MATTERHORN is a randomized, global Phase III trial evaluating IMFINZI as perioperative treatment for patients with resectable Stage II-IVA gastric and gastroesophageal cancers. Perioperative therapy includes treatment before and after surgery, also known as neoadjuvant/adjuvant therapy. Interim analysis was conducted after all randomized patients underwent or were precluded from surgery. Superiority of pCR rate was assessed along with surgical and safety outcomes.

According to the data presented in ESMO 2023, the addition of IMFINZI to fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) resulted in a statistically significant improvement in pathological complete response (pCR) compared to placebo (19% vs. 7%). The combined rate of pCR/near-complete pathological response (pnCR) was 27% with IMFINZI, exceeding the 14% observed with placebo. Upon examining the subgroup analysis, it appears that the inclusion of durvalumab has been advantageous across all subgroups when it comes to achieving pCR. However, highlighting particularly a subset of German patients, as most of the FLOT trials were conducted in Germany, the pCR rate was observed to be 30% in the group receiving the durvalumab-based regimen, in contrast to 13% in the group receiving the placebo regimen.

Surgery rates and resection rates were comparable between IMFINZI (87% and 86%, respectively) and placebo (84% and 86%, respectively). The use of durvalumab demonstrated significant down staging and downsizing effects, as the rate of stage T0 disease was 23% in patients treated with IMFINZI-based regimen compared to 11% in those receiving the placebo-based combination. In Addition, a remarkable increase could also be observed in the status of patients with node negative disease from 37% to 52% with the addition of durvalumab.

The safety and tolerability profile of incorporating IMFINZI into neoadjuvant FLOT chemotherapy remained consistent with the known characteristics of this combination and did not reduce the number of patients able to undergo surgery compared to chemotherapy alone. Adverse event rates were similar between the two groups.

These findings from the MATTERHORN study underscore the promise of initiating a combined immunotherapy and chemotherapy approach in the early stages of treatment of gastric and gastroesophageal junction cancers.

KOL insights

“Disease recurrence after curative-intent surgery is far too common for patients with resectable gastric and gastroesophageal junction cancers. These early MATTERHORN results showing encouraging pathologic complete responses give hope that adding durvalumab to FLOT chemotherapy in the future will offer a much-needed new treatment approach in the perioperative setting.” –MD, Chief Attending Physician, United States

“It is particularly encouraging to note that the safety of the combination of durvalumab plus FLOT did not compromise the potential for patients to undergo surgery. However, while the results are promising, the EFS data are required before any impact on clinical practice can be suggested.”–MD, United Kingdom

Conclusion

Incorporating IMFINZI into perioperative FLOT therapy not only exhibited a clinically significant but also resulted in more than a two-fold increase in the rate of achieving a complete pathological response in patients with resectable early-stage gastric and gastroesophageal junction cancers compared to chemotherapy alone. Furthermore, the approach demonstrated a well-tolerated safety profile. While the MATTERHORN study continues, the trial will proceed as originally scheduled to evaluate the primary endpoint of EFS and the significant secondary endpoint of OS.  In the MATTERHORN trial, the primary endpoint is EFS, defined as the time from randomisation until disease progression or death. A Phase III KEYNOTE-585 trial is also ongoing in the similar setting. The KEYNOTE-585 and the MATTERHORN study have nearly the same design. As per the results presented in the ESMO 2023, KEYTRUDA significantly increased the pathological complete response (pCR), but fell short of reaching the event-free survival endpoint  (#LBA74). Based on the results of both studies, it is too early to say that immune checkpoint inhibitors are safe to be recommended as perioperative therapy options for gastric/gastro-esophageal junction malignancies.

The incidence of gastroesophageal junction cancer is on the rise. At the time of diagnosis, around 40% of patients have metastatic disease, and their 5-year overall survival is low. Owing to the high prevalence of H. pylori infection, certain dietary practices, smoking habits, and strong alcohol intake. Gastric Cancer is highly prevalent in Asian countries. 

For more insight into the patient's burden, epidemiological factors, treatment options, and evolving developments in the market landscape, refer to the Gastroesophageal Adenocarcinoma Market Report