Late-breaking post-hoc exploratory results from the POSEIDON Phase III trial suggest a trend for improved overall survival (OS) with a limited course of five cycles of tremelimumab added to AstraZeneca’s Imfinzi (durvalumab) plus platinum chemotherapy, in the 1st-line treatment of patients with STK11, KEAP1 or KRAS-mutated Stage IV (metastatic) non-small cell lung cancer (mNSCLC).
These results will be presented on 9 August 2022 at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC) (Abstract #OA15.04).
NSCLC tumours with STK11 and KEAP1 mutations are often associated with a poor prognosis and frequently classified as immunologically “cold”, with immune T-cells missing from the tumour.1,2 KRAS-mutated NSCLC is typically responsive to immunotherapy, unless associated with STK11 or KEAP1 co-mutations where outcomes are often poor.1,2 KRAS mutations are the most common tumour growth driver in NSCLC representing approximately 25% of patients; while an estimated 6-15% of NSCLC is KEAP1-mutated and approximately 15% of NSCLC is KRAS-driven and STK11-mutated.1,3-6
A trend for OS improvement was observed in the POSEIDON Phase III trial for patients with these mutations when treated with a limited course of tremelimumab added to Imfinzi (durvalumab) plus platinum chemotherapy compared to chemotherapy. The exploratory analysis reported a hazard ratio (HR) of 0.56 (95% CI 0.30-1.03) for STK11-mutated non-squamous NSCLC, an HR of 0.43 (95% CI 0.16-1.25) for KEAP1-mutated NSCLC, and 0.56 (95% CI 0.36-0.88) for KRAS-mutated non-squamous NSCLC.
Median OS and two-year survival rates across all mutational subgroups also increased with the immunotherapy combination compared to chemotherapy. The STK11 and KRAS subgroup analyses were presented for patients with non-squamous histology; while the KEAP1 subgroup analysis was presented for all mutation-evaluable patients irrespective of tumour histology, due to a small sample size. These subgroup analyses should be interpreted with caution as they are post hoc, exploratory and of smaller sample sizes.
Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “These exploratory analyses for POSEIDON presented at WCLC are an encouraging sign for a group of metastatic lung cancer patients whose prognosis is particularly poor. We are eager to continue following the science to fully understand how patients with these specific mutations and with PD-L1 negative lung cancer respond to immunotherapy combinations including CTLA-4 inhibitors. These initial survival associations warrant further study.”
Also at WCLC, additional exploratory analyses from the POSEIDON Phase III trial evaluated outcomes in patient subgroups whose tumours were PD-L1-negative (tumour cell [TC] expression <1%) versus patients whose tumours expressed PD-L1 (TC≥1%), and further subdivisions based on histology (squamous and non-squamous). While this analysis was exploratory, the data suggest the addition of tremelimumab to Imfinzi and chemotherapy may extend clinical benefit to PD-L1-negative patients across both squamous and non-squamous histologies.
The POSEIDON trial met key endpoints of PFS in 2019 and OS in 2021, reducing the risk of disease progression or death by 28% and the risk of death by 23% in patients with mNSCLC treated with 1st-line tremelimumab, Imfinzi and chemotherapy compared to chemotherapy alone. The combination delivered a broadly similar safety profile to the Imfinzi and chemotherapy combination and addition of tremelimumab did not lead to increased treatment discontinuation. These results were presented at the IASLC 2021 World Conference on Lung Cancer.
Tremelimumab is under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line mNSCLC based on the results of the POSEIDON trial.
Notes
Stage IV NSCLC
Lung cancer is the leading cause of cancer death accounting for about one-fifth of all cancer deaths.7 Patients are commonly diagnosed at Stage IV, when the tumour has spread outside of the lung.8
Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC.8-10 Within NSCLC, patients are classified as squamous, representing 25-30% of patients, or non-squamous, the most common type representing approximately 70-75% of NSCLC patients.8 Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.11 Approximately 5% of patients with metastatic NSCLC will survive 5 years after diagnosis based on data in the UK between 2013-2017.12
POSEIDON
The POSEIDON trial was a randomised, open-label, multi-centre, global, Phase III trial of Imfinzi plus platinum-based chemotherapy or Imfinzi, tremelimumab and chemotherapy versus chemotherapy alone in the 1st-line treatment of 1,013 patients with metastatic NSCLC. The trial population included patients with either non-squamous or squamous disease and the full range of PD-L1 expression levels. POSEIDON excluded patients with certain epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions.
In the experimental arms, patients were treated with a flat dose of 1,500mg of Imfinzi, or Imfinzi and 75mg of tremelimumab with up to four cycles of chemotherapy every three weeks, followed by maintenance treatment with Imfinzi once every four weeks, or Imfinzi and a fifth dose of 75mg of tremelimumab given at week 16. In comparison, the control arm allowed up to six cycles of chemotherapy. Pemetrexed maintenance treatment was allowed in all arms in patients with non-squamous disease if given during the induction phase. Nearly all patients with non-squamous disease (95.5%) had pemetrexed and platinum, while the majority of patients with squamous disease receiving chemotherapy (88.3%) received gemcitabine and platinum.
Primary endpoints included PFS and OS for the Imfinzi plus chemotherapy arm. Key secondary endpoints included PFS and OS in the Imfinzi plus tremelimumab and chemotherapy arm. As both PFS endpoints were met for Imfinzi plus chemotherapy and Imfinzi, tremelimumab and chemotherapy, the prespecified statistical analysis plan allowed for testing OS in the Imfinzi plus tremelimumab and chemotherapy arm. The trial was conducted in more than 150 centres across 18 countries, including the US, Europe, South America, Asia and South Africa.
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 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.
In the past year, Imfinzi combinations have resulted in positive Phase III trials in multiple additional cancer settings with positive Phase III trials in unresectable advanced liver cancer (HIMALAYA), biliary tract cancer (TOPAZ-1) and resectable NSCLC (AEGEAN). The data from HIMALAYA and TOPAZ-1 are under review with global health authorities.
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, ovarian cancer, endometrial 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.
Beyond POSEIDON, tremelimumab is being tested in combination with Imfinzi across multiple tumour types including in bladder cancer (VOLGA and NILE), locoregional HCC (EMERALD-3) and SCLC (ADRIATIC).
Tremelimumab is also under review by global regulatory authorities in combination with Imfinzi in unresectable advanced liver cancer based on the results of the HIMALAYA Phase III trial.
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 (durvalumab) 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 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.
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References
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