AstraZeneca Presents Imfinzi (durvalumab) Plus tremelimumab Combination Data at AACR Annual Meeting

Phase Ib Study 006 long-term follow-up shows clinical activity in PD-L1 greater than or equal to 25% and less than 25% groups in 2nd-line non-small cell lung cancer

Phase I Study 10 data shows clinical activity with combination treatment in 2nd-line metastatic urothelial carcinoma

CAMBRIDGE, United Kingdom, April 16, 2018 (GLOBE NEWSWIRE) -- AstraZeneca and MedImmune, its global biologics research and development arm, today presented efficacy and safety data from two Phase I trials evaluating Imfinzi (durvalumab) in combination with tremelimumab in 2nd-line immunotherapy-naïve patients with either non-squamous advanced non-small cell lung cancer (NSCLC) (Study 006) or metastatic urothelial carcinoma (mUC) (Study 10).^1,2 The data were presented at the American Association for Cancer Research (AACR) Annual Meeting 2018.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "The mature data sets from these Phase I trials help further characterise the overall survival of durvalumab plus tremelimumab combination in 2nd-line non-squamous non-small cell lung cancer and 2nd-line metastatic urothelial carcinoma. We look forward to exploring whether OS is distinguished from durvalumab monotherapy in our Phase III MYSTIC and DANUBE trials, expected to read out later this year and next year, respectively."

Study 006: Safety and activity of 2nd-line  durvalumab   + tremelimumab in non-squamous advanced NSCLC
The Study 006 long-term follow-up results showed clinical activity in both PD-L1 greater than or equal to 25% and less than 25% groups.¹ Tumour PD-L1 expression was assessed with the Ventana PD-L1 (SP263) assay, PD-L1 cut-off: greater than or equal to 25% of tumour cells with membrane staining.¹ The table below shows anti-tumour activity and survival by PD-L1 status.¹

Response and survival	PD-L1 greater than or equal to 25% N = 57	PD-L1 less than 25% N = 136	Total a N = 213
Complete Response (CR)	1 (1.8)	0	1 (0.5)
Partial Response (PR)	19 (33.3)	16 (11.8)	39 (18.3)
Stable Disease (SD)	17 (29.8)	55 (40.4)	77 (36.2)
Progressive Disease (PD)	16 (28.1)	52 (38.2)	77 (36.2)
Confirmed  Objective Response Rate (ORR)  (CR + PR) n (%) 95% CI	20 (35.1) 22.9-48.9	16 (11.8) 6.9-18.4	40 (18.8) 13.8-24.7
Duration of Response (DOR)  Median, weeks 95% CI	51.7 25.1-NE	NR 24.3-NE	51.7 40.3-NE
PFS Median, months 95% CI	7.1 3.4-9.2	3.3 1.7-3.5	3.5 1.8-4.0
OS 12-month OS, %  95% CI	71.6 57.3-81.9	47.3 38.2-55.9	53.8 46.4-60.6
Note: Investigator-assessed anti-tumour activity according to RECIST v1.1. NE, not estimable. a20 patients had unknown PD-L1 expression

The combination of durvalumab and tremelimumab demonstrated a manageable safety profile in patients with advanced NSCLC.¹ The most common treatment-related adverse events (AEs) were fatigue (19%), pruritus (17%), diarrhoea (15%), reduced appetite (14%) and rash (14%).¹ 14 patients (7%) experienced a treatment-related AE that led to treatment discontinuation, and 23% experienced a Grade 3/4 treatment-related AE.¹ There was one treatment-related death (multifactorial hypoxia).¹

Study 10:  durvalumab   + tremelimumab in patients with metastatic urothelial cancer
The combination of durvalumab plus tremelimumab showed clinical activity in previously treated mUC, regardless of PD-L1 status.³ Tumour and immune-cell PD-L1 expression was assessed with the Ventana PD-L1 (SP263) assay, PD-L1 cut-off: greater than or equal to 25% of tumour and immune cells with membrane staining.² The table below shows anti-tumour activity and survival by PD-L1 status.³

Response and survival	PD-L1 greater than or equal to 25% (n=68)	PD-L1 less than 25% (n=86)	PD-L1 unknown (n=14)	Total (N=168)
Confirmed Objective Response Rate (ORR) (CR+PR) (95% CI), %	29.4 (19.0-41.7)	15.1 (8.3-24.5)	14.3 (1.8-42.8)	20.8 (15.0-27.8)
Ongoing ORR, %	60.0	92.3	100	74.3
Disease Control Rate (DCR) (CR+PR+SD greater than or equal to 24 weeks) (95% CI), %	32.4 (21.5-44.8)	24.4 (15.8-34.9)	42.9 (17.7-71.1)	29.2 (22.4-36.7)
Median PFS, months (95% CI)  PFS 6-month rate	3.5 (1.9-3.7)  26.1	1.8 (1.8-1.9)  22.6	4.9 (1.8-NE)  38.5	1.9 (1.8-3.4)  25.4
Median OS, months (95% CI) *  OS 6-month rate	18.9 (8.1-NE)  66.4	8.0 (4.8-10.0)  51.9	16.4 (7.3-16.4)  91.7	9.5 (8.1-18.9)  60.9
NE = not estimable *Should be interpreted with caution due to limited follow-up at data cut-off

The combination of durvalumab and tremelimumab demonstrated a manageable safety profile in patients with mUC.² Treatment-related AEs occurred in 76% of patients and were Grade 3-4 in 29%.² The most common treatment-related AEs were pruritus (26%), fatigue (24%), diarrhoea (20%), rash (14%) and increased lipase (12%). Treatment-related AEs led to discontinuation of therapy in 12% of patients.² There was one treatment-related death (pulmonary haemorrhage).²

NOTES TO EDITORS

For more information on AstraZeneca at AACR, please visit www.twitter.com/AstraZeneca.

About 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.^4-7

In February 2018, durvalumab received US FDA approval for the treatment of patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. Durvalumab also received accelerated approval in the US for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery.⁸

As part of a broad development programme, durvalumab is also being investigated as a monotherapy and/or in combination with tremelimumab, an anti-CTLA-4 monoclonal antibody, as a first line treatment for patients with NSCLC, small cell lung cancer, locally advanced or metastatic urothelial carcinoma, head and neck cancer and other solid tumours.⁹

About tremelimumab
Tremelimumab is an investigational human monoclonal antibody 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 and boosting the immune response to cancer.^10-12 Tremelimumab is being investigated in an extensive clinical trial programme in combination with durvalumab, in NSCLC, locally-advanced or metastatic urothelial carcinoma, head and neck cancer, liver cancer and blood cancers.⁹

About AstraZeneca's Approach to Immuno-Oncology
Immuno-Oncology (IO) is a therapeutic approach designed to stimulate the body's immune system to attack tumours. At AstraZeneca and MedImmune, our biologics research and development arm, our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. We believe that IO-based therapies will offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes durvalumab (anti-PD-L1) as monotherapy and in combination with tremelimumab (anti-CTLA-4) in multiple tumour types, stages of disease, and lines of therapy, 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 our IO portfolio with small, targeted molecules from across our Oncology pipeline, and with those of our research partners, may provide new treatment options across a broad range of tumours.

About 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 at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a growth platform for AstraZeneca, focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our 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.

About MedImmune
MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of small-molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology; Respiratory; Cardiovascular, Renal & Metabolic Diseases; and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, Md., one of AstraZeneca's three global R&D centres, with additional sites in Cambridge, UK, and Mountain View, CA. For more information, please visit www.medimmune.com.

About AstraZeneca
AstraZeneca 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. The Company is also selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

Intended audiences
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References

1. Chaft, J et al. Safety and activity of second-line durvalumab + tremelimumab in non-squamous advanced NSCLC. To be presented at AACR 2018, April 14-18, 2018. Chicago, IL.
2. Balar, A et al. Durvalumab + tremelimumab in patients with metastatic urothelial cancer. To be presented at AACR 2018, April 14-18, 2018. Chicago, IL.
3. Balar, A et al. "Durvalumab + tremelimumab in patients with metastatic urothelial cancer." Abstract. To be presented at AACR 2018, April 14-18, 2018. Chicago, IL.
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6. Haile S et al. Tumor Cell Programmed Death Ligand 1-Mediated T Cell Suppression Is Overcome by Coexpression of CD80. J Immunol 2011; 186: 6822-6829.
7. Haile S et al. Soluble CD80 Restores T Cell Activation and Overcomes Tumor Cell Programmed Death Ligand 1-Mediated Immune Suppression. J Immunol 2013; 191: 2829-2836.
8. US FDA. US Imfinzi (durvalumab) prescribing information. February 2018.
9. AstraZeneca. Clinical Trials Appendix Full-year and Q4 2017 Results Update. Available at: https://www.astrazeneca.com/content/dam/az/PDF/2017/Full-Year/Full-Year%202017%20Results%20Clinical%20trials%20appendix.pdf. Accessed Apr. 2018
10. Bograd AJ, et al. Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma. Cancer Immunol Immunother. 2011;60(11):1509-27.
11. Lee et al. Novel antibodies targeting immune regulatory checkpoints for cancer therapy. Br J Clin Pharmacol. 2013;76(2):233-47.
12. Eroglu, et al. Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab. Eur J Cancer. 2015;51(17):2689-97