On April 15, 2018 NewLink Genetics Corporation (NASDAQ:NLNK), reported initial data from NLG2105, a Phase 1 study evaluating indoximod, its IDO pathway inhibitor, in combination with radiation and chemotherapy for the treatment of pediatric patients with progressive brain tumors during the "Multimodality Immuno-oncology Approaches" session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting in Chicago.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The presentation reviewed NewLink Genetics’ trial evaluating the combination of indoximod with radiotherapy and chemotherapy for children with malignant brain tumors. Indoximod has immunostimulatory effects involving multiple immune cell types. Indoximod works by reversing the effects of low tryptophan by increasing proliferation of effector T cells, and directly reprogramming T regulatory cells into helper T cells. Initially, 29 heavily pretreated patients were enrolled in a dose-escalation protocol with initial data presented at the Society for Neuro-Oncology Conference, November 2017. Seventeen of the 29 patients were appropriate candidates for re-irradiation of their tumors and were treated with a combination therapy including indoximod plus conformational radiotherapy followed by maintenance indoximod combined with temozolomide chemotherapy. The other 12 patients were treated with immuno-chemotherapy consisting of indoximod and temozolomide. In aggregate, with further follow-up, the 29 subjects in the dose-escalation phase of the study had a median progression-free survival (mPFS) of 6.2 months and median time on study (time to regimen failure, TTRF) of 11.7 months. The treatment continued to be well tolerated with minimal toxicity attributed to indoximod.

"These early data, though from a small cohort of pediatric patients, demonstrate the potential of the indoximod plus radiochemotherapy combination without an increase in toxicity for these children," said Dr. Theodore S. Johnson, M.D., Ph.D., Associate Professor of Pediatrics at Augusta University, lead investigator for the trial.

Once initial safety data were generated, an additional pilot cohort of newly-diagnosed patients with diffuse intrinsic pontine glioma (DIPG) was opened using indoximod during front-line radiotherapy (RT) followed by maintenance indoximod plus temozolomide. Six newly diagnosed DIPG patients initiated treatment, with all 6 having completed induction radioimmunotherapy. Treatment was well tolerated with symptomatic improvement in all 6 patients. Site-reported radiographic review indicated near resolution of tumor in one patient at the end of radiotherapy and observable improvement in 5 out of 6 patients overall. A seventh patient with progressive DIPG received re-RT combined with indoximod, which was well tolerated with symptomatic improvement and objective tumor reduction per site-reported assessment on post-RT MRI.

Exhibit 99.1

"These initial findings further support the potential for indoximod in combination with other agents," said Charles J. Link, Jr., M.D., Chairman and Chief Executive Officer. "We look forward to working with our investigators toward gathering more data on the effects of indoximod on this deadly disease."

NewLink will also present during poster session PO.IM02.07, Immunomodulatory Agents and Interventions 1, Abstract 3753, entitled: Indoximod modulates AhR-driven transcription of genes that control immune function, from 8:00 AM – 12:00 PM CT on Tuesday, April 17, 2018.

Separately, the Company has determined that it will not initiate the randomization portion of Indigo301, its study of indoximod in combination with pembrolizumab or nivolumab for patients with advanced melanoma. NewLink’s clinical team will evaluate the design, trial size and feasibility of an alternative randomized evaluation of indoximod in melanoma in the context of the failure of a competitor’s trial of its enzymatic IDO inhibitor in a similar clinical setting. The evaluation will include analysis of the full data set from the Company’s single-arm Phase 2 melanoma study, the differentiated mechanism of action of indoximod, and the opinions of experts in the field. The Company will present final results from its Phase 2 trial in melanoma and its single-arm Phase 2 trial in pancreatic cancer at an upcoming medical conference in the first half of 2018.

About Indoximod
Indoximod is an investigational, orally available small molecule targeting the IDO pathway. The IDO pathway is a key immuno-oncology target involved in regulating the tumor microenvironment and immune escape. Indoximod is being evaluated in combination with treatment regimens including anti-PD-1/PD-L1 agents, cancer vaccines, radiation and chemotherapy across multiple indications such as melanoma, pancreatic cancer and other malignancies.

On April 15, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that presented data from the Phase 3 OlympiAD trial showing the final overall survival (OS) results for LYNPARZA in metastatic breast cancer at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago from April 14-18 (Press release, Merck & Co, APR 15, 2018, View Source [SID1234525311]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The trial compared LYNPARZA with chemotherapy (physician’s choice of capecitabine, eribulin or vinorelbine) for patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer and met its primary endpoint of progression-free survival (PFS).

Results at AACR (Free AACR Whitepaper) include updated findings from the secondary endpoint of overall survival (OS). While the trial was not powered to demonstrate a statistically significant difference, the median OS was 19.3 months in patients treated with LYNPARZA and 17.1 months for patients treated with chemotherapy (HR 0.90, 95% CI 0.66-1.23; p=0.513). At the final OS data cutoff (64% maturity), 13 percent of patients remained on LYNPARZA and no patients remained on chemotherapy.

Sean Bohen, executive vice president, global medicines development and chief medical officer at AstraZeneca, said, "OlympiAD is the first Phase 3 trial to demonstrate disease control with a PARP inhibitor in gBRCA-mutated, HER2-negative metastatic breast cancer. While the trial was not powered to show overall survival compared to chemotherapy, the results are another encouraging factor in the use of LYNPARZA for this patient population."
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "For patients and physicians, these results are meaningful in that they support the progression-free survival endpoint – which showed that patients treated with LYNPARZA gained seven months chemotherapy-free time – and reinforce the importance of identifying BRCA status to optimize metastatic breast cancer management."
When analyzing the predefined subgroups, the results were consistent with the overall analysis, which did not show a statistically significant difference between arms. The greatest difference was seen in patients who had not received chemotherapy in the metastatic setting with a median difference in OS of 7.9 months with LYNPARZA (HR 0.51, 95% CI 0.29-0.90; nominal p=0.02; median 22.6 vs 14.7 months).

The safety profile of LYNPARZA remained consistent with the primary analysis. Serious adverse events (AEs) (Grade ≥3) were reported in 38 percent of patients who received LYNPARZA vs 49.5% of patients in the chemotherapy arm. AEs leading to drug discontinuation were 4.9 percent for LYNPARZA vs 7.7 percent for chemotherapy. AEs leading to dose reductions were 25.4 percent for LYNPARZA vs 30.8 percent for chemotherapy. AEs leading to dose interruptions were 36.1 percent for LYNPARZA vs 28.6 percent for chemotherapy. Please see Important Safety Information below.

These results build on previously reported primary and secondary endpoints, which demonstrated LYNPARZA significantly improved PFS (HR 0.58, 95% CI 0.43-0.80; p=0.0009 median 7.0 vs 4.2 months) and showed data beyond initial disease progression, prolonging time to second progression or death (PFS2) by 3.9 months (HR 0.57, 95% CI 0.40-0.83; P=0.003 median 13.2 months vs 9.3 months). Previously reported findings also showed LYNPARZA doubled objective response rates (52% [95% CI 44-60] vs 23% [95% CI 13-35]). The data from the OlympiAD trial can be found in the August 10 2017 issue of the New England Journal of Medicine.
In January 2018, LYNPARZA was approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of g BRCA-mutated metastatic breast cancer based on the OlympiAD data. A Type 2 Variation application was recently validated by the European Medicines Agency for LYNPARZA in BRCA-mutated, HER2-negative metastatic breast cancer.

A Phase 3 trial (n=1800), OlympiA, is evaluating LYNPARZA as an adjuvant treatment in patients with gBRCA, HER2-negative breast cancer with results expected in 2020. The trial is powered to assess potential benefit in OS.
LYNPARZA is approved in around 60 countries for advanced ovarian cancer and has treated more than 20,000 patients globally. It has the broadest clinical development program of any PARP inhibitor, and AstraZeneca and Merck are working together to bring LYNPARZA to more patients across multiple cancers.
Important Safety Information for LYNPARZA (olaparib)
Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA (olaparib) if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.
Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males
Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.
Adverse Reactions—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions
Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA (olaparib). If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.
Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).
Dosing and Administration

To avoid substitution errors and overdose, do not substitute LYNPARZA tablets with LYNPARZA capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Recommended tablet dose is 300 mg, taken orally twice daily, with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption or dose reduction.
Indications for LYNPARZA (olaparib) in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please see complete Prescribing Information for LYNPARZA (olaparib), including Patient Information (Medication Guide)
NOTES TO EDITORS
About OlympiAD
OlympiAD is a global, randomized, open-label, multi-center Phase 3 trial of 302 patients, assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) compared to chemotherapy (physician’s choice of capecitabine, eribulin or vinorelbine). 205 patients were randomized to receive LYNPARZA and 97 patients were randomized to receive chemotherapy.

Patients in the OlympiAD trial had germline BRCA-mutated, HER2-negative breast cancer and received LYNPARZA for treatment in the metastatic setting. Prior to enrollment, 71 percent of patients had received no more than two previous chemotherapy treatments for metastasized breast cancer and 28 percent of patients had received prior platinum-based chemotherapy. Also enrolled were patients with hormone receptor (HR)-positive breast cancer who had received at least one endocrine therapy (adjuvant therapy or therapy for metastatic disease) and had disease progression during therapy unless they had disease for which the endocrine therapy was considered inappropriate.
The primary endpoint was PFS. Secondary endpoints included OS, time to second progression or death, overall response rate, health-related quality of life, and safety and tolerability.

About Metastatic Breast Cancer
Progesterone receptors (PR), estrogen receptors (ER) and HER2 receptors may be expressed on breast cancer cells. A patient’s breast cancer will test either negative or positive for these three receptors. If a tumor tests positive for PR and/or ER, it is considered HR-positive. If a tumor tests negative for all three receptors, it is considered triple negative. These receptors indicate which hormones or other proteins may be promoting growth of the cancer.
Metastatic breast cancer (MBC) is the most advanced stage of breast cancer (Stage 4), and occurs when cancer cells have spread beyond the initial tumor site to other parts of the body, outside of the breast and nearby lymph nodes.
Despite the increase in treatment options during the past three decades, there is currently no cure for patients diagnosed with MBC and only 26.9 percent of patients survive for five years after diagnosis. Thus, the primary aim of treatment is to slow progression of the disease for as long as possible, improving, or at least maintaining, a patient’s quality of life.

Breast cancer is the most common cancer in women, with an estimated 1.67 million new cases diagnosed worldwide in 2012 alone – one in four of all cancer cases. Approximately 30 percent of women who are diagnosed with early breast cancer will go on to develop advanced disease.
About BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About LYNPARZA (olaparib)
LYNPARZA was the first in class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.
LYNPARZA, which has the broadest clinical development program of any PARP inhibitor, is being investigated in a range of DDR-deficient tumor types

On April 15, 2018 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that an oral presentation featuring FPA150, Five Prime’s first-in-class B7-H4 antibody, was given today at the 2018 AACR (Free AACR Whitepaper) Annual Meeting in Chicago (Press release, Five Prime Therapeutics, APR 15, 2018, View Source [SID1234525310]). The presentation titled "FPA150: A Recombinant, Afucosylated, Fully Human IgG1 Monoclonal Antibody for the Treatment of Malignancies that Express High Levels of B7-H4" by Charles Kaplan is available at View Source

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

FPA150 is a novel B7-H4 antibody that possesses both T cell immune checkpoint blockade and antibody-dependent cellular cytotoxicity (ADCC) activities. FPA150 demonstrates dose-dependent anti-tumor activity in vivo as a monotherapy and elicits complete tumor regressions in preclinical tumor models when given in combination with PD-1 blockade. Five Prime is currently studying FPA150 in a Phase 1 monotherapy trial in patients with solid tumors that overexpress B7-H4.
"Our monoclonal B7-H4 antibody, FPA150, appears to possess both T cell checkpoint blockade activity and enhanced ADCC," said Bryan Irving, Ph.D., Senior Vice President of Research, at Five Prime. "We are studying FPA150 in patients whose tumors overexpress B7-H4 and in which there is high unmet need for immuno-oncology treatments, such as in breast, ovarian and endometrial cancer. Based on the therapeutic properties of FPA150, we believe that this agent has the potential to be an effective therapeutic by improving anti-tumor immune responses in cancer patients."

B7-H4 is a member of the B7-family of T cell immune checkpoint ligands and shares significant homology with other family members, including PD-L1 and PD-L2. B7-H4 is expressed in several human tumors such as carcinomas of the bladder, breast, ovary and endometrium, and its expression tends to correlate with poor prognosis. B7-H4 is also a documented T cell immune checkpoint inhibitory ligand capable of directly suppressing T cell responses.

In Investigational New Drug (IND)-enabling pharmacokinetics (PK) and toxicity studies, FPA150 demonstrated a suitable PK profile and was generally well tolerated. A B7-H4 immunohistochemistry (IHC) assay is in development for clinical use as a companion diagnostic to help identify the patients who might benefit most from this treatment.
Five Prime is studying FPA150 in a Phase 1 monotherapy trial with a dose-escalation phase in patients with solid tumors, followed by dose expansion in pre-specified cohorts in tumor types based on B7-H4 expression levels. The initial targeted tumors are advanced or metastatic breast, ovarian, endometrial and bladder cancers.

About FPA150
FPA150 is a novel, fully human, afucosylated monoclonal antibody targeting B7-H4. B7-H4 expression is observed in multiple solid tumors, including breast, bladder, ovarian and endometrial cancers, and has been documented to correlate with poor prognosis. FPA150 is designed with a dual mechanism of action: blocking the T cell checkpoint activity of B7-H4 as well as delivering potent ADCC against tumor cells expressing B7-H4. FPA150 is currently being studied in a Phase 1 clinical trial in advanced or metastatic breast, ovarian, endometrial and bladder cancers.

On April 15, 2018 Blueprint Medicines Corporation (NASDAQ:BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported proof-of-concept data from the ongoing Phase 1 ARROW clinical trial of BLU-667 in patients with RET-altered solid tumors (Press release, Blueprint Medicines, APR 15, 2018, View Source;p=RssLanding&cat=news&id=2342578 [SID1234525309]). Designed and developed by Blueprint Medicines, BLU-667 is a potent and highly selective inhibitor targeting oncogenic RET fusions and mutations, which are key drivers across multiple cancers, including subsets of patients with non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). The data will be presented today in a clinical trials plenary session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, Illinois.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The data from the dose escalation portion of the ARROW trial showed broad and robust clinical activity for once-daily (QD) dosing of BLU-667 across multiple tumor types and RET genotypes, including in patients whose disease had progressed on prior multi-kinase inhibitor therapy. As of the data cutoff date of April 6, 2018, the data showed radiographic tumor reductions in 84 percent of patients with RET-altered solid tumors with measurable target lesions. In patients evaluable for response, preliminary overall response rates (ORR) were 50 percent in patients with NSCLC and 40 percent in patients with MTC. As of the data cutoff date, QD dosing of BLU-667 was well-tolerated, and most adverse events (AEs) reported by investigators were Grade 1 or 2.
"The data announced today reveal the broad clinical potential of BLU-667, a potent and highly selective RET inhibitor, and further demonstrate the power and reproducibility of Blueprint Medicines’ proprietary drug discovery platform," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "We believe the safety, clinical activity and pharmacodynamic results from the dose escalation portion of the Phase 1 ARROW trial demonstrate compelling proof-of-concept for BLU-667. We are particularly encouraged by the consistency of these early BLU-667 data across multiple tumor types, RET alterations and prior lines of therapy. Based on these data, we are excited to rapidly advance the global expansion portion of the trial, which will further evaluate an optimized dose of BLU-667 across a broad patient population with a focus on durability of activity."
Data from the Ongoing Phase 1 ARROW Clinical Trial
As of the data cutoff date of April 6, 2018, 53 patients had been treated with BLU-667 in the dose escalation portion of the Phase 1 ARROW clinical trial across multiple dose levels ranging from 30 mg to 600 mg QD, including 19 patients with NSCLC, 29 patients with MTC and five patients with other solid tumors. Of these 53 patients, 27 patients (51 percent) had been previously treated with a multi-kinase inhibitor and 18 patients (34 percent) had been previously treated with an immunotherapy.
Pharmacokinetic (PK) data across all QD dose levels demonstrated rapid absorption of BLU-667 and a mean half-life greater than 12 hours, supporting a QD dosing regimen.
Preliminary Safety Data:
As of the data cutoff date, QD dosing of BLU-667 was observed to be well-tolerated. The maximum tolerated dose (MTD) for BLU-667 was determined to be 400 mg QD using a Bayesian optimal interval design. At QD dose levels up to and including the MTD, the majority of AEs reported by investigators were Grade 1 or 2. AEs reported by investigators (≥20 percent) most commonly included constipation (24 percent), increased alanine aminotransferase (ALT) (22 percent) and increased aspartate aminotransferase (20 percent). Investigators reported treatment-related Grade 3 AEs in eight patients (16 percent). Treatment-related Grade 3 AEs occurring in two or more patients included hypertension and neutropenia. There were no treatment-related Grade 4 or 5 AEs.
Across all QD dose levels up to 600 mg QD, seven patients experienced dose-limiting toxicities. Only one patient discontinued treatment with BLU-667 due to a dose-limiting toxicity (Grade 3 ALT increase). An additional 11 patients discontinued treatment, including eight patients due to progressive disease, one patient due to an AE unrelated to BLU-667 and one patient due to non-compliance. One patient passed away, and the death was deemed unrelated to BLU-667. Among all 53 enrolled patients, 41 patients (77 percent) remained on BLU-667 as of the data cutoff date. Duration of treatment ranged from 0.3 to 11.5 months.
Preliminary Clinical Activity Data:
As of the data cutoff date, 40 patients with RET-altered tumors were evaluable for response assessment, including 14 patients with NSCLC, 25 patients with MTC and one patient with papillary thyroid cancer (PTC). CT and MRI imaging was used to measure clinical activity by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Of the remaining 13 enrolled patients who were not evaluable for response assessment, two patients did not have RET-altered tumors, one patient died due to an AE unrelated to BLU-667 prior to any response assessment and 10 recently enrolled patients had not been evaluated for response by the data cutoff date.
Across all evaluable patients, the preliminary ORR was 45 percent. Responses were observed in patients previously treated with multi-kinase therapy, immunotherapy and chemotherapy.
RET-altered NSCLC
85% of NSCLC patients with measurable target lesions had radiographic tumor reductions.
Seven patients achieved a partial response (PR) (five confirmed, two pending confirmation), representing a preliminary ORR of 50 percent.
Responses were observed in patients with the most common RET alterations in NSCLC, including RET-KIF5B and RET-CCDC6 fusions.
Preliminary evidence of anti-tumor activity in the brain was observed in metastatic NSCLC.
RET-altered MTC
83% of MTC patients with measurable target lesions had radiographic tumor reductions.
One patient achieved a confirmed complete response, nine patients achieved a PR (five confirmed, four pending confirmation), representing a preliminary ORR of 40 percent.
Responses were observed in patients with the most common activating RET mutations in MTC, including the RET-M918T mutation.
Other RET-altered solid tumors
One patient with RET-altered PTC achieved a PR (pending confirmation).
Based on the favorable tolerability and encouraging clinical activity observed for BLU-667 to date, Blueprint Medicines initiated and is actively enrolling patients in the global expansion portion of the ARROW trial.
Investor Event and Webcast Information
Blueprint Medicines will host an investor event on Sunday, April 15, 2018 beginning at 7:00 p.m. CT (8:00 p.m. ET) in Chicago to review the preliminary clinical data presented at AACR (Free AACR Whitepaper) for BLU-667. Formal presentations and the live webcast will begin at 7:30 p.m. CT (8:30 p.m. ET). The event can be accessed by dialing 1-855-728-4793 (domestic) or 1-503-343-6666 (international) and providing the passcode 6080608. A live webcast will also be available under "Events & 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 event concludes and will be available for 30 days following the event.
About the Phase 1 ARROW Clinical Trial of BLU-667
ARROW is a Phase 1 clinical trial of BLU-667 designed to evaluate the safety and tolerability of BLU-667 in multiple ascending doses in adults with RET-altered NSCLC, MTC and other advanced solid tumors. The trial consists of two parts: a dose escalation portion and an expansion portion. Enrollment in the dose escalation portion is complete, and the expansion portion has been initiated and is actively enrolling patients in four defined cohorts at the MTD of 400mg QD: (1) RET-altered NSCLC patients previously treated with a tyrosine kinase inhibitor (TKI), (2) RET-altered NSCLC patients who have not previously received any TKI treatment, (3) patients with medullary thyroid cancer, and (4) patients with other RET-altered solid tumors. Trial objectives include assessing response, pharmacokinetics, pharmacodynamics and safety.
Patients and physicians interested in the ARROW trial can contact the Blueprint Medicines study team at [email protected] or 1-617-714-6707. More information about the ARROW trial is also available at www.arrowtrial.com or www.clinicaltrials.gov (Identifier: NCT03037385).
About RET-Altered NSCLC, MTC and Other Solid Tumors
RET activating fusions and mutations are a key disease driver in multiple cancers, including NSCLC and MTC. RET fusions are implicated in approximately 1-2% of patients with NSCLC, while RET mutations are implicated in approximately 60% of patients with MTC. In addition, genomic analyses published by scientists at Blueprint Medicines have identified RET fusions at low frequencies in colon and breast cancer. Currently, there are no approved therapies that selectively target RET-driven cancers, though there are several approved multi-kinase inhibitors with RET activity being evaluated in clinical trials. Thus far, clinical activity attributable to RET inhibition has been uncertain for these inhibitors, likely due to insufficient inhibition of RET and off-target toxicities.
About BLU-667
BLU-667 is an orally available, potent and highly selective inhibitor designed to target RET fusions, mutations and predicted resistance mutations. Blueprint Medicines is developing BLU-667, an investigational medicine, for the treatment of patients with RET-altered NSCLC, MTC and other solid tumors. BLU-667 was discovered by Blueprint Medicine’s research team leveraging its proprietary compound library, and Blueprint Medicines retains worldwide development and commercialization rights for BLU-667.

On April 14,2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that it will present data from across its broad cancer immunotherapy development programme, including approved and investigational medicines, during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting from 14 April to 18 April in Chicago, IL, United States (Press release, Hoffmann-La Roche, APR 14, 2018, View Source [SID1234525313]). More than 42 abstracts have been accepted, including five "late breakers" and seven oral presentations.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Through our extensive research in the areas of tumour characterisation we are developing therapies that help the immune system to mount a deep and long lasting anti-cancer response," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "A personalised combination approach of cancer immunotherapies like TECENTRIQ with various chemotherapies, targeted medicines and other immunotherapies is central to our goal of providing transformative outcomes for people living with cancer."

Key highlights from the Roche cancer immunotherapy portfolio include an updated analysis from the Phase III IMpower150 study of TECENTRIQ and Avastin plus paclitaxel and carboplatin chemotherapy in people with advanced non-squamous non-small cell lung cancer (NSCLC). The study demonstrated significantly improved progression free survival (PFS) across all PD-L1 subgroups (ITT-WT, hazard ratio [HR]=0.61; p<0.0001%; CI: 0.51-0.72), including in people whose tumours are considered PD-L1-negative regardless of the PD-L1 IHC assay used, compared to Avastin plus paclitaxel and carboplatin chemotherapy. A clinically meaningful progression free survival (PFS) advantage was also seen in people with sensitising EGFR mutations, ALK genomic rearrangements, and in people with liver metastases. Importantly, IMpower150 recently met it’s co-primary endpoint of overall survival (OS) and showed that the combination of TECENTRIQ and Avastin plus paclitaxel and carboplatin chemotherapy helped people with advanced lung cancer live longer compared to Avastin plus carboplatin and paclitaxel as an initial treatment for people with advanced NSCLC. These data will be presented at an upcoming oncology meeting in 2018.

There is a scientific rationale for combining TECENTRIQ and abraxane which suggests that the mechanisms of action of each of the medicines may be complementary in the treatment of mTNBC, as they each target different steps in the cancer immunity cycle.

Results from this single arm cohort (N=33) of the Phase 1b study of TECENTRIQ plus nab-paclitaxel chemotherapy in people with metastatic triple negative breast cancer (mTNBC) show encouraging efficacy signals, and the safety of TECENTRIQ plus nab-paclitaxel in this combination is, so far, consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination.
A trend toward higher response rates and longer PFS and OS was seen for patients treated in the 1L setting compared to later lines. The ongoing randomised Phase III trial, IMpassion130, is investigating the same regimen as the Phase 1b study, with topline data expected later in 2018.

A retrospective analysis of the biology underlying primary immune escape and responsiveness to TECENTRIQ in tumour samples of people from the phase II IMvigor210 study for people with metastatic urothelial cancer showed that response to TECENTRIQ was highly associated with tumour mutational burden (TMB) and pre-existing T cell immunity. Additionally, another signalling protein known as transforming growth factor-beta (TGF-β) appears to be a negative indicator of response to TECENTRIQ, especially in the immune-excluded tumour phenotype that is common in mUC. Integration of these three independent biological features provides a foundation for understanding outcomes for people living with mUC.
Overview of key Cancer Immunotherapy data AACR (Free AACR Whitepaper) 2018

About TECENTRIQ (atezolizumab)
TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the activation of T cells. TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

TECENTRIQ is already approved in the European Union, United States and more than 50 countries for people with previously treated metastatic NSCLC and for people with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About the TECENTRIQ (atezolizumab) and Avastin (bevacizumab) combination
There is a strong scientific rationale to support combining TECENTRIQ and Avastin. The TECENTRIQ and Avastin regimen may enhance the potential of the immune system to combat a broad range of cancers, including first-line advanced NSCLC. Avastin, in addition to its established anti-angiogenic effects, may further enhance TECENTRIQ’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumour infiltration and enabling priming and activation of T-cell responses against tumour antigens.
About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with TECENTRIQ to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.
To learn more about the Roche approach to cancer immunotherapy please follow this link: View Source