Imfinzi and tremelimumab with chemotherapy demonstrated sustained survival benefit in metastatic non-small cell lung cancer, nearly doubling the number of patients alive after three years vs. chemotherapy

Exploratory analysis from POSEIDON Phase III trial also showed trends for overall survival benefit with a limited course of tremelimumab added to Imfinzi and chemotherapy in subgroups with high unmet need

LONDON, UK I September 11, 2022 I Updated results after approximately four years of follow-up of the POSEIDON Phase III trial showed a limited course of tremelimumab when added to AstraZeneca’s Imfinzi (durvalumab) plus four cycles of chemotherapy demonstrated a sustained improvement in overall survival (OS) compared to chemotherapy alone in the 1st-line treatment of patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC). Additional post-hoc, exploratory analyses continued to show a trend for OS improvement with this combination in patients with STK11, KEAP1 and KRAS-mutated NSCLC, as well as in patients whose tumours were PD-L1-negative (less than 1% tumour cell expression).

These late-breaking results were presented today at the European Society of Medical Oncology (ESMO) Congress 2022 (Abstract #LBA59).

KRAS mutations are the most common tumour growth driver in NSCLC, occurring in approximately 25% of patients. NSCLC tumours with STK11 and KEAP1 mutations are often associated with poor outcomes and classified as immunologically “cold.” KRAS-mutated NSCLC can be responsive to immunotherapy but also can have poor outcomes, particularly when associated with STK11 or KEAP1 co-mutations.1-6

Melissa Johnson, MD, Director of Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology in Nashville, Tennessee, and a lead investigator in the POSEIDON Phase III trial, said: "Metastatic non-small cell lung cancer is a devastating diagnosis, particularly for patients whose cancers are less responsive to standard treatments such as chemotherapy and immune therapy. These results support the addition of a limited course of tremelimumab to durvalumab plus chemotherapy as a potential new treatment option for patients with these harder-to-treat forms of lung cancer.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These updated POSEIDON results at nearly four years of follow-up show further evidence that the addition of a limited course of tremelimumab to Imfinzi plus chemotherapy improves outcomes for metastatic non-small cell lung cancer patients, including those with specific tumour mutations where a high unmet need for effective, well tolerated treatments remains. We look forward to bringing this potential new treatment option to patients as quickly as possible."

These latest data show that a limited course of five cycles of tremelimumab added to Imfinzi plus platinum-based chemotherapy improved overall survival by 25% compared to chemotherapy alone (hazard ratio [HR] 0.75; 95% CI 0.63-0.88). Updated median OS was 14 months for the combination versus 11.7 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.

A trend for OS improvement continued to be observed in patients with STK11, KEAP1, and KRAS-mutated mNSCLC when treated with the combination, which reduced the risk of death by 38% (based on a HR of 0.62; 95% CI 0.34-1.12), 57% (based on a HR of 0.43; 95% CI 0.16-1.25), and 45% (based on a HR of 0.55; 95% CI 0.36-0.85), respectively. The combination also extended sustained OS benefit to patients with less than 1% PD-L1 tumour cell expression. These post hoc, exploratory subgroup analyses should be interpreted with caution due to the small sample sizes.

Consistent with previous POSEIDON Phase III trial readouts, OS benefit in these updated results appeared more pronounced with tremelimumab plus Imfinzi and chemotherapy in patients with non-squamous NSCLC histology. A 32% improvement in OS compared to chemotherapy alone (HR 0.68; 95% CI 0.55–0.85) was reported for patients with non-squamous histology, with an updated median OS of 17.2 months for the combination versus 13.1 months for chemotherapy. An estimated 31.4% of patients with non-squamous NSCLC treated with the combination were alive at three years versus 17.3% for those receiving chemotherapy alone.

Summary of efficacy resultsi, ii

  Tremelimumab + Imfinzi + chemotherapy Chemotherapy
Intention-To-Treat (ITT) n=338 n=337
Median OS (in months) 14.0 11.7
Hazard ratio (95% CI)iii 0.75 (0.63, 0.88)
OS rate at 3 years (%) 25.0 13.6
     
STK11 mutation n=31 n=22
Median OS (in months) 15.0 10.7
Hazard ratio (95% CI)iv 0.62 (0.34, 1.12)
OS rate at 3 years (%) 25.8 4.5
KEAP1 mutation n=22 n=6
Median OS (in months) 13.7 8.7
Hazard ratio (95% CI)iv 0.43 (0.16, 1.25)
OS rate at 3 years (%) 30.0 0.0
KRAS mutation n=60 n=53
Median OS (in months) 25.7 10.4
Hazard ratio (95% CI)iv 0.55 (0.36, 0.85)
OS rate at 3 years (%) 40.0 15.8

i. 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.
ii. Data cut-off (DCO) date: 11 March 2022. Median follow-up in censored patients at DCO: 46.5 months (range 0.0–56.5)
iii. Stratified analysis by PD-L1 expression (TC ≥50% vs <50%), disease stage (IVA vs IVB) and histology
iv. Unstratified analysis

Tremelimumab plus Imfinzi and chemotherapy continued to be well-tolerated, with no new safety signals identified based on the collection of serious adverse events (AEs) during the approximately four years of follow-up. Serious treatment-related AEs of any grade occurred in 27.6% of patients in the Imfinzi, tremelimumab and chemotherapy arm versus 17.7% in the chemotherapy alone arm as assessed by investigators. Treatment-related AEs leading to death occurred in 3.3% of patients in the combination arm versus 2.4% in the chemotherapy arm.

These updated results build on the primary progression-free survival (PFS) and OS results presented at the 2021 World Conference on Lung Cancer (WCLC) in September 2021 as well as post-hoc exploratory results in patients with STK11, KEAP1 or KRAS-mutated metastatic NSCLC recently presented at WCLC 2022 in August.

Tremelimumab is under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON trial.

Notes

Stage IV NSCLC
Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC. 7-9 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.7 Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.10 Approximately 5% of patients with metastatic NSCLC will survive 5 years after diagnosis.11

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 non-small cell lung cancer (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 currently approved in a number of countries in multiple tumour types including for the treatment of extensive-stage small cell lung cancer (ES-SCLC); for previously treated patients with advanced bladder cancer and for locally advanced or metastatic BTC in combination with chemotherapy (gemcitabine plus cisplatin).

Since the first approval in May 2017, more than 100,000 patients have been treated with Imfinzi.

Imfinzi combinations have demonstrated clinical benefit in multiple additional cancer settings with positive Phase III trials in unresectable advanced liver cancer (HIMALAYA), metastatic NSCLC (POSEIDON) and resectable NSCLC (AEGEAN). The data from HIMALAYA and POSEIDON 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 immuno-oncology (IO)
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.

References

1. Skoulidis F, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov. 2018;8(7):822–835.

2. Donnelly LL, et al. Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers. Carcinog, 2021;42(12):1428–1438.

3. Peters S, et al. Association Between KRAS/STK11/KEAP1 Mutations and Outcomes in POSEIDON: Durvalumab ± Tremelimumab + Chemotherapy in mNSCLC. Presented at IASLC 2022 World Conference on Lung Cancer, 9-13 September 2022. 

4. Frank R, et al. Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). Clin Cancer Res. 2018;24(13):3087-3096.

5. Chen X, et al. Pan-cancer analysis of KEAP1 mutations as biomarkers for immunotherapy outcomes. Annals Transl Med. 2019;8(4):141.

6. Papillon-Cavanagh S, et al. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort. ESMO Open. 2020;5:e000706.

7. Abernethy AP, et al. Real-world first-line treatment and overall survival in non-small cell lung cancer without known EGFR mutations or ALK rearrangements in US community oncology setting. PLoS ONE. 2017;12(6):e0178420.

8. 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.

9. Cancer.net. Lung Cancer - Non-Small Cell: Introduction. Available at: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/introduction. Accessed September 2022.

10. American Lung Association. Lung Cancer Staging. Available at: https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/lung-cancer-staging. Accessed September 2022.

11. Cancer Research UK. Survival. Available at: https://www.cancerresearchuk.org/about-cancer/lung-cancer/survival. Accessed September 2022.​

SOURCE: AstraZeneca

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