On February 19, 2019 Pfizer Inc. (NYSE: PFE) reported the European Commission (EC) has approved ZIRABEV for the treatment of metastatic carcinoma of the colon or rectum, metastatic breast cancer, unresectable advanced, metastatic or recurrent non-small cell lung cancer (NSCLC), advanced and/or metastatic renal cell cancer and persistent, recurrent or metastatic carcinoma of the cervix.1,2 (Press release, Pfizer, FEB 19, 2019, View Source [SID1234533387])

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"Pfizer is dedicated to increasing access to biosimilars for patients suffering from serious illnesses and helping create a more sustainable healthcare system," said Andreas Penk, M.D., regional president, Oncology International Developed Markets at Pfizer. "We are proud that ZIRABEV was approved today as our second oncology biosimilar in Europe. This milestone reflects our ongoing commitment to biosimilars as we continue to bring high-quality medicines to market that may help generate cost savings for cancer care."

* Avastin is a registered trademark of Genentech

The EC approval is based on a comprehensive submission package which demonstrated biosimilarity of ZIRABEV and the originator product. This includes results from the phase 3 REFLECTIONS B739-03 clinical comparative study, which showed clinical equivalence and found no clinically meaningful differences between ZIRABEV and the originator product in patients with advanced non-squamous NSCLC.3 As part of the overall REFLECTIONS clinical trial program, ZIRABEV has been studied in approximately 400 subjects.3,4

This approval follows the positive recommendation from the Committee for Medicinal Products for Human Use in December 2018.5 ZIRABEV has also been filed for regulatory approval with the U.S. Food and Drug Administration.

Pfizer has a robust portfolio of potential biosimilar candidates in mid- to late-stage development.6 ZIRABEV is Pfizer’s fifth biosimilar approved for use in Europe.1,7, 8,9,10

About ZIRABEV (bevacizumab biosimilar)

ZIRABEV is a monoclonal antibody (mAb) biosimilar of the originator biologic medicine, Avastin, which works by inhibiting the formation of new blood cells (angiogenesis) by specifically recognizing and binding to vascular endothelial growth factor (VEGF) protein.11, 12,13 ZIRABEV has been studied in nearly 400 patients.3,4

ZIRABEV safety information

Do not use ZIRABEV if you are allergic to bevacizumab, any of its ingredients, Chinese hamster ovary (CHO) cell products, or other recombinant human or humanised antibodies, or if you are pregnant.

Before starting treatment with ZIRABEV, tell your healthcare provider if:

you have any conditions causing inflammation inside the abdomen (e.g. diverticulitis, stomach ulcers, colitis associated with chemotherapy)
you have persistent, recurrent or metastatic cervical cancer
you are going to have an operation, if you have had major surgery within the last 28 days or if you still have an unhealed wound following surgery
you had holes in the gut wall or problems with wound healing
you have high blood pressure which is not well controlled with blood pressure medicines
you are over 65 years old, if you have diabetes, or if you have had previous blood clots in your arteries
you or your family tend to suffer from bleeding problems or you are taking medicines to thin the blood for any reason
you have metastatic cancer affecting your brain
you have noticed coughing or spitting blood
you have ever received anthracyclines (for example doxorubicin, a specific type of chemotherapy used to treat some cancers) or had radiotherapy to your chest, or if you have heart disease
you have previously experienced problems after injections, such as dizziness/feeling of fainting, breathlessness, swelling or skin rash
you have headache, vision changes, confusion or seizure with or without high blood pressure
you have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth
you need to undergo an invasive dental treatment or dental surgery, in particular when you are also receiving or have received an injection of bisphosphonate into your blood
you are currently using or recently used a medicine called sunitinib malate, are receiving platinum- or taxane-based chemotherapy (medicines used to treat cancer) or are receiving or recently received radiotherapy
you have previously received any other treatment for cancer
ZIRABEV increases the risk of having protein in your urine, especially if you already have high blood pressure. ZIRABEV can also increase the risk of developing blood clots in your veins (a type of blood vessel) and may cause infections and a decreased number of your neutrophils (a type of blood cell important for your protection against bacteria).

Like all medicines, ZIRABEV can cause side effects, although not everybody gets them. If you have an allergic reaction, contact your doctor or a member of medical staff straight away. The signs may include difficulty in breathing or chest pain. You could also experience redness or flushing of the skin or a rash, chills and shivering, feeling sick (nausea) or being sick (vomiting). Very common severe side effects of treatment with ZIRABEV are:

high blood pressure
the feeling of numbness or tingling in hands or feet
a decreased number of cells in the blood, including white cells that help to fight infection (this may be accompanied by fever), and cells that help the blood to clot
feeling weak and having no energy
tiredness
diarrhoea, nausea, vomiting and abdominal pain.
Other very common side effects that are not as severe include constipation, loss of appetite, fever, problems with eyes (including increased tear production), changes in speech, changes in sense of taste, runny nose, dry skin, flaking and inflammation of skin, changes in skin color, loss of body weight and nose bleeds. You should tell your healthcare provider immediately if you notice any of the above symptoms.

Tell your healthcare provider if you are taking, have recently taken or may take any other medicines.

Tell your healthcare provider if you are pregnant, plan to become pregnant, or are breastfeeding.

Ask your healthcare provider about the risks and benefits of ZIRABEV. Only a healthcare provider can decide if ZIRABEV is right for you.

You are encouraged to report negative side effects to the European Medicines Agency. Visit View Source Please refer to the European Summary of Product Characteristics for ZIRABEV for complete safety information.

On February 19, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the US Food and Drug Administration (FDA) has accepted the company’s New Drug Applications (NDAs) and granted Priority Review for entrectinib for the treatment of adult and paediatric patients with neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive, locally advanced or metastatic solid tumours who have either progressed following prior therapies or as an initial therapy when there are no acceptable standard therapies, and for the treatment of people with metastatic, ROS1-positive non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche, FEB 19, 2019, View Source [SID1234533386]). These NDAs are based on results from the integrated analysis of the pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the Phase I/Ib STARTRK-NG study. The FDA is expected to make a decision on approval by 18 August 2019.

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"Entrectinib represents a unique approach to cancer treatment that can potentially target a range of hard-to-treat and rare NTRK fusion-positive tumours regardless of their site of origin, as well as treat ROS1-positive non-small cell lung cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "By combining comprehensive genomic profiling with actionable targeted therapies, like entrectinib, we are advancing our personalised healthcare goal to find the right treatment for each patient. We are working closely with the FDA to make this potential new option available as soon as possible."

The FDA grants Priority Review to medicines determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a serious disease. Entrectinib was also granted Breakthrough Therapy Designation (BTD) by the US Food and Drug Administration (FDA); Priority Medicines (PRIME) designation by the European Medicines Agency (EMA); and Sakigake designation by the Japanese health authorities for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumours in adult and paediatric patients who have either progressed following prior therapies or have no acceptable standard therapies.[1] BTD is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible.

Roche is leveraging its expertise in developing personalised medicines and advanced diagnostics, in conjunction with Foundation Medicine, to develop a companion diagnostic that will help identify people with ROS1 and NTRK gene fusions.

About the integrated analysis
The integrated analysis included data from 53 people with ROS1-activating gene fusions and 54 people with locally advanced or metastatic NTRK fusion-positive solid tumours (10 tumour types, >19 histopathologies) from the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials.[2,3] In addition, data from the Phase I/Ib STARTRK-NG study in paediatric patients were also included in the NDAs. The studies enrolled people across 15 countries and more than 150 clinical trial sites.[2,3] Tumour types evaluated in the studies to date included breast, cholangiocarcinoma, colorectal, gynaecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.[3]

STARTRK-2 is a Phase II, global, multicentre, open-label basket study in people with solid tumours that harbour an NTRK1/2/3, ROS1 or ALK-positive gene fusion.[4] The primary endpoint is objective response rate (ORR), and duration of response (DoR) is a secondary endpoint.[4] Other secondary outcome measures include time to response, clinical benefit rate, intracranial tumour response, progression-free survival (PFS), central nervous system (CNS) PFS and overall survival (OS).[4]
STARTRK-1 is a Phase I, multicentre, open-label dose escalation study of a daily continuous dosing schedule in people with solid tumours with NTRK1/2/3, ROS1 or ALK gene fusions in the US and South Korea.[5] The trial assessed the safety and tolerability of entrectinib via a standard dose escalation scheme and determined the recommended Phase II dose.[5]
ALKA-372-001 is Phase I, multicentre, open-label dose escalation study of an intermittent and continuous entrectinib dosing schedule in people with advanced or metastatic solid tumours with TRKA/B/C, ROS1 or ALK gene fusions in Italy.[1]
STARTRK-NG is a Phase I/II dose-escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumours or primary CNS tumours, with or without TRK, ROS1 or ALK fusions.[6]
Results from the integrated analysis showed entrectinib shrank tumours (ORR) in more than half (57.4 percent) of people with NTRK fusion-positive solid tumours.[3] Objective responses to entrectinib were seen across 10 different solid tumour types (median DoR = 10.4 months), including in people with and without CNS metastases at baseline.[3] In these studies, entrectinib shrank tumours that had spread to the brain in more than half of people (intracranial response [IC ORR] = 54.5 percent), with more than a quarter of these people having a complete response.[3]

Entrectinib shrank tumours in 77.4 percent of people with locally advanced or metastatic ROS1-positive NSCLC.[2] In addition, entrectinib demonstrated a durable response of more than two years (median DoR = 24.6 months).[2] Importantly, entrectinib was shown to shrink intracranial tumours in more than half of people with CNS metastases at baseline (IC ORR = 55.0 percent).[2]

The safety profile of entrectinib was consistent with that seen in previous analyses.[2,3] The most commonly reported adverse reactions included fatigue, constipation, altered sense of taste (dysgeusia), swelling (edema), dizziness, diarrhea, nausea, nervous system disorders (dysesthesia), shortness of breath (dyspnea), pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, joint pain (arthralgia), fever (pyrexia), and muscle pain (myalgia).[2,3]

About entrectinib
Entrectinib (RXDX-101) is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumours that harbour NTRK1/2/3 or ROS1 gene fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer.[7,8] Entrectinib can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions.[7,8] Entrectinib is being investigated across a range of solid tumour types, including breast, cholangiocarcinoma, colorectal, gynaecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.[1,4-6]

About NTRK fusion-positive cancer
Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signaling pathways involved in proliferation of certain types of cancer. NTRK gene fusions are tumour-agnostic, meaning they are present in tumours irrespective of site of origin. These fusions have been identified in a broad range of solid tumour types, including breast, cholangiocarcinoma, colorectal, gynaecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.[3] There is a high unmet medical need for treatments for people with life-threatening and hard-to-treat NTRK fusion-positive tumours.

About ROS1-positive NSCLC
ROS1 is a tyrosine kinase, which plays a role in controlling how cells grow and proliferate. When a ROS1 gene fusion occurs, cancer cells grow and proliferate in an uncontrolled manner. Blocking this abnormal signalling can cause tumour cells to shrink or die.[9]

ROS1 gene fusions account for 1-2% of NSCLC.[9] Lung cancer is the leading cause of cancer-related death across the world.[10] Each year, more than one and a half million people die as a result of the disease globally, equating to more than 4,000 deaths every day.[10] NSCLC is the most common type of lung cancer and accounts for 85% of all lung cancer diagnoses.[11] While the ROS1 gene fusion can be found in any patient with NSCLC, young never-smokers with NSCLC have the highest incidence of ROS1 gene fusions.[9]

On February 19, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s Biologics License Application (BLA) and granted Priority Review for polatuzumab vedotin in combination with bendamustine plus Rituxan (rituximab) (BR) for the treatment of people with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (Press release, Hoffmann-La Roche, FEB 19, 2019, View Source [SID1234533385]). The FDA is expected to make a decision on approval by 19 August 2019.

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"Polatuzumab vedotin, a potential first-in-class antibody drug conjugate, in combination with bendamustine and Rituxan, improved clinical outcomes including survival in some people with relapsed or refractory diffuse large B-cell lymphoma compared to bendamustine and Rituxan alone," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are working with the FDA to bring this important new option to patients with this aggressive disease as quickly as possible."

The BLA is based on results of the GO29365 study, which showed that polatuzumab vedotin plus BR improved median overall survival compared to BR alone (12.4 vs. 4.7 months, HR=0.42; 95% CI 0.24-0.75; exploratory endpoint), in people with R/R DLBCL not eligible for a haematopoietic stem cell transplant. The study also showed that 40% of people treated with polatuzumab vedotin plus BR achieved a complete response (CR), while only 18% of people treated with BR alone achieved a CR (primary endpoint, as measured by positron emission tomography; CR rates assessed by independent review committee). A CR means no cancer could be detected at that time.

Priority Review designation is granted to medicines that the FDA considers to have the potential to provide significant improvements in the safety and effectiveness of the treatment, prevention or diagnosis of a serious disease. Polatuzumab vedotin was also granted Breakthrough Therapy Designation by the FDA and PRIME (PRIority MEdicines) designation by the European Medicines Agency for the treatment of people with R/R DLBCL in 2017. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat a serious condition with preliminary evidence that indicates they may demonstrate substantial improvement over existing therapies.

About the GO29365 study
GO29365 is a global, phase Ib/II randomised study evaluating the safety, tolerability and activity of polatuzumab vedotin in combination with bendamustine and Rituxan (rituximab) or Gazyva (obinutuzumab) in relapsed or refractory (R/R) follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). The phase II stage randomised 80 patients with heavily pre-treated R/R DLBCL to receive either bendamustine plus Rituxan (BR), or BR in combination with polatuzumab vedotin. Patients enrolled had received a median of two prior therapies (a range of 1-7 prior therapies in the polatuzumab vedotin arm and range of 1-5 prior therapies in the BR alone arm). The primary endpoint was complete response (CR) at the end of treatment, as measured by positron emission tomography (PET) and assessed by an independent review committee (IRC). Secondary endpoints included objective response (OR; CR and partial response, PR) by investigator assessment and best objective response at the end of treatment by investigator and IRC assessment. Exploratory endpoints included duration of response (DOR), progression-free survival (PFS), event-free survival (EFS) and overall survival (OS).

40% of people treated with polatuzumab vedotin plus BR achieved a CR while only 18% of people treated with BR alone achieved a CR (primary endpoint, as measured by PET; CR rates assessed by IRC). A CR means no cancer could be detected at that time.
Polatuzumab vedotin in combination with BR showed a median OS of over one year compared to the BR arm (12.4 vs. 4.7 months, HR=0.42; 95% CI 0.24-0.75), in people with R/R DLBCL not eligible for a hematopoietic stem cell transplant. OS was an exploratory endpoint.
Polatuzumab vedotin plus BR increased median PFS and led to a 66% reduction in risk of disease worsening or death compared to BR alone (median PFS: 7.6 months vs. 2.0 months; HR=0.34; 95% CI 0.20-0.57).
Patients treated with polatuzumab vedotin plus BR showed a longer time between first response to treatment and disease worsening than those receiving BR alone (investigator assessed median DOR: 10.3 months vs. 4.1 months; HR=0.44).
Updated safety results are similar to those previously described, with infections and cytopenias remaining the most common Grade 3–4 adverse events (AEs). Polatuzumab vedotin plus BR had higher rates of Grade 3–4 cytopenias compared to BR, however, infection and transfusion rates remained similar between arms.
About polatuzumab vedotin
Polatuzumab vedotin is a first-in-class anti-CD79b antibody drug conjugate (ADC) currently being investigated for the treatment of several types of non-Hodgkin lymphoma (NHL). The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies.[1, 2] Polatuzumab vedotin binds to CD79b and destroys these B-cells through a targeted approach, which is thought to minimise the effects on normal cells while maximising tumour cell death.[3, 4] Polatuzumab vedotin is being developed by Roche utilising Seattle Genetics ADC technology.

About diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for about one in three cases of NHL.[5] DLBCL is an aggressive (fast-growing) type of NHL, which is generally responsive to treatment in the frontline.[6] However, as many as 40% of patients will relapse, at which time salvage therapy options are limited and survival is short.[1, 4] Approximately 150,000 people worldwide are estimated to be diagnosed with DLBCL each year.[7]

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), and Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule which inhibits the interaction of MDM2 with p53 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of Hemlibra (emicizumab), a bispecific monoclonal antibody for the treatment of haemophilia A.

On February 18, 2019 Xspray Pharma AB reported the results of a clinical Phase I pilot study with its HyNap-Sora drug candidate (Press release, Xspray, FEB 18, 2019, View Source [SID1234649548]). The study examined HyNap-Sora’s bioavailability compared to the sorafenib cancer drug, currently marketed as Nexavar for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Both investigated HyNap compositions demonstrated significantly increased bioavailability. The variability between subjects in AUC and Cmax was reduced to half compared to Nexavar for one of the HyNap-Sora formulations.
In the completed Phase I clinical trial in 14 healthy subjects, bioavailability of two different formulations of HyNap-Sora was assessed in comparison with Nexavar. The results are positive and the study achieved its primary purpose to show increased bioavailability compared to the originator product. In addition, and as shown in earlier studies with Xspray’s lead product candidate, HyNap-Dasa, the study also showed reduced between subject variability.

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"Sorafenib has a very different pharmacokinetic profile than our product candidates based on nilotinib and dasatinib. Therefore, I’m very pleased that we achieved the primary purpose of this study with sorafenib which enables continuation of the development program. It confirms and strengthens our belief that HyNap formulations of PKIs have the potential to improve both present and upcoming products with poor solubility, improving efficacy and safety enhancing patients’ quality of life during this type of therapy," says Per Andersson, CEO of Xspray.

The clinical results in summary:

• The HyNap formulations were administered at half the dose compared to Nexavar to account for expected increase in bioavailability

• Area under the curve (AUC) was approximately 80 % for the HyNap-Sora formulations compared to Nexavar, indicating that the bioavailability of Sorafenib from HyNap-Sora was 1.6-fold higher

• The maximum concentration of Sorafenib in plasma (Cmax) was approximately 95 % compared to Nexavar.

• The variability between subjects in AUC and Cmax was reduced to half compared to Nexavar for one of the HyNap-Sora formulations.

Sorafenib is a compound with low aqueous solubility and low bioavailability from the sorafenib tablet (Nexavar). The present study demonstrates that the HyNap technology can increase the extent of absorption of sorafenib and reduce between subject variability by improving the solubility.

On February 18, 2019 Oncopeptides AB (Nasdaq Stockholm, ONCO) reported that the Company will release its Year-end Report on 22 February at 8:00 am CET (Press release, Oncopeptides, FEB 18, 2019, View Source [SID1234533530]). The report will be available on the Company’s web site at www.oncopeptides.com.

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The company’s CEO Jakob Lindberg will summarize the financial year 2018 and address questions from investors, analysts and media at 14:00 CET, 22 February.

An audiocast to the presentation will be available at:

View Source

Time for webcast – 14:00 (CET) on 22 February
Dial in number from Sweden: +46856642706
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