AstraZeneca

Trial will continue to assess primary endpoint of event-free survival.

Positive results from a planned interim analysis of the MATTERHORN Phase III trial showed treatment with AstraZeneca's Imfinzi (durvalumab) in combination with standard-of-care FLOT neoadjuvant chemotherapy (fluorouracil, leucovorin, oxaliplatin, and docetaxel given before surgery) demonstrated a statistically significant and clinically meaningful improvement in the key secondary endpoint of pathologic complete response (pCR) versus neoadjuvant chemotherapy alone for patients with resectable, early-stage and locally advanced (Stages II, III, IVA) gastric and gastroesophageal junction (GEJ) cancers.

These results will be presented today at the European Society for Medical Oncology (ESMO) Congress 2023 in Madrid, Spain (abstract #LBA73).

Treatment with Imfinzi plus neoadjuvant FLOT chemotherapy resulted in a pCR rate of 19% versus 7% for patients treated with neoadjuvant chemotherapy alone as assessed by blinded independent central review (BICR) (difference in pCR rate 12%; odds ratio [OR] 3.08; p<0.00001). The rate of either complete or near-complete responses was 27% with the Imfinzi combination and 14% with neoadjuvant chemotherapy alone.

The trial, which is assessing Imfinzi in combination with FLOT chemotherapy as a perioperative treatment (before and after surgery), will continue as planned to assess the primary endpoint of event-free survival (EFS) and the key secondary endpoint of overall survival (OS) to which the trial team, investigators and participants remain blinded.

Yelena Janjigian, MD, Chief Attending Physician of the Gastrointestinal Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York and principal investigator in the trial said: “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.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “The results from MATTERHORN highlight the potential of early treatment for patients with gastric and gastroesophageal junction cancers using an immunotherapy and chemotherapy combination. These findings reinforce our commitment to improving outcomes in gastrointestinal cancers, where unmet need is high and treatment options are limited.”

Imfinzi was generally well tolerated, and no new safety signals were observed in the neoadjuvant setting. Further, the safety and tolerability of adding Imfinzi to neoadjuvant chemotherapy was consistent with the known profile for this combination. Grade 3 or higher adverse events from all causes were similar between the two arms, occurring in 69% of patients treated with the Imfinzi-based regimen versus 68% for neoadjuvant chemotherapy alone.

Summary of results: MATTERHORN

1. BICR review was scored using Modified Ryan criteria

For patients treated with the Imfinzi-based regimen, 87% completed surgery compared to 84% of patients treated with neoadjuvant chemotherapy alone. In patients who had surgery, including patients with surgery attempted but not completed, the rate of R0 resection (patients having no macroscopic or microscopic residual tumour following surgery) was 86% across both arms. The rate of T0 resection (patients with no evidence of their primary tumour) was 23% for the Imfinzi-based regimen compared to 11% for neoadjuvant chemotherapy alone. The rate of N0 resection (patients with no lymph nodes containing cancer cells) was 52% for the Imfinzi-based regimen compared to 36%.

Notes

Gastric and GEJ cancers
Gastric (stomach) cancer is the fifth most common cancer worldwide and the fourth highest leading cause of cancer mortality.² Approximately one million new patients were diagnosed with gastric cancer in 2020, with 768,000 deaths reported globally.²

GEJ cancer is a type of gastric cancer that arises from and spans the area where the oesophagus connects to the stomach.³

By 2030, approximately 70,000 patients in the US, EU and Japan will be newly diagnosed with Stage II-III gastric or GEJ cancers.⁴ Disease recurrence is common in patients with resectable gastric cancer.¹  Approximately one in four patients with gastric cancer who undergo surgery with curative intent develop recurrent disease within one year, reflecting a high unmet medical need.¹ Additionally, the five-year survival rate remains poor, with only up to a third of patients alive at five years.^5,6

MATTERHORN
MATTERHORN is a randomised, double-blind, placebo-controlled, multi-centre, global Phase III trial evaluating Imfinzi as perioperative treatment for patients with resectable Stage II-IVA gastric and GEJ cancers. Perioperative therapy includes treatment before and after surgery, also known as neoadjuvant/adjuvant therapy. In the trial, patients were randomised to receive 1500mg fixed dose of Imfinzi plus FLOT chemotherapy or placebo plus FLOT chemotherapy every four weeks for two cycles prior to surgery, followed by Imfinzi or placebo every four weeks for up to 12 cycles after surgery (including two cycles of Imfinzi or placebo plus FLOT chemotherapy and 10 additional cycles of Imfinzi or placebo monotherapy).

In the MATTERHORN trial, the primary endpoint is EFS, defined as the time from randomisation until progression that precludes surgery or requires non-protocol therapy, local or distant recurrence or progression of disease, or death due to any cause as assessed by BIRC according to RECIST 1.1 and/or local pathology testing. Key secondary endpoints include pCR rate, defined as the proportion of patients who have no detectable cancer cells in resected tumour tissue following neoadjuvant therapy, and OS. The trial randomised 948 participants at sites in the US, Canada, Europe, South America and Asia.

Imfinzi 
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour's immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer (BTC) and in combination with Imjudo (tremelimumab) in unresectable hepatocellular carcinoma (HCC) in the US, EU, Japan and several other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively.

In addition to its indications in gastrointestinal (GI) cancers, Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small-cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Additionally, Imfinzi is approved in combination with a short course of Imjudo and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial. Imfinzi is approved in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 200,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several GI cancers and other solid tumours. In GI cancers specifically, AstraZeneca has several ongoing registrational trials investigating Imfinzi across multiple liver cancer settings (EMERALD-1, EMERALD-2 and EMERALD-3) and in locally advanced oesophageal cancer (KUNLUN).

AstraZeneca in GI cancers 
AstraZeneca has a broad development programme for the treatment of GI cancers across several medicines and a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new cancer cases leading to approximately 3.6 million deaths.⁷

Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic and colorectal cancers. 

In addition to its indications in BTC and HCC, Imfinzi is being assessed in combinations, including with Imjudo, in liver, oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, is approved in the US and several other countries for HER2-positive advanced gastric cancer and is being assessed in colorectal cancer. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Lynparza (olaparib), a first-in-class PARP inhibitor, is approved the US and several other countries for the treatment of BRCA-mutated metastatic pancreatic cancer. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca also recently entered into a global exclusive license agreement with KYM Biosciences Inc. for CMG901. CMG901 is a potential first-in-class antibody drug conjugate targeting Claudin 18.2, a promising therapeutic target in gastric cancer.

AstraZeneca in immuno-oncology (IO)
AstraZeneca is a pioneer in introducing the concept of immunotherapy into dedicated clinical areas of high unmet medical need. The Company has a comprehensive and diverse IO portfolio and pipeline anchored in immunotherapies designed to overcome evasion of the anti-tumour immune response and stimulate the body's immune system to attack tumours.  

AstraZeneca aims to reimagine cancer care and help transform outcomes for patients with Imfinzi as a single treatment and in combination with Imjudo as well as other novel immunotherapies and modalities. The Company is also exploring next-generation immunotherapies like bispecific antibodies and therapeutics that harness different aspects of immunity to target cancer. 

AstraZeneca is boldly pursuing an innovative clinical strategy to bring IO-based therapies that deliver long-term survival to new settings across a wide range of cancer types. With an extensive clinical programme, the Company also champions the use of IO treatment in earlier disease stages, where there is the greatest potential for cure. 

AstraZeneca in oncology 
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. 

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience. 

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. 

AstraZeneca 
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca.

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References

1. Li Y, et al. Postoperative recurrence of gastric cancer depends on whether the chemotherapy cycle was more than 9 cycles. Medicine. 2022;101(5):e28620.
2. World Health Organisation. International Agency for Research on Cancer. Stomach Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf. Accessed October 2023.
3. National Cancer Institute. Gastroesophageal junction. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/gastroesophageal-junction. Accessed October 2023.
4. Kantar Health, validated with SEER stage at diagnosis and Cabasag et al. and Kuzuu et al. 2021
5. American Cancer Society. Stomach Cancer Survival Rates. Available at: https://www.cancer.org/cancer/types/stomach-cancer/detection-diagnosis-staging/survival-rates.html. Accessed October 2023.
6. Cancer Research UK. Survival for stomach cancer. Available at: https://www.cancerresearchuk.org/about-cancer/stomach-cancer/survival. Accessed October 2023.
7. World Health Organisation. World Cancer Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed October 2023.
   
   Dr. Janjigian provides consulting and advisory services to AstraZeneca.