On February 15, 2019 CStone Pharmaceuticals ("CStone") reported that the National Medical Products Administration (NMPA) recently approved a Phase III clinical trial in China for its partnered drug candidate avapritinib as a third-line treatment against KIT-driven gastrointestinal stromal tumors (GIST) (Press release, CStone Pharmaceauticals, FEB 15, 2019, View Source [SID1234533356]).

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The study will be part of the global VOYAGER Phase III trial comparing avapritinib against the current standard of care regorafenib in GIST patients who have previously received imatinib and one or two additional tyrosine kinase inhibitors (TKIs). The study is designed to evaluate avapritinib’s safety and efficacy, with progression-free survival as the primary efficacy endpoint.

GIST, which is classed as a rare disease, is a form of sarcoma usually found in the walls of the stomach or the small intestine, and is typically diagnosed between the ages of 50 and 80. The most common forms of GIST are linked to mutations that lead to over-activation of the KIT or PDGFRα tyrosine kinases, resulting in deregulated cell growth. Approximately 90% of GIST cases are linked to mutations of KIT or PDGFRα.

According to data from the NAVIGATOR Phase I clinical trial reported as of October 15, 2018, avapritinib was administered to 109 fourth-line or later GIST patients at doses of 300mg or 400mg.

Within that population, 1 patient achieved complete response and there were 21 partial response (ORR[1] of 20%); stable disease was reported in 72 patients (DCR[2] of 66%); 60% of patients had tumor reductions; and mDOR[3] was 7.3 months.
Of 23 third/fourth-line GIST patients not previously treated with regorafenib, 78% experienced tumor reductions, while 6 achieved partial response (ORR of 26%), 13 achieved stable disease (DCR of 83%), and the mDOR was 10.2 months.
In 56 patients with PDGFRα D842V-driven GIST, tumor reduction was observed in 98% of patients, with 5 complete response and 42 partial response (ORR of 84%). The 12-month DoR was 76.3%, and the 12-month progression free survival rate was 81.3%.
Dr. Frank Jiang, chairman and CEO of CStone, commented: "Avapritinib is a first-in-class precision medicine drug that has been awarded Breakthrough Therapy Designation by the U.S. FDA due to its outstanding clinical efficacy. Current available clinical data already demonstrated the drug’s great potential for advanced GIST patients. CStone is delighted to be able to introduce this product to Chinese patients via our partnership with Blueprint Medicines, and we look forward to generating positive clinical data in China."

CStone’s Chief Medical Officer Dr. Jason Yang noted: "Avapritinib is the only inhibitor of KIT and PDGFRα D842V mutant kinases under clinical development in China at present. We aim to advance the Phase III VOYAGER study for avapritinib rapidly to benefit Chinese patients with KIT-mutated GIST. We are also planning trials of avapritinib for the treatment of earlier lines of GIST and systemic mastocytosis. In addition, we will consider exploring the potential of combination therapy with CStone’s IO backbone assets."

About avapritinib

Avapritinib is an orally available, potent and highly selective inhibitor of KIT and PDGFRα. Preclinical data have shown that avapritinib is active across a broad spectrum of KIT and PDGFRα mutations, including KIT D816V, PDGFRα D842V and KIT exon 17 mutations, for which there are limited or no effective treatment options. Blueprint Medicines is initially developing avapritinib, an investigational medicine, as a treatment for patients with advanced GIST and advanced systemic mastocytosis (ASM).

In June 2017, avapritinib received Breakthrough Therapy from the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation. Previously, the FDA awarded avapritinib orphan drug and fast-track designation. In addition, the molecule has also been granted orphan drug status by the European Commission.

At the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting, data from the Phase I EXPLORER clinical trial was published showing that avapritinib produced sustained clinical response in patients with ASM, and the therapeutic effect was found to deepen over time regardless of disease subtype, previous treatment, or initial dose.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of avapritinib and certain other drug candidates in Greater China.

On February 15, 2019 Nektar Therapeutics (Nasdaq: NKTR) reported a presentation of new clinical data for bempegaldesleukin1 (NKTR-214) in combination with nivolumab in patients with first-line (1L) advanced or metastatic urothelial carcinoma at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium (GU) in San Francisco, CA (Press release, Nektar Therapeutics, FEB 15, 2019, View Source [SID1234533355]).

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The preliminary results from patients enrolled in the 1L urothelial cancer cohort in the ongoing PIVOT-02 Phase 1/2 study were shared in a poster presentation today titled, "NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02" by Arlene O. Siefker-Radtke, M.D., Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center and Clinical Co-Leader of the Bladder Cancer SPORE Executive Committee.

"Preliminary data from the ongoing PIVOT-02 trial in metastatic urothelial cancer patients demonstrated important response rates, including complete responses, in patients who were cisplatin-ineligible or refused standard of care," said Mary Tagliaferri, M.D., Chief Medical Officer of Nektar Therapeutics. "These responses were observed regardless of baseline PD-L1 expression and no relapses occurred. In this cohort of Stage IV bladder cancer patients with a median age of 70, the combination therapy was generally well tolerated with no Grade 4 or 5 adverse events reported. Of note, our translational research demonstrated that in patients with the highest unmet medical need – those whose tumors did not express PD-L1 at their baseline scan – treatment with the combination resulted in 70 percent of patients converting to PD-L1 positive expressors. These data support our development strategy in this tumor setting, including the Phase 2 PIVOT-10 study underway in cisplatin-ineligible urothelial cancer patients with low PD-L1 tumor expression."

Highlights from the ASCO (Free ASCO Whitepaper)-GU presentation in 1L metastatic urothelial carcinoma patients include:

Clinical Efficacy
Response measured per RECIST 1.1 for per protocol efficacy-evaluable patients treated at the recommended Phase 2 dose (RP2D) and with ≥1 post-treatment scan as of December 3, 20182:

Best overall response rate (ORR) was 48% (13/27) in efficacy-evaluable patients, with a 19% (5/27) complete response (CR) rate.3
ORR by immune-related RECIST (irRECIST) was 52% (14/27); ORR in patients with visceral non-nodal metastases was 53% (8/15).
ORR in patients that refused standard of care was 55% (6/11); in cisplatin-ineligible patients ORR was 44% (7/16).
Disease control rate (DCR) was 70% (defined as CR + partial response (PR) + stable disease (SD)).
Median percent reduction in target lesions from baseline in all 27 efficacy-evaluable patients was 32%.
Median percent reduction in target lesions from baseline in all 13 responders was 78%.
Median time to response was 2.0 months.
In patients with RECIST response, no patients discontinued due to relapse.
Amongst the 23 patients with known pre-treatment programmed death-ligand 1 (PD-L1) status, ORR in PD-L1 negative patients was 45% (5/11) and in PD-L1 positive patients was 50% (6/12).
Clinical Safety

Treatment was generally well tolerated and the most common (>15%) treatment-related adverse events (TRAEs) were flu-like symptoms4 (71%), fatigue (56%), rash (46%) and pruritus (32%), decreased appetite (27%) and nausea (22%).
A total of 6/41 (15%) of patients experienced a Grade 3 TRAE, with 4 patients discontinuing due to a TRAE.
No patients experienced a Grade 4/5 TRAE.
Biomarkers and Mechanism of Action

70% (7/10) of patients who were PD-L1 negative at baseline converted to PD-L1 positive by Week 3.
All patients who were initially PD-L1 positive at baseline remained PD-L1 positive.
RECIST responses observed were independent of baseline PD-L1 status and CD8+ T cell infiltrate.
A copy of Dr. Siefker-Radtke’s poster presentation of PIVOT-02 data is available on Nektar’s corporate website at View Source
The PIVOT-10 study evaluating bempegaldesleukin in combination with nivolumab in 1L locally advanced or metastatic urothelial carcinoma cisplatin-ineligible patients with low PD-L1 expression is currently recruiting patients (NCT03785925).

Analyst Call with Urothelial Cancer Specialist
Nektar will webcast an analyst conference call featuring Dr. Siefker-Radtke today, Friday, February 15, 2019 at 2:00 p.m. Pacific Time. The conference call may be accessed by dialing 877-881-2183 (toll-free) or 970-315-0453 (international) with the conference call passcode 9688945. The webcast and slides for the conference call can be accessed through a link posted on the Investors section of the Nektar website at View Source The webcast of the conference call will be available for replay through March 15, 2019.

About Bempegaldesleukin (NKTR-214)
Bempegaldesleukin is an investigational, first-in-class, CD-122-preferential IL-2 pathway agonist designed to provide rapid activation and proliferation of cancer-killing immune cells, known as CD8+ effector T cells and natural killer (NK) cells, without over activating the immune system. Bempegaldesleukin stimulates these cancer-killing immune cells in the body by targeting CD122 specific receptors found on the surface of these immune cells. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these effector T cells.5 In clinical and preclinical studies, treatment with bempegaldesleukin resulted in expansion of these cells and mobilization into the tumor micro-environment.6,7 Bempegaldesleukin has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

On February 15, 2019 Rainier Therapeutics, Inc., a privately-held clinical stage drug development company, reported the presentation of preliminary data from its Phase 2 trial of vofatamab, a fibroblast-growth-factor-receptor 3 (FGFR3) targeted antibody, at the 2019 ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium in San Francisco (Press release, Rainier Therapeutics, FEB 15, 2019, View Source [SID1234533354]). The study, FIERCE-21, is evaluating vofatamab in combination with docetaxel and vofatamab as monotherapy in patients with locally advanced or metastatic bladder cancer with FGFR3 mutation/fusions who have relapsed after, or are refractory to, at least one prior line of chemotherapy.

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"There are limited and, in some cases, no approved treatment options for patients with advanced metastatic bladder cancer who have failed chemotherapy and, if indicated, checkpoint inhibitors. FGFR3 inhibitors have the potential to revolutionize the clinical management of metastatic bladder cancer in biomarker-selected and potentially poor checkpoint responding patients," said Andrea Necchi, M.D., Urologic Oncology, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. "Vofatamab has the potential to be a differentiated FGFR3 inhibitor with a tolerability and activity profile that may provide a much-needed therapeutic option to patients."

"We are pleased with this preliminary data in the FIERCE-21 trial that indicate vofatamab is providing clinical benefit in a group of patients at a very advanced stage of disease. Vofatamab in combination with docetaxel is showing a benefit to patients in the trial that has surpassed historical results of single-agent docetaxel in other trials. In addition, single agent activity was also observed with vofatamab in a heavily pretreated patient group," said Steve Abella, M.D., Chief Medical Officer, Rainier Therapeutics. "We look forward to reporting further data later this year and believe the data reported today supports moving forward with the planning of a pivotal trial of vofatamab in combination with docetaxel intended to improve treatment outcomes for this patient population."

Details from the oral abstract presentation: "FIERCE-21: Phase II study of vofatamab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC)" (abstract #409) are as follows:

FIERCE-21 Study Design/Prior Treatments

A total of 42 patients with bladder cancer previously treated with one or more prior lines of chemotherapy and, if available, a checkpoint inhibitor, were enrolled in two groups of 21. One study group received a combination of docetaxel (75mg/m2) followed by an infusion of vofatamab (25mg/kg). The other group received vofatamab (25mg/kg) as monotherapy. Study treatment was administered on day one of each 21-day cycle.
In the combination group receiving vofatamab and docetaxel, 57 percent of patients had received a median of two or more prior lines of therapy (range 1-4) and 71 percent of patients in the vofatamab monotherapy group had received a median of three or more prior therapies (range 1-7). More than 50 percent of patients in both arms had received prior checkpoint therapy treatment.
The primary endpoints of the study are safety and efficacy as measured by objective response rate (ORR), progression free survival (PFS) and overall survival (OS).
Preliminary FIERCE-21 Results

Of 21 evaluable patients who received the combination therapy of vofatamab plus docetaxel:
A preliminary disease control rate (DCR) of 27 percent (at 180 days) was reported.
Fifty-seven percent of these patients remain on study and 43 percent remain on treatment at the time of the data analysis.
Patients continue to be followed for ORR, PFS and OS.
Of 21 evaluable patients in the vofatamab monotherapy cohort:
A median PFS of 4 months was reported in fourth line patients
A preliminary DCR of 21 percent (at 180 days) was reported.
Fifty-seven percent of these patients remain on study and 19 percent remain on treatment at the time of the data analysis.
Patients continue to be followed for ORR and OS.
In both groups, treatment was generally well-tolerated, with the most common vofatamab-related adverse events being asthenia, diarrhea, decreased appetite and rash; all were Grade 1 or 2. There were few dose interruptions and discontinuations. No cases of severe skin/nail toxicity, hyperphosphatemia, or ocular events were reported.
The full poster can be viewed on the Rainier Therapeutics website at: View Source

About Bladder Cancer

Bladder cancer is the fifth most common cancer in each of the United States and Europe. Over the past 30 years, the only novel therapies approved in the United States for bladder cancer patients have been checkpoint inhibitors for patients who failed first line chemotherapies. Several immune check point inhibitors targeting the programmed cell death-1 or PD-1 or programmed cell death ligand-1, or PDL-1 pathway, have been approved by the FDA for use in bladder cancer patients who have failed platinum-based chemotherapy. Despite these developments, objective response rates in clinical trials with checkpoint inhibitors have been between 15% and 21%, when used as salvage therapy, with median overall survival reported between 8-10 months and limited benefit in progression-free survival, leaving patients with bladder cancer with a high unmet need for effective and tolerable therapies.

In addition, studies have shown that bladder cancer tumors with genetic alterations in FGFR3 have inappropriate FGFR3 signaling driven by these genetic alterations or overexpression and are implicated in the development of bladder cancer. Tolerable and effective therapies for these patients in advanced and metastatic bladder cancer are needed.

About Vofatamab

Vofatamab is an antibody specifically targeted against the fibroblast growth factor receptor 3 (FGFR3), a known driver of bladder and potentially other FGFR-driven cancers. Vofatamab is the most advanced targeted biologic specific for FGFR3 known by Rainier Therapeutics to be in clinical development.

In addition to FIERCE-21, Rainier Therapeutics has an ongoing Phase 2 clinical trial, FIERCE-22. FIERCE-22 is evaluating vofatamab in combination with pembrolizumab, an immune checkpoint inhibitor, to determine safety, tolerability and efficacy in the treatment of patients with locally advanced or metastatic bladder cancer, who have progressed following platinum-based chemotherapy and who have not received prior immune checkpoint inhibitor therapy. For additional information on FIERCE-21, please visit www.clinicaltrials.gov NCT02401542 and for more information on FIERCE-22, please visit www.clinicaltrials.gov (NCT03123055).

Rainier Therapeutics also plans to study vofatamab in non-muscle invasive bladder cancer (NMIBC) – the FIERCE-23 trial. This trial is planned to start in 2019.

On February 15, 2019 Allergan plc (NYSE: AGN), a leading global biopharmaceutical company, reported that Chairman and CEO Brent Saunders will participate in a fireside chat at the 8th Annual SVB Leerink Global Healthcare Conference in New York, NY (Press release, Allergan, FEB 15, 2019, View Source [SID1234533353]). The presentation will begin at 9:30 a.m. Eastern Time on Wednesday, February 27, 2019.

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The presentation will be webcast live and can be accessed on Allergan’s Investor Relations website at View Source;. The webcast can also be accessed through the following URL: View Source;

An archived version will be available within approximately one hour of the live presentation and can be accessed at the same location for 90 days.

On February 15, 2019 Phio Pharmaceuticals Corp. (Nasdaq: PHIO) reported that Gerrit Dispersyn, Dr. Med. Sc., currently President and COO, has been appointed by the Board of Directors as the Company’s new CEO, effective March 1 (Press release, Phio Pharmaceuticals, FEB 15, 2019, View Source [SID1234533352]). He will succeed Geert Cauwenbergh, Dr. Med. Sc., who will retire as CEO of the Company. Dr. Cauwenbergh will be available to support the transition and will remain as a member of the Board of Directors.

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Dr. Cauwenbergh was elected President and CEO of Phio Pharmaceuticals when the business was spun-off from its parent company, then known as Galena Biopharma, Inc., in April 2012. He was also elected to serve as a member of the Board of Directors. During his tenure, he has helped guide Phio Pharmaceuticals from a platform company with products in dermatology and ophthalmology to a company developing groundbreaking immuno-oncology therapeutics.

Robert Bitterman, Chairman of the Board, said, "We are very grateful for Dr. Cauwenbergh’s past leadership, energy and vision and we are pleased he will remain a member of the Board of Directors to continue to offer guidance based on his extensive experience in the health care sector."

Prior to his current role, Dr. Dispersyn was elected Chief Development Officer of the Company in April 2017. Over the past two years, Dr. Dispersyn has provided exemplary leadership to the research and development team at Phio Pharmaceuticals. He has been a catalyst in Phio Pharmaceuticals’ transformation into an immuno-oncology therapeutics company and has been instrumental in finalizing the clinical work in its dermatology and ophthalmology programs, with the closure and report-out of various successful clinical studies.

Dr. Cauwenbergh commented, "I am very happy that Dr. Dispersyn has accepted this new responsibility as CEO of Phio Pharmaceuticals. Since joining the Company, Gerrit has demonstrated leadership, team-building capability and an ability to relate to our shareholders and the rest of our Board. As a continuing member of the Board of Directors, I look forward to working with Dr. Dispersyn to help him build our Company into one of the leaders in immuno-oncology. Our recent financing provides cash into the third quarter of 2020 and creates a stable foundation for Dr. Dispersyn to carry out Phio’s mission."

Dr. Dispersyn said, "I’m extremely excited and feel privileged to be appointed the next CEO of Phio Pharmaceuticals. I want to thank the Board of Directors for their vote of confidence in appointing me to this role. I look forward to advancing Dr. Cauwenbergh’s vision to develop a very promising next generation of immuno-oncology therapeutics based on our self-delivering RNAi platform."