On May 29, 2020 AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) reported that Results from the ongoing Phase II DESTINY-Lung01 trial showed Enhertu (trastuzumab deruxtecan) achieved a clinically meaningful tumour response in patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) whose disease had progressed following one or more systemic therapies (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558676]).

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Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1 There are currently no medicines approved specifically for the treatment of HER2m NSCLC, which affects approximately 2-4% of patients with NSCLC.2,3

The primary endpoint of confirmed objective response rate (ORR), assessed by independent central review, was 61.9% for patients treated with Enhertu monotherapy (6.4mg/kg). Patients achieved a disease control rate (DCR) of 90.5% with an estimated median progression-free survival (PFS) of 14.0 months. Median duration of response (DoR) and overall survival (OS) had not yet been reached at the time of data cut-off.

Egbert F. Smit, MD, PhD, Professor, Department of Thoracic Oncology at the Netherlands Cancer Institute, Amsterdam, Netherlands and principal investigator in the Phase II DESTINY-Lung01 trial, said: "While there have been important advances in the treatment of lung cancer over the past decade, there are still patients whose tumours continue to progress despite treatment with newer targeted agents or immunotherapies. Understanding additional molecular targets for treatment, such as HER2, is critical to advancing treatment options for these patients, and the results seen in the DESTINY-Lung01 trial are very encouraging."

José Baselga, Executive Vice President, Oncology R&D, said: "The results seen with Enhertu in patients with metastatic HER2-mutant non-small cell lung cancer are very exciting and highlight the role Enhertu may have as a new treatment option for patients facing a devastating prognosis. Further, the results demonstrate the potential of Enhertu to treat another tumour type among patients with extremely high unmet need."

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "While the role of anti-HER2 treatment is well-established in breast and gastric cancers, there are no HER2-directed therapies specifically approved for lung cancer. These results validate HER2 mutations as actionable targets in lung cancer and offer further evidence that Enhertu has the potential to transform outcomes for these patients."

Summary of results

CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable
i. Enhertu 6.4 mg/kg.
ii. As assessed by independent central review.
iii. ORR is (CR + PR).
iv. DCR is (CR + PR + SD).

Patients were treated with a median of two prior lines of therapy (1-6) with most receiving platinum-based chemotherapy (90.5%) and anti-PD-1 or PD-L1 treatment (54.8%). Median treatment duration was 7.76 months (0.7-14.3) with a median duration of follow-up of 8.0 months (1.4-14.2). As of data cut-off on 25 November 2019, 45.2% of patients with HER2m metastatic NSCLC remained on treatment with Enhertu.

The overall safety and tolerability profile of Enhertu in DESTINY-Lung01 was consistent with that seen in the Phase I lung cancer trial and previously reported Enhertu trials.4 The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (26.2%) and anaemia (16.7%). There were five cases (11.9%) of confirmed treatment-related interstitial lung disease (ILD) and pneumonitis as determined by an independent adjudication committee. All ILD and pneumonitis cases were Grade 2. One Grade 1 ILD is still undergoing adjudication.

Results from the DESTINY-Lung01 trial were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on 29 to 31 May 2020. Several other presentations featured during the meeting will showcase AstraZeneca’s leadership in lung cancer across early and late-stage disease and reinforce the Company’s biomarker-driven approach.

Enhertu was recently granted Breakthrough Therapy Designation in the US for the treatment of HER2m metastatic NSCLC.

HER2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers. In some tumours, HER2 overexpression is associated with a specific HER2 gene alteration known as amplification and is often associated with aggressive disease and poorer prognosis.5

Other HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets.3,6 These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis.2,3,6

NSCLC

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths globally.1

Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC. 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. Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.7 For these patients with metastatic disease, prognosis is particularly poor, only 6-10% will be alive five years after diagnosis.8,9 The introduction of targeted therapies and checkpoint inhibitors in recent years has improved outcomes for patients with advanced NSCLC; however, new approaches are needed for those who are not eligible for available treatments, or whose cancer continues to progress.10 Currently, no medicine is specifically approved to treat patients with HER2m NSCLC.

DESTINY-Lung01

DESTINY-Lung01 is a global, Phase II, open-label, multi-centre, two-cohort trial testing the safety and efficacy of Enhertu in 170 patients with HER2m or HER2-overexpressing, defined as IHC3+ or IHC2+, unresectable and/or metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is confirmed ORR by independent central review. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappears. Key secondary endpoints include DoR, DCR, PFS and OS.11

Enhertu

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed antibody drug conjugate (ADC) and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Enhertu (5.4 mg/kg) is approved in the US and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

In May 2020, Enhertu received BTD from the US FDA for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab and Orphan Drug Designation for patients with gastric cancer, including gastroesophageal junction cancer. In March 2018, Enhertu received a SAKIGAKE designation for potential use in the same HER2-positive gastric cancer patient population and a supplemental New Drug Application was recently submitted to the Japan Ministry of Health, Labour and Welfare.

In May 2020, Enhertu also received a BTD for the treatment of patients with metastatic NSCLC whose tumours have a HER2 mutation and with disease progression on or after platinum-based therapy.

Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

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 histology, 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 LAURA, and FLAURA2.12-14 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, a HER2-directed ADC, is in development for HER2m metastatic non-squamous NSCLC including trials in combination with other anticancer medicines.11

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.15 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 trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline including Enhertu.

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 investment 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 Resistance, DNA Damage Response and ADCs – 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 May 29, 2020 AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) reported that Results from the Phase II DESTINY-CRC01 trial of s Enhertu (trastuzumab deruxtecan) demonstrated clinically meaningful activity in patients with HER2-positive unresectable and/or metastatic colorectal cancer who received at least two prior lines of standard treatment (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558675]).

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Colorectal cancer is the third most common cancer and second most common cause of cancer death globally.1 There are currently no medicines approved to specifically treat HER2-positive colorectal cancer, which affects approximately 2-5% of patients with colorectal cancer.2

The primary endpoint of confirmed objective response rate (ORR), assessed by independent central review, showed 45.3% of patients with HER2-positive (defined as IHC3+ or IHC2+/ISH+) advanced colorectal cancer treated with Enhertu monotherapy (6.4mg/kg) achieved a tumour response. A disease control rate (DCR) of 83.0% was observed with a median progression-free survival (PFS) of 6.9 months. Median duration of response (DoR) and overall survival (OS) had not yet been reached at the time of data cut-off.

Salvatore Siena, MD, Professor of Medical Oncology, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, and Niguarda Cancer Center, Milan, Italy and principal investigator of the DESTINY-CRC01 trial, said: "Understanding new ways we can treat patients with colorectal cancer, such as targeting HER2, is critical as patients have few remaining treatment options once progression occurs in the advanced disease setting. The results from DESTINY-CRC01 in patients with HER2-positive advanced colorectal cancer are striking and warrant further research, especially considering many of these patients have had numerous prior therapies."

José Baselga, Executive Vice President, Oncology R&D, said: "These clinically meaningful and durable responses in patients with advanced HER2-positive colorectal cancer support our belief that HER2 is an important treatment target in this disease. Enhertu has now demonstrated impressive clinical activity in four different cancer settings, reinforcing the potential of this remarkable medicine to transform patient outcomes across a range of HER2-targetable tumours."

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "Metastatic colorectal cancer has a devastating prognosis and there have been limited treatment advances following progression on 1st-line treatment and there are no therapies approved that specifically target HER2. We are encouraged by the tumour response rates seen in patients with previously treated advanced colorectal cancer and we will continue to explore the potential of Enhertu to address this unmet medical need."

Summary of results

CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable
i. Enhertu 6.4 mg/kg.
ii. Primary cohort included patients with HER2-positive disease (defined as IHC3+ or IHC2+/ISH+).
iii. As assessed by independent central review.
iv. ORR is (CR + PR).
v. DCR is (CR + PR + SD).

Two exploratory cohorts enrolled patients with tumours with lower levels of HER2 expression (IHC2+/ISH- and IHC1+, respectively). There were no responses seen in these exploratory cohorts.

Prespecified exploratory analysis evaluated ORR in subgroups including patients previously treated with a prior anti-HER2 regimen (n=16). In these patients an ORR of 43.8% (95% CI, 19.8-70.1) was seen. Patients were treated with a median of four prior lines of therapy (2-11), with all patients having received prior chemotherapy treatment with irinotecan and oxaliplatin. The median treatment duration was 4.8 months (1-11). As of data cut-off on 9 August 2019, 38.5% (30 out of 78) remained on treatment across cohorts.

The overall safety and tolerability profile of Enhertu in DESTINY-CRC01 was consistent with that seen in previously reported Enhertu trials. The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (25.6%) and anaemia (14.1%). There were five cases (6.4%) of interstitial lung disease (ILD) and pneumonitis determined by an independent adjudication committee. Two were Grade 2 and one was Grade 3. Two deaths (Grade 5) were determined to be due to ILD.

Results from DESTINY-CRC01 were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on 29 to 31 May 2020.

Colorectal cancer

Colorectal cancer is the third most common cancer and second most common cause of cancer death globally.1

Approximately 25% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs, and about 50% of patients with colorectal cancer will eventually develop metastases.3 Overexpression and amplification of HER2, a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers, occurs in approximately 2-5% of all patients with colorectal cancer.2,4 Research indicates that HER2 amplification may be associated with resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.4,5

DESTINY-CRC01

DESTINY-CRC01 is a global, Phase II, open-label, multi-centre trial testing the safety and efficacy of Enhertu in patients (n=78) with HER2-expressing, unresectable and/or metastatic colorectal cancer. DESTINY-CRC01 excluded patients with a mutation in the RAS or BRAF gene. The primary cohort of the trial enrolled patients (n=53) with HER2-positive disease (defined as IHC3+ or IHC2+/ISH+). The primary endpoint of the trial is confirmed ORR by independent central review in the primary cohort. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappears. Secondary endpoints include DCR, DoR, PFS and OS. Two additional exploratory cohorts enrolled patients whose tumours had lower levels of HER2 expression [HER2 IHC2+/ISH- (n=7) and HER2 IHC1+ (n=18), respectively].6

Enhertu

Enhertu (trastuzumab deruxtecan, fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed antibody drug conjugate (ADC) and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Enhertu (5.4mg/kg) is approved in the US and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

In May 2020, Enhertu received Breakthrough Therapy Designation (BTD) from the US FDA for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab and Orphan Drug Designation for patients with gastric cancer, including gastroesophageal junction cancer. In March 2018, Enhertu received a SAKIGAKE designation for potential use in the same HER2-positive gastric cancer patient population and a supplemental New Drug Application was recently submitted to the Japan Ministry of Health, Labour and Welfare.

In May 2020, Enhertu also received a BTD for the treatment of patients with metastatic non-small cell lung cancer whose tumours have a HER2 mutation and with disease progression on or after platinum-based therapy.

Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

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 investment 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 Resistance, DNA Damage Response and ADCs – 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 May 29, 2020 AstraZeneca reported that results from the global Phase II Study 22 trial testing tremelimumab, an anti-CTLA4 antibody, added to Imfinzi (durvalumab) demonstrated promising clinical activity and tolerability in patients with advanced hepatocellular carcinoma (HCC) (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558674]). HCC is the most common type of liver cancer.1

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In the primary endpoint of the trial evaluating safety, all experimental arms demonstrated an acceptable profile and no new safety signals were identified. Patients treated with a single, priming dose of tremelimumab 300mg added to durvalumab every four weeks (T300+D regimen) achieved a median overall survival (OS) of 18.7 months in a key secondary endpoint. The OS result for the T300+D regimen was the longest among treatments tested in the trial, which included Imfinzi monotherapy, tremelimumab monotherapy and two regimens of the two combined.

In other key secondary endpoints, objective response rate (ORR) confirmed by independent central review was 24% with the T300+D regimen, and median duration of response (DoR) was not yet reached at the time of data cut-off. A unique T-cell profile for patients in the T300+D arm was associated with treatment response, suggesting complementary biological activity.

R. Kate Kelley, MD, Associate Professor of Clinical Medicine, Department of Medicine, University of California San Francisco and principal investigator said: "In Study 22, we were able to induce a stronger immune response and enhance the clinical activity of Imfinzi in patients with advanced liver cancer by combining with a single dose of tremelimumab, a novel approach designed to prime the immune response using CTLA-4 inhibition at the start of therapy. These exciting results suggest that dual checkpoint blockade with tremelimumab and Imfinzi may have a role in a challenging cancer where patients have few treatment options."

José Baselga, Executive Vice President, Oncology R&D, said: "Based on these compelling results, we see the potential for a single, priming dose of tremelimumab plus Imfinzi to change the treatment landscape and improve outcomes for patients with advanced liver cancer, a setting where new treatments are urgently needed. The Study 22 data are also an encouraging sign for our Phase III HIMALAYA trial testing this regimen in liver cancer, with data expected later this year."

Summary of Results

i. Tremelimumab
ii. Durvalumab
iii. Treatment-related adverse events
iv. Not reached

Results evaluating safety and efficacy from parts two and three of the Phase II Study 22 trial were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on Friday, 29 May 2020.

Imfinzi is not currently approved to treat HCC in any country, alone or in combination with tremelimumab. In January 2020, Imfinzi and tremelimumab were granted Orphan Drug Designation in the US for the treatment of HCC.

Liver Cancer

Liver cancer is the third leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide, with approximately 20% of patients alive five years after diagnosis.2,3 HCC represents about 80-90% of all primary liver cancers.1 Approximately 700,000 people were estimated to be diagnosed with HCC around the world in 2018.2 Between 80-90% of all patients with HCC also have chronic liver disease, which is primarily caused by infection with the hepatitis B or C viruses.4,5 Chronic liver disease is associated with inflammation that, over time, results in immunosuppression and can lead to the development of HCC.6,7 The unique immune environment of liver cancer provides clear rationale for researching medicines that harness the power of the immune system to treat HCC.8 A critical unmet need exists for patients with HCC who face limited treatment options. More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.9

Study 22

Study 22 is an open-label, multicentre, global, four-part Phase II trial evaluating the safety and efficacy of several treatments in 433 patients with advanced HCC in the 1st- or 2nd-line setting. The first part of the trial evaluated the safety of the tremelimumab plus Imfinzi combination. Parts two and three are evaluating Imfinzi monotherapy, tremelimumab monotherapy, and tremelimumab plus Imfinzi combination therapy, and part four evaluates bevacizumab plus Imfinzi combination therapy. Results presented are for 332 patients in parts two and three, who were evaluated for safety and efficacy with a data cut-off of 28 February 2020. The trial is being conducted in 45 centres across 9 countries, including in the US, Europe, and Asia. Primary endpoints include number of patients reporting adverse events and serious adverse events, and number of patients experiencing dose-limiting toxicities. Secondary endpoints include overall survival, objective response rate, and duration of response.

HIMALAYA

HIMALAYA is a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and the T300+D regimen including a single, priming dose of tremelimumab 300mg added to Imfinzi every four weeks versus the standard-of-care medicine sorafenib, a multi-kinase inhibitor, in 1,324 patients with unresectable, advanced HCC who have not been treated with prior systemic therapy and are not eligible for locoregional therapy (treatment localised to the liver and surrounding tissue). The trial is being conducted in 189 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint is overall survival and key secondary endpoints include objective response rate and progression-free survival. HIMALAYA is the first Phase III trial to test dual immune checkpoint blockade in the 1st-line advanced HCC setting.

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 non-small cell lung cancer (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 extensive-stage small cell lung cancer (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’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 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 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 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 May 29, 2020 Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported final results from the overall survival (OS) analysis of the Phase 3 PROSPER trial, which evaluated XTANDI (enzalutamide) plus androgen deprivation therapy (ADT) versus placebo plus ADT in men with non-metastatic castration-resistant prostate cancer (nmCRPC) (Press release, Astellas, MAY 29, 2020, View Source [SID1234558673]). In the trial, XTANDI plus ADT reduced the risk of death by 27% (n=1,401; hazard ratio [HR]=0.73; [95% confidence interval [CI]: 0.61-0.89]; p=0.001) compared to placebo plus ADT. The median OS was 67.0 months (95% CI: 64.0 to not reached) for men who received XTANDI plus ADT compared to 56.3 months (95% CI: 54.4 to 63.0) with placebo plus ADT. OS was a key secondary endpoint of the trial.

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These data were simultaneously published online in the New England Journal of Medicine and presented during the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #5515).

"Overall survival is a critical endpoint in evaluating a prostate cancer medicine," said Cora N. Sternberg, M.D., F.A.C.P., Clinical Director, Englander Institute for Precision Medicine and Professor of Medicine in Hematology & Oncology, Weill Cornell Medicine and NewYork-Presbyterian. "These results add to the body of evidence supporting XTANDI’s potential to reduce the risk of death in men with castration-resistant prostate cancer."

In findings published in the New England Journal of Medicine in 2018, the PROSPER trial met its primary endpoint of metastasis-free survival (MFS), demonstrating a significant reduction in the risk of developing metastasis or death with XTANDI plus ADT compared to ADT alone in men with nmCRPC (HR=0.29 [95% CI: 0.24-0.35]; p<0.001). MFS was measured as the time from patients entering the trial until their cancer was radiographically detected as having metastasized, or until death, within 112 days of treatment discontinuation.

The safety profile observed in the final OS analysis was consistent with the 2018 primary analysis and the established safety profile of enzalutamide. The most common adverse reactions irrespective of relationship to study drug that occurred more frequently (≥10%) in XTANDI plus ADT-treated patients in the PROSPER OS analysis were fatigue (37% vs 16%), hypertension (17% vs 6%), asthenia (10% vs 7%), back pain (13% vs 8%), dizziness (12% vs 6%), diarrhea (12% vs 10%), nausea (13% vs 9%), hot flush (14% vs 8%), fall (18% vs 5%), arthralgia (13% vs 8%), constipation (13% vs 8%), hematuria (10% vs 9%), headache (11% vs 5%) and decreased appetite (12% vs 5%). In this analysis of the PROSPER trial, Grade 3 or higher adverse reactions were reported in 48% of men treated with XTANDI plus ADT and in 27% of men treated with placebo plus ADT.

About Non-Metastatic Castration-Resistant Prostate Cancer
Castration-resistant prostate cancer (CRPC) refers to the subset of men whose prostate cancer progresses on androgen deprivation therapy (ADT) despite castrate levels of testosterone (i.e., less than 50 ng/dL).1 Non-metastatic CRPC means there is no clinically detectable evidence of the cancer spreading to other parts of the body (metastases), and there is a rising prostate-specific antigen (PSA) level.2 Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.3

PROSPER Trial
The Phase 3 randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,401 patients with nmCRPC at sites in the United States, Canada, Europe, South America and the Asia-Pacific region. PROSPER enrolled patients with prostate cancer that had progressed, based on a rising PSA level despite ADT, but who had no symptoms and no prior or present evidence of metastatic disease. Of the total patients enrolled, 933 patients were treated with XTANDI at a dose of 160 mg taken orally once daily plus ADT and 468 patients were treated with placebo plus ADT.

The primary endpoint of the PROSPER trial, MFS, was measured as the time from patients entering the trial until their cancer was radiographically detected as having metastasized, or until death, within 112 days of treatment discontinuation. Key secondary endpoints included OS, time to PSA progression and time to first use of antineoplastic therapy.

For more information on the PROSPER trial, go to www.clinicaltrials.gov.

About XTANDI (enzalutamide)
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Important Safety Information for XTANDI

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.

Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI.

Adverse Reactions (ARs)
In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.
Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

On May 29, 2020 Alligator Bioscience (Nasdaq Stockholm: ATORX), reported that the company today presents additional novel data from the ongoing Phase I clinical trial with the bispecific drug candidate ATOR-1015 developed as tumor-directed therapy for metastatic cancer, which further validates the potential of the drug (Press release, Alligator Bioscience, MAY 29, 2020, View Source [SID1234558672]). The presentation will be held at the ASCO (Free ASCO Whitepaper) (American Society of Clinical Oncology) Annual Meeting, which this year is being held virtually.

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The results from the evaluation of doses up and including 600 mg (about 10 mg/kg) show that ATOR-1015 is well tolerated, and dose-escalation has continued to 750 mg (12.5 mg/kg). In this presentation, 21 patients with varying cancer types (colon cancer, eye melanoma, pancreatic cancer, ovarian cancer, gallbladder cancer, gastric cancer, and melanoma) are included and evaluated in terms of safety. The drug related adverse events in the study have generally been mild and transient. No dose-limiting toxicity or severe immune-related adverse events have been reported.

"The results presented at ASCO (Free ASCO Whitepaper) truly support the fact that ATOR-1015 could be a safer and more efficacious drug than current treatment options for spread cancer disease. We are consequently very much looking forward to moving ATOR-1015 into efficacy studies," said Per Norlén, CEO of Alligator Bioscience.

Due to the positive tolerability profile of ATOR-1015, dose escalation will continue at even higher doses than expected but still allows for a preliminary efficacy readout in melanoma patients already towards the end of 2021.

The ASCO (Free ASCO Whitepaper) poster presentation with the title "A first-in-human phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of ATOR-1015, a CTLA-4 x OX40 bispecific antibody" is available on the company website View Source

For further information, please contact:
Cecilia Hofvander, Director Investor Relations & Communications
Phone +46 46 540 82 06
E-mail: [email protected]

This information is such information as Alligator Bioscience AB (publ) is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact person set out above, at 2:00 p.m. CEST on May 29, 2020.

About the ATOR-1015 Phase I study
The Phase I study with ATOR-1015 is a dose escalation study in patients with metastatic cancer (NCT03782467). The primary endpoint of the study is to investigate the safety and tolerability of ATOR-1015 and to determine the recommended dose for subsequent Phase II studies. The first patient was dosed in March 2019 and following the establishment of the maximum tolerable dose or recommended dose for Phase II, further clinical development of ATOR-1015 is planned, primarily for the treatment of malignant melanoma.

About ATOR-1015
ATOR-1015, wholly owned by Alligator, is a bispecific CTLA-4 antibody developed as tumor targeted immunotherapy with increased capacity for killing regulatory T cells. ATOR-1015 binds to two different immune receptors – the checkpoint receptor CTLA-4 and the co-stimulatory receptor OX40. The immune activation is increased in areas where both target molecules are expressed at high levels, notably in the tumor microenvironment, which can lead to reduced side effects.