On September 29, 2016 AstraZeneca today reported that the US Food and Drug Administration (FDA) has approved a blood-based companion diagnostic for TAGRISSO (osimertinib) (Press release, AstraZeneca, SEP 29, 2016, View Source [SID:SID1234515502]). The companion diagnostic for TAGRISSO is the only FDA-approved and clinically validated companion diagnostic test that uses either tissue or a blood sample to confirm the presence of a T790M mutation in patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), who have progressed on or after an EGFR tyrosine kinase inhibitor (TKI) medicine.

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"Blood-based testing has the potential to rapidly identify patients eligible for targeted therapy, who may not be eligible for biopsy. Availability of this blood-based test may help aid treatment decisions"

The approval provides a new, non-invasive option to identify patients with metastatic EGFR T790M mutation-positive NSCLC, ensuring that those patients who may not be suitable for biopsy procedures have an opportunity to be tested. Blood-based testing for the presence of the mutation is recommended only when a tumor biopsy cannot be obtained. Patients who test negative for the T790M mutation with the blood-based test, and their physicians, should re-evaluate the feasibility of tissue-based testing to confirm the presence of the EGFR T790M mutation.

The companion diagnostic, cobas EGFR Mutation Test v2, was developed by Roche Molecular Systems. The test enables identification of patients who have the T790M mutation at disease progression, and is initially available through Baystate Health, Carolinas HealthCare System, Laboratory Corporation of America Holdings (LabCorp), and PhenoPath.

"Blood-based testing has the potential to rapidly identify patients eligible for targeted therapy, who may not be eligible for biopsy. Availability of this blood-based test may help aid treatment decisions," said Balazs Halmos, MD, Montefiore Medical Park, Albert Einstein College of Medicine.

"The availability of an FDA-approved, blood-based companion diagnostic is a tremendous step forward for patients with lung cancer in need of a high-quality test that provides results with a rapid turnaround time. This development offers an important option for the identification of the T790M mutation in patients with metastatic EGFR mutation-positive NSCLC who have progressed on an EGFR TKI medicine, for whom a tissue biopsy may not be feasible," said Andrew Coop, Vice President, US Medical Affairs, Oncology, AstraZeneca. "Delivering targeted therapies, such as TAGRISSO, to the right patients at the right time demonstrates our commitment to testing and quality companion diagnostics."

Nearly two-thirds of cases of progression with first-generation EGFR TKIs are related to an acquired EGFR T790M mutation — for which there have been limited treatment options in the past. TAGRISSO is the only FDA-approved targeted medicine for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after an EGFR TKI medicine, and was approved by the FDA in November 2015. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

The TAGRISSO tolerability profile showed that no individual severe grade 3+ adverse events occurred at ≥ 3.5%. The most common adverse events were generally mild to moderate and included diarrhea (42% all grades; 1.0% grade 3/4), rash (41% all grades; 0.5% grade 3/4), dry skin (31% all grades; 0% grade 3/4), and nail toxicity (25% all grades; 0% grade 3/4).

Important Safety Information About TAGRISSO (osimertinib)

There are no contraindications for TAGRISSO.
Interstitial Lung Disease (ILD)/Pneumonitis occurred in 3.3% and were fatal in 0.5% of 813 TAGRISSO patients. Withhold TAGRISSO and promptly investigate for ILD in any patient presenting with worsening of respiratory symptoms indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed
QTc interval prolongation occurred in TAGRISSO patients. Of the 411 patients in two Phase II studies, 0.2% were found to have a QTc greater than 500 msec, and 2.7% had an increase from baseline QTc greater than 60 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life threatening arrhythmia
Cardiomyopathy occurred in 1.4% and were fatal in 0.2% of 813 TAGRISSO patients. Left Ventricular Ejection Fraction (LVEF) decline >10% and a drop to <50% occurred in 2.4% of (9/375) TAGRISSO patients. Assess LVEF before initiation and then at 3 month intervals of treatment. Withhold TAGRISSO if ejection fraction decreases by 10% from pretreatment values and is less than 50%. For symptomatic congestive heart failure or persistent asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during TAGRISSO treatment and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose.
The most common adverse reactions (>20%) observed in TAGRISSO patients were diarrhea (42%), rash (41%), dry skin (31%) and nail toxicity (25%).
TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see accompanying complete Prescribing Information including Patient Information.

On September 29, 2016 Threshold Pharmaceuticals, Inc. (Nasdaq:THLD), a clinical-stage biopharmaceutical company specializing in the development of novel pharmaceutical products and technologies for the treatment of cancer, reported interim data from its two Phase 2 proof-of-concept clinical trials of tarloxotinib and outlined its plans to focus company resources on the more clinically-advanced evofosfamide program as well as an earlier-stage anticancer candidate, TH-3424 (Press release, Threshold Pharmaceuticals, SEP 29, 2016, View Source [SID:SID1234515499]).

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"While the response observed in our squamous cell carcinoma of the skin study with tarloxotinib was encouraging, the overall results from the two studies didn’t meet the activity thresholds required to move forward the molecule forward despite the promising results seen in preclinical translational studies," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "As a result, we are making no further investment in this program. Instead, we plan to build on the efforts of our collaborator, Dr. Michael Curran of The University of Texas MD Anderson Cancer Center, to demonstrate the potential therapeutic value of adding evofosfamide to immune checkpoint inhibition, to continue to pursue discussions with Japanese regulatory authorities regarding potential registration pathways for evofosfamide, and to advance TH-3424 through IND-enabling toxicology studies with the goal of reaching the clinic in 2017. We plan to provide additional operational guidance in the fourth quarter of 2016."

About the Tarloxotinib Program
Tarloxotinib bromide (the International Nonproprietary Name, previously known as TH-4000), or "tarloxotinib", is a prodrug designed to selectively release a covalent (irreversible) EGFR tyrosine kinase inhibitor under severe hypoxia, a feature of many solid tumors. The interim results from the two Phase 2 proof-of-concept clinical trials evaluating the efficacy and safety of tarloxotinib are outlined below. Both clinical trials utilized a Simon two-stage design to ensure adequate efficacy as measured by tumor response to justify continued enrollment. Tumor response was evaluated at baseline and every eight weeks using the Response Evaluation Criteria in Solid Tumors (RECIST). As a result, and taking into consideration the totality of the clinical data with tarloxotinib, enrollment in both Phase 2 clinical trials and further development of tarloxotinib will be discontinued.

Tarloxotinib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS) (TH-CR-602):

In the first stage of the SCCS arm of the trial, a confirmed partial response was observed in 1 of 7 patients. According to the study design, the response rate was sufficient to expand the trial to evaluate additional patients.
However, of the 22 SCCHN patients who were assessed, although 8 achieved stable disease, none achieved a confirmed partial response.


Tarloxotinib in patients with EGFR-mutant, T790M-negative, advanced non-small cell lung cancer (NSCLC) (TH-CR-601):


Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.

About the Evofosfamide Program
Evofosfamide (previously known as TH-302) is an investigational hypoxia-activated prodrug of a bis-alkylating agent that is preferentially activated under severe hypoxic tumor conditions, a feature of many solid tumors. On December 6, 2015, the Company announced the outcomes of two Phase 3 studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide stating that neither study met its primary endpoint. However, the Phase 3 trial (MAESTRO) data demonstrated meaningful improvement in overall survival in a subgroup of 116 patients from Japan, in which the risk of death was reduced by 48 percent for patients on the treatment arm compared to patients on the control arm. In addition, translational data evaluating the role of hypoxia in mediating treatment resistance to cancer immunotherapy conducted at The University of Texas MD Anderson Cancer Center suggests that evofosfamide may play a role in improving the efficacy of "checkpoint antibodies" such as ipilumimab. The Company’s evofosfamide efforts are as follows:

Plan to initiate a Phase I clinical trial with four disease specific expansions of evofosfamide in combination with immune checkpoint antibodies in collaboration with researchers and clinicians at The University of Texas MD Anderson Cancer Center.
Pursue discussions with Japanese regulatory authorities regarding potential registration pathways for evofosfamide for treatment of pancreatic cancer.

About the TH-3424 Program
TH-3424 is the Company’s new, small-molecule drug candidate, discovered at Threshold, being evaluated for the potential treatment of hepatocellular (liver) cancer (HCC), castrate resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemias (T-ALL), and other cancers expressing high levels of aldo-keto reductase family 1 member C3 (AKR1C3). Tumors overexpressing AKR1C3 can be resistant to radiation therapy and chemotherapy. TH-3424 is a prodrug that selectively releases a potent DNA cross-linking agent in the presence of AKR1C3. Preliminary nonclinical toxicology studies suggested an adequate therapeutic index that the Company believes warrants continued development as follows:

Continue to conduct Investigational New Drug (IND)-enabling toxicology studies of TH-3424 in collaboration with Ascenta Pharmaceuticals, Ltd.
A comprehensive summary of TH-3424’s preclinical profile including biochemical, in vitro cell-based, and in vivo animal-based characterization of its pharmacological properties was presented at the 2016 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in April 2016. Copies of the poster are available at the Company’s website at: View Source

As a result of the Company’s focus on evofosfamide and TH-3424, Stewart M. Kroll, the Company’s Chief Operating Officer, and the members of the biostatistics and data management group will be departing the company. Kristen Quigley, Executive Director of Clinical Operations at Threshold, will retain leadership of all clinical trial operational responsibilities. The Company estimates that it will incur a one-time charge in the fourth quarter of approximately $0.9 million related to the reduction in headcount, including severance, benefits and related costs. This charge is expected to include approximately $300,000 of non-cash expense related to the extension of the post-termination exercise period for the outstanding vested stock options for the affected employees.

On September 29, 2016 Hanmi Pharmaceutical Co. Ltd (Hanmi)(KRX: 128940), a Korea-based pharmaceutical company, reported that it has entered into an exclusive development and license agreement with Genentech, a member of the Roche Group, for the development and commercialization of Hanmi’s pan-RAF inhibitor, HM95573 which is currently in Phase I clinical development (Press release, Hanmi, SEP 29, 2016, View Source [SID:SID1234515495]).

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Under the terms of the agreement, Genentech will obtain exclusive worldwide rights, except South Korea, to develop and commercialize HM95573. Hanmi will receive an initial upfront payment of $80 million and is eligible to receive payments based on achievement of certain predetermined development, regulatory and commercialization milestones totaling up to $830 million. In addition, Hanmi is eligible to receive tiered double digit royalties on sales of certain products resulting from the license agreement. Full financial terms have not been disclosed.

The completion of this agreement is subject to US customary closing conditions, including clearance under the Hart-Scott-Rodino Antitrust Improvements Act, which is expected to occur during the fourth quarter of 2016.

"We are pleased to collaborate with Genentech, which has significant expertise in the field of oncology," said Dr. Gwan Sun Lee, CEO/President of Hanmi Pharmaceutical. "We are excited at the potential this license agreement with Genentech will bring to the development of HM95573 and the potential benefit this may offer to cancer patients worldwide".

"This collaboration demonstrates our commitment to bringing the best science in the world to Genentech with the ultimate goal of developing life-changing therapies for people with cancer," said James Sabry, M.D., Ph.D., Senior Vice President and Global Head of Genentech Partnering. "We are excited to partner with Hanmi and leverage their scientific insights to develop novel therapies that target the MAPK pathway."

On September 29, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, and Zai Lab (Shanghai) Co., Ltd., a biopharmaceutical company based in China, reported a collaboration to support the development and commercialization of niraparib for patients in China and the potential to advance two immuno-oncology programs outside of China (Press release, TESARO, SEP 29, 2016, View Source [SID:SID1234515493]). This partnership reflects the commitment of both companies to develop novel therapeutic approaches for people living with cancer around the world.

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Within this collaboration, TESARO has granted to Zai Lab an exclusive license for the development of niraparib specifically for the China market, which includes an option for TESARO to participate in the commercialization of niraparib in greater China. The companies will establish a joint steering committee to review and oversee all development and commercialization plans. In addition, TESARO has the option to license two novel, discovery-stage immuno-oncology programs from Zai Lab.

"TESARO is devoted to providing transformative therapies for people bravely facing cancer, and this partnership will enable us to globalize our mission," said Lonnie Moulder, CEO of TESARO. "The Zai Lab team has a track record of regulatory and development successes in China, and we are excited to work with them to quickly advance new treatment options for patients."

Samantha Du, Chairman and CEO of Zai Lab, added, "We are delighted to partner with TESARO, a leader in global oncology drug development. Ovarian and other cancer types that niraparib is being evaluated in are areas of large unmet medical need in China, with very limited treatment options. Our collaboration with TESARO will bring this exciting new product candidate quickly to the Chinese patients, and we look forward to working with TESARO."

In addition to an upfront payment, TESARO will be eligible to receive milestone payments contingent upon Zai Lab achieving certain specified development and commercial goals. Should TESARO elect not to participate in the commercialization of niraparib in China, TESARO will be eligible to receive tiered, double-digit royalty payments on annual net sales from Zai Lab. Additional financial details were not disclosed.

About Niraparib
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in four ongoing pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes a Phase 3 trial in patients with recurrent ovarian cancer (the NOVA trial); a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial); a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial); and a Phase 3 trial for the treatment of patients with BRCA-mutant breast cancer (the BRAVO trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab and bevacizumab. Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to niraparib for the treatment of patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. TESARO has initiated a rolling submission of a New Drug Application (NDA) for niraparib to the FDA, and intends to complete this submission during the fourth quarter. The Marketing Authorization Application (MAA) for niraparib is planned for submission to the European Medicines Agency (EMA) in the fourth quarter.