Imfinzi, Chemo Improves Outcomes in GI Cancers, Regardless of Region

Adding Imfinzi (durvalumab) to a standard presurgical chemotherapy regimen improved pathologic complete response (pCR; disappearance of cancer) compared to chemotherapy alone in patients with resectable, early-stage, locally advanced gastric and gastroesophageal junction (GEJ) cancers, regardless of where they are located, according to a subgroup analysis from the phase 3 MATTERHORN trial.

Prior findings from an interim analysis showed that Imfinzi plus the chemotherapy regimen known as FLOT (made up of 5-fluorouracil [5-FU], leucovorin, oxaliplatin and docetaxel), which was given to a group of 474 patients, elicited a pCR rate of 19% compared with 7% with placebo plus FLOT, given to another group of 474 patients, meeting a secondary endpoint of the trial.The Imfinzi regimen also improved combined complete and near-complete pathological response versus placebo plus FLOT, at 27% and 14%, respectively.

Data presented at the 2024 Gastrointestinal Cancers Symposium demonstrated a consistent pCR improvement with the addition of Imfinzi to FLOT versus FLOT alone when broken down by region.Those in Asia who received Imfinzi plus FLOT (90 patients) achieved a pCR of 19% versus 6% with placebo plus FLOT (90 patients). Those in the non-Asia group who received Imfinzi/FLOT (384 patients) experienced a pCR of 19% versus 8% for those given placebo/FLOT (384 patients).

When the non-Asia subgroup was broken down further into countries, those in Europe (506 patients) who received Imfinzi plus FLOT (256 patients) achieved a pCR of 18% versus 8% with placebo plus FLOT (250 patients). Within the North American subgroup (82 patients), Imfinzi plus FLOT (42 patients) led to a pCR of 29% versus 8% with placebo plus FLOT (40 patients). In the South America subgroup (180 patients), the pCRs were achieved with Imfinzi/FLOT (86 patients) and placebo/FLOT (94 patients), at 17% and 5%, respectively.

“MATTERHORN is the first global phase 3 study that successfully randomized patients to receive perioperative FLOT globally in gastric and gastroesophageal adenocarcinoma (with) placebo (or) (Imfinzi) and we demonstrated that the addition of (Imfinzi) to perioperative FLOT showed consistent improvement in pCR vs placebo across the globe,” Dr. Yelena Janjigian, 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; however, global data on this chemotherapy regimen, Janjigian noted. For those with metastatic disease, standard treatment generally consists of PD-1 blockade paired with chemotherapy, she added.

The global, double-blind, placebo-controlled MATTERHORN study enrolled patients from Asia, Europe, North America and South America who had stage 2, 3 and 4A gastric or GEJ adenocarcinoma and an ECOG performance status of 0 or 1, indicating that they could perform all or most of their daily tasks independently. Patients could not have evidence of metastasis, nor could they have received prior treatment.

A total of 948 participants were randomly assigned to the Imfinzi or placebo group. After the treatment, patients then underwent surgery and received two doses of Imfinzi or placebo plus four doses of FLOT, followed by Imfinzi or placebo monotherapy given on day 1 every four weeks for 10 further cycles.

“They received up to one year of total adjuvant therapy,” Janjigian said.

Randomization was stratified by geographic region (Asia vs non-Asia), clinical lymph node status (positive versus negative), and PD-L1 status (tumor area positivity [TAP] <1% versus TAP ≥1%).

The trial’s main goal point is event-free survival (EFS; time a patient lives without complications from cancer or disease worsening), and key secondary endpoints 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 explained. 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 “well matched” across the Imfinzi and placebo treatment arms, Janjigian said. The median age was 62.5 years (range, 26-84), and most patients were male (69% versus 75%) and had an ECOG performance status of 0 (71% vs 77%). More than half of patients had gastric cancer (68% versus 67%) and the remainder had GEJ cancer (32% versus 33%). Most patients had a disease that grew through the connective tissue of the stomach (65% versus 68%), positive clinical lymph nodes (69% versus 70%), and non-MSI-H disease (92% versus 93%). Moreover, patients had intestinal histology (37% versus 35%), diffuse histology (22% versus 18%) or an unspecified adenocarcinoma or other (41% versus 47%).

In the Imfinzi arm, 10% had a PD-L1 tumor area positivity (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.

“Across the exploratory analysis for the subgroups, you can see the OR favor the addition of (Imfinzi) 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 Imfinzi/FLOT arm and 43% of those in the placebo/FLOT arm were still receiving treatment.

“When it comes to exposure, we actually 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 the pathologic staging of patients who underwent surgery, 52% and 36% of patients in the respective Imfinzi and placebo arms had node-negative status. She added that there was also a higher percentage of patients who achieved a disappearance of cancer with Imfinzi/FLOT versus 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 metastatic disease. “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 (Imfinzi) across the regions, which is very reassuring to see,” Janjigian said.

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

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

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