On December 7, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that a biomarker analysis of the NSABP FB-7 Phase II clinical trial of Puma’s investigational drug PB272 (neratinib) was presented at the 2016 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 7, 2016, View Source [SID1234516991]). The presentation entitled "An exploratory correlative biomarker analysis of NSABP FB-7, a phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer" was presented as a poster presentation. This trial was sponsored by the NSABP Foundation, Inc.

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The FB-7 trial is a randomized Phase II clinical trial for women with HER2-positive locally advanced stage IIB-IIIC invasive breast cancer. Patients were randomly assigned to receive trastuzumab (T) or neratinib (N) or the combination (T+N) with weekly paclitaxel (P) followed by standard doxorubicin and cyclophosphamide chemotherapy (AC) administered prior to surgery. 126 U.S., Canadian, and European patients were randomly assigned to Arm 1 (T+P followed by AC), Arm 2 (N+P followed by AC) or Arm 3 (T+N+P followed by AC). The primary endpoint of the trial was pathological complete response rate (pCR) in the breast and lymph nodes. The clinical safety and efficacy data from this trial was presented at the 2015 SABCS.

A key secondary endpoint of the FB-7 trial was to evaluate molecular and genetic markers for correlation with response. Pre-treatment core biopsy samples (n=59) and post treatment surgical samples (n=17) were obtained from a subset of patients treated in the FB-7 trial. pCR data were available for 51 patients from the biomarker cohort. After excluding low tumor content non-evaluable samples, correlative biomarker analysis was performed in 42 patients.

Expression levels and the activation status of EGFR/HER2 signaling proteins were investigated. The results of the phosphorylated HER2 (phosphoHER2) showed that median levels of phosphoHER2 were higher in the patients who achieved a pCR with neratinib (n=7) than in the patients who did not achieve a pCR who received either trastuzumab (n=8, p=0.07) or the combination of trastuzumab plus neratinib (n=4, p=0.035). There was not a significant difference in the median levels of phosphoHER2 in the patients who achieved a pCR with neratinib (n=7), trastuzumab (n=8, p=0.16) or the combination of trastuzumab plus neratinib (n=4, p=0.10).

The truncated form of HER2 known as p95HER2 was measured by the proprietary assay of Pierian Bioscience. p95HER2 represents a truncated form of the HER2 receptor that lacks the extracellular trastuzumab binding domain. It is believed to represent a mechanism of trastuzumab resistance. Median p95HER2 levels were higher in samples from patients who achieved a pCR with neratinib than in the patients who did not achieve a pCR who received either trastuzumab (p=0.027) or the combination of trastuzumab plus neratinib (p=0.009). There was not a significant difference in the median levels of p95HER2 in the patients who achieved a pCR with neratinib (n=7), trastuzumab (n=8, p=0.16) or the combination of trastuzumab plus neratinib (n=4, p=0.35).

The MammaPrint assay was performed on 59 samples to determine if there was any imbalance between arms. This assay is a genomic test that analyzes the activity of 70 genes and then calculates a recurrence score that is either low risk or high risk. The results of the MammaPrint showed that the patients in all three arms of the FB-7 trial were balanced with the median MammaPrint risk score being similar across arms. There were only three patients with a MammaPrint low score.

Dr. Samuel Jacobs, Emeritus Clinical Professor in the Department of Medicine, University of Pittsburgh School of Medicine, and the Director of Medical Affairs for the NSABP Foundation, Inc., said, "We are pleased to see the results of this exploratory biomarker analysis which suggests that activation of the HER pathway based on p95HER2 and phosphoHER2 may correlate with pCR to neratinib. Further biomarker analysis in additional datasets will be needed to determine which patients may derive the greatest benefit from neratinib."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to complete this biomarker analysis of neratinib. Further results of the biomarker analysis should help us to determine the best path forward for neratinib in the neoadjuvant treatment of HER2-positive early stage breast cancer."

On December 7, 2016 PharmaCyte Biotech, Inc. (OTCQB:PMCB), a clinical stage biotechnology company focused on developing targeted treatments for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported the first article in a series of Q&A articles that will be conducted with some of the key team members of PharmaCyte’s planned clinical trial in locally advanced, inoperable pancreatic cancer (LAPC) (Press release, PharmaCyte Biotech, DEC 7, 2016, View Source [SID1234516987]). PharmaCyte’s first Q&A article is with Dr. Matthias Löhr of the famed Karolinska Institute in Stockholm, Sweden. Dr. Löhr was the Principal Investigator of the two earlier clinical trials using the Cell-in-a-Box technology in patients with advanced, inoperable pancreatic cancer.

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As PharmaCyte prepares to meet with the FDA in a Pre-IND meeting, what are your general thoughts of the Cell-in-a-Box plus low dose ifosfamide therapy for pancreatic cancer once again getting a chance to prove itself in patients?

Dr. Matthias Löhr: "I feel very confident and also happy to see the revival of this treatment concept. I consider Cell-in-a-Box as a platform technology. The previously raised concerns relating to the consistent reproducibility of the micro-capsules have been met by Austrianova in the meantime. Pancreatic cancer is a medical emergency (View Source) and is rising amongst the cancer related deaths, this year surpassing breast cancer to become number three, and by 2030 to become number two."

As the Principle Investigator of both of the earlier clinical trials, what are some of the highlights you recognized that you feel will once again be seen in PharmaCyte’s upcoming trial?

Dr. Matthias Löhr: "When we treated the first patients, they did not believe that they were receiving chemotherapy because there were NO side effects at all in the initial trial. That should be the case in PharmaCyte’s upcoming trial. Besides this very subjective impression, albeit repeated by all patients, we measured the quality of life, which was excellent – considering the dire disease. We will be measuring the quality of life in the upcoming trial as well. Further, we saw an effect not only on the primary tumor in the pancreas (where the capsules were injected) but also in some patients on the liver metastasis. This can only be explained by an immunological bystander effect that will likely be investigated in more depth in the upcoming clinical trial. Finally, in the first trial, certain patients’ tumors went from inoperable to operable. That is certainly a possibility in PharmaCyte’s trial, especially since we will be giving more than two courses of ifosfamide like we did in the first trial."

Why do you feel this new trial design can succeed?

Dr. Matthias Löhr: "The locally advanced pancreatic cancers are not sufficiently covered by guidelines – there is no standard of care, hence a highly unmet medical need. This refers particularly to those patients who received first line therapy, e.g. a very strong one (FOLFIRINOX) or combination of gemcitabine with Abraxane. AFTER this therapy, there is nothing left, especially an alternative with a low likelihood of side effects. The selection of these patients (group) is certainly to an advantage of the Cell-in-a-Box technology, which is mostly localized, may have a systemic (immunological) effect and has virtually no side effects. We consider this an ideal setting to the advantage of our patients in this upcoming clinical trial."

What are your thoughts on the benefits of using more rounds of the chemotherapy prodrug ifosfamide as PharmaCyte’s trial design calls for in this upcoming clinical trial?

Dr. Matthias Löhr: "This will definitively improve the outcome of the patients in this upcoming clinical trial. We couldn’t do this in the original trial(s) as we had no information on the stability of the capsules and activity of the cells converting the chemotherapy drug ifosfamide. This has changed now with the data developed from the first two trials. We will continue to administer ifosfamide until the patients receive no further benefit from our therapy. We can do that because we know the capsules are robust for at least two years and that the cells within them continue to convert ifosfamide during the life of the patient."

What are your thoughts on going head to head with gemcitabine?

Dr. Matthias Löhr: "No sweat. Gemcitabine is still the standard, due to the excellent tolerability of the drug and will be the drug used second line, especially after heavy protocols such as FOLFIRINOX or gemcitabine/ Abraxane. In this pretreated patient group, one has to use something with a very low profile on side effects. This is certainly the case with our Cell-in-A-Box."

What are your impressions of the team that surrounds the technology as PharmaCyte heads into its planned clinical trial?

Dr. Matthias Löhr: "PharmaCyte has the visionary capacity to see the potential of this platform technology, with pancreatic cancer being the first indication. They reached out to the original team, both those developing the technology and conducting the early phase clinical trials. Taking this knowledge on board is certainly the most important factor to ensure success. Further, with both Dr. Manuel Hidalgo and Dr. Daniel Von Hoff, two eminent oncologists with a lifetime track record in oncology and especially pancreatic cancer, the starting conditions could not be better."

On December 7, 2016 Celgene Corporation (NASDAQ:CELG) reported that the results of its randomized phase II tnAcity trial of ABRAXANE for injectable suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) will be presented at the 2016 San Antonio Breast Cancer Symposium (SABCS) December 6-10, 2016 (Press release, Celgene
, DEC 7, 2016, View Source [SID1234516986]). The trial found that an investigational weekly combination regimen of ABRAXANE + carboplatin had significantly longer progression-free survival (PFS) (7.4 months) compared to weekly regimens of either ABRAXANE + gemcitabine (5.4 months) or of carboplatin + gemcitabine (6.0 months) as first-line treatment of patients with metastatic triple-negative breast cancer (mTNBC).i

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The phase II trial randomized 191 women with mTNBC to receive one of three weekly regimens (dosed 2 out of 3 weeks): ABRAXANE + carboplatin, ABRAXANE + gemcitabine, or carboplatin + gemcitabine as first-line treatment. The study findings demonstrated that ABRAXANE + carboplatin resulted in significantly longer PFS (7.4 months) than combination regimens with ABRAXANE + gemcitabine (5.4 months; P=0.02, HR 0.60 (95% CI, 0.39-0.93)) or carboplatin + gemcitabine (6.0 months; P= 0.03, HR 0.61 (95% CI, 0.39-0.94)). tnAcity also found that those treated with the ABRAXANE + carboplatin regimen experienced a longer median treatment duration (25 weeks) than those treated with ABRAXANE + gemcitabine (18.1 weeks) or carboplatin + gemcitabine (20.1 weeks).i

The most common grade ≥3 treatment emergent adverse events (TEAEs) observed in the ABRAXANE + carboplatin, ABRAXANE + gemcitabine, and carboplatin + gemcitabine arms, respectively, during the study were mainly hematologic and included neutropenia (42%, 27%, 52%), anemia (13%, 12%, 27%), thrombocytopenia (9%, 7%, 28%), leukopenia (6%, 3%, 11%), febrile neutropenia (5%, 2%, 0%), peripheral neuropathy (5%, 7%, 2%) and fatigue (3%, 15%, 3%). A median of 8 treatment cycles were initiated for the ABRAXANE + carboplatin arm and 6 cycles for both the ABRAXANE + gemcitabine and carboplatin + gemcitabine arms. The percentage of patients that discontinued any study drug due to a TEAE was 45% for ABRAXANE + carboplatin and 25% for each of the other arms. The most common AEs leading to discontinuation of any study drug included thrombocytopenia, anemia, neutropenia and drug hypersensitivity.i

"Metastatic triple negative breast cancer is one of the most challenging types of cancers for treating physicians and patients alike, and there remains an important unmet need in these patients to find more effective treatment options," said Dr. Denise A. Yardley, Senior Investigator, Breast Cancer Research Program; Principal Investigator, Sarah Canon Research Institute. "These data add to the body of knowledge about ABRAXANE in metastatic triple negative breast cancer, a disease that requires additional research."

After taking into consideration the rapidly changing breast cancer treatment landscape, which has a significant focus on immuno-oncology treatments, Celgene had determined not to move forward with the phase III portion of tnAcity. The Company will instead focus its breast cancer research support on ABRAXANE/Immunotherapy combinations and remains committed to applying the findings of tnAcity to ongoing and future research of ABRAXANE in breast cancer for patients with high unmet needs.

"The findings of tnAcity are encouraging, illustrating that an ABRAXANE-containing regimen may have activity in a type of breast cancer with few viable treatments and these findings give researchers additional insight into how to treat metastatic triple negative breast cancer," said Michael Pehl, President, Hematology and Oncology for Celgene. "Celgene is committed to continuing to support research in breast cancer to identify regimens for patients with aggressive disease and in areas with limited treatment options."

ABRAXANE is not indicated for the first-line treatment of metastatic breast cancer, or for the treatment regimens studied in tnAcity.

ABOUT tnAcityi,ii

tnAcity is a phase II/III multicenter, open-label, randomized clinical trial conducted in 139 centers in 12 countries. The study evaluated the safety and efficacy of the investigational use of a weekly treatment regimen of ABRAXANE in combination with carboplatin or gemcitabine as a first-line treatment of women with metastatic triple negative breast cancer (mTNBC) compared to a gemcitabine + carboplatin regimen.ii

The phase II portion of the tnAcity trial evaluated 191 patients with metastatic triple negative breast cancer (mTNBC) who had received no prior systemic chemotherapy treatment for their mTNBC and had an ECOG performance status of 0 or 1. Patients were randomized to one of three treatment arms: ABRAXANE 125 mg/m2 + carboplatin AUC 2, ABRAXANE 125 mg/m2 + gemcitabine 1000 mg/m2, or carboplatin AUC 2 + gemcitabine 1000 mg/m2 dosed weekly on days 1 and 8 of a 21-day cycle. The median age in each treatment arm was 55 (ABRAXANE + carboplatin), 53 (ABRAXANE + gemcitabine) and 59 (carboplatin + gemcitabine) years. The primary endpoint of the phase II trial was investigator assessed progression free survival (PFS). Secondary endpoints evaluated in the study included overall survival (OS) and objective response rate (ORR).

Additional ABRAXANE Data Presented at SABCS

Additional investigator initiated studies presented at SABCS also evaluated the investigational uses of ABRAXANE in the neoadjuvant setting in patients with previously untreated breast cancer (GeparSepto; P5-16-03) and as induction and maintenance therapy for women with HER2-negative metastatic breast cancer (SNAP; P5-15-05).

ABOUT ABRAXANE

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRADINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC)
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3
In the case of severe neutropenia ( < 500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with MBC
Resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level > 1500 cells/mm3 and platelets recover to > 100,000 cells/mm3
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold until resolution to Grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For MBC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

The most common adverse reactions (≥20%) with single-agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, < 1%), nausea (any 30%, 22%; severe 3%, < 1%), diarrhea (any 27%, 15%; severe < 1%, 1%) and infections (24%, 20%), respectively
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, < 1%), mucositis (any 7%, 6%; severe < 1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe < 1%, < 1%), neutropenic sepsis ( < 1%, < 1%), and injection site reactions ( < 1%, 1%), respectively. Dehydration and pyrexia were also reported
Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years or older who received ABRAXANE for MBC in a pooled analysis of clinical studies
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
Reduce starting dose in MBC patients with moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

On December 7, 2016 Progenics Pharmaceuticals, Inc. (Nasdaq:PGNX), an oncology company developing innovative medicines and other products for targeting and treating cancer, reported that the first patient has been dosed in the Company’s Phase 2/3 clinical trial evaluating the diagnostic accuracy of its PSMA-targeted PET/CT imaging agent, 18F-DCFPyL (PyLTM) (Press release, Progenics Pharmaceuticals, DEC 7, 2016, View Source [SID1234516983]). PyL was discovered by a team led by Martin G. Pomper, M.D., Ph.D., William R. Brody Professor of Radiology at the Center for Translational Molecular Imaging at the Johns Hopkins University School of Medicine.

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"There exists a significant need for approved molecular imaging modalities with both high sensitivity and specificity to detect high risk recurrent or metastatic prostate cancer early," said Lawrence Saperstein, M.D., Assistant Professor, Department of Radiology and Biomedical Imaging, Chief, Nuclear Medicine Program Director, Nuclear Radiology Fellowship, Yale University School of Medicine, where the first patient was dosed. "We believe PyL, when used with a PET/CT scan, can provide treating physicians with more accurate disease detection, potentially leading to earlier diagnoses, more informed treatment decisions as well as the ability to monitor responses, and ultimately improved patient outcomes."

The Phase 2/3 study will enroll approximately 300 patients with high risk prostate cancer with recurrence or metastatic disease in the United States and Canada. Primary endpoints of the study include the assessment of sensitivity and specificity of PyL PET/CT imaging to detect prostate cancer in the prostate gland and regional lymph nodes, as well as sensitivity in sites of metastasis or recurrence. Secondary endpoints include safety and tolerability, detection rate, and pharmacokinetic parameters.

"This trial initiation represents a significant milestone for our PyL program, and is designed to help support registration of this novel imaging agent," stated Mark Baker, Chief Executive Officer of Progenics. "The early clinical data for PyL have been quite impressive, underscoring its potential to transform disease management for prostate cancer, and we look forward to further demonstrating its diagnostic performance as we advance the trial."

About PyL for PET Imaging of Prostate Cancer

PyL (also known as 18F-DCFPyL) is a clinical-stage, fluorinated PSMA-targeted PET imaging agent for prostate cancer that was discovered and developed at the Center for Translational Molecular Imaging at the Johns Hopkins University School of Medicine. A proof-of-concept study published in the April 2015 issue of the Journal of Molecular Imaging and Biology demonstrated that PET imaging with PyL showed high levels of PyL uptake in sites of putative metastatic disease and primary tumors, while rapidly clearing from other organs, suggesting the potential for high sensitivity and specificity in detecting prostate cancer while appearing to be safe and well tolerated.

On December 7, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA), a rare cancer-focused innovative biotechnology company, reported clinical data on brigatinib, its investigational anaplastic lymphoma kinase (ALK) inhibitor, from the pivotal ALTA trial in ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients who had experienced disease progression on crizotinib therapy (Press release, Ariad, DEC 7, 2016, View Source;p=RssLanding&cat=news&id=2228143 [SID1234516982]). As of May 31, 2016, the data show that of patients on the 180-mg regimen with a median follow-up of 11 months, 55 percent achieved confirmed objective response as assessed by the investigator. In this arm, the median progression-free survival (PFS) was 15.6 months in this post-crizotinib setting, by both investigator and independent review committee (IRC) assessment. Additionally, in this arm, 67 percent of patients with measurable brain metastases achieved a confirmed intracranial objective response, and intracranial PFS was 18.4 months among patients with any brain metastases at baseline. These data will be presented today at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer (WCLC) being held in Vienna.

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"These updated ALTA trial data show that with additional follow-up, median progression-free survival from brigatinib given post-crizotinib is now 15.6 months, and that this is the same whether assessed by the investigators or an independent review committee," said D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the University of Colorado. "Whether this is a reflection of broader suppression of potential resistance mutations, or its effects on protecting the central nervous system, or both, requires further investigation but by itself these progression-free survival data should be very encouraging for physicians and patients alike. These data really support the idea to pursue brigatinib, not just post-crizotinib, but also in the ongoing ALTA 1L study, which aims to assess its potential in the ALK-treatment naive setting."

The ALTA Trial

The ALTA (ALK in Lung Cancer Trial of AP26113) trial enrolled 222 patients with ALK+ NSCLC who had been treated with and experienced disease progression on their most recent crizotinib therapy. Patients were randomized one-to-one to receive either 90 mg of brigatinib once per day (QD) (Arm A), or 180 mg QD, preceded by a lead-in dose of 90 mg QD for seven days (Arm B). In addition, patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib therapy.

The primary endpoint of the ALTA trial is investigator-assessed confirmed objective response rate (ORR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Key secondary endpoints include PFS, confirmed ORR assessed by an IRC, overall survival (OS), CNS response and PFS, duration of response, safety and tolerability.

Key Data from the ALTA Trial Update

Brigatinib Efficacy and Safety in ALK+ NSCLC Patients:
Clinical Data as of May 31, 2016 with IRC Data as of July 13, 2016

A total of 222 patients with ALK+ NSCLC treated with prior crizotinib therapy were randomized in the study (110 patients in Arm B at the 180-mg dose level with a seven-day lead-in at 90 mg and 112 patients in Arm A at the 90-mg dose level). The last patient was enrolled in the study in September 2015.
The median follow-up was 11 months in Arm B and 10.2 months in Arm A. ALTA trial data presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting, as of February 29, 2016, had median follow-up of 8.3 months in Arm B and 7.8 months in Arm A.
Investigator-assessed confirmed ORR in Arm B was 55 percent. IRC-assessed confirmed ORR in Arm B was 54 percent. Investigator-assessed confirmed ORR in Arm A was 45 percent. IRC-assessed confirmed ORR in Arm A was 49 percent.
In a subgroup analysis of confirmed ORR by baseline characteristics, there was no difference in confirmed ORR based on prior chemotherapy versus no prior chemotherapy.
The subgroup analysis by best response to prior crizotinib (partial or complete response versus other) suggests that patients who had achieved partial or complete responses on prior crizotinib treatment had a significantly higher confirmed ORR, compared with patients who did not achieve these responses.
Responses in Arm B included a confirmed partial response in a patient with the ALK kinase domain G1202R mutation at baseline, which is associated with resistance to all approved tyrosine kinase inhibitors (TKIs).
Median PFS was 15.6 months by both investigator assessment and IRC assessment in Arm B. Median PFS was 8.8 months by investigator assessment and 9.2 months by IRC assessment in Arm A.
Probability of OS at one year was 82 percent and 71 percent in Arm B and Arm A, respectively. The median OS had not been reached in either arm.
Of the 44 patients with measurable intracranial brain metastases at baseline, the IRC-assessed intracranial ORR was 67 percent (12/18) in Arm B and 46 percent (12/26) in Arm A.
The median IRC-assessed intracranial PFS was 18.4 months in Arm B and 15.6 months in Arm A.
The most common treatment-emergent adverse events (TEAEs; ≥ 30% of all patients, [Arm B/A]), regardless of relationship to treatment, were nausea (43%/36%), diarrhea (39%/21%), cough (36%/23%), headache (30%/28%) and increased blood creatine phosphokinase (CPK) (33%/11%).
TEAEs, grade ≥3, occurring in ≥4 percent of all patients (excluding neoplasm progression; Arm B/A), were increased CPK (10%/3%), hypertension (6%/6%), pneumonia (5%/3%) and increased lipase (3%/5%).
A subset of pulmonary adverse events (AEs) with early onset (median: Day 2; range: Day 1-9) occurred in six percent of all patients (grade ≥3 in 3% of patients); no such events with early onset occurred after dose escalation to 180 mg QD in Arm B.
Discontinuations and dose reductions due to AEs (Arm B/A) were 10 percent/three percent and 23 percent/eight percent, respectively. Discontinuations due to documented progressive disease (Arm B/A) were 23 percent and 30 percent.
"We are encouraged by the maturing efficacy and safety profile of brigatinib in this later data cut, which adds three months of follow up compared to the data presented at ASCO (Free ASCO Whitepaper)," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "These data are intended to be submitted to the European Medicines Agency in early 2017 for marketing approval. Pending regulatory review, we expect that brigatinib may become an important therapeutic option for the crizotinib-resistant population."

The poster presentation, "Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Central Assessment and Updates from ALTA, a Pivotal Randomized Phase 2 Trial," (Abstract #4046, Poster ID P3.02a-013) will be presented today, Wednesday, December 7, 2016 from 14:30 – 15:45 GMT.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. Brigatinib received Breakthrough Therapy designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted orphan drug designation by the FDA for the treatment of ALK+ NSCLC. The FDA has accepted brigatinib’s New Drug Application and has granted ARIAD’s request for Priority Review and set an action date of April 29, 2017 under the Prescription Drug User Fee Act (PDUFA). ARIAD intends to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency (EMA) in early 2017.

ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.