On January 19, 2024 Astrazeneca reported that Positive results from the EMERALD-1 Phase III trial showed Imfinzi (durvalumab) in combination with TACE and bevacizumab demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of progression-free survival (PFS) compared to TACE alone in patients with hepatocellular carcinoma (HCC) eligible for embolisation (Press release, AstraZeneca, JAN 19, 2024, View Source [SID1234639367]).
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These results will be presented today at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco, California (#LBA432).
Approximately 20-30% of patients with HCC, the most common type of liver cancer, are eligible for embolisation, a procedure that blocks the blood supply to the tumour and can also deliver chemotherapy or radiation therapy directly to the liver.1-8 Despite being the standard of care in this setting, most patients who receive embolisation experience disease progression or recurrence within eight months.9-11
In EMERALD-1, treatment with Imfinzi plus TACE and bevacizumab reduced the risk of disease progression or death by 23% compared to TACE alone (based on a hazard ratio [HR] of 0.77; 95% confidence interval [CI] 0.61-0.98; p=0.032). Median PFS was 15 months in patients treated with the Imfinzi combination versus 8.2 months with TACE. The PFS benefit observed was generally consistent across key prespecified subgroups. The secondary endpoint of time to progression (TTP) further supports the clinical benefit of Imfinzi plus TACE and bevacizumab in this setting, with a median TTP of 22 months versus 10 months for TACE (HR 0.63; 95% CI 0.48-0.82).
The trial will continue as planned to assess the key secondary endpoint of overall survival (OS).
Bruno Sangro, MD, PhD, Director of the Liver Unit and Professor of Medicine at Clínica Universidad de Navarra, Pamplona, Spain and a lead investigator in the EMERALD-1 trial, said: "In this earlier liver cancer setting, embolisation alone has been the standard of care for more than 20 years, and rates of disease progression have remained high. Adding durvalumab and bevacizumab to TACE reduced the risk of disease progression or death by twenty-three per cent for patients with liver cancer eligible for embolisation, showing for the first time that combining a systemic treatment with TACE meaningfully improves this clinically relevant outcome in earlier-stage disease."
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "With Imfinzi-based treatment, patients with liver cancer eligible for embolisation lived nearly seven additional months before their disease progressed. We are discussing these positive EMERALD-1 data with global regulatory authorities while awaiting the final overall survival results from the trial."
Summary of results: EMERALD-1i
Imfinzi plus TACE and bevacizumab
(n=204)
Placebo plus TACE
(n=205)
Median PFS (months; 95% CI)ii, iii
15.0 (11.1-18.9)
8.2 (6.9-11.1)
PFS HR (95% CI)ii, iv
0.77 (0.61-0.98)
p-valuev
0.032
PFS rate at 12 months (%)iii
55.5
39.8
PFS rate at 18 months (%)iii
43.1
28.3
Median TTP (months; 95% CI)iii, v
22.0 (16.6-24.9)
10.0 (7.1-13.6)
TTP HR (95% CI)iv, v
0.63 (0.48-0.82)
Subjects with measurable disease
Imfinzi plus TACE and bevacizumab
(n=202)
Placebo plus TACE
(n=203)
Objective Response Rate (ORR) (%)iii
43.6
29.6
i The data cut-off date was 11 Sep 2023.
ii PFS, TTP and ORR by Blinded Independent Central Review (BICR) per RECIST v1.1
iii Calculated using Kaplan-Meier method
iv Calculated from stratified Cox proportional hazards method
v The threshold of significance for this analysis was 0.0435 based on the alpha spend at the PFS interim analysis (2.27%) and the actual number of events at PFS final analysis.
The safety profile for Imfinzi plus TACE and bevacizumab was generally manageable and consistent with the known profile of each medicine. The number of TACE procedures was consistent across arms. No new safety signals were observed. Grade 3 and 4 adverse events due to any cause occurred in 45.5% of patients treated with Imfinzi plus TACE and bevacizumab and 23% of patients treated with TACE alone.
Notes
Liver cancer
Liver cancer, of which HCC is the most common type, is the third-leading cause of cancer death, with an estimated 900,000 people worldwide diagnosed each year and a high prevalence in certain regions of Asia.12-14 An estimated 80-90% of all patients with HCC also have cirrhosis.15 Chronic liver diseases such as cirrhosis are associated with inflammation that over time can lead to the development of HCC.15 Immunotherapy is a proven treatment modality in HCC with approved options available for patients in later-line settings.16
EMERALD-1
EMERALD-1 is a randomised, double-blind, placebo-controlled, multicentre, global Phase III trial of Imfinzi plus TACE concurrently, followed by Imfinzi with or without bevacizumab until progression versus TACE alone in a total of 616 patients with unresectable HCC eligible for embolisation.
The trial was conducted in 157 centres across 18 countries, including in North America, Australia, Europe, South America and Asia. The primary endpoint was PFS for Imfinzi plus TACE and bevacizumab versus TACE alone, and secondary endpoints include PFS for Imfinzi plus TACE, OS, patient-reported outcomes and ORR.
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 HCC in the US, EU, Japan, China and many other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively. Following HIMALAYA in the advanced setting, EMERALD-1 is AstraZeneca’s second positive Phase III trial in HCC.
In non-small cell lung cancer (NSCLC), 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 also the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial, the results of which have been confirmed in the real-world setting in the PACIFIC-R study. In 2023, AstraZeneca announced positive results from the AEGEAN Phase III trial evaluating Imfinzi in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy after surgery in resectable NSCLC.
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. 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, breast cancer and other solid tumours. In 2023, AstraZeneca announced positive results for several Phase III trials evaluating Imfinzi in various combinations, including in ovarian (DUO-O) and endometrial (DUO-E) cancers with Lynparza (olaparib).
In GI cancers specifically, AstraZeneca has an extensive clinical development programme further assessing Imfinzi across multiple settings. In addition to EMERALD-1, Imfinzi is also being investigated in combination with bevacizumab in adjuvant HCC (EMERALD-2), in combination with Imjudo, lenvatinib and TACE in embolisation-eligible HCC (EMERALD-3), in resectable gastric and gastroesophageal junction cancers (MATTERHORN) and in locally advanced oesophageal cancer (KUNLUN). In June 2023, Imfinzi added to standard-of-care neoadjuvant chemotherapy met a key secondary endpoint of pathologic complete response in the MATTERHORN Phase III trial.