On June 16, 2019 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported updated interim efficacy and safety data from the ongoing, pivotal Phase 2 HORIZON trial (Press release, Oncopeptides, JUN 16, 2019, View Source [SID1234537103]). The oral presentation was included in the "Novel strategies in multiple myeloma" session and was led by Professor Paul G. Richardson, Professor of Medicine at Harvard Medical School and Clinical Program Leader, Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute in Boston, Massachusetts, USA.

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The presentation will be available on the company webpage under: www.oncopeptides.com / Investors & media / Presentations / 2019 EHA (Free EHA Whitepaper)

Comment from CEO Jakob Lindberg
"HORIZON is an all-comer trial for patients with very advanced multiple myeloma. A majority of patients have extra medullary disease (EMD) as well as high-risk cytogenetics. Notably patients with EMD at relapse have limited response from treatment in clinical trials even in the era of modern therapies. In light of this patient population, the response rate of 28% coupled with the manageable side effect profile in HORIZON is very encouraging and indicates that melflufen plus dexamethasone can offer these patients a reasonable treatment alternative. These data form the basis of the upcoming New Drug Application (NDA) submission that we are currently preparing for accelerated approval of melflufen for the treatment of patients with triple-class refractory multiple myeloma" said Jakob Lindberg, CEO of Oncopeptides.

Overall Conclusions – HORIZON Presentation
At the time for the data cut-off, May 6th, 35 out of the 121 patients included were still on treatment.
The Overall Response Rate (ORR) was 28% and the Clinical Benefit Rate (CBR) was 40%, 36% of patients had receved 3+ treatment regimens over the last 12 months.
Extra-medullary disease patients had an ORR of 29%.
The majority of patients 86%, achieved disease stabilization (SD or better)
The median Progression Free Survival (PFS) was 4.0 months in the ongoing study.
Treatment was generally well tolerated with manageable toxicity, nonhematologic AEs were infrequent and the rate of discontinuation due to AEs was low.
Comment from Professor Paul G. Richardson
"The number of patients with resistant myeloma characterized by extra-medullary disease and high-risk cytogenetics is increasing, despite recent advances, and there is a real need for additional treatment options based on new mechanisms of action. Melflufen continues to demonstrate promising activity and manageable toxicity in the relapsed and refractory setting, and in particular amongst patients who are triple-class refractory " said Paul Richardson, MD, the RJ Corman Professor of Medicine at Harvard Medical School and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, USA.

About the OP-106 HORIZON study
Patient recruitment in the HORIZON study is ongoing. The interim data presented at EHA (Free EHA Whitepaper) is based on a data cut-off dated May 6th 2019 with 121 patients treated. 108 patients had recivied two or more cycles of treatment. The goal is to include 150 patients in the study. The patients in the study are refractory to pomalidomide and/or daratumumab after failing on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

More information can be found at: View Source;rank=2

Summary of the OP-106 HORIZON interim data
The study continues to develop positively in this heavily pretreated patient group. Melflufen continues to demonstrate promising activity in patients that have stopped responding to lenalidomide and PI based regimens and subsequently become resistant to salvage therapy based on daratumumab and/or pomalidomide.

The median age of the patients was 64 years. 62% of patients in the study had high-risk cytogenetics, 29% of patients were ISS stage III and 60% of the patients had extramedullary disease (EMD). The median number of prior lines of therapy was five and the median time since initial diagnosis was 6.2 years.

All patients in the study were investigator assessed as non-responsive or non-tolerant to IMiDs and PIs.

91% of patients were double class refractory (IMiD + PI) and 79% anti-CD38 mAb refractory. 74% of the patients were triple class (IMiD + PI + Anti-CD38 mAb) refractory and 59% were alkylator refractory. 98% of the patients were refractory in last line of therapy.

Efficacy
Analysis of the interim efficacy results showed an ORR of 28% and that 86% of the patients achieved disease stabilization (SD or better), see table below.

8 pts did not have available response information at data cutoff; 2 pts response evaluable, PI exposed, but refractoriness to PI subject to confirmation, so excluded from subgroup analysis
One pt with sCR also confirmed as MRD negative (10-6 sensitivity), with ongoing progression-free period of 13.6 mos
Median time to response 1.2 mos
CBR, clinical benefit rate; CR, complete response; MR, minimal response; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent CR; SD, stable disease; VGPR, very good PR.

For patients with extra-medullary disease the ORR was 29% as described in the table below.

Safety and tolerability
At time of data cut-off, treatment-related SAEs occurred in 20% of patients, most commonly febrile neutropenia (5%) and thrombocytopenia (2%). The overall incidence of nonhematologic AEs was low.

Discontinuation rate because of AEs was 20%. There were no treatment-related deaths. Six patients (6%) experienced treatment-related bleeding: grade 1 in four patients, grade 3 in two patients.

For further information, please contact:
Jakob Lindberg, CEO of Oncopeptides
E-mail: [email protected]
Telephone: +46 8 615 20 40

Rein Piir, Head of Investor Relations at Oncopeptides
E-mail: [email protected]
Cell phone: +46 70 853 72 92

The information in the press release is information that Oncopeptides is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact person above, on June 16, 2019 at 08.45 (CET).

About melflufen
Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. It belongs to the novel class Peptidase Enhanced Cytotoxics (PEnC), which is a family of lipophilic peptides that exhibit increased activity via peptidase cleavage and have the potential to treat many cancers. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and immediately cleaved by peptidases to deliver an entrapped hydrophilic alkylator payload. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the peptidase cleavage, and induces irreversible DNA damage and apoptosis. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.

On June 16, 2019 Amgen (NASDAQ:AMGN) reported the five-year overall survival (OS) analysis from the single-arm, Phase 2 BLAST study that evaluated BLINCYTO (blinatumomab) in patients with minimal residual disease (MRD)-positive acute lymphoblastic leukemia (ALL) (Press release, Amgen, JUN 16, 2019, View Source;p=RssLanding&cat=news&id=2401504 [SID1234537102]). The study found that with a median follow-up of 59.8 months, the median OS for BLINCYTO-treated patients was 36.5 months (95 percent CI: 22 months – not estimable [NE]). More than half of patients who achieved a complete MRD response following the first cycle of BLINCYTO treatment were alive at five years. These results from the largest prospective trial ever conducted in MRD-positive ALL were presented today during an oral presentation at the 24th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam.

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"As the only CD19-targeted immuno-oncology therapy with five-year survival data, BLINCYTO continues to demonstrate compelling results for ALL patients," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We are proud of the science behind our BiTE technology. These data in an MRD-positive ALL patient population give us increased confidence in the clinical benefit of BLINCYTO, especially when these patients are treated earlier."

The Phase 2 open-label BLAST study enrolled 116 patients with MRD-positive Philadelphia chromosome-negative (Ph-) B-cell precursor ALL in first or subsequent complete hematologic remission after at least three intensive chemotherapy blocks of treatment. Of the 116 enrolled patients, OS was evaluated for 110 patients with less than five percent leukemic blasts, including 74 patients who received hematopoietic stem cell transplantation (HSCT) in continuous complete remission (CCR) after BLINCYTO treatment.

Results presented at EHA (Free EHA Whitepaper) showed that in 84 patients who achieved a complete MRD response (had no measurable MRD), median OS was not reached (95 percent CI: 29.5 months – NE) compared to 14.4 months for those who had measurable MRD (n=23; 95 percent CI: 3.8 – 32.3 months). Among patients with MRD in first complete remission (CR1), median OS was not reached for those who achieved a complete MRD response (95 percent CI: 29.5 months – NE) versus 10.6 months (95 percent CI: 2.7 – 39.7 months) for those who did not achieve complete MRD response (n=13; p=0.008).

"The presence of MRD is a strong predictor of relapse in patients with B-cell precursor ALL," said Nicola Gökbuget, M.D., principal investigator for the BLAST study and head of the German Multicenter Study Group for Adult ALL in Frankfurt, Germany. "Results from the final follow-up of the BLAST trial at five years demonstrate that early achievement of complete molecular remission with BLINCYTO is associated with prolonged survival."

Safety results among MRD-positive patients were consistent with the known safety profile of BLINCYTO.

MRD refers to the presence of cancer cells that remain detectable, despite a patient having achieved complete remission by conventional assessment.1 The presence of MRD is broadly considered the most important independent prognostic factor in ALL.2-8 MRD is only measurable through the use of highly sensitive testing methods that detect cancer cells in the bone marrow with a sensitivity of at least one cancer cell in 10,000 cells – versus about one in 20 with a conventional microscope-based evaluation.1,9,10

BLINCYTO, a bispecific CD19-directed CD3 T cell BiTE (bispecific T cell engager) molecule, is the first approved molecule from Amgen’s BiTE immuno-oncology platform, and the first and only therapy to receive regulatory approval globally for the treatment of MRD.

About the BLAST Study
The BLAST study is the largest prospective trial in patients with MRD-positive ALL. It is an open-label, multicenter, single-arm, Phase 2 study that evaluated the efficacy, safety and tolerability of BLINCYTO in adult patients with MRD-positive B-cell precursor ALL in complete hematologic remission after three or more cycles of intensive chemotherapy. Patients received continuous intravenous infusion of BLINCYTO 15 μg/m2/d for four weeks, followed by two weeks off. Patients received up to four cycles of treatment and could undergo HSCT at any time after the first cycle, if eligible. Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). Results from the primary analysis BLAST study were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in 2015 and published in Blood in 2018. Additional secondary endpoints included incidence and severity of adverse events, OS, time to hematological remission and duration of complete MRD response. Survival follow-up visits for assessment of hematological RFS and OS took place every six months until completion of a five-year period after treatment start with BLINCYTO. Three-year OS data results from the BLAST study were also featured in an oral presentation during the 60th ASH (Free ASH Whitepaper) Annual Meeting & Exposition on Dec. 3, 2018.

About ALL and MRD
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.11,12 Poor outcomes have been observed in patients who achieve first or second complete hematologic remission but are persistently MRD-positive, which currently remains detectable at the molecular level after treatment.1,8 For more information about MRD, please visit AmgenOncology.com.

About BiTE Technology
BiTE (Bispecific T cell engager) technology is a targeted immuno-oncology platform that is designed to engage patients’ own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells with the goal of eliminating detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has the goal of off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing more than a dozen BiTE molecules across a broad range of solid and hematologic malignancies, further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell BiTE (bispecific T cell engager), immunotherapy that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration in 2014, and carries full approval in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. In the U.S., BLINCYTO is also approved for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent. This indication is approved under accelerated approval based on MRD response rate and hematological RFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In the European Union (EU), BLINCYTO is indicated for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor ALL and for the treatment of Ph- CD19-positive B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent.

BLINCYTO is now approved in 57 countries, including all member countries in the EU and European Economic Area, Canada, Japan and Australia.

Important EU BLINCYTO (blinatumomab) Safety Information

This product is subject to additional monitoring in the EU. All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in clinical studies of patients with B-precursor ALL (N = 843). The most serious adverse reactions that may occur during blinatumomab treatment include: infections (24.8%), neurologic events (13.8%), neutropenia/febrile neutropenia (10.1%), cytokine release syndrome (3.3%), and tumour lysis syndrome (0.7%). The most common adverse reactions were: pyrexia (69.2%), infusion-related reactions (43.4%), infections – pathogen unspecified (42.1%), headache (32.9%), anaemia (22.8%), thrombocytopenia (20.9%), febrile neutropenia (20.2%), oedema (20.0%), neutropenia (19.7%), rash (16.7%), increased liver hepatic enzymes (16.1%), bacterial infectious disorders (15.4%), tremor (15.2%), cough (15.1%), leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension (12.8%), viral infectious disorders (12.7%), decreased immunoglobulins (12.5%), cytokine release syndrome (11.6%), tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders (10.6%) and pain in extremity (10.2%).

Please refer to the Summary of Product Characteristics for full European prescribing information.

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS is 2 days after the start of infusion. Closely monitor patients for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). In clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL and in 7% of patients with MRD-positive ALL. Interrupt or discontinue BLINCYTO for evidence of CRS, as outlined in the PI.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment, and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life‐threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms of neurological toxicity and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia, infusion related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increase (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO.

About Amgen Oncology
Amgen Oncology is searching for and finding answers to incredibly complex questions that will advance care and improve lives for cancer patients and their families. Our research drives us to understand the disease in the context of the patient’s life – not just their cancer journey – so they can take control of their lives.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

At Amgen, we are driven by our commitment to transform the lives of cancer patients and keep them at the center of everything we do.

On June 15, 2019 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported positive data from the Phase I/II STARTRK-NG study, evaluating the investigational medicine entrectinib in children and adolescents with recurrent or refractory solid tumors with and without neurotrophic tyrosine receptor kinase (NTRK), ROS1 or anaplastic lymphoma kinase (ALK) gene fusions (Press release, Nerviano Medical Sciences, JUN 15, 2019, View Source [SID1234537210]). The study showed entrectinib shrank tumors (objective response rate; ORR) in all children and adolescents who had NTRK, ROS1 or ALK fusion-positive solid tumors (11 of 11 patients), including two patients achieving a complete response. Of the 11 patients, five patients with primary high-grade tumors in the central nervous system (CNS) had an objective response, including one patient with a complete response. The safety profile of entrectinib was consistent with that seen in previous analyses. Data will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Sunday, June 2, 2019, from 8:00 – 8:12 a.m. CDT (Abstract 10009), and was part of today’s official ASCO (Free ASCO Whitepaper) presscast.

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"We are encouraged by the results we have seen with entrectinib in children with pediatric and adolescent cancers, including those with tumors in the brain," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "The STARTRK-NG study underscores the importance of combining comprehensive genomic profiling with targeted therapies and supports our approach to providing people with personalized medicines developed specifically for their type of cancer."

Additional data for entrectinib across different tumor types and patient populations will also be presented at ASCO (Free ASCO Whitepaper), highlighting the company’s unique approach to personalized healthcare through advances in targeted therapies, diagnostics and data analytics:

Initial results from an integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials evaluating the efficacy of entrectinib in adults with solid tumors and CNS metastases will be presented on Saturday, June 1, 2019, in a poster session from 3:00 – 4:30 p.m. CDT (Abstract 3017).
Results from a real-world data study evaluating time-to-treatment discontinuation and progression-free survival as endpoints for comparative efficacy analysis of clinical trials of entrectinib and crizotinib for the treatment of people with ROS1-positive non-small cell lung cancer (NSCLC) will be presented during a poster session on Sunday, June 2, 2019, from 8:00 – 11:00 a.m. CDT (Abstract 9070).
The FDA recently granted Priority Review for entrectinib for both the treatment of pediatric and adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors who have either progressed following prior therapies or as an initial therapy when there are no acceptable standard therapies, and for the treatment of people with metastatic ROS1-positive NSCLC. These NDAs are based on results from the integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the STARTRK-NG study. The FDA is expected to make a decision on approval by August 18, 2019.

About the STARTRK-NG study

STARTRK-NG is a Phase I/II open-label dose-escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without NTRK, ROS1 or ALK fusions. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using Response Assessment in Neuro-Oncology (RANO) for CNS tumors, Response Evaluation Criteria in Solid Tumors (RECIST), and Curie score (CS) for neuroblastoma. The study enrolled 29 children and adolescents aged 4.9 months through 20 years (median age of 7 years) who had recurrent or refractory solid tumors, and 28 were evaluated for response. Of the 28 children and adolescents evaluated, 11 children were identified to have tumors with NTRK, ROS1 or ALK fusions and one with ALK F1174L-mutated neuroblastoma. A summary of the results are included below.

Complete responses were observed in two patients with tumors harboring NTRK and ALK fusions: one with an NTRK fusion-positive primary CNS tumor and one with an ALK fusion-positive inflammatory myofibroblastic tumor. Another complete response was observed in one neuroblastoma patient with an ALK F1174L mutation.
Partial responses were observed in nine patients, three unconfirmed at the time of the clinical cut-off date, across NTRK, ROS1 and ALK fusion-positive primary CNS (n=4) and extracranial (n=5) solid tumors.
Median duration of therapy for confirmed fusion-positive responders was 10.51 months (3.8 to 17.7 months), and median time to response was 1.89 months (1 to 1.9 months).
The safety profile of entrectinib was consistent with that seen in previous analyses. Treatment-related adverse events were most frequently National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2, leading to discontinuation in 6.9 percent of patients.
About NTRK fusion-positive cancer

Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signaling pathways involved in proliferation of certain types of cancer. NTRK gene fusions are tumor-agnostic, meaning they are present in tumors irrespective of site of origin. These fusions have been identified in a broad range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About entrectinib

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

On June 15, 2019 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported updated data from the ongoing, registration-enabling EXPLORER trial of avapritinib in patients with systemic mastocytosis (SM) (Press release, Blueprint Medicines, JUN 15, 2019, View Source [SID1234537104]). The updated data showed a confirmed overall response rate (ORR) of 77 percent in advanced SM patients, as assessed by a central review committee of SM clinical experts. In addition, the data showed durable clinical activity across advanced, smoldering and indolent forms of SM, with patients on therapy up to 34 months and responses continuing to deepen over time. Avapritinib was generally well-tolerated, with most adverse events (AEs) reported by investigators as Grade 1 or 2. The results are being presented today in an oral presentation at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam, The Netherlands.

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These updated data from the EXPLORER trial support Blueprint Medicines’ plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for avapritinib for the treatment of advanced SM in the first quarter of 2020, subject to continued discussions with the FDA regarding the data required to support an NDA submission. Avapritinib has received FDA Breakthrough Therapy Designation for the treatment of patients with advanced SM, including the subtypes of aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL).

"I believe that potently and selectively targeting KIT D816V, the disease driver in nearly all systemic mastocytosis patients, represents a promising therapeutic approach," said Dr. Deepti Radia, a hematologist and an investigator on the EXPLORER trial. "These new data showed avapritinib led to profound reductions of objective mast cell burden and durable clinical responses across a broad patient population. In advanced systemic mastocytosis, I am particularly encouraged by the strong activity shown in patients with especially poor survival rates, such as those with mast cell leukemia or high-risk genotypes. These data further reinforce the broad potential of avapritinib to address important medical needs across the spectrum of the disease."

"These results highlight the promise of avapritinib, a potent and selective KIT D816V inhibitor, to be an important disease-modifying treatment in patients with systemic mastocytosis," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "The updated data, including high confirmed response rates per central review, support our plans to submit a New Drug Application for advanced systemic mastocytosis in the first quarter of 2020. Avapritinib had strong activity in patients with indolent or smoldering systemic mastocytosis as well, providing further confidence in our approach for our ongoing registration-enabling PIONEER trial. By selectively targeting the common driver across all forms of systemic mastocytosis, avapritinib has the potential to address the spectrum of disease manifestations that significantly affect patients with different subtypes."

Highlights from EHA (Free EHA Whitepaper) Presentation of EXPLORER Trial Data

As of the data cutoff date of January 2, 2019, 69 patients were treated with avapritinib in the Phase 1 EXPLORER clinical trial, including seven patients with ASM, 37 patients with SM-AHN, nine patients with MCL, 15 patients with indolent or smoldering SM, and one patient without SM who had chronic myelomonocytic leukemia. Diagnoses were centrally reviewed by a committee of SM experts following an initial assessment by local investigators. Forty-two patients (61 percent) had a prior treatment, including 15 patients (22 percent) who had previously received the multi-kinase inhibitor midostaurin.

Clinical Activity Data

Thirty-nine patients with advanced SM (three ASM, 28 SM-AHN, eight MCL) were evaluable for response by the modified IWG-MRT-ECNM criteria, a rigorous method for assessing clinical response in advanced SM patients with regulatory precedent in the U.S. and Europe. Confirmation of response was defined as a response duration of at least 12 weeks. Evaluable patients generally had more advanced disease at baseline than the overall trial population.

In evaluable patients across all doses studied, the confirmed ORR was 77 percent. Nine patients had complete remission with a full or partial recovery of peripheral blood counts (CR/CRh; 23 percent), 18 patients had partial remission (46 percent) and three patients had clinical improvement (8 percent). No patients had progressive disease as the initial response. In addition, the 12-month duration of response (DOR) rate was 74 percent, and 49 patients (71 percent) remained on treatment with durations up to nearly three years (34 months).

Across all enrolled patients, the median overall survival (OS) was not reached. The estimated 24-month OS rate was 78 percent in all advanced SM patients: 100 percent in ASM patients, 70 percent in SM-AHN patients and 88 percent in MCL patients.

Avapritinib demonstrated strong clinical activity in patients with SRSF2, ASXL1 and/or RUNX1 (S/A/R) mutation positive genotypes, who historically have particularly poor prognoses. In 22 evaluable patients with S/A/R genotypes, the confirmed ORR was 73 percent and five patients had a CR/CRh (23 percent).

Nearly all patients had significant declines on objective measures of mast cell burden. Across all patients evaluable on these measures, 100 percent had a ≥50 percent decline in serum tryptase, 93 percent had a ≥50 percent reduction in bone marrow mast cells, 84 percent had palpable spleens become non-palpable, and 88 percent had a ≥50 percent reduction in KIT D816V mutation allele fraction.

Clinical Activity Data – Indolent or Smoldering SM

Avapritinib showed strong clinical activity in patients with indolent or smoldering SM. Nearly all patients had ≥50 percent reductions in serum tryptase, bone marrow mast cells and KIT D816V mutation allele fraction. In addition, improvements on these measures were deep and rapid. Thirteen of 15 evaluable patients had normalized serum tryptase levels, and 12 of 13 evaluable patients had complete clearance of mast cell aggregates from the bone marrow. All indolent and smoldering SM patients achieved a ≥50 percent reduction in serum tryptase by the first post-baseline assessment.

Safety Data

Avapritinib was generally well-tolerated with most AEs reported by investigators as Grade 1 or 2. Across all grades, the most common non-hematologic treatment-emergent AEs (regardless of relationship to avapritinib) reported by investigators (>15 percent) were periorbital edema, diarrhea, nausea, fatigue, peripheral edema, vomiting, cognitive effects, hair color changes, arthralgia, abdominal pain, dizziness, decreased appetite, pruritis, constipation and dysgeusia. The most common hematologic treatment-emergent AEs reported by investigators (>10 percent) were anemia, thrombocytopenia and neutropenia. In addition, intracranial bleeding occurred in six patients with pre-existing thrombocytopenia, a known risk factor for intracranial bleeding, and one patient who had a life-threatening fall prior to intracranial bleeding. Five of these patients resumed and remain on treatment with avapritinib following dose modifications. Updated dose modification procedures have been implemented for patients with thrombocytopenia, and to date, no new intracranial bleeding events have been observed. Cytopenias were the most common Grade 3 and 4 treatment-related AEs. No Grade 5 treatment-related AEs were reported by investigators.

Only three patients (4 percent) discontinued treatment with avapritinib due to treatment-related AEs. Nine patients (13 percent) discontinued treatment with avapritinib due to disease progression, with the majority due to either acute myeloid leukemia (n=3) or associated hematologic neoplasm (n=3).

These updated data on avapritinib are being presented at the 24th Congress of EHA (Free EHA Whitepaper) on Saturday, June 15 (Abstract Number: S830). A copy of the oral presentation is available in the "Science—Publications and Presentations" section of Blueprint Medicines’ website at www.BlueprintMedicines.com.

Conference Call Information

Blueprint Medicines will host a live conference call and webcast on Monday, June 17, 2019 at 8:30 a.m. ET to review the updated data for avapritinib in SM, as well as the recently announced NDA submission to the FDA for avapritinib for the treatment of PDGFRA Exon 18 mutant gastrointestinal stromal tumors (GIST), regardless of prior therapy, and fourth-line GIST. The conference call may be accessed by dialing (855) 728-4793 (domestic) or (503) 343-6666 (international) and referring to conference ID 8549897. A live webcast of the conference call will be available under the "Investors & Media—Events & Presentations" section of Blueprint Medicines’ website at www.BlueprintMedicines.com. A replay of the webcast will be available approximately two hours after the call and will be available for 30 days following the call.

About the Clinical Development Program for Avapritinib in SM

Blueprint Medicines is pursuing a broad clinical development program for avapritinib across advanced, indolent and smoldering forms of SM. Avapritinib is currently being evaluated in three ongoing, registration-enabling clinical trials for SM: the Phase 1 EXPLORER trial, the Phase 2 PATHFINDER trial and the Phase 2 PIONEER trial.

The Phase 1 EXPLORER trial was designed to identify the recommended Phase 2 dose for further study and demonstrate proof-of-concept in advanced SM, including patients with ASM, SM-AHN and MCL. The dose escalation portion is complete, and the expansion portion of the trial is ongoing at multiple sites in the United States and United Kingdom. Trial objectives include assessing safety and tolerability, response per modified IWG-MRT-ECNM criteria and patient-reported outcomes.

The Phase 2 PATHFINDER trial is an open-label, single-arm, registration-enabling trial in patients with advanced SM. Patient dosing is ongoing in the trial, which is designed to enroll up to 60 advanced SM patients at sites in the United States, Canada and European Union. The primary efficacy endpoints are ORR and DOR based on modified IWG-MRT-ECNM criteria.

The Phase 2 PIONEER trial is a randomized, placebo-controlled, registration-enabling trial in patients with indolent and smoldering SM. Patient dosing is ongoing in the trial, which is designed to enroll up to 112 indolent and smoldering SM patients at sites in the United States, Canada and European Union. The primary endpoint is symptom reductions for avapritinib versus placebo based on the Indolent and Smoldering SM Assessment Form Total Symptom Score. All patients who complete the dose-finding (part 1) and placebo-controlled efficacy (part 2) portions of this trial will have an opportunity to receive avapritinib in an open-label extension (part 3).

SM patients and clinicians interested in ongoing clinical trials can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. Additional details are available at www.blueprintclinicaltrials.com/SM/ or www.clinicaltrials.gov.

About SM

SM results from the abnormal proliferation and survival of mast cells, which mediate allergic responses. The clinical presentation of SM is heterogeneous, ranging from indolent or smoldering SM to three advanced subtypes – ASM, SM-AHN and MCL. The KIT D816V mutation drives approximately 95 percent of all SM cases, causing debilitating and difficult-to-manage symptoms such as pruritus, flushing, headaches, bone pain, nausea, vomiting, diarrhea, anaphylaxis, abdominal pain and fatigue. While these effects occur across SM patients, symptom burden and poor quality of life are the predominant disease manifestations of indolent and smoldering SM. Advanced SM patients experience organ damage and a median overall survival of about 3.5 years in ASM, two years in SM-AHN and less than six months in MCL.

Currently, there are no approved therapies that selectively inhibit KIT D816V in advanced SM, and no approved therapies for indolent and smoldering SM. New treatments are needed that are more effective and better tolerated than existing advanced SM therapy, as well as for indolent and smoldering SM patients whose symptoms are often not well controlled with symptom-directed therapies.

About Avapritinib

Avapritinib is an investigational, oral precision therapy that selectively and potently inhibits 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, including potent activity against activation loop mutations that are associated with resistance to currently approved therapies. In contrast to approved multi-kinase inhibitors, avapritinib has shown marked selectivity for KIT and PDGFRA over other kinases. In addition, avapritinib is uniquely designed to selectively bind and inhibit D816V mutant KIT, the common driver of disease in approximately 95 percent of all 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 for the treatment of advanced GIST, advanced SM, and indolent and smoldering SM. The FDA has granted Breakthrough Therapy Designation to avapritinib for two indications: one for the treatment of unresectable or metastatic GIST harboring the PDGFRα D842V mutation and one for the treatment of advanced SM, including the subtypes of ASM, SM-AHN and MCL.

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 June 15, 2019 Sutro Biopharma, Inc. (NASDAQ: STRO), a clinical-stage drug discovery, development and manufacturing company focused on the application of precise protein engineering and rational design to create next-generation oncology therapeutics, reported encouraging interim safety data from an ongoing Phase 1 dose escalation clinical trial of its product candidate STRO-001, a novel, specific and homogeneous anti-CD74 antibody-drug conjugate (ADC), as a potential therapy for patients with B-cell malignancies (Press release, Sutro Biopharma, JUN 15, 2019, View Source [SID1234537101]). The interim data from the trial includes 21 patients and separate dosing cohorts for multiple myeloma (10 MM patients) and non-Hodgkin lymphoma (11 NHL patients), was presented at the 24th European Hematology Association (EHA) (Free EHA Whitepaper) Congress in Amsterdam. The data also showed encouraging preliminary anti-tumor activity for the ADC, including one complete response (CR) and one partial response (PR) among a cohort of heavily pre-treated patients with DLBCL. Overall, STRO-001 was generally well-tolerated.

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"CD74 is expressed on B cells throughout differentiation and appears to be an attractive target for the treatment of non-Hodgkin lymphoma and multiple myeloma," said Dr. Nirav Shah, Assistant Professor of Medicine at Medical College of Wisconsin. "The interim safety results from the early dose escalation cohorts of the STRO-001 Phase 1 clinical trial are encouraging, especially considering the complete response seen in one of our patients."

Bill Newell, Sutro’s Chief Executive Officer added, "There is a continuing need for new treatment options for patients with B-cell malignancies as many patients relapse or become refractory to even the newest treatment regimens. STRO-001 was designed to directly target cancer cells to deliver a cytotoxic payload, an approach that enables greater precision in treating tumors. We view the data as encouraging and believe that STRO-001 can be an important new treatment option to address an unmet need for patients with B-cell malignancies."

The ongoing Phase 1, open-label, multicenter, dose escalation trial of STRO-001 is designed to evaluate the safety, tolerability and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies. Based on interim data from the clinical trial through May 14, 2019, STRO-001 has been generally well-tolerated. The most common treatment emergent adverse events included fatigue, nausea, chills and infusion reactions. Neither ocular toxicity signals nor anti-drug antibodies have been observed and the maximum tolerated dose for both dosing cohorts has not been reached.

Sutro’s cell-free protein synthesis and site-specific conjugation (XpressCF+) platform technology was used to discover and develop STRO-001, a CD74-targeting ADC. STRO-001 contains a potent maytansinoid warhead conjugated to two specific sites (drug-to-antibody ratio of 2) using a stable non-cleavable linker. The interim data as of May 14, 2019, included 21 patients across two cohorts: cohort A for MM and cohort B for NHL. The patients enrolled in the trial were generally heavily pre-treated with a median of six lines of prior therapy. STRO-001 was administered as a 60-minute IV infusion on Days 1 and 15 of a 28-day cycle until disease progression or dose limiting toxicity. As of May 14, 2019, the MM cohort was at dose level 0.65 mg/kg and the NHL dose cohort was at 0.91 mg/kg. The trial continues to enroll patients in dose escalation in both MM and NHL cohorts. This trial is registered with clinicaltrials.gov identifier NCT03424603.