Editor’s Note:
The 2023 ESMO Annual Meeting took place from October 20th to 24th in Madrid, Spain. As a highly authoritative annual event in the field of oncology, it unveils cutting-edge advancements in cancer research each year. In the gastric cancer domain this year, the global Phase III MATTERHORN study on the anti-PD-L1 monoclonal antibody durvalumab was presented as a Late-breaking Abstract (LBA) with mid-term analysis results (Abstract No: LBA73). The interim analysis revealed a clinically and statistically significant increase in the pathologic complete response (pCR) rate with the neoadjuvant treatment regimen of durvalumab in combination with FLOT. The MATTERHORN study holds promise as the first positive neoadjuvant Phase III immunotherapy regimen for gastric cancer. “Oncology Frontier” is pleased to invite Professor Han Liang from Tianjin Medical University Cancer Institute to provide an in-depth interpretation of this study.
Durvalumab in combination with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) improves the pathologic complete response (pCR) in resectable gastric and gastroesophageal junction adenocarcinoma (GC/GEJC): Mid-term results of the global Phase III MATTERHORN study (Abstract No: LBA73) [1]
Study Design
The MATTERHORN study (NCT04592913) is a global, randomized, double-blind, placebo-controlled Phase III clinical trial designed to evaluate the efficacy and safety of durvalumab in combination with FLOT for neoadjuvant treatment in resectable GC/GEJC patients. The reported results here are from the pre-specified interim analysis (IA).
Patients with resectable (＞T2N0-3M0/T0-4N1-3M0) GC/GEJC were enrolled and randomly assigned (1:1) to the durvalumab group or placebo group. Patients in the durvalumab group received two cycles of durvalumab (1500mg, D1, Q4W) or placebo in combination with FLOT (D1/D15, Q4W) preoperatively and postoperatively, followed by 10 cycles of durvalumab or placebo (D1, Q4W) as adjuvant therapy. The primary endpoint of the study was event-free survival (EFS) in the intention-to-treat population (ITT). Key secondary endpoints included pCR rate and overall survival (OS). Pre-specified IA was performed in all randomized patients after surgery or exclusion, assessing the pCR rate effectiveness (two-sided α=0.1%) through central review (Modified Ryan), along with the evaluation of surgical and safety outcomes.
Baseline Characteristics
A total of 474 patients were enrolled in each of the two arms, and baseline characteristics were well-balanced between the groups. Asian patients accounted for 19% of the total, with 66% having clinical T3 (CT3) tumors, 25% having clinical T4 (CT4) tumors, and 70% having lymph node involvement (CLN+).
Research Results
Comparing with the placebo group, the combination of durvalumab and FLOT showed a significant improvement in pathologic complete response (pCR) (19% vs. 7%; Δ12%; OR 3.08, P＜0.00001). The proportion of patients achieving pCR and near-complete pathologic response (pnCR) in the durvalumab group was 27%, nearly doubling the rate observed in the control group (14%).
The surgical resection rates in the durvalumab group and placebo group were 87% and 84%, respectively. Among patients undergoing surgery, both the durvalumab and placebo groups had an R0 resection rate of 86%. However, the downstaging rate in the durvalumab group was higher than that in the placebo group (pT0: 23% vs. 11%; pN0: 52% vs. 37%).
The median exposure times were similar between the two groups. The rates of adverse events were comparable, with the occurrence of grade 3/4 adverse events in the durvalumab group and placebo group being 69% and 68%, respectively.
Research Conclusion
For resectable GC/GEJC patients, the addition of durvalumab to neoadjuvant FLOT treatment demonstrates a clinically and statistically significant improvement in pCR, and the treatment is safe and well-tolerated. The MATTERHORN study is still ongoing, and we await the disclosure of the primary endpoint, event-free survival (EFS).
Expert Commentary
Locally advanced gastric cancer (LAGC) is defined as cancer tissue invading the intrinsic muscle layer of the stomach wall or penetrating through the muscle layer to the serosal layer (clinical staging as cT1-2N+M0 or cT3-4bNanyM0). In China, LAGC accounts for as much as 60% [2], and the 5-year survival rate still needs improvement, with the 5-year OS rate for patients in stages IIa to IIIb dropping from 81.9% to 18.4% [3]. Although surgical resection remains a crucial means for patients to achieve a cure, the recurrence rate after D2 radical surgery and postoperative chemotherapy in surgically treatable GC/GEJC patients is still as high as 50% to 80% [4]. Surgical combined with neoadjuvant treatment is an essential strategy to reduce recurrence and improve survival [5]. Currently, neoadjuvant treatment for GC/GEJC primarily involves chemotherapy. The 2023 version of the CSCO Gastric Cancer Guidelines recommends: for surgically resectable patients with cT2-T4 and cT1N+, it is recommended to perform D2 lymph node dissection combined with perioperative or adjuvant chemotherapy. The preferred approach varies based on the tumor’s primary site (esophagogastric junction or non-esophagogastric junction) and different stages (II and III) [6].
After the success of immune checkpoint inhibitors in the advanced GC/GEJ field [7-9], they have also started entering the neoadjuvant treatment arena. Several Phase III clinical trials, including ATTRACTION-5 (NCT03006705), KEYNOTE-585 (NCT03221426), HLX10-006-GCneo (NCT04139135), MATTERHORN (NCT04592913), have been initiated.
ATTRACTION-5 is a Phase III trial investigating postoperative adjuvant immunotherapy in combination with chemotherapy, and data presented at this year’s ASCO conference revealed negative results [10]. The study included 755 patients with stage III GC/GEJC who underwent D2 or extended gastrectomy, randomly assigned (1:1) to receive nivolumab or placebo in combination with adjuvant SOX/CAPOX therapy. The primary endpoint analysis for recurrence-free survival (RFS) showed no significant difference between the nivolumab and placebo groups (3-year RFS rate: 68.4% vs. 65.3%; HR 0.90, 95% CI: 0.69–1.18; P=0.4363), falling short of the expected 71%.
KEYNOTE-585, another Phase III trial reported at this year’s ESMO conference (LBA74), also presented negative results [11]. The study comprised four arms (two cohorts): the first cohort received three cycles of pembrolizumab (200mg q3w) or placebo in combination with chemotherapy (platinum-based combined with 5-FU or capecitabine) before surgery, followed by 11 cycles of pembrolizumab or placebo in the adjuvant phase; the second cohort had a similar design but used the FLOT chemotherapy regimen. The results showed a significant increase in pCR in the pembrolizumab group compared to the placebo group in the FLOT cohort (13.0% vs. 2.4%, P＜0.0001). However, the difference in the primary endpoint, event-free survival (EFS), did not reach the pre-specified level of statistical significance (45.8 vs. 25.7 months, HR 0.81, P=0.011); overall survival (OS) was comparable between the two groups (60.7 months vs. not reached, HR 0.93).
The HLX10-006-GCneo study enrolled patients with clinical stage cT3N+M0, providing a more detailed subset of the patient population than the other three studies. The neoadjuvant treatment involved a combination of HLX10 (anti-PD-1 monoclonal antibody) or placebo with SOX, followed by adjuvant treatment with HLX10 or SOX. This study is currently ongoing.
After the initiation of the MATTERHORN study, there has been preliminary exploration of the use of durvalumab in the neoadjuvant treatment of microsatellite-high (MSI-H) gastric cancer. The multicenter, multi-cohort, single-arm Phase II INFINITY study reported at the 2023 ASCO-GI included 18 patients with dMMR/MSI-H, clinically staged as T2-4NanyM0 GC/GEJC. These patients received neoadjuvant treatment with a combination of durvalumab and Tremelimumab (anti-CTLA-4 monoclonal antibody) for three cycles, achieving a pCR rate of 60% (9/15).
In summary, the immunotherapy model for resectable GC/GEJC still requires further exploration. Questions such as the need for patient stratification based on clinical stage and tumor markers (PD-L1, MSI-H) to identify the optimal treatment approach (single or combination immunotherapy) remain unanswered. The impact of anti-PD-L1 monoclonal antibodies versus anti-PD-1 monoclonal antibodies on patient benefit also needs clarification. Additionally, the choice of chemotherapy regimens poses another set of questions. MATTERHORN adopted an all-comer approach, demonstrating clinical benefits of neoadjuvant durvalumab in combination with FLOT (significant increase in pCR rate). The inclusion of a significant proportion of Asian populations in the study may provide valuable insights for future treatments in Chinese patients. The release of future EFS results is anticipated to bring greater benefits to a larger patient population.
Reference :
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Professor, Chief Physician
Director, Gastric Cancer Center, Tianjin Medical University Cancer Institute and Hospital
Chairman, Gastric Cancer Professional Committee, China Anti-Cancer Association
Chairman-elect, Oncology Surgery Professional Committee, Chinese Medical Doctor Association
Vice Chairman, Gastric Cancer Expert Committee, Chinese Society of Clinical Oncology
Vice Chairman, Gastrointestinal Stromal Tumor Professional Committee, China Anti-Cancer Association
Deputy Group Leader, Gastrointestinal Group, Chinese Society of Clinical Oncology
Committee Member, National Cancer Standardized Diagnosis and Treatment Expert Committee, Ministry of Health
Executive Deputy Editor-in-Chief, Chinese Journal of Cancer Clinical Medicine
Selected as one of the First Tianjin Famous Doctors
Selected as a Highly Cited Scholar in China by Elsevier in 2021 and 2022
Recipient of the 2021 Peak Value Award in the “Research” Category of the China Cancer Research Expert Nomination List
Principal Investigator for over 10 national and provincial-level research projects; received the National Science and Technology Progress Award (Second Prize), First Prize of the Chinese Medical Association and the Ministry of Education for Scientific and Technological Progress, First Prize of Hubei Province for Scientific and Technological Progress, Second Prize of Tianjin Science and Technology Progress, and the Third Prize of the China Anti-Cancer Association. Author of over 10 monographs and translations, with more than 460 published papers, including over 150 SCI papers.
