Results from the global Phase II Study 22 trial testing AstraZeneca's tremelimumab, an anti-CTLA4 antibody, added to Imfinzi (durvalumab) demonstrated promising clinical activity and tolerability in patients with advanced hepatocellular carcinoma (HCC). HCC is the most common type of liver cancer.[1]

In the primary endpoint of the trial evaluating safety, all experimental arms demonstrated an acceptable profile and no new safety signals were identified. Patients treated with a single, priming dose of tremelimumab 300mg added to durvalumab every four weeks (T300+D regimen) achieved a median overall survival (OS) of 18.7 months in a key secondary endpoint. The OS result for the T300+D regimen was the longest among treatments tested in the trial, which included Imfinzi monotherapy, tremelimumab monotherapy and two regimens of the two combined.

In other key secondary endpoints, objective response rate (ORR) confirmed by independent central review was 24% with the T300+D regimen, and median duration of response (DoR) was not yet reached at the time of data cut-off. A unique T-cell profile for patients in the T300+D arm was associated with treatment response, suggesting complementary biological activity.

R. Kate Kelley, MD, Associate Professor of Clinical Medicine, Department of Medicine, University of California San Francisco and principal investigator said: "In Study 22, we were able to induce a stronger immune response and enhance the clinical activity of Imfinzi in patients with advanced liver cancer by combining with a single dose of tremelimumab, a novel approach designed to prime the immune response using CTLA-4 inhibition at the start of therapy. These exciting results suggest that dual checkpoint blockade with tremelimumab and Imfinzi may have a role in a challenging cancer where patients have few treatment options."

José Baselga, Executive Vice President, Oncology R&D, said: "Based on these compelling results, we see the potential for a single, priming dose of tremelimumab plus Imfinzi to change the treatment landscape and improve outcomes for patients with advanced liver cancer, a setting where new treatments are urgently needed. The Study 22 data are also an encouraging sign for our Phase III HIMALAYA trial testing this regimen in liver cancer, with data expected later this year."

Summary of Results

[][][][][][][][][][][][][][][][][][][][][][][][][][][][][]
Study 22 Safety
and
Efficacy
T300[i]+D[ii] D[ii] T[i] T75[i]+D[ii]
Dosing T300[i ]mg x 1 dose D1500[ii] mg T750[i ]mg T75[i] mg x 4
+ D1500[ii] mg Q4W Q4W Q4W x 7 doses
doses, + D1500[ii] mg Q4W
Q12W
thereafter
Median Total 3.7 (0.8-27.1) 3.7 (0.7 3.7 (0.9 2.4 (0.6-31.4)
Treatment -34.3) -31.2)
Duration,
months (min.
-max.)
Safety
T300[i]+D[ii](n=74) D[ii](n=101) T[i](n=69) T75[i]+D[ii](n=82)
Grade 3/4 26 (35.1) 20 (19.8) 30 (43.5) 20 (24.4)
trAEs[iii], n
(%)
Serious 12 (16.2) 11 (10.9) 17 (24.6) 12 (14.6)
trAEs[iii], n
(%)
Grade 5 1 (1.4) 3 (3.0) 0 1 (1.2)
trAEs[iii], n
(%)
Discontinuation 8 (10.8) 8 (7.9) 9 (13.0) 5 (6.1)
due to
trAEs[iii], n
(%)
Efficacy
T300[i]+D[ii](n=75) D[ii](n=104) T[i](n=69) T75[i]+D[ii](n=84)
Median OS, 18.73 (10.78-27.27) 13.57 (8.74 15.11 11.30 (8.38-14.95)
months (95% -17.64) (11.33
CI) -20.50)
ORR, % (95% CI) 24.0 (14.9-35.3) 10.6 (5.4 7.2 (2.4 9.5 (4.2-17.9)
-18.1) -16.1)
Median DoR, NR[iv] 11.17 23.95 13.21
months

i. Tremelimumab
ii. Durvalumab
iii. Treatment-related adverse events
iv. Not reached

Results evaluating safety and efficacy from parts two and three of the Phase II Study 22 trial were presented during the 2020 American Society of Clinical Oncology ASCO20 Virtual Scientific Program on Friday, 29 May 2020.

Imfinzi is not currently approved to treat HCC in any country, alone or in combination with tremelimumab. In January 2020, Imfinzi and tremelimumab were granted Orphan Drug Designation (https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/imfinzi-and-tremelimumab-granted-orphan-drug-designation-in-the-us-for-liver-cancer-20012020.html) in the US for the treatment of HCC.

Liver Cancer

Liver cancer is the third leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide, with approximately 20% of patients alive five years after diagnosis.[2,3] HCC represents about 80-90% of all primary liver cancers.[1] Approximately 700,000 people were estimated to be diagnosed with HCC around the world in 2018.[2] Between 80-90% of all patients with HCC also have chronic liver disease, which is primarily caused by infection with the hepatitis B or C viruses.[4,5] Chronic liver disease is associated with inflammation that, over time, results in immunosuppression and can lead to the development of HCC.[6,7 ]The unique immune environment of liver cancer provides clear rationale for researching medicines that harness the power of the immune system to treat HCC.[8 ]A critical unmet need exists for patients with HCC who face limited treatment options. More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.[9]

Study 22

Study 22 is an open-label, multicentre, global, four-part Phase II trial evaluating the safety and efficacy of several treatments in 433 patients with advanced HCC in the 1st- or 2nd-line setting. The first part of the trial evaluated the safety of the tremelimumab plus Imfinzi combination. Parts two and three are evaluating Imfinzi monotherapy, tremelimumab monotherapy, and tremelimumab plus Imfinzi combination therapy, and part four evaluates bevacizumab plus Imfinzi combination therapy. Results presented are for 332 patients in parts two and three, who were evaluated for safety and efficacy with a data cut-off of 28 February 2020. The trial is being conducted in 45 centres across 9 countries, including in the US, Europe, and Asia. Primary endpoints include number of patients reporting adverse events and serious adverse events, and number of patients experiencing dose-limiting toxicities. Secondary endpoints include overall survival, objective response rate, and duration of response.

HIMALAYA

HIMALAYA is a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and the T300+D regimen including a single, priming dose of tremelimumab 300mg added to Imfinzi every four weeks versus the standard-of-care medicine sorafenib, a multi-kinase inhibitor, in 1,324 patients with unresectable, advanced HCC who have not been treated with prior systemic therapy and are not eligible for locoregional therapy (treatment localised to the liver and surrounding tissue). The trial is being conducted in 189 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint is overall survival and key secondary endpoints include objective response rate and progression-free survival. HIMALAYA is the first Phase III trial to test dual immune checkpoint blockade in the 1st-line advanced HCC setting.

Imfinzi

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

Imfinzi is approved in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the Phase III PACIFIC trial. Imfinzi is approved for the 1st-line treatment of extensive-stage small cell lung cancer (ES-SCLC) in combination with SoC chemotherapy in the US and Singapore. Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer and other solid tumours.

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. Tremelimumab is being tested in a clinical trial programme in combination with Imfinzi in NSCLC, SCLC, bladder cancer, head and neck cancer and liver cancer.

AstraZeneca's approach to Immuno-Oncology (IO)

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body's immune system to attack tumours. The Company's IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. 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 monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, 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, small targeted 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 has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca's main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms - Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates - and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, 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 (http://www.astrazeneca.com/) and follow the Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

Contacts

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References

1. ASCO Cancer.net. Liver Cancer: Statistics. Available at https://www.cancer.net/cancer-types/liver-cancer/statistics. Accessed May 2020.
2. World Health Organization. IARC Globocan 2018 World Fact Sheet. Available at http://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed May 2020.
3. National Cancer Institute. Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. Available at: https://seer.cancer.gov/statfacts/html/livibd.html. Accessed May 2020.
4. Dos Santos P, et al. Incidence of hepatocellular carcinoma in patients with chronic liver disease due to hepatitis B or C and coinfected with the human immunodeficiency virus: a retrospective cohort study. World J Gastroenterol. 2018 February 7; 24(5): 613-622. DOI: 10.3748/wjg.v24.i5.613.
5. Hiotis SP, et al. Hepatitis B vs. hepatitis C infection on viral hepatitis-associated hepatocellular carcinoma. BMC Gastroenterol 12, 64 (2012) doi:10.1186/1471-230X-12-64.
6. Makarova-Rusher OV, et al. The yin and yang of evasion and immune activation in HCC. J Hepatol. 2015; 62 (6): 1420-1429.
7. Del Campo JA., et al. Role of inflammatory response in liver diseases: Therapeutic strategies. World journal of hepatology. 2018; 10(1), 1-7. doi:10.4254/wjh.v10.i1.1.
8. Han Y, et al. Human CD141CTLA-41Regulatory Dendritic Cells Suppress T-Cell Response by Cytotoxic T-LymphocyteAntigen-4-Dependent IL-10 and Indoleamine-2,3-Dioxygenase Production in Hepatocellular Carcinoma. Hepatology. 2014 Feb; 59 (2): 567-79.
9. Bupathi M, et al. Hepatocellular carcinoma: Where there is unmet need. Molecular Oncology. 2015;9(8):1501-1509. doi:10.1016/j.molonc.2015.06.005.