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2020-03-30

AstraZeneca: Imfinzi approved in the US for extensive-stage small cell lung cancer

Only PD-1/PD-L1 immunotherapy to demonstrate a significant survival
benefit in combination with etoposide and a choice of carboplatin or
cisplatin chemotherapy

AstraZeneca's Imfinzi (durvalumab) has been approved in the US as a
1st-line treatment for adult patients with extensive-stage small cell
lung cancer (ES-SCLC) in combination with standard-of-care (SoC)
chemotherapies, etoposide plus either carboplatin or cisplatin
(platinum-etoposide).

The approval by the Food and Drug Administration was based on positive
results from the Phase III CASPIAN trial showing Imfinzi in
combination with SoC platinum-etoposide demonstrated a statistically
significant and clinically meaningful improvement in overall survival
(OS) versus SoC alone.

SCLC is a highly aggressive, fast-growing form of lung cancer that
typically recurs and progresses rapidly despite initial response to
chemotherapy.[1,2]

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
said: "The US approval of Imfinzi brings a new medicine to
extensive-stage small cell lung cancer patients in urgent need of new
options. Imfinzi is the only immunotherapy to show both a significant
survival benefit and improved response rate in combination with
chemotherapy for these patients, an important step forward in
treating this devastating disease."

Jonathan Goldman, MD, Associate Professor of Hematology & Oncology,
UCLA Medical Center, Santa Monica, California and a lead investigator
in the Phase III CASPIAN trial, said: "Patients with extensive-stage
small cell lung cancer continue to face a poor prognosis, and finding
new medicines to improve outcomes in this setting has been a
formidable challenge. The CASPIAN trial enables clinicians to choose
durvalumab in combination with etoposide and either carboplatin or
cisplatin, making this an important new 1st-line treatment option for
patients that is both effective and well-tolerated."

The Phase III CASPIAN trial had two primary endpoints comparing
experimental arms to SoC. In the Imfinzi plus SoC arm, the risk of
death was reduced by 27% (equal to a hazard ratio of 0.73; 95% CI
0.59-0.91; p=0.0047), with median OS of 13.0 months versus 10.3
months for SoC alone. Results also showed an increased confirmed
objective response rate in the Imfinzi plus SoC arm (68% versus 58%
for SoC alone). The safety and tolerability for Imfinzi plus SoC was
consistent with the known safety profiles of these medicines. The
Imfinzi plus SoC data from the CASPIAN trial were published in The
Lancet
(https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2819%293...).[3]

The second experimental arm testing tremelimumab added to Imfinzi and
SoC recently completed
(https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2...),
but did not meet its primary endpoint. Details will be presented at a
forthcoming medical meeting.

The CASPIAN trial used a fixed dose of Imfinzi (1500mg) administered
every three weeks for four cycles while in combination with
chemotherapy and then every four weeks until disease progression. As
part of a broad development programme, Imfinzi is also being tested
following concurrent chemoradiation therapy in patients with
limited-stage SCLC in the Phase III ADRIATIC trial with data
anticipated in 2021.

Imfinzi received its first approval based on the Phase III CASPIAN
trial in Singapore for patients with ES-SCLC in February 2020.
Imfinzi in combination with etoposide and either carboplatin or
cisplatin is currently under regulatory review for the treatment of
ES-SCLC in the 1st-line setting based on the Phase III CASPIAN trial
in the EU and Japan.

Small cell 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.[4] Lung
cancer is broadly split into non-small cell lung cancer (NSCLC) and
SCLC, with about 15% classified as SCLC.[5] About two thirds of SCLC
patients are diagnosed with ES-SCLC, in which the cancer has spread
widely through the lung or to other parts of the body.[6] Prognosis
is particularly poor, as only 6% of all SCLC patients will be alive
five years after diagnosis.[6]

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.

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 Phase III
PACIFIC trial. Imfinzi is approved for the 1st-line treatment of
ES-SCLC in combination with SoC chemotherapy in the US and Singapore.
Imfinzi is also approved for previously treated patients with
advanced bladder cancer in the US and a small number of other
countries.

As part of a broad development programme, Imfinzi is also being tested
as a monotherapy and in combination 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 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. Tremelimumab is being tested
in a clinical trial programme in combination with Imfinzi in NSCLC,
SCLC, bladder cancer, head and neck cancer and liver cancer.

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. We
aim to address the unmet needs of patients with EGFR-mutated tumours
as a genetic driver of disease, which occur in 10-15% of NSCLC
patients in the US and EU and 30-40% of NSCLC patients in Asia, with
the approved medicines Iressa (gefitinib) and Tagrisso (osimertinib),
and its ongoing Phase III trials ADAURA, LAURA, and FLAURA2.[7-9 ]We
are also committed to addressing tumour mechanisms of resistance
through the ongoing Phase II trials SAVANNAH and ORCHARD which test
Tagrisso in combination with savolitinib, a selective inhibitor of
c-MET receptor tyrosine kinase, along with other potential new
medicines. Enhertu (trastuzumab deruxtecan), a HER2-directed antibody
drug conjugate is in development for metastatic non-squamous
HER2-overexpressing or HER2-mutated NSCLC including trials in
combination with other anticancer treatments.

An extensive late-stage Immuno-Oncology programme focuses on lung
cancer patients without a targetable genetic mutation which
represents up to three-quarters of all patients with lung cancer.[10]
Imfinzi, an anti-PDL1 antibody, is in development for patients with
advanced disease (Phase III trials POSEIDON and PEARL) and for
patients in earlier stages of disease including potentially-curative
settings (Phase III trials AEGEAN, ADJUVANT BR.31, PACIFIC-2,
PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in
combination with tremelimumab and/or chemotherapy. Imfinzi is also in
development in the Phase II combination trials NeoCOAST, COAST and
HUDSON in combination with potential new medicines from the
early-stage pipeline.

AstraZeneca's approach to Immuno-Oncology (IO)

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 believes that
IO-based therapies offer the potential for life-changing cancer
treatments for the clear majority of patients.

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 of new medicines that has the potential to
transform patients' lives and the Company's future. With six new
medicines launched between 2014 and 2020, and a broad pipeline of
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. In addition to
AstraZeneca's main capabilities, the Company is actively pursuing
innovative partnerships and investments that accelerate the delivery
of our strategy, as illustrated by the investment in Acerta Pharma in
haematology.

By harnessing the power of four scientific platforms -
Immuno-Oncology, Tumour Drivers and Resistanc...

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