Approvals based on significant survival benefits in HIMALAYA and POSEIDON Phase III trials

LONDON, UK I February 22, 2023 I AstraZeneca’s Imfinzi (durvalumab) and Imjudo (tremelimumab) immunotherapy combinations have been approved in the European Union (EU) for the treatment of advanced liver and lung cancers.

The approvals authorise Imfinzi in combination with Imjudo for the 1st-line treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) and Imfinzi in combination with Imjudo and platinum-based chemotherapy for the treatment of adult patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC).

The two approvals by the European Commission follow positive recommendations by The Committee for Medicinal Products for Human Use of the European Medicines Agency in December 2022 and are based on positive results from the HIMALAYA Phase III trial, published in the New England Journal of Medicine Evidence and the POSEIDON Phase III trial, published in the Journal of Clinical Oncology.

Bruno Sangro, MD, PhD, Director of the Liver Unit and Professor of Internal Medicine at Clínica Universidad de Navarra, and a lead investigator in the HIMALAYA Phase III trial, said: “This approval in Europe is welcome news for eligible patients with advanced liver cancer, who face a poor prognosis and are in need of well-tolerated treatments that can meaningfully extend overall survival. In HIMALAYA, an estimated 31% of patients treated with this novel combination of tremelimumab with durvalumab were alive at three years, while only 20% of patients treated with sorafenib were still alive at the same duration of follow-up.”

Solange Peters, MD, PhD, Head of the Medical Oncology Service and Chair of Thoracic Oncology at Hospitalier Universitaire Vaudois, Lausanne, Switzerland, and principal investigator in the POSEIDON Phase III trial, said: “Patients with metastatic non-small cell lung cancer continue to need new therapies that can meaningfully extend survival, including for many patients whose disease does not respond to current therapies. The approval of tremelimumab added to durvalumab and chemotherapy means that patients in Europe with this devastating cancer now have a valuable new treatment approach with demonstrated long-term survival benefits.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “Lung cancer is one of the most prevalent and deadly cancers in Europe, and rates of liver cancer are rising steadily across the region. These approvals for Imfinzi and Imjudo bring critically needed, novel immunotherapy-based treatment regimens that will potentially deliver life-extending benefits for European patients with advanced liver and non-small cell lung cancers.”

Imjudo and Imfinzi approved in liver cancer
The approval for the treatment of HCC is based on results from the HIMALAYA Phase III trial, where the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen, comprised of a single dose of the anti-CTLA-4 antibody Imjudo (300mg) combined with anti-PD-L1 antibody Imfinzi (1500mg dose) followed by Imfinzi every four weeks significantly reduced the risk of death by 22% versus sorafenib (hazard ratio [HR] 0.78; 95% confidence interval [CI], 0.66-0.92; p=0.0035). Median overall survival (OS) was 16.4 months versus 13.8 for sorafenib. An estimated 31% of patients treated with the combination were still alive after three years with 20% of patients treated with sorafenib still alive at the same duration of follow-up.

The safety profile of the combination of Imjudo added to Imfinzi were consistent with the known profiles of each medicine, and no new safety signals were identified.

Liver cancer is the third-leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide.1,2 Approximately 87,000 Europeans were diagnosed with liver cancer in 2020, with 51% of patients at an advanced cancer stage at time of diagnosis. Rates of liver cancer continue to rise rapidly, with a 70% increase of liver cancer-related mortality in Europe from 1990-2019.3

Imfinzi and Imjudo approved in NSCLC
The approval for the treatment of metastatic NSCLC is based on results from the POSEIDON Phase III trial, which showed a limited course of five cycles of the anti-CTLA-4 antibody Imjudo added to Imfinzi plus four cycles of platinum-based chemotherapy significantly reduced the risk of death by 23% versus a range of chemotherapy options (HR 0.77; 95% CI, 0.65-0.92; p=0.00304). Median OS was 14.0 months versus 11.7 months for chemotherapy. An estimated 33% of patients were alive at two years versus 22% for chemotherapy. This treatment combination also reduced the risk of disease progression or death by 28% compared to chemotherapy alone (HR 0.72; 95% CI, 0.60-0.86; p=0.00031) with a median progression-free survival (PFS) of 6.2 months versus 4.8 months, respectively.

Updated results from the POSEIDON Phase III trial after approximately four years of follow-up presented at the European Society for Medical Oncology Congress 2022 demonstrated sustained survival benefit, reducing the risk of death by 25% compared to chemotherapy alone (HR 0.75; 95% CI, 0.63-0.88). Updated median OS was 14 months for the combination versus 11.7 months for chemotherapy alone. An estimated 25% of patients treated with the combination were alive at three years versus 13.6% for those treated with chemotherapy alone.

The safety profile for Imjudo plus Imfinzi and chemotherapy was consistent with the known profiles of each medicine, and no new safety signals were identified.

Metastatic lung cancer is the most advanced form of lung cancer.4,5 Approximately 40% of people with NSCLC have metastatic disease at the time of diagnosis.6 An estimated 5% of patients with metastatic NSCLC in Europe will survive five years after diagnosis.7-8

For the POSEIDON indication in the EU, Imjudo will be temporarily marketed under the name Tremelimumab AstraZeneca until the second half of 2023.


Liver cancer
About 75% of all primary liver cancers in adults are HCC.1 Between 80-90% of all patients with HCC also have cirrhosis.9 Chronic liver diseases are associated with inflammation that over time can lead to the development of HCC.9

More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.10 A critical unmet need exists for patients with HCC who face limited treatment options.10 The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the power of the immune system to treat HCC.10

Lung cancer is the leading cause of cancer-related death and is the second most common form of cancer globally, with more than two million patients diagnosed in 2020.11 Lung cancer is broadly split into NSCLC and small-cell lung cancer (SCLC), with 80-85% classified as NSCLC. Within NSCLC, patients are classified as squamous, representing 25-30% of patients, or non-squamous, in approximately 70-75% of patients.4, 12-13

HIMALAYA is a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and a regimen comprising a single priming dose of Imjudo 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 randomised 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 was OS for the combination versus sorafenib and key secondary endpoints included OS for Imfinzi versus sorafenib, objective response rate and PFS for the combination and for Imfinzi alone.

POSEIDON is 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 either Imfinzi (1,500mg) or Imfinzi plus Imjudo (75mg) with up to four cycles of chemotherapy every three weeks before either Imfinzi maintenance once every four weeks or Imfinzi and a fifth dose of Imjudo 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 Imjudo and chemotherapy arm. As PFS endpoints were met for both experimental arms, the prespecified statistical analysis plan allowed for testing OS in the Imfinzi plus Imjudo and chemotherapy arm. The OS trend observed in the Imfinzi plus chemotherapy arm did not achieve statistical significance. The trial was conducted in more than 150 centres across 18 countries, including the US, Europe, South America, Asia and South Africa.

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 SCLC based on the CASPIAN Phase III trial. In an exploratory analysis 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 in combination with Imjudo and chemotherapy in metastatic NSCLC in the US, EU and Japan; in combination with chemotherapy in locally advanced or metastatic biliary tract cancer (BTC) in the US, EU, Japan and several other countries; in combination with Imjudo in unresectable HCC in the US, EU and Japan; as monotherapy in unresectable HCC in Japan; and in 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 SCLC, NSCLC, bladder cancer, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer and other solid tumours. 

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

In addition to its approved indications in liver and lung cancers, Imjudo is being tested in combination with Imfinzi across multiple tumour types including locoregional HCC (EMERALD-3 trial), SCLC (ADRIATIC trial) and bladder cancer (VOLGA and NILE trials).

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.14

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

In addition to its approved indications in biliary tract and liver cancers, Imfinzi is being assessed in combinations, including with Imjudo, in liver, oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, is approved in the US, EU and several other countries for HER2-positive advanced gastric cancer and is being assessed in colorectal cancer. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Lynparza (olaparib), a first-in-class PARP inhibitor, is approved in the US, EU and several other countries for the treatment of BRCA-mutated metastatic pancreatic cancer. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

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 Imjudo (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 immuno-oncology (IO)
AstraZeneca is a pioneer in introducing the concept of immunotherapy into dedicated clinical areas of high unmet medical need. The Company has a comprehensive and diverse IO portfolio and pipeline anchored in immunotherapies designed to overcome evasion of the anti-tumour immune response and stimulate the body’s immune system to attack tumours.

AstraZeneca aims to reimagine cancer care and help transform outcomes for patients with Imfinzi as a single treatment and in combination with Imjudo as well as other novel immunotherapies and modalities. The Company is also exploring next-generation immunotherapies like bispecific antibodies and therapeutics that harness different aspects of immunity to target cancer.

AstraZeneca is boldly pursuing an innovative clinical strategy to bring IO-based therapies that deliver long-term survival to new settings across a wide range of cancer types. With an extensive clinical programme, the Company also champions the use of IO treatment in earlier disease stages, where there is the greatest potential for cure.

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 (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 and follow the Company on Twitter @AstraZeneca.


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SOURCE: AstraZeneca