rate.”

Moreover, a higher percentage of patients in Asia had an ECOG performance status of 0, gastric cancer, lymph node positivity, and T4 stage tumors. “Despite this imbalance in the patient characteristics between Asia vs non-Asia, there was a balance between each arm—it’s just regional differences,” she noted, adding that the pCRs achieved in the Asia and non-Asia groups were comparable.

“Across Europe, North America, and South America, there was a nice and steady improvement in [pCR] with the addition of durvalumab across the regions, which is very reassuring to see,” Janjigian said.

In countries with at least 20 randomly assigned patients, the same improvement trend in pCR with the addition of durvalumab to FLOT was observed.

“We’re all eagerly awaiting the EFS and PFS [data] in these patients,” Janjigian concluded.

Editor’s Note: Dr Janjigian disclosed that research funding was received from Arcus Biosciences, AstraZeneca, Bayer, Bristol Myers Squibb, Cycle for Survival, Department of Defense, Eli Lilly, Fred’s Team, Genentech/Roche, Merck, NCI, RGENIX, and Transcenta. She serves on advisory boards or in a consulting capacity for AbbVie; Amerisource Bergen; Arcus Biosciences; Ask-Gene Pharma, Inc; Astellas; AstraZeneca; Basilea Pharmaceutica; Bayer; Bristol Myers Squibb; Clinical Care Options; Daiichi-Sankyo; Eli Lilly; Geneos Therapeutics; GSK; Guardant Health, Inc; Imedex; Imugene; Lynx Health; Merck; Merck Serono; Mersana Therapeutics; Michael J. Hennessy Associates; Paradigm Medical Communications; PeerView Institute; Pfizer; Research to Practice; RGENIX; Seagen; Silverback Therapeutics; and Zymeworks Inc. Other disclosures include stock options re: Inspirna.

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References

1. Janjigian YY, Al-Batran S-E, Wainberg ZA, et al. Pathological complete response to 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) with or without durvalumab in resectable gastric and gastroesophageal junction cancer: subgroup analysis by region from the phase 3 randomized, double-blind MATTERHORN study. J Clin Oncol. 2024;42(suppl 3):LBA246. doi:10.1200/JCO.2024.42.3_suppl.LBA246
2. Janjigian YY, Al-Batran S-E, Wainberg ZA, et al. Pathological complete response (pCR) to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): interim results of the global, phase III MATTERHORN study. Ann Oncol. 2023;34(suppl 2):S1315-S1316. doi:10.1016/j.annonc.2023.10.074