On November 15, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported that data from the dose escalation portion of its Phase 1 trial of SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, demonstrated proof-of-mechanism at tolerable doses in patients with advanced solid tumors (Press release, Syros Pharmaceuticals, NOV 15, 2018, View Source [SID1234531367]). These data, the first clinical data reported on a selective CDK7 inhibitor, were highlighted in an oral plenary session at the 30th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium in Dublin.

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"These initial data on SY-1365 are highly encouraging," said Dejan Juric, M.D., Director of the Termeer Center for Targeted Therapies at Massachusetts General Hospital and a clinical investigator in the Phase 1 study of SY-1365. "Patient data from the SY-1365 dose escalation study confirm the unique mechanism-of-action of this agent and demonstrate an acceptable tolerability profile along with early signs of single-agent activity. These data, coupled with preclinical evidence showing robust anti-tumor activity in a range of relapsed and treatment-refractory cancer models, support the ongoing development of SY-1365 for patients who currently have few, if any, effective treatment options."

"As the first clinical data ever reported on a selective CDK7 inhibitor, these results mark an important milestone for SY-1365 and for the field of CDK7 inhibition," said David A. Roth, M.D., Syros’ Chief Medical Officer. "We believe CDK7 inhibition is a potentially transformative new approach for treating many cancers that have eluded effective treatment with existing approaches. Now that we have demonstrated proof-of-mechanism at tolerable doses, we are committed to thoroughly exploring the potential of CDK7 inhibition for currently underserved patients. We are working to rapidly enroll the expansion cohorts in our ongoing Phase 1 study, focused initially on ovarian and breast cancers, while building on our leadership by advancing our highly selective and potent oral CDK7 inhibitor, SY-5609, as our next development candidate."

Dose Escalation Data

The dose escalation portion of the Phase 1 trial characterized the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of SY-1365 in patients with advanced solid tumors to establish a dose and regimen for the expansion portion of the trial. PD assays used to establish proof-of-mechanism included a CDK7 occupancy assay to evaluate SY-1365 binding and a custom gene expression assay to evaluate downstream transcriptional changes in patients. Preliminary anti-tumor activity was also assessed.

Enrollment in the dose escalation portion of the trial was completed in September. In total, 32 patients were treated with SY-1365 as a single agent at doses ranging from 2 mg/m2 to 112 mg/m2 using either a weekly or twice weekly dosing regimen. Patients were treated for three weeks out of each four-week cycle. Patients had a range of solid tumors, the most prevalent being ovarian cancer (eight patients), breast cancer (eight patients) and endometrial cancer (five patients). Patients’ median age was 63 (ranging from 25 to 87), with a median of five prior therapies (ranging from one to 13). As of an October 15th data snapshot, the median treatment duration was 46.5 days (ranging from two to 147 days) and four patients remained on treatment.

Safety

Adverse events (AEs) were predominantly low-grade, reversible and generally manageable.
The most commonly reported AEs were headache, nausea, vomiting and fatigue.
No neutropenia was reported.
Dose-limiting toxicities were headache, coronary vasospasm and fatigue.
A maximum tolerated dose was not defined.
Pharmacokinetics

Plasma PK exposures were linear over the doses tested.
No drug accumulation was observed with repeat dosing.
Proof-of-Mechanism

SY-1365 demonstrated dose-dependent effects on CDK7 occupancy and downstream gene expression changes in blood cells.
At doses of 32 mg/m2 and higher, CDK7 occupancy was greater than 50 percent when measured three days following dose administration, exceeding target occupancy levels in preclinical models that correlated with anti-tumor activity.
CDK7 occupancy in blood cells was similar to target occupancy in tumor tissue biopsies available from two patients in the clinical trial.
Early Signs of Clinical Activity

As of the October 15th data snapshot, clinical activity per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was observed in seven of the 19 patients (37%) who were evaluable for clinical responses, including:

One patient with ovarian cancer in her fourth relapse who had a confirmed partial response (PR) after two cycles of treatment at the 80 mg/m2 twice-weekly dose. The patient remained in PR at her CT assessment after six cycles and recently entered her seventh month on study treatment.
Six additional patients who had stable disease, lasting between 50 and 127 days. Most of these patients received doses equal to or greater than 32 mg/m2.
Based on these data, Syros selected a twice-weekly dose of 80 mg/m2 of SY-1365 when administered as a single agent, and a once-weekly target dose of 80 mg/m2 of SY-1365 when administered in combination with other agents, for further evaluation in the ongoing Phase 1 expansion cohorts in multiple ovarian and breast cancer patient populations.

Ongoing Expansion of Phase 1 Trial

Upon completing enrollment in the dose-escalation portion of the trial, Syros opened expansion cohorts to further assess the safety and anti-tumor activity of SY-1365 in multiple ovarian and breast cancer patient populations. The initial expansion strategy is based on preclinical data showing anti-tumor activity in these tumor types, a strong mechanistic rationale and high unmet need. The expansion cohorts are evaluating SY-1365: as a single agent in primary platinum-refractory ovarian cancer patients; as a single agent in ovarian cancer patients who have relapsed after three or more therapies; in combination with carboplatin in ovarian cancer patients who have relapsed after one or more prior therapies; and in combination with fulvestrant in patients with hormone-receptor positive (HR+) metastatic breast cancer who have progressed after treatment with a CDK4/6 inhibitor. An additional cohort is enrolling patients with any solid tumor accessible for biopsy to further evaluate the mechanism of action of SY-1365. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov.

The dose escalation data presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) meeting is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

Conference Call and Webcast

Syros will host a conference call today at 4:00 p.m. ET to discuss the data from the dose escalation portion of its Phase 1 trial.

The live call may be accessed by dialing (866) 595-4538 for domestic callers or (636) 812-6496 for international callers and referencing conference ID number: 4567679. A live webcast of the conference call will be available online on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 90 days.

On November 15, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that Center for Drug Evaluation of China’s National Medical Product Administration (NMPA, formerly known as CFDA) has granted priority review status to the New Drug Applications (NDAs) for the company’s investigational BTK inhibitor zanubrutinib in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) and for its investigational anti-PD-1 antibody tislelizumab in patients with R/R classical Hodgkin’s lymphoma (cHL) (Press release, BeiGene, NOV 15, 2018, View Source;p=irol-newsArticle&ID=2377287 [SID1234531352]).

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"We’re excited that the NDAs for both zanubrutinib and tislelizumab are receiving priority review by the NMPA," commented Wendy Yan, Senior Vice President, Global Head of Regulatory Affairs at BeiGene. "We look forward to working closely with the NMPA and CDE in the coming months and hope to bring more treatment options to cancer patients."

Zanubrutinib and tislelizumab were both discovered in BeiGene’s research facilities in Beijing, China. Zanubrutinib is being developed globally by BeiGene as a monotherapy and in combination with other therapies to treat various hematologic malignancies. The NDAs for zanubrutinib as a potential treatment for patients with R/R MCL and for patients with R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) were accepted by the NMPA in August and October 2018, respectively. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid and hematologic cancers. The NDA for tislelizumab as a potential treatment for patients with R/R cHL was accepted by the NMPA in August 2018.

Priority review and approval was established in China to facilitate drug registration management and accelerate the development of new drugs with clinical value under the guidance of Opinions on the Reform of the Review & Approval System for Drugs and Medical Devices issued by the State Council in August 2015, and Opinions on Encouraging Pharmaceutical Innovation via Priority Review & Approval issued by CFDA in December 2017. According to these guidelines, the regulatory authority will prioritize the review process and evaluation resources for applications under priority review should expect prioritized review and inspection resource and reduced review and approval timelines.

About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib was discovered in BeiGene’s research facilities in Beijing, China, and is being developed globally by BeiGene as a monotherapy and in combination with other therapies to treat various hematologic malignancies.

About Tislelizumab
Tislelizumab (BGB-A317) is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. Discovered by BeiGene scientists in Beijing, tislelizumab is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. Tislelizumab has demonstrated high affinity and specificity for PD-1 in pre-clinical studies. It is potentially differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells, based on preclinical data. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumor cancers outside of Asia (except Japan).

On November 15, 2018 NantHealth, Inc. (NASDAQ-GS: NH), a next-generation, evidence-based, personalized healthcare company, reported financial results for its third quarter ended September 30, 2018 (Press release, NantHealth, NOV 15, 2018, View Source [SID1234531369]).

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Sequencing and Molecular Analysis – Highlights

In September 2018, at the IASLC 19th World Conference on Lung Cancer, the company and NantOmics presented two posters and a mini-oral presentation titled "Blood Based Biomarkers: RNA, KRAS and PD-L1 Strongly Matching with Tissue and Showing Correlation with Clinical Responses In NSCLC Patients," with investigational data showing (i) association between clinical response and changes in plasma cfRNA levels and (ii) that plasma levels of PD-L1 expression, while on immunotherapy, could be used to monitor clinical responses.
In October 2018, at ESMO (Free ESMO Whitepaper), the world’s second largest cancer symposium, the company, along with NantOmics, conducted one oral presentation and presented four papers, including papers demonstrating the promise of Liquid GPS, the company’s blood-based molecular test that provides oncologists with a powerful tool for non-invasive tumor profiling and quantitative monitoring of treatment response.
Expanded Sequencing and Molecular Analysis Reimbursement Arrangements: In Q3, the company expanded its GPS reimbursement contract with a large, national employer in the healthcare industry to include reimbursement for its Liquid GPS test and, in Q4, the company expanded GPS Cancer and Liquid GPS coverage for firefighters through the execution of an additional reimbursement contract benefiting members of a city-wide firefighter union.
"We recently made two oral presentations at major medical congresses, highlighting the unique aspects of our liquid biopsy platform that are different from ctDNA platforms offered by Guardant Health, Foundation Medicine and other laboratories," said Sandeep (Bobby) Reddy, M.D., Chief Medical Officer of NantHealth. "Only Liquid GPS can produce this type of data on chemotherapy selection and immunotherapy selection. Moreover, the review committees of two different organizations felt that this data was sufficiently important to warrant oral presentation. This further validates our belief that circulating RNA expression, not DNA alone, is the liquid biopsy technology that will transform medical practice."

Software and Services Highlights:

Payer Engagement (NaviNet):
In Q3, executed a large-scale implementation of NaviNet Open Authorizations with a key customer, adding more than 40,000 end users, bringing total active number of users to 862,000
Clinical Decision Support (Eviti):
Released new functionality with drug specific justifications, enabling the capture of key data to ensure quicker pre-authorization and clinical integrity.
Completed a new statewide implementation with a large existing payer in Kentucky, adding 250,000 covered lives. This implementation followed a similar success in Florida in Q2 for the same national payer.
Connected Care:
In Q4, collaborated with B. Braun Australia, GE Healthcare and iProcedures to demonstrate the exchange of data between patient devices and medical records at the HIMSS Interoperability Showcase as part of the Healthcare Information and Management Systems Society (HIMSS) Asia Pacific Conference.
"We are pleased to report that total net revenue for the 2018 third quarter increased to $22.3 million, up from the comparable prior year period, as well as on a sequential quarterly basis," said Bob Petrou, Interim Chief Financial Officer of NantHealth. "Looking ahead, the recent addition of two new executives to lead our strategy and business development, and global sales efforts will help us expand our business in both the U.S. and international markets."

Business and Financial Highlights

The company adopted a new revenue recognition standard on January 1, 2018. Please note that the financial results presented below include both amounts "as presented," which reflect implementation of the new revenue recognition standard, as well as amounts prior to the impact of the new revenue recognition standard to allow for comparability against historical results. Starting in fiscal year 2019, the company will no longer present its GAAP and Non-GAAP financial results under the previous revenue recognition standard. For additional information and reconciliations of our financial results between the new and previous revenue recognition standard, see the additional tables included in this press release and in the company’s Form 10-Q to be filed with the Securities and Exchange Commission.

For the 2018 third quarter, total net revenue as presented was $22.3 million. Total 2018 third quarter net revenue prior to the impact of the new revenue recognition standard increased to $22.0 million from $21.8 million in 2017 third quarter. Gross profit as presented was $11.1 million, or 50% of total net revenue. Gross profit prior to the impact of the new revenue recognition standard was $10.8 million, or 49% of total net revenue, compared with $10.3 million, or 47% of total net revenue, for the prior-year third quarter. Selling, general and administrative (SG&A) expenses as presented were $17.0 million. SG&A prior to the impact of the new revenue recognition standard was $16.9 million compared with $17.5 million in 2017 third quarter. Research and development (R&D) expenses as presented decreased to $4.8 million from $7.7 million; the new revenue recognition standard did not impact R&D expenses.

Financial results for the third quarter of 2018 included a non-cash charge for loss from related party equity method investment, including impairment, of $83.3 million. Net loss from continuing operations, net of tax, as presented was $97.4 million, or $0.89 per share. Net loss from continuing operations, net of tax, prior to the impact of the new revenue recognition standard was $97.5 million, or $0.89 per share, from $23.0 million, or $0.20 per share for the 2017 third quarter. Loss from discontinued operations, net of tax, as presented was $32,000, or $0.00 per share, compared with $19.4 million, or $0.17 per share; the new revenue recognition standard did not impact loss from discontinued operations. Net loss as presented was $97.5 million, or $0.89 per share. Net loss prior to the impact of the new revenue recognition standard was $97.5 million, or $0.89 per share, compared with $42.4 million, or $0.37 per share, for 2017 third quarter.

For the 2018 third quarter, on a non-GAAP basis, adjusted net loss from continuing operations as presented was $10.8 million, or $0.10 per share. On a non-GAAP basis, adjusted net loss from continuing operations prior to the impact of the new revenue recognition standard was $10.9 million, or $0.10 per share, compared with $14.9 million, or $0.13 per share, for the 2017 third quarter.

In August 2017, NantHealth sold its provider/patient engagement assets to Allscripts to focus on core competencies and accelerate the plan to achieve profitability. As a result, the company has classified the current and prior period operating results of its provider/patient engagement business as discontinued operations. All results presented above represent the company’s continuing operations.

Conference Call Information and Forward-Looking Statements

Later today, the company will host a conference call at 1:30 p.m. PT (4:30 p.m. ET) to review its results of operations for the third quarter ended September 30, 2018. The conference call will be available to interested parties by dialing 844-309-3709 from the U.S. or Canada, or 281-962-4864 from international locations, passcode 9992769. The call will be broadcast via the Internet at www.nanthealth.com. Listeners are encouraged to visit the website at least 10 minutes prior to the start of the scheduled presentation to register, download and install any necessary audio software. A playback of the call will be archived and accessible on the same website for at least three months.

Discussion during the conference call may include forward-looking statements regarding topics such as the company’s financial status and performance, regulatory and operational developments, and other comments the company may make about its future plans or prospects in response to questions from participants on the conference call.

Use of Non-GAAP Financial Measures

This news release contains references to Non-GAAP financial measures, including adjusted net loss and adjusted net loss per share, which are financial measures that are not prepared in conformity with United States generally accepted accounting principles (U.S. GAAP). The Company’s management believes that the presentation of Non-GAAP financial measures provides useful supplementary information regarding operational performance, because it enhances an investor’s overall understanding of the financial results for the Company’s core business. Additionally, it provides a basis for the comparison of the financial results for the Company’s core business between current, past and future periods. Other companies may define these measures in different ways. Non-GAAP financial measures should be considered only as a supplement to, and not as a substitute for or as a superior measure to, financial measures prepared in accordance with U.S. GAAP. Non-GAAP per share numbers are calculated based on one class of common stock and do not incorporate the effects, if any, of using the two-class method.

On November 15, 2018 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported updated data for the registration-enabling NAVIGATOR clinical trial of avapritinib, a potent and highly selective KIT and PDGFRA inhibitor in development for patients with advanced gastrointestinal tumors (GIST) (Press release, Blueprint Medicines, NOV 15, 2018, View Source [SID1234531353]). The data showed that avapritinib was highly active across all lines of therapy for patients with PDGFRα D842V-driven GIST and in second-, third- and fourth-line for other GIST patients. In addition, avapritinib was well-tolerated with most adverse events (AEs) reported by investigators as Grade 1 or 2. These results will be presented today in an oral presentation at the Connective Tissue Oncology Society 2018 Annual Meeting in Rome, Italy.

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The updated data from the ongoing Phase 1 NAVIGATOR trial support Blueprint Medicines’ plans to submit a New Drug Application (NDA) in the first half of 2019 to the U.S. Food and Drug Administration (FDA) for the treatment of PDGFRA Exon 18 mutant GIST, which primarily includes patients with the D842V mutation, and fourth-line GIST. There are currently no approved or effective therapies in these patient populations. In patients with PDGFRα D842V-driven GIST, avapritinib demonstrated an objective response rate (ORR) of 84 percent and a 12-month duration of response (DoR) of 76 percent. In heavily pre-treated patients with fourth-line or later GIST, avapritinib demonstrated an ORR of 20 percent, tumor reductions in 60 percent of patients and a median DoR of 7.3 months. ORR and DoR per central radiographic review will be the primary endpoints for the NDA submission, consistent with regulatory precedent for accelerated approvals based on single-arm oncology studies. In addition, avapritinib demonstrated an ORR of 26 percent in regorafenib-naïve third- and fourth-line GIST and an ORR of 25 percent in second-line GIST. Patients with PDGFRα D842V-driven GIST were excluded from both of these populations.

"With an increased understanding of molecular drivers of GIST over the last decade, it is encouraging to see an investigational drug, like avapritinib, bring a precision therapy approach to GIST," said Michael Heinrich, M.D., Professor of Medicine at Oregon Health & Science University and an investigator on the NAVIGATOR trial. "Avapritinib has the potential to be a significant therapeutic advance in GIST, a rare cancer with high medical needs across lines of treatment. In particular, the updated data demonstrate the broad clinical impact of avapritinib for patients with PDGFRα D842V-driven GIST and fourth-line GIST, where there are currently no effective therapies. In addition, the data strongly support clinical development of avapritinib in early lines, including second- and third-line treatment."

"These data highlight the potential of avapritinib, a potent and highly selective inhibitor of KIT and PDGFRA mutant kinases, to be a cornerstone precision therapy in GIST," said Andy Boral, M.D., Ph.D., Chief Medical Officer of Blueprint Medicines. "The results validate Blueprint Medicines’ approach to designing precision therapies that specifically target genetic drivers of disease, with the goals of delivering transformative benefit to patients and enabling rapid progress toward registration. Avapritinib’s highly potent anti-tumor activity in PDGFRα D842V-driven GIST, combined with differentiated activity across treatment lines in KIT-driven GIST, reflect its promise as a potentially foundational treatment option across multiple GIST populations. We are committed to advancing a comprehensive and scientifically driven clinical development program with the goal of improving the lives of GIST patients."

Data Highlights from the Ongoing Phase 1 NAVIGATOR Clinical Trial

As of the data cutoff date of October 15, 2018, 231 patients were treated with avapritinib in the dose escalation and expansion portions of the Phase 1 clinical trial at eight dose levels, ranging from 30 mg once daily (QD) to 600 mg QD. This population consisted of 167 patients with KIT-driven GIST, 56 patients with PDGFRα D842V-driven GIST and eight patients with other PDGFRA mutations. Patients in the expansion portion of the clinical trial were treated at the recommended Phase 2 dose of 300 mg QD.

Safety Data

As of the data cutoff date, avapritinib was well-tolerated, and most AEs reported by investigators were Grade 1 or 2. Across all doses, 20 patients (8.7 percent) discontinued treatment with avapritinib due to treatment-related AEs.

Across all grades, the most common treatment-emergent AEs (regardless of relationship to avapritinib) reported by investigators (≥20 percent) included nausea (61 percent), fatigue (55 percent), anemia (46 percent), periorbital edema (40 percent), diarrhea (39 percent), vomiting (38 percent), decreased appetite (35 percent), peripheral edema (33 percent), increased lacrimation (31 percent), memory impairment (26 percent), constipation (23 percent), face edema (23 percent), hair color changes (21 percent) and dizziness (20 percent).

Investigator-reported Grade 3 or 4 treatment-related AEs (≥2 percent) included anemia, fatigue, hypophosphatemia, increased bilirubin, decreased white blood count/neutropenia and diarrhea.

Clinical Activity Data

As of the data cutoff date, the following patients were evaluable for response assessments: 56 patients with PDGFRα D842V-driven GIST, 109 patients with fourth-line or later GIST, 23 patients with third- or fourth-line GIST who did not receive prior regorafenib (which is comparable to the VOYAGER trial population) and do not harbor the PDGFRα D842V mutation, and 20 patients with second-line GIST who do not harbor the PDGFRα D842V mutation. Patients were evaluable if they had at least one centrally reviewed radiographic scan, and data are based on modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1 criteria) for GIST.

Across multiple lines of therapy, avapritinib demonstrated important clinical activity in patients with PDGFRA- and KIT-driven GIST.

GIST Population

Evaluable
Patients

ORR

Clinical Benefit Rate
at Four Months
(≥Two Scans)

Median DoR

Median PFS

Central Review
(Investigator Review)

PDGFRα D842Va

56

84%f

96%

Not estimable;
76% at 12 months

Not reached

Fourth-line or laterb,c

109

20%g

40%

7.3 months

3.7 months
(5.4 months)

Regorafenib-naïve third-
or fourth-lineb,d

23

26%

70%

10.2 months

8.6 months
(10.2 months)

Second-lined,e

20

25%h

NRi

NRi

NRi

Notes: (a) Treated at all doses; (b) Treated at doses of 300 or 400 mg QD; (c) Included patients with the PDGFRα D842V mutation, whose proportion was consistent with the known mutational prevalence in this GIST population; (d) Did not include patients with the PDGFRα D842V mutation, whose proportion was greater than the known mutational prevalence in this GIST population; (e) Treated at doses up to and including 300 or 400 mg QD; (f) Four PR pending confirmation; (g) One PR pending confirmation; (h) Three PR pending confirmation; (i) NR, not reported, as data are too early to estimate.

Additional Data Support Clinical Development Strategy in Earlier Lines of Therapy

Third- and Fourth-Line GIST

Preliminary data showed robust clinical activity in regorafenib-naïve third- and fourth-line GIST patients lacking the PDGFRα D842V mutation. As of the data cutoff date, the ORR was 26 percent, tumor reductions were demonstrated in 78 percent of patients, and the median PFS was 8.6 months per central radiographic review and 10.2 months per investigator review. In contrast, historical data showed a 5 percent ORR and a median PFS of 4.8 months for regorafenib, the current standard-of-care treatment in third-line GIST.

In regorafenib-naive patients with PDGFRα D842V-driven third- or fourth-line GIST, the ORR was 80 percent (eight out of 10 evaluable patients, with one response pending confirmation). Blueprint Medicines’ ongoing Phase 3 VOYAGER trial of avapritinib versus regorafenib in third- or fourth-line GIST permits enrollment of patients with both KIT- and PDGFRA-driven GIST, including patients with the PDGFRα D842V mutation. Blueprint Medicines anticipates completing enrollment of the VOYAGER trial in the second half of 2019.

Second-Line GIST

Preliminary data showed a 25 percent ORR in second-line GIST, excluding patients with the PDGFRα D842V mutation. In patients with second-line PDGFRα D842V-driven GIST, the ORR was 94 percent (15 out of 16 evaluable patients, with two responses pending confirmation).

In addition, analyses of circulating tumor DNA (ctDNA) from the NAVIGATOR trial across all lines showed increased activity for avapritinib in patients without the secondary KIT V654A or T670I mutations, which are estimated to occur in about 20 to 25 percent of GIST patients following treatment with imatinib (second-line or later). Independently published data for sunitinib, the current standard of care therapy for second-line GIST, have shown activity against these mutations.

Based on the totality of data, Blueprint Medicines believes a precision medicine approach has the potential to optimize patient outcomes in second-line GIST. The company plans to initiate the registration-enabling Phase 3 COMPASS-2L clinical trial in the second half of 2019 using a ctDNA-guided patient selection strategy. The planned trial will select patients with PDGFRA- and KIT-driven second-line GIST who do not have the KIT V654A or T670I mutations, and randomize them to receive avapritinib or sunitinib with an anticipated primary endpoint of PFS.

Conference Call Information

Blueprint Medicines will host a live conference call and webcast on November 15, 2018 at 7:30 a.m. ET to review the updated data for avapritinib in GIST. The conference call may be accessed by dialing (855) 728-4793 (domestic) or (503) 343-6666 (international) and referring to conference ID 3479587. A live webcast of the conference call will be available under "Events and Presentations" in the Investors section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the conference call and will be available for 30 days following the call.

About the Avapritinib Clinical Development Program in GIST

Blueprint Medicines is pursuing a broad clinical development program for avapritinib across all lines of GIST. Avapritinib is currently being evaluated in two ongoing registration-enabling clinical trials for GIST: the Phase 1 NAVIGATOR trial and the Phase 3 VOYAGER trial.

The NAVIGATOR trial is designed to evaluate the safety and tolerability of avapritinib in patients with advanced GIST. The trial consists of two parts, a dose escalation portion and an expansion portion. The dose escalation portion is complete, and trial objectives include assessing response, pharmacokinetics and pharmacodynamic measures. Response assessments use blinded, central radiology review. The expansion cohorts of the trial are designed to enroll a total of approximately 200 patients at multiple sites in the United States, United Kingdom and European Union.

The VOYAGER trial is a global, open-label, randomized, Phase 3 trial designed to evaluate the safety and efficacy of avapritinib versus regorafenib in patients with third- or fourth-line advanced GIST. The trial is designed to enroll approximately 460 patients randomized 1:1 to receive either avapritinib or regorafenib at multiple sites in the United States, United Kingdom, European Union, Australia and Asia.

In the second half of 2019, Blueprint Medicines plans to initiate COMPASS-2L, a global, randomized, Phase 3 precision medicine trial. The trial will evaluate the safety and efficacy of avapritinib versus sunitinib in patients with second-line advanced GIST and pre-specified disease genotypes.

Patients and physicians interested in the Phase 3 VOYAGER trial can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. For more information about the VOYAGER trial, please visit www.voyagertrial.com. Additional details are available on www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03465722).

About GIST

GIST is a sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction.

Most GIST cases are caused by a spectrum of clinically relevant mutations that force the KIT or PDGFRA protein kinases into an increasingly active state. Because currently available therapies only bind to the inactive protein conformations, certain primary and secondary mutations typically lead to treatment resistance and disease progression.

Treatment options for KIT-driven GIST patients whose disease progresses or develops resistance are currently limited. There are no effective treatment options for patients with PDGFRA-driven GIST, and progression often occurs in as little as three months with available therapies. In advanced GIST, clinical benefits from existing treatments can vary by mutation type. Early testing is critical to help guide therapy that effectively treats the underlying driver of disease and is recommended in expert guidelines.

About Avapritinib

Avapritinib is a potent and selective oral inhibitor of KIT and PDGFRA mutant kinases. It is a type 1 inhibitor designed to target the active kinase conformation; all oncogenic kinases signal via this conformation. Avapritinib has demonstrated broad inhibition of KIT and PDGFRA mutations associated with GIST, and the most potent activity against activation loop mutations, which currently approved therapies do not inhibit. In contrast with existing multi-kinase inhibitors, avapritinib has shown marked selectivity for KIT and PDGFRA over other kinases. In addition, avapritinib is uniquely designed to bind and inhibit the KIT D816V mutation, the primary driver of disease in up to 95 percent of systemic mastocytosis (SM) patients. Preclinical studies have shown avapritinib potently inhibited KIT D816V at sub-nanomolar potencies with minimal off-target activity.

Blueprint Medicines is initially developing avapritinib, an investigational medicine, for the treatment of advanced GIST, advanced SM, and indolent and smoldering SM. The FDA has granted avapritinib two Breakthrough Therapy Designations, one for the treatment of PDGFRα D842V-driven GIST and one for advanced SM.

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 Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for avapritinib in the rest of the world.

On November 15, 2018 Deciphera Pharmaceuticals, Inc. (NASDAQ:DCPH), a clinical-stage biopharmaceutical company focused on addressing key mechanisms of tumor drug resistance, reported completion of enrollment in the INVICTUS pivotal Phase 3 clinical study evaluating the safety and efficacy of DCC-2618, a broad-spectrum KIT and PDGFRα inhibitor, in fourth-line and fourth-line-plus gastrointestinal stromal tumor (GIST) patients (Press release, Deciphera Pharmaceuticals, NOV 15, 2018, View Source [SID1234531370]).

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"We are very pleased to have completed enrollment in the INVICTUS pivotal Phase 3 study, initiated in January 2018. We expect to report top-line data from this randomized, double-blind study in mid-2019 and, if successful, we believe the results would support a New Drug Application (NDA) for full approval in fourth-line and fourth-line-plus GIST patients," said Michael D. Taylor, Ph.D., President and Chief Executive Officer of Deciphera. "Currently there are no treatments approved for fourth-line and fourth-line-plus GIST and we are grateful to those patients who participated in our study and to the GIST community for its support. In addition, we look forward to initiating later this year a second pivotal Phase 3 study, the INTRIGUE study, in second-line GIST patients who have progressed or are intolerant to front-line therapy with imatinib, including those with any KIT or PDGFRα mutation."

On October 19, 2018, Deciphera presented updated data from its ongoing Phase 1 clinical trial of DCC-2618 in patients with GIST at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany.
View Source

About the INVICTUS Phase 3 Study
The INVICTUS Phase 3 clinical study is a randomized, double-blind, placebo-controlled, international, multicenter trial to evaluate the safety, tolerability, and efficacy of DCC-2618 compared to placebo in patients with advanced GIST whose previous therapies have included imatinib, sunitinib, and regorafenib. This study was designed to provide the definitive evidence of clinical benefit in fourth-line and fourth-line-plus GIST patients that would be required to secure a full regulatory approval. Patients were randomized 2:1 to either 150 mg of DCC-2618 or placebo once daily. The primary efficacy endpoint is median progression-free survival (PFS) as determined by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints as determined by independent radiologic review using modified RECIST include Objective Response Rate (ORR), Time to Tumor Progression (TTP), and Overall Survival (OS). See www.clinicaltrials.gov for further information (NCT03353753).

About DCC-2618
DCC-2618 is an investigational KIT and PDGFRα kinase switch control inhibitor in clinical development for the treatment of KIT and/or PDGFRα-driven cancers, including gastrointestinal stromal tumors, or GIST, systemic mastocytosis, or SM, and other cancers. DCC-2618 was specifically designed to improve the treatment of GIST patients by inhibiting a broad spectrum of mutations in KIT and PDGFRα. DCC-2618 is a KIT and PDGFRα inhibitor that blocks initiating and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST as well as the primary D816V exon 17 mutation involved in SM. DCC-2618 also inhibits primary PDGFRα mutations in exons 12, 14 and 18, including the exon 18 D842V mutation, involved in a subset of GIST.