Yelena Janjigian, MD

GI Oncology Now

Yelena Janjigian, MD, Memorial Sloan Kettering Cancer Center, shares why the <a href="https://www.gioncologynow.com/post/matterhorn-practice-changing-treatment-paradigm-for-resectable-g-gej-cancers" target="_blank" rel="noopener">MATTERHORN trial</a> was selected for the plenary session and how its findings build on past studies to advance perioperative care in G/GEJ cancer.She highlights the study&rsquo;s global scope, strong safety profile, and promising efficacy signals&mdash;including improved event-free survival&mdash;and previews upcoming biomarker analyses that could personalize treatment even further.&mdash;Before we dive into MATTERHORN, could you frame for us the unmet need in resectable G/GEJ cancer and why this study is so important?Dr. Janjigian: This study addresses a significant unmet need. Globally, 1.2 million people will develop and die from gastric and esophageal adenocarcinoma. For early-stage disease, we have not seen major breakthroughs in preventing recurrence or reducing the risk of relapse using targeted therapies. MATTERHORN is the first perioperative study to demonstrate that immunotherapy can improve survival in this patient population.The global burden of this disease and the fact that MATTERHORN was a randomized, phase III, placebo-controlled study conducted with rigorous standards in a difficult-to-treat cancer made it especially impactful. That is likely why it was selected for a plenary session and published in the New England Journal of Medicine.Despite perioperative FLOT being the standard of care, recurrence remains a major issue. Why is that, and what is the rationale behind an immunotherapy-plus-chemotherapy approach in the perioperative setting?Dr. Janjigian: Two phase III studies published in the New England Journal of Medicine within the past year have confirmed FLOT as the preferred regimen in the perioperative setting.Historically, particularly in the US, some patients with adenocarcinoma received chemoradiation, what is known as the CROSS regimen. Now, we have solid level-one evidence that FLOT is the optimal approach. The timing of the MATTERHORN publication aligned well with that shift in practice.We know immunotherapy works in metastatic disease. We have also shown that combining it with chemotherapy is effective, and many anti&ndash;PD-1 agents are already approved in advanced settings. Bringing an anti&ndash;PD-L1 agent like durvalumab into early-stage disease offered a significant opportunity.MATTERHORN is a level-one-evidence positive study. We already knew immunotherapy was active in advanced tumors, so there was great anticipation around MATTERHORN. Particularly because KEYNOTE-585, which tested a less modern cisplatin-based regimen with tislelizumab, failed to meet its endpoint.With MATTERHORN, we saw improvements across key outcomes: event-free survival, pathologic complete response rate, and disease-free survival&mdash;each of those boxes is checked. Overall survival appears to be trending positive, which is exciting.Benefit was achieved without increased surgical delays or Grade 3/4 toxicity. What does this tell us about the feasibility of integrating immunotherapy into curative-intent perioperative regimens for G/GEJ cancer?Dr. Janjigian: That is an important point because safety and feasibility are paramount. Patients, surgeons, and oncologists are always concerned about compromising the chance for cure in early-stage disease.What we demonstrated is that perioperative therapy was well tolerated. Delivery was close to 100% in both the durvalumab and placebo groups. FLOT administration was excellent. The R0 resection rate was identical between arms, indicating no compromise in surgical outcomes. Additionally, more than half of patients in both arms completed adjuvant therapy.This is an important advance for the field because it supports a unified global approach. Patients from four continents were enrolled. Many of these individuals are nutritionally frail, and yet we were able to safely deliver FLOT, even in patients over age 65, including some octogenarians.FLOT is now the modern standard. Clinicians, surgeons, and patients are embracing it. Notably, the placebo arm in our study actually outperformed historical FLOT data, which suggests that our teams are getting better at managing this disease. Despite that strong performance, we were still able to demonstrate added benefit with durvalumab.Given the global nature of the study and stratification by geography, lymph node status, and PD-L1 status, were there any notable subgroup signals that could inform more personalized perioperative strategies moving forward?Dr. Janjigian: We have a large volume of data forthcoming, including detailed biomarker analyses that will be presented at upcoming congresses.We are analyzing both baseline and on-treatment tumor samples, as well as peripheral blood, to assess T-cell clone expansion, circulating tumor DNA, and minimal residual disease. These data will be a treasure trove to help us tailor treatment decisions&mdash;for example, determining how long patients should remain on adjuvant therapy.The disease-free survival benefit with this regimen suggests that even patients who achieved a complete resection experienced fewer recurrences.Looking at the pre-specified subgroups&mdash;tumor location, histology, PD-L1 expression, geographic region, age&mdash;all demonstrated a benefit from the addition of durvalumab. The treatment effect was consistent across the board.While PD-L1&ndash;positive tumors did show benefit, so did PD-L1&ndash;negative ones. That group made up only about 10% of the cohort, yet the hazard ratio still favored durvalumab. This underscores the need for better biomarker selection, as PD-L1 expression alone is likely not sufficient.You mentioned the positive trends in EFS, pCR, and OS. How do you think these endpoints, taken together, might influence regulatory decisions or updates to clinical guidelines, both in the US and internationally?Dr. Janjigian: Most regulatory agencies focus on the primary endpoint, which in this case was event-free survival, and that result was strongly positive.The next step is to evaluate whether the totality of the data supports that primary outcome. Here, we also saw improvements in pathologic complete response and disease-free survival&mdash;both of which are final&mdash;and overall survival appears promising, though it is still a secondary and not yet mature endpoint.The early separation and plateauing of the OS curves are encouraging. Taken together, the consistency of the data should lead to favorable regulatory review.

Emily Menendez

CABINET: Cabozantinib Preserves Quality of Life in Patients With Pancreatic Cancer

Pancreatic Cancer

Inside MATTERHORN: Immunotherapy’s Role in Early-Stage Gastric, GEJ Cancer

Gastric Cancer

Filippo Pietrantonio, MD

DESTINY-Gastric04: Analyzing the Role of T-DXd in Second-Line HER2+ Gastric Cancer Treatment

Latest News

Dr. Janjigian shares why MATTERHORN was picked for the plenary and how its findings build on past studies in G/GEJ cancer.