AstraZeneca presented data for Imfinzi (durvalumab) combinations from the HIMALAYA and TOPAZ-1 Phase III trials at the European Association for the Study of the Liver's International Liver Congress 2022 (EASL 2022) and the European Society for Medical Oncology’s World Congress on Gastrointestinal Cancer (ESMO World GI 2022).

Exploratory sub-analyses from HIMALAYA and TOPAZ-1 were presented at ESMO World GI 2022, 29 June to 2 July in Barcelona. Additionally, health-related quality of life data from HIMALAYA was presented at EASL 2022, 22 to 26 June in London.

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “The HIMALAYA results show a consistent survival benefit with the STRIDE regimen in patients with unresectable liver cancer regardless of baseline liver functional reserve, and TOPAZ-1 data show that Imfinzi plus chemotherapy improved outcomes for biliary tract cancer patients regardless of where their tumour was located or where they lived. These important subgroup analyses add to the body of evidence demonstrating the potential for Imfinzi combinations to meaningfully improve outcomes for these patients who are in need of effective and generally well tolerated treatments.”

HIMALAYA Phase III analyses in unresectable liver cancer at ESMO World GI 2022 and EASL 2022
An exploratory sub-analysis from the HIMALAYA Phase III trial evaluated the efficacy and safety of the STRIDE regimen (single tremelimumab, regular interval durvalumab) or durvalumab monotherapy versus sorafenib by baseline liver function, and liver function over time in patients with unresectable liver cancer. Liver function was determined using the ALBI (albumin-bilirubin) scoring system, a model for assessing the severity of liver dysfunction that describes worsening severity across three grades (ALBI grades 1 through 3).

Patients with liver cancer tend to have underlying liver cirrhosis, leading to impaired liver function and poor prognosis.¹ Systemic therapies for advanced liver cancer have the potential to exacerbate pre-existing liver disease and increase the risk of liver-related adverse events.

Data presented at ESMO World GI 2022 showed that the STRIDE regimen improved survival

regardless of liver function scores at baseline, with overall survival (OS) hazard ratios (HR) that were generally consistent with the primary analysis in both the ALBI grade 1 subgroup (HR 0.79; 95% confidence interval [CI] 0.62-1.01) and ALBI grade 2/3 subgroup (HR 0.83; 95% CI 0.65-1.05).² The overall response rate, duration of response and tolerability profile for STRIDE were consistent regardless of ALBI score.² Further, liver function was stable over time for patients treated with STRIDE who remained on the trial.

An additional analysis from the HIMALAYA trial was conducted using a self-reported questionnaire to assess the impact of treatment and treatment status on health-related quality of life in patients with unresectable liver cancer. Results presented at EASL 2022 demonstrated that patients treated with the STRIDE regimen had better quality of life than those treated with sorafenib, with fewer patients experiencing moderate to severe problems in domains including mobility, self-care, pain/discomfort and anxiety/depression.³ Further, treatment discontinuation was associated with a larger magnitude of worsening health status than disease progression. Following discontinuation, more patients reported experiencing moderate to extreme problems on all domains.³ These results highlight the impact of treatment discontinuation and the potential quality-of-life benefits for maintaining patients on treatment with the STRIDE regimen.

Primary results from the HIMALAYA Phase III trial were presented during the 2022 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium in January 2022 and published in New England Journal of Medicine (NEJM) Evidence in June 2022. The trial met its primary endpoint demonstrating a statistically significant improvement of OS with a single priming dose of tremelimumab plus durvalumab every four weeks versus sorafenib.⁴ The safety profiles of the STRIDE regimen and for durvalumab alone were consistent with the known profiles of each medicine, and no new safety signals were identified.⁴

TOPAZ-1 Phase III trial subgroup analysis in advanced biliary tract cancer at ESMO World GI 2022
An exploratory subgroup analysis of patients enrolled in the TOPAZ-1 Phase III trial evaluated the efficacy and safety of durvalumab plus standard-of-care chemotherapy (gemcitabine plus cisplatin) compared to placebo plus chemotherapy by primary tumour location, including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer.

The analysis showed a consistent OS benefit for patients treated with durvalumab and chemotherapy (gemcitabine plus cisplatin) compared to chemotherapy alone across all primary tumour locations, with an improved OS with durvalumab: intrahepatic cholangiocarcinoma (HR 0.76; 95% CI 0.58-0.98), extrahepatic cholangiocarcinoma (HR 0.76; 95% CI 0.49-1.19) and gallbladder cancer (HR 0.94; 95% CI 0.65-1.37).⁵ This consistent OS benefit was observed regardless of geographic location, with patients in North America, Europe and Asia all showing benefit. The incidence of grade 3 or 4 adverse events and treatment-related adverse events were generally comparable among treatment groups, irrespective of primary tumour locations.

Primary results from the TOPAZ-1 trial were presented during the ASCO GI Symposium in January 2022 and published in NEJM Evidence in June 2022. Durvalumab in combination with standard-of-care chemotherapy demonstrated a statistically significant and clinically meaningful OS benefit versus chemotherapy alone, meeting the primary endpoint.⁶ Durvalumab plus chemotherapy did not increase the discontinuation rate due to adverse events compared to chemotherapy alone.⁶

Notes

Liver cancer
Liver cancer is the third-leading cause of cancer death and sixth most commonly diagnosed cancer worldwide.⁷ About 75% of all primary liver cancers in adults are HCC.⁸ Between 80-90% of all patients with HCC also have cirrhosis.¹ Chronic liver diseases are associated with inflammation that over time can lead to the development of HCC.¹

More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.⁹ A critical unmet need exists for patients with HCC who face limited treatment options.⁹ The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the immune system to treat HCC.⁹

Biliary tract cancer
Biliary tract cancer (BTC) is a group of rare and aggressive gastrointestinal (GI) cancers that form in the cells of the bile ducts (cholangiocarcinoma), gallbladder or ampulla of Vater (where the bile duct and pancreatic duct connect to the small intestine).^10,11

Cholangiocarcinoma is more common in China and South-East Asia and is on the rise in Western countries^.10,12 Gallbladder cancer is more common in certain regions of South America, India and Japan.¹³ Approximately 50,000 people in the US, Europe and Japan and about 210,000 people worldwide are diagnosed with BTC each year.^14-16

Early-stage BTC affecting the bile ducts and gallbladder often presents without clear symptoms and most new cases of BTC are therefore diagnosed at an advanced stage, when treatment options are limited and the prognosis is poor.^12,13,17 Approximately 5% to 15% of patients with BTC survive five years. ¹²

HIMALAYA
HIMALAYA was a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and the STRIDE regimen, comprising a single priming dose of tremelimumab 300mg added to Imfinzi 1500mg followed by Imfinzi every four weeks versus sorafenib, a standard-of-care multi-kinase inhibitor.

The trial included a total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localised to the liver and surrounding tissue).

The trial was conducted in 181 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint is OS for STRIDE versus sorafenib and key secondary endpoints included OS for Imfinzi versus sorafenib, objective response rate and progression-free survival (PFS) for STRIDE and for Imfinzi alone.

TOPAZ-1
TOPAZ-1 is a randomised, double-blind, placebo controlled, multicentre, global Phase III trial of Imfinzi in combination with chemotherapy (gemcitabine plus cisplatin) versus placebo in combination with chemotherapy as a 1st-line treatment in 685 patients with unresectable advanced or metastatic BTC including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer. Patients with ampullary carcinoma were excluded.

The primary endpoint is OS and key secondary endpoints included PFS, objective response rate and safety. The trial was conducted in 105 centres across 17 countries including in the US, Europe, South America and several countries in Asia including South Korea, Thailand, Japan and China.

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 the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy, and is the global standard of care in this setting 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 (ES-SCLC) based on the CASPIAN Phase III trial. In 2021, updated results from the CASPIAN trial showed Imfinzi plus chemotherapy tripled patient survival at three years versus chemotherapy alone.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

Since the first approval in May 2017, more than 100,000 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 small cell lung cancer (SCLC), NSCLC, bladder cancer, several GI cancers, ovarian cancer, endometrial cancer, and other solid tumours.

In the past year, Imfinzi has demonstrated clinical benefit in multiple additional cancer settings with positive Phase III trials in advanced BTC (TOPAZ-1), unresectable advanced liver cancer (HIMALAYA) and metastatic NSCLC (POSEIDON).

Tremelimumab
Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

Beyond HIMALAYA, tremelimumab is being tested in combination with Imfinzi across multiple tumour types including locoregional HCC (EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and NILE).

Tremelimumab is also under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON Phase III trial, which showed the addition of a short course of tremelimumab to Imfinzi plus chemotherapy improved both OS and PFS compared to chemotherapy alone.

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 worldwide.¹⁸

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

Imfinzi is being assessed in combinations in liver, BTC, oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease.

The Company aims to understand the potential of Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, in the two most common GI cancers, colorectal and gastric cancers. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Lynparza (olaparib) is a first-in-class PARP inhibitor with a broad and advanced clinical trial programme across multiple GI tumour types including pancreatic and colorectal cancers. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s Immuno-Oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumour immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.

In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

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 Twitter @AstraZeneca.