Updated results from the PACIFIC Phase III trial showed AstraZeneca's Imfinzi (durvalumab) demonstrated a sustained, clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who had not progressed following concurrent chemoradiation therapy (CRT).

One in three patients with NSCLC are diagnosed at Stage III, where the majority of tumours are unresectable (cannot be removed with surgery).[1,2] Prior to the approval of Imfinzi in this setting, no new treatments beyond CRT had been available to these patients for decades.[3,4,5]

The results from the updated post-hoc analyses showed an estimated four-year overall survival rate of 49.6% for Imfinzi versus 36.3% for placebo after CRT. Median OS was 47.5 months for Imfinzi versus 29.1 for placebo. With a maximum treatment course of one year, an estimated 35.3% of patients treated with Imfinzi had not progressed four years after enrolment versus 19.5% for placebo. These data build on The New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa1809697?query=featured_home)publication from 2018 demonstrating a significant benefit for Imfinzi in the OS primary endpoint.[6]

Corinne Faivre-Finn, Professor at The University of Manchester and The Christie NHS Foundation Trust, and a lead investigator in the PACIFIC Phase III trial, said: "Previously, only 15 to 30 per cent of patients with unresectable, Stage III non-small cell lung cancer survived five years, and the majority eventually progressed to metastatic disease. These data show about half of patients treated with Imfinzi survived four years, and an estimated 35 per cent had not progressed, a remarkable advance in this curative-intent setting."

José Baselga, Executive Vice President, Oncology R&D, said: "These unprecedented four-year results reinforce Imfinzi as the established standard of care in unresectable, Stage III non-small cell lung cancer and set a new survival benchmark in a setting where cure is the treatment goal. With data also at ESMO for CASPIAN in small cell lung cancer patients, Imfinzi continues to deliver impressive long-term benefits across different types of lung cancer."

In the primary OS analysis of the PACIFIC Phase III trial, the most common adverse events (AE) (greater than or equal to 20%) among patients treated with Imfinzi versus placebo were cough (35.2% versus 25.2%), fatigue (24.0% versus 20.5%), dyspnoea (22.3% versus 23.9%) and radiation pneumonitis (20.2% versus 15.8%). A grade 3 or 4 AE was experienced by 30.5% of patients treated with Imfinzi versus 26.1% for placebo, and 15.4% of patients discontinued treatment due to AEs with Imfinzi versus 9.8% for placebo.

CASPIAN Phase III trial exploratory subgroup analyses in extensive-stage small cell lung cancer (ES-SCLC) at the European Society for Medical Oncology (ESMO) Virtual Congress 2020

New exploratory subgroup analyses from the CASPIAN Phase III trial of Imfinzi were conducted to characterise patients deriving long-term benefit. More than three times as many patients treated with Imfinzi plus chemotherapy were alive and progression free for one year or more (PFS ≥12 months) versus chemotherapy alone (17% versus 4.5%). Across all treatment arms, the subgroup of patients who were progression free at one year had a 75% chance of being alive at two years. In comparison, the subgroup of patients whose disease had progressed within one year (PFS <12 months) had a 10% chance of being alive at two years. Clinical characteristics did not appear to identify patients who derived long-term benefit.

Patients with PFS ≥12 months received more cycles of Imfinzi treatment compared to patients with PFS <12 months (median of 25 cycles versus 7). Although patients with greater exposure to Imfinzi had numerically higher rates of immune-mediated AEs, the two subgroups had similar rates of severe AEs, serious AEs and AEs leading to discontinuation.

The CASPIAN trial met the primary endpoint of OS in 2019 (https://www.astrazeneca.com/media-centre/press-releases/2019/imfinzi-improves-overall-survival-at-interim-analysis-in-the-phase-iii-caspian-trial-in-1st-line-extensive-stage-small-cell-lung-cancer-27062019.html), reducing the risk of death by 27% in patients with ES-SCLC treated with Imfinzi plus a choice of chemotherapy versus chemotherapy alone. The safety and tolerability of Imfinzi plus chemotherapy were consistent with the known safety profiles of these medicines. These results were published in The Lancet (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2819%2932222-6/fulltext) in 2019 and formed the basis of regulatory approvals around the world.[7]

Results from the PACIFIC and CASPIAN Phase III trials were presented during the ESMO Virtual Congress 2020, 19 to 21 September.

Lung cancer

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one fifth of all cancer deaths.[8] Lung cancer is broadly split into NSCLC and SCLC, with about 85% classified as NSCLC and 15% classified as SCLC.[9]

Stage III NSCLC (locally advanced) is commonly divided into three sub-categories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery.[10] Stage III disease is different from Stage IV disease, when the cancer has spread (metastasised), as the majority of Stage III patients are treated with curative intent.[10,11] In 2015, Stage III NSCLC was estimated to affect nearly 200,000 patients in the following eight key countries: China, France, Germany, Italy, Japan, Spain, UK, and the US, with approximately 43,000 cases in the US alone.[2]

SCLC is a highly aggressive, fast-growing form of lung cancer that typically recurs and progresses rapidly, despite initial response to chemotherapy.[12,13] About two thirds of SCLC patients are diagnosed with extensive-stage disease, in which the cancer has spread widely through the lung or to other parts of the body.[14] Prognosis is particularly poor, as only 6% of all SCLC patients will be alive five years after diagnosis.[14]

PACIFIC

The PACIFIC trial was a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in `all-comer' patients (regardless of PD-L1 status) with unresectable, Stage III NSCLC whose disease had not progressed following concurrent platinum-based CRT.

The trial was conducted at 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial were PFS and OS, and secondary endpoints included landmark PFS and OS, objective response rate and duration of response.

CASPIAN

CASPIAN was a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of 805 patients with ES-SCLC. The trial compared Imfinzi in combination with etoposide and either carboplatin or cisplatin chemotherapy, or Imfinzi and chemotherapy with the addition of a second immunotherapy, tremelimumab, versus chemotherapy alone. In the experimental arms, patients were treated with four cycles of chemotherapy. In comparison, the control arm allowed up to six cycles of chemotherapy and optional prophylactic cranial irradiation.

The trial was conducted in more than 200 centres across 23 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was OS in each of the two experimental arms. In June 2019, AstraZeneca announced the CASPIAN trial had met one primary endpoint of demonstrating OS for Imfinzi plus chemotherapy at a planned interim analysis. In March 2020, it was announced that the second experimental arm with tremelimumab did not meet its primary endpoint of OS.

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.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the PACIFIC Phase III trial. Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and several other countries. Additionally, it is approved in the US, the EU, Japan and other countries for ES-SCLC.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combinations including with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer, endometrial cancer and other solid tumours.

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action.

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation which represent up to three-quarters of all patients with lung cancer.[15] Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (POSEIDON and PEARL Phase III trials) and for patients in earlier stages of disease including potentially curative settings (MERMAID-1, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC Phase III trials) both as monotherapy and in combination with tremelimumab and/or chemotherapy. 

Imfinzi is also in development in the NeoCOAST, COAST and HUDSON Phase II trials in combination with potential new medicines from the early-stage pipeline including Enhertu.

AstraZeneca's approach to Immuno-Oncology

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body's immune system to attack tumours. The Company's IO portfolio is anchored by 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 monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, 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 has a deep-rooted heritage in oncology and offers a quickly growing portfolio ofnew medicines that has the potential to transform patients' lives and the Company's future. With seven new medicines launched between 2014 and 2020, and a broad pipelineof small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

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.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) 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 & 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 (http://www.astrazeneca.com/) and follow the Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

Contacts

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References

1. Antonia SJ, et al. PACIFIC Investigators. Durvalumab After Chemoradiotherapy In Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929.

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

3. 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.

4. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8. 2017 Aug 3.

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. Antonia SJ, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.

7. Paz-Ares, et al. Durvalumab Plus Platinum-Etoposide Versus Platinum-Etoposide in First-Line Treatment of Extensive-Stage Small Cell Lung Cancer (CASPIAN): A Randomized, Controlled, Open-Label, Phase 3 Trial. The Lancet. 2019;394(10,212):1929-1939.

8. World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed September 2020.

9. LUNGevity Foundation. Types of Lung Cancer. Available at https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed September 2020.

10. ASCO. Cancer.net. Lung Cancer - Non-Small Cell. Available at: https://www.cancer.net/cancer-types/lung-cancer/view-all. Accessed September 2020.

11. 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.

12. Kalemkerian GP, et al. Treatment Options for Relapsed Small-Cell Lung Cancer: What Progress Have We Made? J Oncol Pract. 2018;14(6):369-370.

13. National Cancer Institute. NCI Dictionary - Small Cell Lung Cancer. Available at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/small-cell-lung-cancer. Accessed September 2020.

14. Cancer.Net. Lung Cancer - Small Cell. Available at https://www.cancer.net/cancer-types/33776/view-all. Accessed September 2020.

15. Pakkala, S, et al. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018;3(15):e120858.