On June 2, 2019 Celgene Corporation (NASDAQ: CELG) reported the first clinical results evaluating iberdomide (CC-220) in combination with dexamethasone in patients with relapsed and refractory multiple myeloma from the ongoing phase 1/2 CC-220-MM-001 study during an oral presentation at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Celgene, JUN 2, 2019, View Source [SID1234536749]).

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The results included preliminary safety and efficacy data from the ongoing multicenter, open-label, dose-escalation study, which aims to determine the maximum tolerated dose and the recommended phase 2 dose of iberdomide in combination with dexamethasone. Iberdomide is Celgene’s proprietary cereblon E3 ligase modulator (CELMoD) compound with enhanced tumoricidal and immune stimulatory effects demonstrated in preclinical studies. The phase 1/2 study is expected to enroll approximately 300 participants.

"Nearly half a million people globally are affected by multiple myeloma, a cancer of plasma cells. The management of patients with late relapsed or refractory multiple myeloma continues to be challenging due to the complex nature of the disease’s pathophysiology. Despite the introduction of newer agents, patients continue to experience disease relapse therefore new therapeutic options are needed for patients who have failed multiple prior treatments," said Sagar Lonial, MD, Chief Medical Officer at Winship Cancer Institute of Emory University. "The early data on iberdomide in combination with dexamethasone in these heavily pretreated patients show promising activity, and we look forward to advancing our understanding of this combination’s potential in this patient population."

As of April 2019, 66 patients at a median age of 65 received the iberdomide plus dexamethasone combination, with iberdomide being administered in 8 incremental doses ranging from 0.3 mg to 1.3 mg. Escalating doses of iberdomide were given on days 1 through 21 in combination with dexamethasone (40 mg; 20 mg in patients older than 75) on days 1, 8, 15, and 22 of each 28-day cycle. Patients had a median of five prior multiple myeloma treatment regimens, which could have included stem cell transplant, immunomodulatory drugs including lenalidomide and pomalidomide, proteasome inhibitors and daratumumab.

Grade 3-4 adverse events (AE) reported included neutropenia (29%), infection (26%), anemia (24%), thrombocytopenia (12%), pulmonary embolism (1.5%) and peripheral sensory neuropathy (1.5%). Six patients (9%) discontinued treatment due to adverse events.

Of the 66 patients who received the iberdomide plus dexamethasone combination, 59 were evaluable for response. The overall response rate was 32% (19/59), with 29% (17/59) achieving a partial response and two patients achieving a very good partial response.

Patients (n=51) who were refractory to IMiD compounds, which included lenalidomide and pomalidomide, had an overall response rate of 35% (18/51) with 33% (17/51) of patients achieving a partial response and one patient achieving a very good partial response. Further, patients who were refractory to both daratumumab and pomalidomide (n=27) had an overall response rate of 29% (8/27), with 25% (7/27) achieving a partial response and one patient achieving a very good partial response. Maximum tolerated dose and the recommended phase 2 dose have not yet been determined.

"While we have made tremendous progress in treating multiple myeloma, there is still a significant need for new options to address the heterogeneous nature of the disease. We are focused on exploring the potential of our next generation CELMoD compounds to help fill this gap," said Dr. Alise Reicin, President, Global Clinical Development for Celgene. "The preliminary clinical activity and favorable safety data observed with the combination of iberdomide and dexamethasone are encouraging, particularly in patients who have failed multiple lines of therapy including patients who were refractory to lenalidomide, pomalidomide and/or daratumumab."

The phase 1/2 study is also evaluating iberdomide as monotherapy and in combination with daratumumab or bortezomib or carfilzomib. Iberdomide is investigational and has not been approved in any country.

About Iberdomide (CC-220)

Iberdomide is an investigational cereblon E3 ligase modulator (CELMoD) compound that induces degradation of transcription factors Aiolos and Ikaros, thereby inhibiting growth of myeloma cells in vitro. In pre-clinical models, iberdomide has demonstrated ability to destroy tumor cells, stimulate an immune response, overcome resistance to immunomodulatory drugs, and synergize with dexamethasone, daratumumab and bortezomib.

About CC-220-MM-001

The open-label phase 1/2 CC-220-MM-001 dose escalation study (NCT02773030) seeks to determine the maximum tolerated dose and recommended phase 2 dose of iberdomide (CC-220) as monotherapy and in combination with dexamethasone, as well as further evaluate safety and preliminary efficacy in patients with relapsed/refractory multiple myeloma. The study consists of a dose-escalation portion (Part 1) as well as an expansion of these two cohorts at the recommended phase 2 dose to further evaluate safety and estimate preliminary efficacy (Part 2). The study also seeks to establish the maximum tolerated dose and recommended phase 2 dose of iberdomide when administered in combination with daratumumab or bortezomib or carfilzomib.

About Multiple Myeloma

Multiple myeloma is a life-threatening blood cancer that is characterized by tumor proliferation and suppression of the immune system.1 It is a rare but deadly disease – more than 32,000 new cases will be diagnosed in the United States in 2019, and approximately 13,000 deaths will occur in 2019, representing about 2.1% of all cancer-related deaths.2 The typical multiple myeloma disease course includes periods of symptomatic myeloma followed by periods of remission, and eventually, the disease becomes refractory (nonresponsive).

On June 2, 2019 BerGenBio ASA (OSE: BGBIO) a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for multiple cancer indications, reported updated data from its Phase II clinical trial (BGBC008, NCT03184571) with bemcentinib and Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with advanced non-small cell lung cancer (NSCLC) at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois (31 May – 4 June 2019) (Press release, BerGenBio, JUN 2, 2019, View Source [SID1234536748]).

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At data cut off, 35 out of 46 enrolled patients were evaluable; 58% were AXL +ve, and 53% were PD-L1 negative (<1%TPS), and a further 39% were PD-L1 (1-49% TPS). An objective response rate of 40% was achieved in AXL +ve patients, irrespective of the patients PD-L1 score; and an overall response rate of 29% was achieved. The median survival rate of 12.2 months was observed at the time of data cut-off, significantly surpassing what has been shown historically in second line treatment with PD-1 inhibitor monotherapy.

The combination treatment of bemcentinib and pembrolizumab was overall well-tolerated; the most common adverse events included transaminase increase (35%), fatigue (30%), and diarrhoea (26%). No grade 5 treatment related adverse events were reported and all events were reversible.

Principal investigator Enriqueta Filip, Vall d’Hebron University Hospital, Barcelona
" Following the rapid uptake of checkpoint inhibitors in first-line lung cancer therapy, treatment options for NSCLC cancer patients that have not responded to anti-PD-1 therapies such as KEYTRUDA represent a significant unmet medical need. These data, which suggest that combination therapy with bemcentinib has the potential to enhance patient responses to these novel agents, particularly in patients with no or limited expression of PD-L1, is a very significant and encouraging development."

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "The clinical activity we are presenting here today surpasses what has been shown historically in previously-treated, PD-L1 low patients on PD-1 inhibitor monotherapy, and supports the hypothesis that AXL is implicated in the failure of anti-PD-L1 therapies. Further investigation is warranted and having recently extended the trial to include patients showing disease progression on checkpoint inhibitors, we will continue to test this hypothesis and look forward to providing further updates during 2019."

-END–

About NSCLC
It is estimated that more than 230,000 new cases of lung cancer have been diagnosed in the US in 2018 and it is the leading cause of cancer deaths. 65% of non-small cell lung cancers (NSCLC) are of adenocarcinoma pathology. Although various treatments exist for NSCLC, they are often curtailed by acquired resistance to therapy and immune evasion. Novel treatments overcoming these mechanisms in NSCLC are urgently required.

About the BGBC008 trial
The BGBC008 trial is a Phase II open-label study of bemcentinib in combination with KEYTRUDA (pembrolizumab) in previously treated patients with advanced adenocarcinoma of the lung, run at centres in the US, UK, Spain and Norway. The objective of the trial is to determine the anti-tumour activity of this novel drug combination and responses will be correlated with biomarker status (including AXL kinase and PD-L1 expression).

Patients eligible for participation in Cohort A must have progressed on or after prior therapy excluding immunotherapy whereas patients in Cohort B will be actively progressing on a therapy regimen containing an anti-PD(L)-1 therapy.

Both cohorts follow a two-stage design, Cohort A has previously successfully progressed into the second stage after meeting its first efficacy endpoint. Cohort B will evaluate advancement into stage 2 after 13 patients have been assessed for response.

For more information please access trial NCT03184571 at www.clinicaltrials.gov.

On June 2, 2019 AstraZeneca has reported three-year overall survival (OS) results from the Phase III PACIFIC trial of Imfinzi (durvalumab) in unresectable, Stage III non-small cell lung cancer (NSCLC) during the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, AstraZeneca, JUN 2, 2019, View Source [SID1234536744]).

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These latest results show a durable and sustained OS benefit in patients with unresectable, Stage III NSCLC who had not progressed following concurrent chemoradiation therapy (CRT), a previous standard-of-care (SoC) treatment. The OS rate was 57% at three years for patients receiving Imfinzi vs. 43.5% for placebo following concurrent CRT. Median OS was not yet reached with the Imfinzi arm vs. 29.1 months for placebo.

Dave Fredrickson, Executive Vice President, Oncology Business Unit said: "These findings for Imfinzi are another example of our focus on bringing long-term survival benefits to patients who still have a chance of being cured. These three-year survival results further establish the PACIFIC regimen as the standard of care for these patients, and we are optimistic this survival trend will continue as we move towards the five-year landmark in this curative-intent setting."

Results build on the primary two-year OS analysis that was published in The New England Journal of Medicine in September 2018 and demonstrated a significant OS benefit for treatment with Imfinzi vs. placebo after CRT, regardless of PD-L1 expression. The primary analysis showed Imfinzi reduced the risk of death by 32% (HR 0.68, [99.73% CI, 0.47-0.997], p=0.0025).

With the additional year of follow up, the latest results for Imfinzi showed consistent and durable efficacy, maintaining a 31% reduction in the risk of death vs. placebo after CRT (HR 0.69, [95% CI 0.55-0.86]).

Jhanelle Gray, MD, Director of Clinical Research in the Thoracic Oncology Department at Moffitt Cancer Center in Tampa, Florida, and an investigator in the PACIFIC trial, said: "In the past, patients with unresectable, Stage III non-small cell lung cancer faced five-year survival rates of only 15% to 30%. It is remarkable to see that more than half of patients treated with the PACIFIC regimen remain alive at three years, an important milestone that raises the bar for treatments in this curative-intent setting."

The safety and tolerability profile for Imfinzi was consistent with the results reported at the time of the previous OS analysis. Among patients receiving Imfinzi, the most common adverse events (AE) (greater than or equal to 20% of patients) vs. placebo were cough (35.2% vs. 25.2%), fatigue (24.0% vs. 20.5%), dyspnoea (22.3% vs. 23.9%) and radiation pneumonitis (20.2% vs. 15.8%). 30.5% of patients experienced a grade 3 or 4 AE with Imfinzi vs. 26.1% with placebo, and 15.4% of patients discontinued treatment due to AEs with Imfinzi vs. 9.8% of patients on placebo.

Building on PACIFIC

AstraZeneca has several ongoing trials focused on testing Imfinzi in earlier stages of NSCLC (Stages I-III) in potentially-curative settings. The Phase III PACIFIC-2 trial design, presented today at the ASCO (Free ASCO Whitepaper) Annual Meeting, is evaluating Imfinzi given concurrently with CRT in patients with unresectable, Stage III NSCLC. In the Phase II PACIFIC-6 trial, Imfinzi is being tested in the same population following sequential chemotherapy and radiation therapy.

Additional trials assess Imfinzi in the neoadjuvant setting (prior to other treatments) in Stage II and III NSCLC patients (AEGEAN) and in the adjuvant setting (following the primary treatment) in Stage I to III (BR.31). The Phase III PACIFIC-4 trial is testing Imfinzi in unresected Stage I and II NSCLC patients following definitive stereotactic body radiation therapy (SBRT).

AstraZeneca is also testing novel combinations with Imfinzi in two Phase II platform trials in both unresectable, Stage III disease (COAST) and in resectable Stage I-III disease starting before surgery (NeoCOAST), to help find solutions for NSCLC patients not benefiting from currently-available therapies.

Immuno-Oncology trials in early-stage non-small cell lung cancer (NSCLC)

Trial name

Phase

Population

Trial arms

Stages I-III

PACIFIC-4

Phase III

Unresected, Stage I/II NSCLC

Imfinzi monotherapy vs. placebo following definitive SBRT

AEGEAN

Phase III

Resectable, Stage II and III NSCLC, neoadjuvant (incl. EGFR/ALK positive)1

SoC chemotherapy + Imfinzi vs. SoC chemotherapy + placebo followed by surgery

ADJUVANT BR.312

Phase III

Completely resected, Stage Ib-IIIa NSCLC (incl. EGFR/ALK positive)1

Placebo vs. Imfinzi monotherapy

NeoCOAST

Phase II

Resectable, Stage I-IIIA NSCLC

Imfinzi in combination with potential new medicines vs. Imfinzi monotherapy followed by surgery

COAST

Phase II

Unresectable, Stage III NSCLC following concurrent CRT

Imfinzi in combination with potential new medicines vs. Imfinzi monotherapy

Stage III

PACIFIC-2

Phase III

Unresected, Stage III NSCLC

Concurrent CRT + placebo vs. concurrent CRT + Imfinzi

PACIFIC-5

Phase III

Unresected, Stage III NSCLC (ex US global trial, China focus)

Placebo following concurrent CRT vs. Imfinzi following concurrent CRT

PACIFIC-6

Phase II

Unresectable, Stage III NSCLC

Imfinzi following sequential CRT

1. EGFR = epidermal growth factor receptor, ALK = anaplastic lymphoma kinase
2. BR.31 is an externally-sponsored research study led by the Canadian Cancer Trials Group (CCTG)

Imfinzi is approved for the treatment of unresectable, Stage III non-small cell lung cancer in more than 45 countries, including the US, EU and Japan, based on the Phase III PACIFIC trial. Since the first approval in February 2018, more than 20,000 patients in this setting have been treated with Imfinzi.

About PACIFIC

The PACIFIC trial is a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in ‘all-comer’ patients (i.e. regardless of PD-L1 status) with unresectable, Stage III (locally-advanced) NSCLC whose disease has not progressed following platinum-based chemotherapy and radiation therapy (CRT).

The trial is being conducted in 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial are progression-free survival (PFS) and OS, and secondary endpoints include landmark PFS and OS, objective response rate, and duration of response.

About Stage III NSCLC

Stage III (locally-advanced) NSCLC 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.1 Stage III disease is different from Stage IV disease, when the cancer has spread (metastasised) to distant organs, as Stage III is currently treated with curative intent.1,2

Stage III NSCLC represents approximately one-third of NSCLC incidence and was estimated to affect nearly 200,000 patients in the top-eight countries (China, France, Germany, Italy, Japan, Spain, UK, US) in 2015.3,4 The majority of Stage III NSCLC patients are diagnosed with unresectable tumours.5 No new treatments beyond chemoradiation therapy, followed by active surveillance to monitor for progression, have been available to patients for decades.6-9

About 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 for unresectable, Stage III NSCLC in more than 45 countries including the US, in the EU, and Japan based on the Phase III PACIFIC trial. Imfinzi is also approved for previously-treated patients with advanced bladder cancer in the US, Canada, Brazil, Australia, Israel, India, United Arab Emirates, Qatar, Macau and Hong Kong.

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, small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, cervical cancer, biliary tract cancer and other solid tumours.
About AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning 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 our approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and ongoing Phase III trials FLAURA, ADAURA and LAURA as well as the Phase II exploratory combination trials SAVANNAH and ORCHARD.10-12

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a known genetic mutation which represents up to 50% of all patients with lung cancer. Imfinzi (durvalumab), an anti-PDL1 antibody, is in development as monotherapy (Phase III trials ADJUVANT BR.31, PACIFIC-4, PACIFIC-5, and PEARL) and in combination with tremelimumab and/or chemotherapy (AEGEAN, PACIFIC-2, NEPTUNE, POSEIDON, ADRIATIC and CASPIAN Phase III trials).

About AstraZeneca’s approach to Immuno-Oncology (IO)

IO is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. Our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. We believe that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes Imfinzi (anti-PDL1) as monotherapy and in combination with tremelimumab (anti-CTLA4) in multiple tumour types, stages of disease, and lines of therapy, 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 our IO portfolio with small, targeted molecules from across our Oncology pipeline, and from our research partners, may provide new treatment options across a broad range of tumours.

About 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 at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

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.

On June 2, 2019 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported detailed results from the Phase III POLO trial at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US (Abs #LBA4) (Press release, AstraZeneca, JUN 2, 2019, View Source [SID1234536743]). Results are today also published in The New England Journal of Medicine (NEJM).

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The POLO trial tested Lynparza (olaparib) tablets as 1st-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic cancer) whose disease had not progressed following standard-of-care platinum-based 1st-line chemotherapy.

Results from the trial showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for Lynparza vs. placebo, improving the time without disease progression by a median of 7.4 months for patients treated with Lynparza vs. 3.8 months for those on placebo (HR 0.53 [95% CI, 0.35-0.82], p=0.004). More than twice as many patients showed no disease progression both at one year (34% on Lynparza vs. 15% on placebo) and two years (22% vs. 10%, respectively).

José Baselga, Executive Vice President, Oncology R&D, said: "These unprecedented results raise new hope for patients that have seen little progress over a long period of time. From as early as six months after initiation, more than twice as many patients taking Lynparza lived without progression of their disease compared to those on placebo and we are now working with regulatory authorities to bring Lynparza to patients as quickly as possible."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "We are encouraged by the results of the POLO trial which showed a considerable reduction in risk of disease progression or death with Lynparza for germline BRCA-mutated metastatic pancreatic cancer patients who did not progress on chemotherapy. Currently less than 3% of metastatic pancreatic cancer patients survive more than five years after diagnosis. The results of this trial reinforce MSD and AstraZeneca’s commitment to develop innovative treatments for cancers with few options."

Hedy L. Kindler, MD, co-principal investigator of the POLO trial and Professor of Medicine, University of Chicago Medicine, said: "Despite efforts to identify therapies, targeted or combination treatments to improve patient outcomes, pancreatic cancer remains an area of high unmet need. The results of the POLO trial may open the door to a new era of personalised, biomarker-led care in metastatic pancreatic cancer and reinforces the importance of knowing BRCA status at diagnosis."

Kaplan-Meier estimates of PFS by blinded, independent central review

From The New England Journal of Medicine, Golan T, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer, Jun 2 [Epub ahead of print] Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.

The safety and tolerability profile of Lynparza in the POLO trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% were fatigue/asthenia (60%), nausea (45%), abdominal pain (29%), diarrhoea (29%), anaemia (28%), decreased appetite (25%) and constipation (23%). The most common ≥ grade 3 AEs were anaemia (11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). AEs led to dose interruption in 16% of patients on Lynparza while 5% of patients discontinued treatment.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for multiple indications in advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients worldwide.

About POLO

POLO is a Phase III randomised, double-blinded, placebo-controlled, multicentre trial of Lynparza tablets (300mg twice daily) as maintenance monotherapy vs. placebo. The trial randomised 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomised (3:2) to receive Lynparza or placebo until disease progression. The primary endpoint was PFS and key secondary endpoints included overall survival, time to second disease progression, overall response rate, disease control rate and health-related quality of life.

About pancreatic cancer

Pancreatic cancer is the 12th most common cancer worldwide,1 with 458,918 new cases in 2018 alone.1 With the worst survival rate of all the most common cancers,2 it is the 4th leading cause of cancer death,3 and less than 3% of patients with metastatic disease survive more than five years after diagnosis.4 Early diagnosis of pancreatic cancer is difficult, as often there are no symptoms until it is too late.5 Around 80% of patients are diagnosed at the metastatic stage.6

There are two types of pancreatic cancer. Exocrine tumours, of which the most common type is pancreatic ductal adenocarcinoma (PDAC),7 start in the exocrine cells, where enzymes help to digest food. Neuroendocrine tumours start in neuroendocrine cells, which produce hormones, such as insulin,6 that control different functions of the body.

About BRCA mutations

Breast cancer susceptibility genes 1/2 (BRCA1 and BRCA2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR.

Lynparza is currently approved in over 60 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved in the US, Canada and Brazil as 1st-line maintenance treatment of BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in nearly 40 countries, including the US and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. Regulatory reviews are underway in other jurisdictions for both ovarian cancer and breast cancer.

Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About 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 at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.

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.

On June 2, 2019 Amgen (NASDAQ: AMGN) reported new data from Phase 1 studies evaluating investigational bispecific T cell engager (BiTE) molecules were presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Press release, Amgen, JUN 2, 2019, View Source;p=RssLanding&cat=news&id=2400287 [SID1234536742]). Data presented included updated investigational AMG 420 safety and efficacy results in patients with relapsed and/or refractory multiple myeloma (R/R MM), as well as initial results from the investigational AMG 212 (pasotuxizumab) first-in-human trial in patients with metastatic castration-resistant prostate cancer (mCRPC). BiTE technology is a targeted immuno-oncology platform that is designed to engage patients’ own T cells to a tumor-specific antigen, activating the cytotoxic potential of T cells.

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"Our BiTE immuno-oncology platform offers unique versatility, with the potential to treat various tumors through targeting tumor-associated antigens," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "As a leader in the development of targeted immuno-oncology therapies, we continue to investigate and advance more than a dozen BiTE molecules across a broad range of hematologic malignancies and solid tumors. These data at the ASCO (Free ASCO Whitepaper) Annual Meeting reinforce the potential of BiTE technology for patients with difficult-to-treat cancers like multiple myeloma and prostate cancer."

ASCO Annual Meeting Abstract #8007: Evaluation of AMG 420, An Anti-BCMA Bispecific T Cell Engager (BiTE) Immunotherapy, In R/R Multiple Myeloma (MM) Patients: Updated Results of a First-in-Human (FIH) Phase 1 Dose-Escalation Study

Updated results from a Phase 1, first-in-human dose-escalation trial of investigational AMG 420, a B-cell maturation antigen (BCMA)-targeting BiTE molecule, in patients with R/R MM were shared during an oral presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting. This abstract was also selected for inclusion in the Best of ASCO (Free ASCO Whitepaper) educational program. The objectives of the study included assessment of the safety, tolerability and anti-tumor activity of AMG 420 per International Myeloma Working Group 2006 Uniform Response Criteria for Multiple Myeloma. In the study, 42 patients with R/R MM who had progression after at least two prior lines of treatment (including a proteasome inhibitor and an immunomodulatory imide drug) received AMG 420 at varying doses [0.2 to 800 µg/day (d)]. Of the doses tested in this study, 400 µg/d was the maximum tolerated dose (MTD).

As of the latest readout, AMG 420 induced clinical responses in 13 of 42 patients across the dosing cohorts. Of the six patients that achieved a minimal residual disease (MRD)-negative complete response (CR), five were treated at the 400 µg/d dose. In addition, at the 400 µg/d dose, one patient achieved a very good partial response, and one achieved a partial response. The overall response rate at 400 µg/d was 70 percent (7/10). The median duration of response was nine months (range 5.8-13.6 months). Median time to response was one month, with 11 of 13 patients responding in the first cycle.

Serious adverse events (AEs) were reported in 19 patients (45 percent). Sixteen required hospitalization and four had prolonged hospitalization. No grade 3 or 4 central nervous system toxicities were observed. Serious AEs occurring in more than one patient included infections (n=13) and peripheral polyneuropathy (n=2). Treatment-related serious AEs included polyneuropathy (n=2, both grade 3) and edema (n=1, grade 3). Grade 3 cytokine release syndrome (CRS) was seen in one patient. Two patients died during the study from AEs not considered treatment-related: one patient died from acute respiratory distress due to concurrent flu and aspergillosis, and the second patient died from liver failure secondary to a viral infection during the course of treatment.

"These updated results presented at the ASCO (Free ASCO Whitepaper) Annual Meeting showed that AMG 420 at the 400 µg/d dose was efficacious with no new safety concerns in heavily pre-treated patients with relapsed and/or refractory multiple myeloma," said Max S. Topp, M.D., professor, University Hospital of Wuerzburg, Germany, and AMG 420 clinical study investigator. "Based on these results, we recommend AMG 420 at the 400 µg/d dose for further investigation."

ASCO 2019 Abstract #5034: Phase 1 Study of Pasotuxizumab (BAY 2010112), a PSMA-targeting BiTE (Bispecific T Cell Engager) Immunotherapy for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Initial results from a Phase 1 dose-escalation study of investigational AMG 212 (pasotuxizumab, formerly known as BAY 2010112), in patients with mCRPC who are refractory to standard therapy were presented in a poster at the ASCO (Free ASCO Whitepaper) Annual Meeting. AMG 212 is an investigational BiTE molecule which is designed to target prostate-specific membrane antigen (PSMA), a promising target in mCRPC. In the trial, 16 patients with mCRPC were enrolled into five dosing cohorts, with a target dose range of 5 to 80 µg/d delivered by continuous intravenous infusion. The primary objective was to determine safety and MTD and secondary objectives included pharmacokinetics (PK), biomarkers and tumor response. Antitumor activity as indicated by decline in serum level of prostate-specific antigen (PSA) was dose dependent. PSA decreases of ≥ 50 percent occurred in three patients (n=1 each in 20 µg/d, 40 µg/d and 80 µg/d cohorts). One long-term responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter patient showed a complete regression of soft-tissue metastases and marked regression of bone metastases, as well as a significant and durable improvement in disease-related symptoms. Recruitment in the trial was stopped before MTD was reached to facilitate initiation of a new study sponsored by Amgen.

"Metastatic castrate-resistant prostate cancer is considered a heterogenous disease and despite advances made over the last few years, the majority of patients face a poor outlook1," said Horst-Dieter Hummel, M.D., University Hospital of Wuerzburg, Germany, and AMG 212 clinical study investigator. "In the first clinical study investigating the potential of a BiTE molecule in solid tumors, AMG 212 showed clinical activity, including two long-term responders. We look forward to studying AMG 212 further in this patient population."

The most common drug-related AEs were fever (94 percent, n=15) and chills (69 percent, n=11). A drug-related serious AE (fatigue) was reported in one patient. CRS was reported for three patients (19 percent); two were grade 2 and one was grade 3. No grade 5 AEs occurred.

Additional Updates on Amgen’s BiTE Immuno-Oncology Platform at ASCO (Free ASCO Whitepaper) 2019
Amgen continues to investigate the BiTE immuno-oncology platform across a broad range of solid and hematologic malignancies with the goal of enhancing patient experience and therapeutic potential. Amgen is investigating more than a dozen BiTE molecules across a range of solid and hematologic malignancies, with an additional two trials-in-progress being presented at the ASCO (Free ASCO Whitepaper) Annual Meeting.

During poster sessions, researchers shared information on the studies of AMG 596, an investigational BiTE molecule targeting epidermal growth factor receptor variant III (EGFRvIII) in glioblastoma (GBM), and AMG 757, an investigational BiTE molecule targeting delta-like ligand 3 (DLL3) in small-cell lung cancer (SCLC). GBM and SCLC are both aggressive and difficult-to-treat forms of cancer where there is a significant unmet medical need for patients.

Forty-three percent of GBM tumors test positive for amplification or mutation of the EGFR, the most common of which is the EGFRvIII gain-of-function mutation.2 A Phase 1, first-in-human, open-label, sequential dose-escalation and dose-expansion study is ongoing for investigational AMG 596, evaluating its safety, tolerability, and PK and pharmacodynamics in patients with EGFRvIII-postive glioblastoma. The study is expected to enroll 82 patients in two groups: one with recurrent GBM and a second in newly diagnosed patients in the maintenance treatment phase following standard of care treatment.

DLL3 is an inhibitory ligand of notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues.3 An ongoing open-label, ascending, multiple-dose, Phase 1 study is evaluating investigational AMG 757 in adult patients with SCLC which has progressed or recurred after at least one platinum-based chemotherapy regimen. Primary objectives are to evaluate safety and tolerability and to determine the MTD or recommended Phase 2 dose. Secondary objectives are to characterize PK and evaluate preliminary anti-tumor activity.

For more information on these and other ongoing clinical trials, visit www.AmgenTrials.com.

Amgen Webcast Investor Meeting
Amgen will host a webcast investor meeting at ASCO (Free ASCO Whitepaper) 2019 on Monday, June 3 at 6:30 p.m. CT. David M. Reese, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team and clinical investigators, will participate at the investor meeting to discuss Amgen’s oncology program and data presented at ASCO (Free ASCO Whitepaper) 2019.

Live audio of the conference call will be broadcast over the internet simultaneously and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given at certain investor and medical conferences, can be accessed on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

About BiTE Technology
BiTE (Bispecific T cell engager) technology is a targeted immuno-oncology platform that is designed to engage patients’ own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells with the goal of eliminating detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has the goal of off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing more than a dozen BiTE molecules across a broad range of solid and hematologic malignancies, further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential.