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Mirati Therapeutics Presents Positive Preliminary Data From On-Going Clinical Trials Of Sitravatinib In Non-Small Cell Lung Cancer

On September 14, 2017 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical stage targeted oncology biotechnology company, reported that positive preliminary data from two ongoing clinical trials of sitravatinib in non-small cell lung cancer (NSCLC) will be presented Friday, September 15th, 2017 at the IASLC 2017 Chicago Multidisciplinary Symposium in Thoracic Oncology (learn more at www.iaslc.org) (Filing, 8-K, Mirati, SEP 14, 2017, View Source [SID1234520523]).

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Initial safety data and efficacy information will be presented from the ongoing Phase 2 study of sitravatinib in combination with nivolumab (OPDIVO) as a treatment for NSCLC patients with cancer progression following previous treatment with a checkpoint inhibitor. Additionally, a case study will be presented, documenting an objective response of a NSCLC patient with a CBL inactivating mutation. This was the first evaluable NSCLC patient harboring a CBL mutation treated in the ongoing Phase 1b study of sitravatinib as a single agent. In both clinical studies, sitravatinib alone and in combination with nivolumab was well tolerated with a manageable safety profile.

"For the majority of NSCLC patients who progress following checkpoint therapy, there is a need for new therapeutic options," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer. "We are evaluating sitravatinib in combination with nivolumab in this checkpoint resistant population and are very encouraged by the responses observed, since responses would not be expected from re-treatment with a checkpoint inhibitor alone."

"In addition, in the single agent trial, the objective partial response is the first example of clinical activity in a patient with a CBL mutation. Inactivating mutations in CBL occur in approximately 1.5% of NSCLC patients and currently represent an unmet medical need."

Sitravatinib and Nivolumab Combination Study

Poster Presentation: Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitor Therapy

Clinical Trial: NCT02954991, A Phase 2 study evaluating the tolerability and clinical activity of sitravatinib in combination with nivolumab in patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with checkpoint inhibitor therapy.

Presenter: Ticiana A. Leal, M.D.

This presentation provides a preliminary safety and efficacy update of the Phase 2 trial of sitravatinib in combination with nivolumab in NSCLC patients who have experienced progression of disease on or after treatment with checkpoint inhibitor therapy. In the efficacy data presented, 3 patients experienced a confirmed partial response out of 11 evaluable patients. Early safety data demonstrated an acceptable profile and manageable adverse events. Based on the data presented, the pre-defined criteria have been met for expansion from stage 1 to stage 2, which will enroll a combined total of 34 patients.

This study is designed to assess the potential of sitravatinib to inhibit several important immunosuppressive pathways that may be important in overcoming resistance to checkpoint inhibitor therapy.

Sitravatinib Single Agent Study

Poster Presentation: CBL Mutations as Potential Mediators of EGFR TKI Resistance Effectively Treated with Sitravatinib

Clinical Trial: NCT02219711, A Phase 1b study evaluating safety, PK, metabolism, PD and clinical activity of Sitravatinib in patients with advanced solid tumor malignancies

Presenter: Lyudmila A. Bazhenova. M.D.

The poster describes a case study of a NSCLC patient with a CBL mutation treated with sitravatinib. CBL loss of function mutations result in the increased activation of multiple oncogenic receptor tyrosine kinases (RTKs) in tumors, including PDGFRA, VEGFR2, KIT, Axl, and Mer. In preclinical models, sitravatinib has demonstrated the ability to potently inhibit these RTKs and induce tumor regression in NSCLC models harboring inactivating CBL mutations. In the case study presented, a heavily pre-treated NSCLC patient harboring an inactivating CBL mutation was treated with sitravatinib and demonstrated a confirmed partial response (PR) with a maximum decrease of 77% in target lesions. Early safety data is also provided; sitravatinib was well tolerated and the side effects observed were manageable. This trial is on-going and actively recruiting patients harboring CBL and other genetic mutations.

CBL mutations are present in 1.5% of NSCLC, 3.5% of melanoma, and 2% of cancers of unknown origin.

Both posters will be available on the Company’s website on the sitravatinib page, located in the Pipeline section, at: View Source

About Sitravatinib

Sitravatinib (MGCD-0516) is a spectrum-selective kinase inhibitor which potently inhibits receptor tyrosine kinases (RTKs) including RET, TAM family receptors (TYRO3, Axl, Mer), and split family receptors (VEGFR2, KIT). Sitravatinib is being evaluated as a single agent in a Phase 1b expansion trial enrolling patients that harbor RET, CHR4Q12, and CBL genetic mutations in NSCLC and other tumors.
As an immuno-oncology agent, sitravatinib is being tested in combination with BMS’ anti PD-1 checkpoint inhibitor nivolumab (OPDIVO) in NSCLC patients who have progressed after prior

treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family receptors may help overcome resistance to checkpoint inhibitor therapy through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells and myeloid-derived suppressor cells and increasing antigen presentation capacity of dendritic cells in the tumor microenvironment.

Janssen Submits Supplemental New Drug Application to U.S. FDA for ZYTIGAÂ® (abiraterone acetate) to Treat Men with Earlier Stages of Metastatic Prostate Cancer

On September 14, 2017 – Janssen Biotech, Inc. reported the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) seeking to expand the indication of ZYTIGA in combination with prednisone and ADT to include treatment of patients with high-risk metastatic hormone naïve prostate cancer (HNPC) or newly diagnosed, high-risk metastatic hormone sensitive prostate cancer (HSPC). The filing is based on Phase 3 data from the pivotal LATITUDE clinical trial, which found that in newly diagnosed patients with high-risk mHNPC, ZYTIGA in combination with prednisone and ADT significantly increased overall survival (OS) and radiographic progression-free survival (rPFS), compared to placebo plus ADT.

"We are excited about the promising results from the LATITUDE study which suggest that ZYTIGA can benefit men with newly diagnosed, high-risk metastatic prostate cancer, rather than waiting for them to become resistant to conventional hormonal treatments," said Craig Tendler, M.D., Vice President, Late-Stage Development and Global Medical Affairs for Oncology, Hematology and Supportive Care at Janssen. "We look forward to working with the FDA on the review of this application to provide a new therapeutic option for men with newly diagnosed, high-risk metastatic prostate cancer."

LATITUDE was a multinational, multicenter, randomized, double-blind, placebo-controlled clinical trial which examined the use of ZYTIGA 1,000 mg once daily in combination with prednisone 5 mg once daily and ADT, compared to placebo plus ADT (N=1,199) in patients with newly diagnosed, high-risk mHNPC. The study was presented at the plenary session of the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, and simultaneously published in the New England Journal of Medicine.Additional data from the study were presented at the 2017 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Conference on September 8 in Madrid, Spain.1 2
The LATITUDE study showed ZYTIGA in combination with prednisone and ADT reduced the risk of death by 38 percent compared to placebo plus ADT (median OS not reached vs. 34.7 months, respectively; hazard ratio: 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001) in patients with mHNPC. Additional study results found patients with mHSPC who received ZYTIGA in combination with prednisone and ADT had a 53 percent lower risk of radiographic progression or death, compared to placebo plus ADT (median rPFS 33.0 months vs. 14.8 months, respectively, HR: 0.47; 95% CI, 0.39 to 0.55; P<0.001). Concerning the secondary end points, ZYTIGA in combination with prednisone and ADT, reduced the risk of pain progression by 31 percent (HR=0.695; 95% CI: 0.583, 0.829; P<0.0001) and skeletal-related events by 30 percent (HR=0.703; 95% CI: 0.539, 0.916; p=0.0086) and reduced the risk of needing to start chemotherapy by 56 percent (HR=0.443; 95% CI: 0.349, 0.561, P<0.0001) compared to placebo plus ADT.
Additional data, presented at ESMO (Free ESMO Whitepaper), demonstrated clinically meaningful and statistically significant improvements in patient reported outcomes (PRO) in patients with high-risk mHNPC who received ZYTIGA in combination with prednisone and ADT compared to placebo plus ADT alone. ZYTIGA in combination with prednisone and ADT, significantly delayed the time to health-related quality of life degradation by 15 percent (HR=0.853; 0.736, 0.989; p=0.0322) and significantly delayed the time to worst fatigue intensity progression by 35 percent (HR=0.652; 95% CI: 0.527, 0.805; P=0.0001) for patients with mHNPC.
Overall, the safety profile of ZYTIGA in combination with prednisone and ADT, was similar to prior studies in patients with metastatic castration resistant prostate cancer (mCRPC). Grade 3/4 events reported in ≥5 percent of patients were hypertension (20%/0% vs. 10%/0.2%), hypokalemia (10%/0.8% vs. 1%/0.2%) and increase in alanine aminotransferase (5%/0.3% vs. 1%/0%) in ZYTIGA in combination with prednisone and ADT vs. placebo plus ADT groups, respectively.

Since its first approval in the U.S. in 2011, ZYTIGA has been approved in combination with prednisone or prednisolone in 105 countries. In April 2017, Janssen submitted a Type II variation application to the European Medicines Agency (EMA), seeking to expand the existing marketing authorization for ZYTIGA in combination with prednisone or prednisolone to include the treatment of men with mHNPC. Similar submissions have been made in Japan, Canada, Mexico, Brazil, Switzerland, Taiwan, Singapore, and the Philippines. If approved, these submissions will broaden the use of ZYTIGA in combination with prednisone or prednisolone to include an earlier stage of prostate cancer than its current indications.

Kancera and Recipharm collaborate to manufacture clinical trial supply

On September 14, 2017 Kancera pharmaceutical reported that KAND567 works by blocking the Fractalkine system and has been shown in preclinical disease models to effectively counteract the onset of autoimmune disorders, as well as neuritis and pain in connection with chemotherapy against cancer (Press release, Kancera, SEP 14, 2017, View Source [SID1234520517]). In future clinical studies, Kancera intends to treat patients with the pharmaceutical candidate KAND567 filled into capsules and taken orally.

As part of the collaboration, Recipharm will develop the preparation that is required for effective release of KAND567 from the capsules, as well as manufacturing the pharmaceutical product. The work will be performed at Recipharm’s development facility in Solna.

Thomas Olin, CEO of Kancera said: "The decision to commence development of capsules for an active dosage of KAND567 shows that Kancera has reached an important milestone in the Fractalkine project. We are delighted to now be collaborating with Recipharm to produce the pharmaceutical product that will be used to study how KAND567 can help patients."

Torkel Gren, General Manager at Recipharm in Solna commented: "We are happy to be able to contribute to the development of a new drug with the potential to be of great medical value. We have extensive experience in developing drugs for clinical trials as well as commercial manufacture and this will be very valuable in the collaboration with Kancera."

Bayer receives FDA approval for Copanlisib in adults with relapsed follicular lymphoma after two prior systemic therapies (for specialized target groups only)

On September 14, 2017 Bayer reported that the U.S. Food and Drug Administration (FDA) has approved copanlisib under the brand name Aliqopa 60 mg vial for injection for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies (Press release, Bayer, SEP 14, 2017, View Source [SID1234520516]). Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Copanlisib is a novel intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with inhibitory activity predominantly against the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. The FDA granted approval under the accelerated approval pathway based on data from the open-label, single-arm Phase II CHRONOS-1 [NCT01660451] trial investigating copanlisib in 104 adult patients with follicular B-cell non-Hodgkin’s lymphoma (NHL) who had relapsed disease following at least two prior systemic therapies.

"The U.S. approval of copanlisib in follicular lymphoma is the first of many milestones we look forward to at Bayer across several new promising compounds in our oncology pipeline," said Robert LaCaze, Executive Vice President and Head of the Oncology Strategic Business Unit at Bayer. "We are pleased that the FDA has recognized the promising results of the CHRONOS-1 trial and look forward to offering this important new treatment option to patients with lymphoma, who currently have a high unmet need for effective therapies."

Follicular lymphoma (FL) is the most common subtype of indolent, or slow-growing, non-Hodgkin’s lymphoma (NHL). Response rates and duration of response decline with each line of therapy, underscoring the need for patients whose disease has already progressed.

Developed by Bayer, copanlisib is the only approved PI3K inhibitor with inhibitory activity predominantly against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. It is also the only one to be administered intravenously on an intermittent schedule. Copanlisib will be available in the U.S. market immediately.

The New Drug Application for copanlisib received priority review, which is reserved for medicines that would provide significant improvements in the safety or effectiveness of the treatment of serious conditions. The product was approved under FDA regulations 21 CFR Part 314 Subpart H (accelerated approval). The FDA had previously granted copanlisib fast track designation in FL as well as Orphan Drug designation for the treatment of patients with FL and for the treatment of splenic, nodal, and extranodal subtypes of marginal zone lymphoma.

Efficacy and Safety Data Supporting Copanlisib Approval

The Phase II CHRONOS-1 (ClinicalTrials.gov Identifier: NCT01660451) trial included 104 subjects with follicular B-cell non-Hodgkin’s lymphoma (NHL) who had relapsed disease following at least two prior systemic therapies. In the trial, copanlisib achieved an overall response rate (ORR) of 59% [n=104 (95% CI 49, 68)], with 14% of patients achieving a complete response, and a median duration of response of 12.2 months (0+, 22.6). Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed ORR.

Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%), and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in copanlisib-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%). The safety data reflect exposure to copanlisib in 168 adults with follicular lymphoma and other hematologic malignancies treated with copanlisb 60 mg or 0.8 mg/kg equivalent in clinical trials. Patients with small lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom’s macroglobulinemia and marginal zone lymphoma were also enrolled in the study and included in the safety analysis.

About Follicular Lymphoma (FL)
Follicular lymphoma (FL) is the most common histological subtype of indolent, or slow growing, non-Hodgkin’s lymphoma (NHL) that accounts for 22 percent of all newly diagnosed NHL cases worldwide. NHL is the most common hematologic malignancy and the tenth most common cancer worldwide, with nearly 386,000 new cases diagnosed in 2012.

About Copanlisib (Aliqopa)
Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. The PI3K pathway is involved in cell growth, survival and metabolism, and its dysregulation plays an important role in follicular lymphoma. Copanlisib is administered as a 1-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule. Treatment should be continued until disease progression or unacceptable toxicity.

The broad clinical development program for copanlisib also includes ongoing Phase III studies in indolent NHL (iNHL) patients who have relapsed or are refractory to prior therapies. The CHRONOS-3 Phase III study is evaluating copanlisib in combination with rituximab in relapsed iNHL and the CHRONOS-4 Phase III study is evaluating copanlisib in combination with standard immunochemotherapy in relapsed iNHL. More information about these trials can be found at www.clinicaltrials.gov.

Copanlisib is currently not approved by the European Medicines Agency (EMA) or other authorities outside of the U.S.

FDA Approves Amgen And Allergan’s MVASIâ„¢ (bevacizumab-awwb) For The Treatment Of Five Types Of Cancer

On September 14, 2017 Amgen (NASDAQ: AMGN) and Allergan plc. (NYSE: AGN) reported that the U.S. Food and Drug Administration (FDA) has approved MVASI (bevacizumab-awwb) for all eligible indications of the reference product, Avastin (bevacizumab) (Press release, Amgen, SEP 14, 2017, View Source [SID1234520515]). MVASI is the first anti-cancer biosimilar, as well as the first bevacizumab biosimilar, approved by the FDA. MVASI is approved for the treatment of five types of cancer, including in combination with chemotherapy for non-squamous non-small cell lung cancer (NSCLC), in combination with chemotherapy for metastatic colorectal cancer (mCRC), glioblastoma, metastatic renal cell carcinoma in combination with interferon alfa and in combination with chemotherapy for persistent, recurrent, or metastatic carcinoma of the cervix.

"The approval of MVASI marks a significant milestone for healthcare practitioners and patients as the first anti-cancer biosimilar approved in the United States," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "With decades of experience in oncology and biologics, Amgen continues to expand its biosimilar and oncology portfolios, and MVASI has the potential to advance access to high-quality, targeted cancer therapy."

Amgen is committed to developing high-quality biosimilars with a robust analytic and clinical package. Approval is based on the totality of evidence which includes structure, function, toxicity, pharmacokinetics, pharmacodynamics, immunogenicity, clinical safety and efficacy.1 The approval of MVASI was based on a comprehensive data package that demonstrated MVASI and bevacizumab are highly similar, with no clinically meaningful differences in terms of the efficacy, safety and immunogenicity between the products. Clinical studies included results from a Phase 3 trial in patients with NSCLC.

"MVASI is the first product from our collaboration with Amgen to be approved by the FDA and underscores our joint commitment to bring cancer biosimilars to market to help patients," said David Nicholson, chief research and development officer at Allergan. "We are committed to developing safe and effective therapies in critical disease areas, and MVASI is leading the way for additional oncology biosimilars from Amgen and Allergan."

Amgen and Allergan’s bevacizumab biosimilar is also undergoing review by the European Medicines Agency, following a Marketing Authorization Application submitted in December 2016. The companies are collaborating on the development and commercialization of four oncology biosimilars. Amgen has a total of 10 biosimilars in its portfolio, two of which have been approved by the FDA including MVASI.

About MVASI (bevacizumab-awwb) in the U.S.

MVASI is a biosimilar to bevacizumab, a recombinant immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to vascular endothelial growth factor (VEGF) and inhibits the interaction of VEGF with its receptors, VEGF receptor-1 and VEGF receptor-2, thus inhibiting establishment of new blood vessels necessary for the maintenance and growth of solid tumors.

MVASI is indicated for the treatment of mCRC, with intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment.

MVASI is indicated for the treatment of mCRC, with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen.
MVASI is not indicated for adjuvant treatment of colon cancer.

MVASI is indicated for the treatment of NSCLC, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.

MVASI is indicated for the treatment of glioblastoma, as a single agent for adult patients with progressive disease following prior therapy.
The effectiveness of bevacizumab products in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with bevacizumab products.

MVASI is indicated for the treatment of metastatic renal cell carcinoma with interferon alfa.

MVASI is indicated for the treatment of cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic disease.

MVASI U.S. Important Safety Information

Boxed WARNINGS

Gastrointestinal (GI) Perforations

The incidence of gastrointestinal perforation, some fatal, in bevacizumab product-treated patients ranges from 0.3-3.2%. Fatal outcome was reported in <1% of bevacizumab-treated patients. Discontinue MVASI in patients with gastrointestinal perforation.

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab product-treated patients. Discontinue MVASI in patients with wound dehiscence. The appropriate interval between termination of bevacizumab products and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate MVASI for at least 28 days prior to elective surgery. Do not initiate MVASI for at least 28 days after surgery and until the surgical wound is fully healed.

Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving bevacizumab products. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 6.9%. Do not administer MVASI to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue MVASI in patients with serious hemorrhage (ie, requiring medical intervention).

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI fistulae (up to 2% in metastatic colorectal cancer)
Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial)
Arterial thromboembolic events (grade ≥3, 2.6%)
Proteinuria (nephrotic syndrome, <1%)
Additional serious adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
Venous thromboembolism (grade 3-4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with chemotherapy and bevacizumab product
Hypertension (grade 3-4, 5%-18%)
Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
Infusion reactions with the first dose of bevacizumab product-treated patients were uncommon (<3%), and severe reactions occurred in 0.2% of patients
Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with MVASI
Pregnancy warning

Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
Advise female patients that MVASI may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with MVASI and for 6 months after the last dose of MVASI
Advise nursing women that breastfeeding is not recommended during treatment with MVASI
MVASI may impair fertility
Most Common Adverse Events

Across indications, the most common adverse reactions observed in bevacizumab product-treated patients at a rate of >10% and at least twice the control arm rate were: epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab product was discontinued in 8.4% to 21% of patients because of adverse reactions.
Please see full Prescribing Information, including Boxed WARNINGS, at www.Amgen.com.