Results from the large, randomised COAST Phase II trial showed oleclumab, an anti-CD73 monoclonal antibody, or monalizumab, an anti-NKG2A monoclonal antibody, in combination with Imfinzi (durvalumab) improved progression-free survival (PFS) and objective response rate (ORR) compared to Imfinzi alone in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who had not progressed after concurrent chemoradiation therapy (CRT).

After a median follow-up of 11.5 months, the results of an interim analysis showed Imfinzi in combination with oleclumab reduced the risk of disease progression or death by 56% (hazard ratio [HR] of 0.44; 95% confidence interval [CI] 0.26-0.75), and in combination with monalizumab by 35% (HR of 0.65; 95% CI 0.49-0.85), when compared to Imfinzi alone in Stage III NSCLC patients following CRT. The 10-month PFS rate was 64.8% for the durvalumab plus oleclumab combination and 72.7% for durvalumab plus monalizumab, versus 39.2% with durvalumab alone.

The results, presented during the European Society for Medical Oncology (ESMO) Congress 2021 today, also showed an increase in the primary endpoint of confirmed ORR for Imfinzi plus oleclumab over Imfinzi alone (30% vs. 18%) and for Imfinzi plus monalizumab over Imfinzi alone (36% vs. 18%).

One in four patients with NSCLC are diagnosed at Stage III, where the majority of tumours are unresectable (cannot be removed with surgery).[1,2] Imfinzi after CRT is the global standard of care for patients in this setting, based on the PACIFIC Phase III trial.[3-5]

Roy S. Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT and Chair of the COAST Steering Committee said: "Imfinzi is the established standard of care for patients with unresectable, Stage III NSCLC, but solutions are still needed for patients who do not benefit from currently available therapies. The remarkable improvement observed with the addition of oleclumab or monalizumab to Imfinzi, along with the strong safety profile, suggests these novel combinations could further redefine outcomes for these patients."

Susan Galbraith, Executive Vice President, Oncology R&D, said: "Imfinzi has transformed the treatment of patients with unresectable, Stage III NSCLC, and we're excited by the promise of extending its benefit through novel combinations with two potential first-in-class monoclonal antibodies demonstrating strong clinical activity. Based on the stand-out results from COAST, we plan to start a registrational trial with the hope of bringing these new treatment options to patients that further increase the potential for cure in this setting."

Safety was similar across treatment arms with no new safety signals identified for either Imfinzi combination. Incidence of Grade 3 or higher treatment-emergent adverse events (TEAE; all cause) were 39.4% with Imfinzi, 40.7% with Imfinzi plus oleclumab, and 27.9% with Imfinzi plus monalizumab.

The most common Grade 3/4 TEAE was dyspnoea (reported in 3.0%, 1.7% and 1.6% of patients, respectively). Grade 3/4 pneumonitis was only reported for one patient (1.6%), who received Imfinzi plus monalizumab.

PACIFIC-real world observational study (PACIFIC-R) demonstrated benefit of Imfinzi in real-world setting at the ESMO Congress 2021

Data from a planned analysis of real-world PFS (rwPFS) from the PACIFIC-R observational study was also presented during ESMO, showing the first effectiveness data from over a thousand patients with unresectable, Stage III NSCLC who were treated with Imfinzi in the real-world setting as part of AstraZeneca's global PACIFIC Early Access Programme. The analysis showed a median rwPFS of 21.7 months in the real-world setting.

In comparison, a median PFS of 16.9 months was observed among patients treated with Imfinzi in the randomised, double-blinded, placebo-controlled PACIFIC Phase III trial. These results demonstrate the long-term effectiveness of Imfinzi in this real-world patient population and reinforce the PACIFIC regimen as the established standard of care today following platinum-based CRT.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after CRT in the US, Japan, China, across the EU and in many other countries with more than 80,000 patients treated with Imfinzi in this setting since its first approval in February 2018. Imfinzi is also approved for the 1st-line treatment of extensive-stage small cell lung cancer (ES-SCLC) in combination with etoposide and either carboplatin or cisplatin in more than 55 countries, including the US, Japan, China and across the EU, based on the CASPIAN Phase III trial.

AstraZeneca has several ongoing registrational trials focused on evaluating Imfinzi in earlier stages of lung cancer, including in potentially curative settings (PACIFIC-2, 4 and 5, MERMAID-1 and 2, AEGEAN, ADJUVANT BR.31, and ADRIATIC Phase III trials). The Company is also testing novel combinations with Imfinzi in the Phase II NeoCOAST trial in the neoadjuvant early-stage setting.

Stage III NSCLC

In 2020, an estimated 2.2 million people were diagnosed with lung cancer worldwide.[6] Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.[2,3,7] Stage III NSCLC represents approximately one quarter of NSCLC incidence.[1]

Stage III (locally advanced) NSCLC is commonly divided into three subcategories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally. In contrast to Stage IV, when cancer has spread (metastasised), the majority of Stage III patients are currently treated with curative intent.[2,8]

The majority of Stage III NSCLC patients are diagnosed with unresectable tumours.[1,2] Prior to the approval of Imfinzi in this setting, no new treatments beyond CRT had been available to these patients for decades.[3-5]

COAST

COAST is a Phase II, multi-arm, randomised trial investigating Imfinzi alone or in combination with either oleclumab (anti-CD73 monoclonal antibody) or monalizumab (anti-NKG2A monoclonal antibody) in 189 patients with locally advanced, unresectable Stage III NSCLC who had not progressed after CRT.

COAST is being conducted in 82 centres across 9 countries in North America, Europe and Asia. The primary endpoint of the trial is ORR as a measure of anti-tumour activity. Secondary endpoints include safety, duration of response, overall survival and PFS.

PACIFIC-R

PACIFIC-Real World (PACIFIC-R) is an international, observational study of 1,399 patients with unresectable, Stage III NSCLC previously treated with Imfinzi as part of an early access program (EAP) between September 2017 and December 2018. Patients were enrolled in the PACIFIC-R study after discontinuation of the EAP in participating countries. Eligible patients had not progressed after CRT and were enrolled regardless of PD-L1 status at trial initiation.

Imfinzi

Imfinzi 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.

In addition to approvals in unresectable, Stage III NSCLC and ES-SCLC, Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

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 NSCLC, SCLC, bladder cancer, hepatocellular carcinoma, biliary tract cancer (a form of liver cancer), oesophageal cancer, gastric and gastroesophageal cancer, cervical cancer, ovarian cancer, endometrial cancer, and other solid tumours.

Oleclumab

Oleclumab is a potentially first-in-class, anti-CD73 monoclonal antibody that selectively binds to and inhibits the activity of CD73. CD73 is a cell surface enzyme which is overexpressed in the tumour microenvironment and promotes tumour growth by limiting anti-tumour immunity via the adenosine receptor pathway.

Preclinical studies have demonstrated that CD73 blockade improved anti-tumour activity in combination with radiotherapy, chemotherapy and immunotherapy. Oleclumab is also being examined in various Phase II trials for solid tumour malignancies.

Monalizumab

Monalizumab is a potentially first-in-class, anti-NKG2A antibody. NKG2A is a checkpoint receptor expressed on tumour-infiltrating cytotoxic T-cells and natural killer cells that inhibits their anti-cancer functions.

Monalizumab is also being studied in the ongoing INTERLINK-1 Phase III trial, evaluating monalizumab in combination with cetuximab for the treatment of patients with previously-treated recurrent or metastatic head and neck squamous cell carcinoma.

Monalizumab is being developed in collaboration with Innate Pharma. AstraZeneca obtained full oncology rights to monalizumab in October 2018 through a co-development and commercialisation agreement initiated in 2015.

AstraZeneca in lung cancer

AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company's comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

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 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 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, 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 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 (https://twitter.com/AstraZeneca).

Contacts

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References

1. EpiCast Report: NSCLC Epidemiology Forecast to 2025. GlobalData. 2016.

2. Provencio M, et al. Inoperable Stage III Non-Small Cell Lung Cancer: Current Treatment and Role Of Vinorelbine. J Thorac Dis. 2011;3:197-204.

3. Cheema PK, et al. Perspectives on Treatment Advances for Stage III Locally Advanced Unresectable Non-Small-Cell Lung Cancer. Curr Oncol. 2019;26(1):37-42.

4. Curran WJ, et al. Sequential vs Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410. J Natl Cancer Inst. 2011;103(19):1452-1460.

5. Hanna N, et al. Current Standards and Clinical Trials in Systemic Therapy for Stage III Lung Cancer: What is New? Am Soc Clin Oncol Educ Book. 2015:e442-447.

6. World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed September 2021.

7. LUNGevity Foundation. Types of Lung Cancer. Available at  https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed September 2021.

8. ASCO. Cancer.net. Lung Cancer - Non-Small Cell. Available at https://www.cancer.net/cancer-types/lung-cancer/view-all. Accessed September 2021.