On September 18, 2020 AstraZeneca reported that Updated results from the PACIFIC Phase III trial showed Imfinzi (durvalumab) demonstrated a sustained, clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who had not progressed following concurrent chemoradiation therapy (CRT) (Press release, AstraZeneca, SEP 18, 2020, View Source [SID1234565338]).

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

The results from the updated post-hoc analyses showed an estimated four-year overall survival rate of 49.6% for Imfinzi versus 36.3% for placebo after CRT. Median OS was 47.5 months for Imfinzi versus 29.1 for placebo. With a maximum treatment course of one year, an estimated 35.3% of patients treated with Imfinzi had not progressed four years after enrolment versus 19.5% for placebo. These data build on The New England Journal of Medicine publication from 2018 demonstrating a significant benefit for Imfinzi in the OS primary endpoint.6

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

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

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

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

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

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

The CASPIAN trial met the primary endpoint of OS in 2019, reducing the risk of death by 27% in patients with ES-SCLC treated with Imfinzi plus a choice of chemotherapy versus chemotherapy alone. The safety and tolerability of Imfinzi plus chemotherapy were consistent with the known safety profiles of these medicines. These results were published in The Lancet in 2019 and formed the basis of regulatory approvals around the world.7

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

Lung cancer

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

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

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

PACIFIC

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

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

CASPIAN

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

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

Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

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

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

AstraZeneca in lung cancer

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

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

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

AstraZeneca’s approach to Immuno-Oncology

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad 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.

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 September 18, 2020 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical need, reported that CEO Richard Godfrey will be presenting at the Sachs Annual Biotech in Europe Forum (Press release, BerGenBio, SEP 18, 2020, View Source [SID1234565337]).

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Date and time: Wednesday 23 September at 1pm CET.

Register for the event here: View Source

The presentation will be made available on the Company website in the Presentations section on the day.

www.bergenbio.com/investors/presentations/

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL expression defines a very poor prognosis subgroup in most cancers. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potentially first-in-class selective AXL inhibitor in a broad phase II clinical development programme. Ongoing clinical trials are investigating bemcentinib in multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers.

On September 18, 2020 Ipsen (Euronext: IPN; ADR: IPSEY) reported the release of first efficacy and safety data from the CLARINET FORTE study, with the abstract to be presented as a mini-oral presentation at the 2020 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, taking place virtually from 19-21 September 2020 (Press release, Ipsen, SEP 18, 2020, View Source [SID1234565336]). The prospective single-arm, open-label, exploratory, international Phase II study investigated the efficacy and safety of increasing the dose frequency of Somatuline Autogel (lanreotide) in patients with pancreatic or midgut NETs with centrally-assessed progression within the last two years while on a standard lanreotide regimen for ≥24 weeks. An extension of progression-free survival (PFS) rates and encouraging disease-control rates (DCR) were recorded in both tumor types, with no new safety signals.

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"These results support a clinically meaningful benefit to a population of patients with high unmet medical need by potentially delaying escalation to more toxic treatments. This means patients with progressive NETs are able to remain on a more tolerable first-line standard of care for longer," said Professor Marianne Pavel, Friedrich-Alexander University of Erlangen, Germany, Senior Physician and Chair of Endocrinology, and lead investigator of the study.

Lanreotide is a synthetic form of a natural hormone called somatostatin and is used to control and treat the growth of some advanced tumors of the midgut and the pancreas called gastroenteropancreatic NETs or GEP-NETs. Previous studies have shown efficacy in tumor control for the 28-day regimen of lanreotide 120 mg, and positive effects on relief of clinical symptoms.2

Currently, patients with progressive disease after treatment with lanreotide (120 mg every 28 days) have limited treatment options and receive less well-tolerated systemic chemotherapy or molecular targeted therapies. As lanreotide has a favorable tolerability profile, an increased dosing frequency might delay the need for such therapies and could potentially maintain patients’ quality of life for longer.

The CLARINET FORTE study found that increasing the dose frequency of lanreotide from a first line standard dose of 120 mg every 28 days, to an increased dose of 120 mg every 14 days, a median PFS of 8.3 months (95% confidence interval [CI]: 5.5–8.3) was achieved in patients with progressive midgut NETs (n=51) and 5.6 months (95% CI: 5.5–8.3) in patients with progressive pancreatic NETs (n=48). Post-hoc subgroup analysis in the pancreatic NETs cohort showed median PFS of 8.0 months (95% CI: 5.6–8.3) in patients with Ki67 ≤10% (n=43).

"The CLARINET FORTE study is another example of Ipsen’s commitment to delivering scientific and medical advances that translate into patient outcomes. Progressive pancreatic or midgut NETs are among the fastest growing class of cancers worldwide, so we are delighted that these data presented at ESMO (Free ESMO Whitepaper) may mean that for these patients, the need for aggressive second-line therapies could be delayed for longer whilst also benefitting from continued progression-free survival," said Professor Steven Hildemann, Executive Vice President, Chief Medical Officer, Head of Global Medical Affairs and Patient Safety, Ipsen.

The study found no new safety signals associated with this increased dose regimen. The increased lanreotide dosing frequency was well-tolerated, with treatment-related adverse events (TRAEs) remaining consistent with previous clinical studies and occurring in 37.5% and 51.0% of patients in the pancreatic NETs and midgut NETs cohorts, respectively; only one TRAE was Grade ≥3 (pancreatic NETs: fatigue [n=1], Grade 3). The most common (≥10%) classes of TRAEs were gastrointestinal disorders (pancreatic NETs, 25.0%; midgut NETs, 37.3%) and general disorders/administration-site conditions (midgut NETs, 13.7%).

Together, these efficacy and safety results may represent an important therapeutic approach for patients living with pancreatic or midgut NETs. The full data will be presented as an on-demand mini-oral presentation on Friday 18 September at the ESMO (Free ESMO Whitepaper) Virtual Congress 2020.

To complement the format of the ESMO (Free ESMO Whitepaper) Virtual Congress 2020, Ipsen’s new virtual congress platform includes a virtual press office View Source to support media in accessing further information. Highlights include insights around our data and contributions to the ESMO (Free ESMO Whitepaper) 2020 scientific program, our mission to advance oncology research and our commitment to address patients’ unmet needs. Registration for a digital media briefing for selected ESMO (Free ESMO Whitepaper) data is available here.

Follow Ipsen on Twitter via @IpsenGroup and keep up to date with ESMO (Free ESMO Whitepaper) Virtual Congress 2020 news and updates by using the hashtag #ESMO20.

About NETs

Neuroendocrine tumors, or NETs, are a group of uncommon tumors that develop in the cells of the neuroendocrine system, throughout the body.3,4 NETs occur in both men and women, in general aged 50 to 60 years old, although they can affect anyone of any age.1

The three main areas where NETs are found in the body are the gastrointestinal tract, the pancreas and the lungs.3,5

Gastrointestinal NETs are found in the gastrointestinal tract or digestive system and are the most common type of NETs.5
Pancreatic NETs are formed in the islet cells of the pancreas and include several uncommon types of NETs.5
Lung NETs are less common, accounting for about one quarter of NETs.5
The symptoms of NETs are often not distinct and difficult to identify, and can take between five to seven years to fully diagnose.6 The number of people being newly diagnosed with NETs overall is believed to be rising.1 This is mainly due to increased awareness of the condition and diagnostic testing.1 NETs are now among the fastest growing class of cancers worldwide, accounting for around 2% of all cancers.1

About CLARINET FORTE

CLARINET FORTE is a prospective single-arm, open-label, exploratory, international Phase II study to explore the efficacy and safety of an increased Somatuline Autogel (lanreotide) dosing interval (120 mg every 14 days) in patients with metastatic or locally advanced unresectable pancreatic NETs or midgut NETs, with centrally-accessed progression within the last two years while on a standard lanreotide regimen (120 mg every 28 days) for more than 24 weeks.7
About Somatuline (lanreotide)

Somatuline Autogel/Depot is made of the active substance lanreotide, which is a long-acting somatostatin analogue that inhibits the secretion of growth hormone and certain hormones secreted by the digestive system. The main indications of lanreotide are: 8

The treatment of individuals with acromegaly when the circulating levels of Growth Hormone (GH) and/or Insulin-like Growth Factor-1 (IGF-1) remain abnormal after surgery and/or radiotherapy, or in patients who otherwise require medical treatment.
The treatment of grade 1 and a subset of grade 2 (Ki-67 index up to 10%) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of midgut, pancreatic or unknown origin where hindgut sites of origin have been excluded, in adult patients with unresectable locally advanced or metastatic disease.
The treatment of symptoms associated with neuroendocrine (particularly carcinoid) tumors.
The detailed recommendations for the use of lanreotide are described in the Summary of Product Characteristics (SmPC), available here.

On September 18, 2020 GlaxoSmithKline (GSK) plc reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending Zejula (niraparib), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, as a first-line maintenance treatment in women with advanced ovarian cancer who responded to platinum-based chemotherapy, regardless of biomarker status (Press release, GlaxoSmithKline, SEP 18, 2020, View Source [SID1234565335]).

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Dr Axel Hoos, Senior Vice President and Head of Oncology R&D, GSK said: "Only 20% of women with ovarian cancer are currently eligible to be treated with a PARP inhibitor in the first-line maintenance setting. Today’s positive opinion from the CHMP will give all women in response to platinum-based chemotherapy the option to receive Zejula in the maintenance setting, reinforcing our belief in the important role this innovative medicine may play in helping these patients and the physicians working to treat them."

The CHMP opinion is one of the final steps in the marketing authorisation procedure prior to approval by the European Commission. This opinion follows the expansion of Zejula’s indication in the US with approval by the US Food and Drug Administration earlier this year.

The Type II variation application is based on data from the phase 3 PRIMA study (ENGOT-OV26/GOG-3012), which demonstrated a clinically meaningful progression-free survival benefit of Zejula treatment in the first-line maintenance setting. The PRIMA study enrolled women with newly diagnosed advanced ovarian cancer who responded to first-line treatment with platinum-based chemotherapy, a population with high unmet needs and limited treatment options.

Zejula has the potential to be the first monotherapy PARP inhibitor approved for first-line maintenance treatment following platinum response regardless of BRCA mutational status, addressing a high unmet need in ovarian cancer.

About Ovarian Cancer
In Europe, ovarian cancer is the sixth deadliest cancer among women and more than 65,000 women are diagnosed each year.[1] Most women are diagnosed with advanced (stage III or IV) ovarian cancer and have a five-year survival rate of ~30%.[2] Despite high response rates to platinum-based chemotherapy in the first-line, approximately 85% of women with advanced ovarian cancer will see their disease return.[3] With each recurrence, the time a woman may spend without her cancer progressing until the next recurrence gets shorter.

About Zejula (niraparib)
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in multiple pivotal trials. GSK is building a robust niraparib clinical development programme by assessing activity across multiple tumour types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development programme for niraparib includes several combination studies.

GSK in Oncology
GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, cancer epigenetics and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody drug conjugates and cell therapy, either alone or in combination.

Important Information for ZEJULA

Zejula approved indication:

Zejula is indicated as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.

Important Safety Information

Contraindications: Hypersensitivity to niraparib or to any of the excipients and breast-feeding.

Warnings and precautions: Test complete blood counts weekly for the first month of treatment, followed by monthly monitoring for the next 10 months of treatment and periodically after this time is recommended to monitor for clinically significant changes in any haematologic parameter during treatment. If a patient develops severe persistent haematologic toxicity (thrombocytopenia, anaemia and neutropenia including pancytopenia) that does not resolve within 28 days following interruption, Zejula should be discontinued. Patients with lower body weight or lower baseline platelet count may be at increased risk of Grade 3+ thrombocytopenia. Due to the risk of thrombocytopenia, anticoagulants and medicinal products known to reduce the thrombocyte count should be used with caution. If MDS and/or AML are confirmed while being prescribed Zejula, treatment should be discontinued, and the patient treated appropriately. Hypertension, including hypertensive crisis, has been reported with the use of Zejula. Pre‑existing hypertension should be adequately controlled before starting Zejula treatment. Zejula should be discontinued in case of hypertensive crisis or if medically significant hypertension cannot be adequately controlled with antihypertensive therapy. There have been reports of Posterior Reversible Encephalopathy Syndrome (PRES) in patients receiving Zejula. In case of PRES, it is recommended to discontinue treatment. Patients with galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine. Tartrazine may cause allergic reactions. Paediatric safety and efficacy has not yet been established.

Undesirable effects: The most common serious adverse reactions were thrombocytopenia and anaemia.

Very common (≥1/10): anaemia, thrombocytopenia, nausea, fatigue, constipation, vomiting, headache, insomnia, platelet count decreased, neutropenia, abdominal pain, decreased appetite, diarrhoea, dyspnoea, hypertension, asthenia, dizziness, neutrophil count decreased, cough, arthralgia, back pain, white blood cell count decreased, and hot flush.

Common (≥1/1000 to <1/10): bronchitis, conjunctivitis, leukopenia, hypersensitivity, hypokalemia, anxiety, depression, dysgeusia, tachycardia, hypertension, epistaxis, dry mouth, abdominal distension, mucosal inflammation (including mucositis), stomatitis, photosensitivity, rash, myalgia, oedema peripheral, fatigue, asthenia, Gamma-glutamyl transferase increased, AST increased, blood creatinine increased, ALT increased, blood alkaline phosphatase increased and weight decreased.

On September 18, 2020 EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported the publication of detailed results from the Phase III JAVELIN Bladder 100 study online ahead of print in The New England Journal of Medicine (Press release, EMD Serono, SEP 18, 2020, View Source [SID1234565319]). These results were published simultaneously with additional analyses being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 and describe the efficacy of BAVENCIO (avelumab) as a first-line maintenance treatment across various subgroups of patients with locally advanced or metastatic urothelial carcinoma (UC) and highlight exploratory biomarkers as well as patient-reported outcomes. In June, the US Food and Drug Administration (FDA) approved BAVENCIO for the maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy based on the JAVELIN Bladder 100 results.

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In the JAVELIN Bladder 100 study, BAVENCIO plus best supportive care (BSC) significantly extended overall survival (OS) compared with BSC alone in the two primary populations of all randomized patients and patients whose tumors were PD-L1+, and significantly more patients who received BAVENCIO as first-line maintenance were alive at one year.1 The clinical benefits of BAVENCIO were seen across a range of patient populations.1,2

"These data, which supported the recent FDA approval and updates to NCCN and ESMO (Free ESMO Whitepaper) guidelines, establish that BAVENCIO first-line maintenance treatment could fundamentally change clinical practice for the treatment of patients with locally advanced or metastatic urothelial carcinoma," said Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Queen Mary University of London, and Director of Barts Cancer Centre, London, UK. "It is notable that the longer overall survival with BAVENCIO maintenance therapy was observed across all pre-specified subgroups examined and that this prolonged overall survival was gained without a detrimental impact on patients’ quality of life."

Primary Analysis
In the JAVELIN Bladder 100 study, OS was significantly longer with BAVENCIO plus BSC compared to BSC alone in the primary population of all randomized patients (n=700) whose disease had not progressed on first-line platinum-containing chemotherapy:

Median OS was 21.4 months (95% CI, 18.9 to 26.1) vs 14.3 months (95% CI, 12.9 to 17.9), respectively (HR 0.69; 95% CI, 0.56 to 0.86; P<0.001).1
At one year, 71.3% of patients (95% CI, 66.0% to 76.0%) in the BAVENCIO arm were alive vs 58.4% (95% CI, 52.7% to 63.7%) of patients who received BSC alone.1
In the other primary population of patients with PD-L1+ tumors (n=358):

OS was also significantly longer with BAVENCIO plus BSC vs BSC alone (HR 0.56; 95% CI, 0.40 to 0.79; P<0.001).1
At one year, 79.1% (95% CI, 72.1% to 84.5%) of patients who received BAVENCIO were alive vs 60.4% (95% CI, 52.0% to 67.7%) in the BSC arm.1
All endpoints were measured from the time of randomization, after completion of four to six cycles of chemotherapy.

Subgroup Analysis
Results of an exploratory subgroup analysis show that consistent results were observed with the JAVELIN Bladder regimen of BAVENCIO first-line maintenance across pre-specified subgroups, including best response to first-line chemotherapy, type of chemotherapy regimen, site of baseline metastasis, and other baseline factors.1 In particular, hazard ratios for OS based on response to first-line chemotherapy were as follows:

0.69 for complete or partial response
0.70 for stable disease
With regard to first-line chemotherapy regimen, hazard ratios were as follows:

0.69 with gemcitabine plus cisplatin
0.66 with gemcitabine plus carboplatin
Further detail from the subgroup analysis were presented in an on-demand mini oral session at the meeting (Presentation #704MO). Additional data evaluating the association between clinical outcomes and exploratory biomarkers will be presented in the Proffered Paper 1 – GU, non prostate session on Saturday, September 19 (Presentation #699O), and patient-reported outcomes are featured in an on-demand e-poster display (Presentation #745P).

Safety
No new safety signals were identified in the JAVELIN Bladder 100 study, and the safety profile was consistent with previous studies of BAVENCIO monotherapy.1 Treatment-related adverse events of grade 3 or higher occurred in 57 patients (16.6%) treated with BAVENCIO plus BSC; no grade 3 or higher treatment-related events occurred in the control arm.1 No grade 4 or fatal immune-related adverse events occurred.1 Investigators attributed two patient deaths in the BAVENCIO plus BSC arm (0.6%), due to sepsis and ischemic stroke, to study treatment toxicity.1

About JAVELIN Bladder 100
JAVELIN Bladder 100 (NCT02603432) is a Phase III, multicenter, multinational, randomized, open-label, parallel-arm study investigating first-line maintenance treatment with BAVENCIO plus BSC versus BSC alone in patients with locally advanced or metastatic UC. The primary endpoint was OS in the two primary populations of all patients and patients with PD-L1+ tumors defined by the Ventana SP263 assay. Secondary endpoints included progression-free survival, anti-tumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers and patient-reported outcomes in the co-primary populations. All primary and secondary endpoints are measured from the time of randomization.

About Urothelial Carcinoma
Bladder cancer is the tenth most common cancer worldwide.4 In 2018, there were over half a million new cases of bladder cancer diagnosed, with around 200,000 deaths from the disease globally.4 In the US, an estimated 80,470 cases of bladder cancer were diagnosed in 2019, with around 12,500 locally advanced or metastatic cases presented annually.5,6 UC, which accounts for about 90% of all bladder cancers,7 becomes harder to treat as it advances, spreading through the layers of the bladder wall.8 Only 25% to 55% of patients receive any second-line therapy after first-line chemotherapy.9-15 In the US and EU5 markets, approximately 40% to 50% of patients receive an immune checkpoint inhibitor in second-line therapy.3 For patients with advanced UC, the five-year survival rate is 5%.5

About BAVENCIO (avelumab)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.16-18 In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications
BAVENCIO (avelumab) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

BAVENCIO in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIO is currently approved for patients with MCC in 50 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

BAVENCIO Important Safety Information from the US FDA-Approved Label
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with fatal, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with fatal, and 11 (0.6%) with Grade 3.

BAVENCIO in combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold BAVENCIO and axitinib for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed. In patients treated with BAVENCIO in combination with axitinib, Grades 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and control hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with axitinib: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO in combination with axitinib can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient with locally advanced or metastatic urothelial carcinoma (UC) receiving BAVENCIO plus best supportive care (BSC) as first-line maintenance treatment. In patients with previously treated locally advanced or metastatic UC, fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.

The most common adverse reactions (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO plus BSC (vs BSC alone) as first-line maintenance treatment were fatigue (35% vs 13%), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2.3%). In patients with previously treated locally advanced or metastatic UC receiving BAVENCIO, the most common adverse reactions (all grades, ≥20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Selected laboratory abnormalities (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO plus BSC (vs BSC alone) as first-line maintenance treatment were blood triglycerides increased (34% vs 28%), alkaline phosphate increased (30% vs 20%), blood sodium decreased (28% vs 20%), lipase increased (25% vs 16%), aspartate aminotransferase (AST) increased (24% vs 12%), blood potassium increased (24% vs 16%), alanine aminotransferase (ALT) increased (24% vs 12%), blood cholesterol increased (22% vs 16%), serum amylase increased (21% vs 12%), hemoglobin decreased (28% vs 18%), and white blood cell decreased (20% vs 10%).

Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).

Please see full US Prescribing Information and Medication Guide available at View Source

About Merck KGaA, Darmstadt, Germany-Pfizer Alliance
Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany and Pfizer. The global strategic alliance between Merck KGaA, Darmstadt, Germany and Pfizer enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of BAVENCIO, an anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance is jointly developing and commercializing BAVENCIO. The alliance is focused on developing high-priority international clinical programs to investigate BAVENCIO as a monotherapy as well as combination regimens, and is striving to find new ways to treat cancer.

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