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Mateon Therapeutics Announces Termination of FOCUS Study in Ovarian Cancer and Restructuring to
Prioritize OXi4503 for AML

On September 26, 2017 Mateon Therapeutics, Inc. (OTCQX:MATN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported results from its third scheduled interim analysis of the phase 2/3 FOCUS study evaluating CA4P in combination with bevacizumab (Avastin) and physician’s choice chemotherapy in patients with platinum-resistant ovarian cancer (Press release, Mateon Therapeutics, SEP 27, 2017, View Source [SID1234520671]).

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FOCUS was designed to evaluate whether the addition of CA4P improved progression-free survival (PFS), the primary endpoint of the study, as well as objective response rate (ORR) and other measures. All patients enrolled in the FOCUS study received either CA4P or placebo plus the current standard-of-care for platinum-resistant ovarian cancer: bevacizumab (Avastin) and chemotherapy. The current analysis is based on initial results from the first 70 patients in the study who have been treated for at least two months or discontinued from the trial. A total of 91 patients were enrolled in FOCUS.

Efficacy Results

ORR data is summarized in the table below.

CA4P Control
Complete Response
0 (0%) 0 (0%)
Partial Response
8 (23.5%) 13 (36.1%)
Stable Disease
16 (47.1%) 17 (47.2%)
Progressive Disease
5 (14.7%) 3(8.3%)
Not Evaluable
5 (14.7%) 3(8.3%)

PFS, the primary endpoint of the study, favored the CA4P group, with a 32 day increase in median PFS for the patients receiving CA4P compared to patients receiving control (202 days vs. 170 days; HR=0.844; p=0.688). Progression events are available from 24 of 70 (34.3%) patients: 12 patients (35.3%) in the CA4P arm and 12 (33.3%) patients in the control arm progressed or died while in the study.

Due to the lack of a meaningful improvement in PFS, combined with the unfavorable partial response data, the company does not believe that continuation of the study is appropriate. Therefore, Mateon is immediately terminating the FOCUS Study and further development of CA4P. Mateon will continue to support investigator-sponsored studies and preclinical studies in combination with immuno-oncology agents.

"We are clearly disappointed that CA4P did not show a clinically meaningful benefit when it was added to the current standard of care in platinum-resistant ovarian cancer," said William D. Schwieterman, M.D., President and Chief Executive Officer. "I want to thank our investigators and advisors, as well as the patients that we treated, for their efforts to advance future cancer care. These external participants, along with our internal team, did a great job planning and executing the study, but the outcome is clear, and unfortunately negative."

Safety Results

The safety profile of CA4P was favorable. Similar to prior analyses, most patients receiving CA4P experienced transient increases in blood pressure compared to the control arm. Other adverse events occurring more often in the CA4P arm than in the control arm included: hypertension, fatigue, nausea, vomiting, and abdominal pain. Most adverse events were mild or moderate in severity, with blood pressure increase being the only adverse event with a
significant increase in Grade 3 or above (29.4% in CA4P arm versus 5.6% in control). Six patients in the treatment arm (17.6%) withdrew from the study for adverse events compared to three in the control arm (8.3%).
Reduction in Expenses

Given the company’s limited financial resources, Mateon is implementing various near-term cost reduction measures, which include a significant reduction in personnel, representing a decrease in the company’s workforce of approximately 60% since the beginning of the year. The remaining members of the senior management team will take 50% salary reductions, effective immediately.

"We assembled a great team that, within the last two years, has planned, initiated and completed the FOCUS Study ahead of schedule. The team has also planned, initiated and completed five cohorts of an on-going OXi4503 study for relapsed/refractory AML. With the company’s needs now very different, it is disheartening to terminate most of these employees following their solid work performances," concluded Dr. Schwieterman. "Going forward, our immediate focus is to obtain value from our OXi4503 program in AML, which, within the last two months, has shown clear positive clinical outcomes in relapsed/refractory patients. As always, we are exploring all options for additional fundraising and adding value for our stockholders, which includes continuing to look for buyers for any or all of our assets."

Bristol-Myers Squibb: Advancing Research Across Thoracic Cancers with New Data at IASLC 18th World Conference on Lung Cancer

On September 27, 2017 Bristol-Myers Squibb Company (NYSE: BMY) reported the presentation of 28 abstracts for Opdivo (nivolumab), alone and in combination with Yervoy (ipilimumab), targeted therapy or chemotherapy, at the International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan, from October 15-18. Data from company-sponsored studies, clinical collaborations and investigator-sponsored research demonstrate the Company’s ongoing commitment to Immuno-Oncology research across many types of thoracic cancers (Press release, Bristol-Myers Squibb, SEP 27, 2017, View Source [SID1234520667]). Presentations will include late-breaking data in malignant pleural mesothelioma, clinical and real-world evidence in Opdivo in previously treated advanced non-small cell lung cancer (NSCLC), as well as research on Opdivo-based combinations in advanced NSCLC and patient-reported outcomes in advanced small cell lung cancer (SCLC).

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"Bristol-Myers Squibb is dedicated to driving scientific innovation and investigating potential treatment options for patients with difficult-to-treat cancers and will share new data from our broad thoracic development program at the upcoming WCLC," said Nick Botwood, M.D., development lead, thoracic cancers, Bristol-Myers Squibb. "We are committed to researching the potential of Opdivo and Opdivo-based combinations in high unmet need areas, such as NSCLC, SCLC and mesothelioma, with the goal of bringing I-O treatment options to more patients."

Research from the following abstracts will be presented:

Late-Breaking Data in Malignant Pleural Mesothelioma

•

A phase 2 study of nivolumab: a multicenter, open-label, single arm study in malignant pleural mesothelioma (MERIT)
Author: Goto
Abstract #MA 19.01
Late Breaking Abstracts Session
Wednesday, October 18, 11:00 AM – 12:30 PM, Room 315

Clinical and Real-World Data in NSCLC and SCLC

•
Nivolumab versus chemotherapy as post-platinum therapy for advanced NSCLC in a real-world setting (CheckMate -118)
Author: Garon
Abstract # P1.01-051
Poster Session: P1.01
Monday, October 16, 9:30 AM – 4:00 PM, Hall B and C

•
Non-small cell lung cancer patient characteristics and clinical care insights in Sweden: the SCAN-LEAF study
Author: Sandelin
Abstract #P1.06-012
Poster Session: P1.06
Monday, October 16, 9:30 AM – 4:00 PM, Hall B and C

•
Survival by response to first-line platinum-based therapy among patients with extensive disease SCLC
Author: Yuan
Abstract #P1.15-003
Poster Session: P1.15
Monday, October 16, 9:30 AM – 4:00 PM, Hall B and C

•
Treatment patterns in extensive disease SCLC across the United States, Europe and Japan
Author: Yuan
Abstract #MA 01.09
Mini Oral Presentation: MA 01
Monday, October 16, 11:00 AM – 12:30 PM, Room 503

•
Health status in patients with SCLC treated with nivolumab alone or combined with ipilimumab: CheckMate -032
Author: Camidge
Abstract #P2.07-034
Poster Session: P2.07
Tuesday, October 17, 9:30 AM – 4:00 PM, Hall B and C

•
CheckMate -169: safety/efficacy of nivolumab in Canadian pretreated advanced NSCLC (including elderly and PS 2) patients
Author: Juergens
Abstract #P2.07-029
Poster Session: P2.07
Tuesday, October 17, 9:30 AM – 4:00 PM, Hall B and C

•
Impact of brain metastases on the humanistic burden incurred by patients with advanced NSCLC
Author: Chirita
Abstract #P2.01-012
Poster Session: P2.01
Tuesday, October 17, 9:00 AM – 4:00 PM, Hall B and C

•
Efficacy and safety of nivolumab therapy for advanced NSCLC in the expanded access named patient program in Taiwan
Author: Liao
Abstract #P2.07-027
Session P2.07
Tuesday, October 17, 2017, 9:30 AM – 4:00 AM, Hall B and C

•
Non-small cell lung cancer treatment and survival in Scandinavia: the SCAN-LEAF study
Author: Ekman
Abstract #MA 18.14
Mini Oral Presentation: Global Tobacco Control and Epidemiology II
Tuesday, October 17, 3:45–5:30 PM, Rooms 511 and 512

•
Nivolumab versus docetaxel in patients with previously treated advanced NSCLC and liver metastases (CheckMate -017 and CheckMate -057)
Author: Crino
Abstract #P3.07-012
Poster Session: P3.07
Wednesday, October 18, 9:30 AM – 4:00 PM, Hall B and C

•
Impact of tobacco smoking on the humanistic and financial burden of advanced NSCLC
Author: Chirita
Abstract #OA 11.01
Oral Abstract Session: Reducing Burden: Patient-Centered Care
Wednesday, October 18, 11:00 AM – 12:30 PM, Rooms 313 and 314

•
CheckMate -870 TiP: an open-label safety study of nivolumab in previously treated patients with NSCLC in Asia
Author: Lu
Abstract #P1.04-010
Poster Session: P1.04
Monday, October 16, 9:30 AM – 4:00 PM, Hall B and C

Research Evaluating Opdivo-based Combinations

•
Interim results of a Phase 1 study of nivolumab plus nab-paclitaxel/carboplatin in patients with NSCLC
Author: Goldman
Abstract #P1.03-026
Session: P1.03
Monday, October 16, 9:30 AM – 4:00 PM, Hall B and C

•
PIVOT-02: Phase 1/2 study of NKTR-214 and nivolumab in patients with locally advanced or metastatic solid tumor malignancies
Author: Papadimitrakopoulou
Abstract #P2.07-062
Session: P2.07
Tuesday, October 17, 9:30 AM – 4:00 PM, Hall B and C

•
Long follow up from Phase 1 study of nivolumab and chemotherapy in patients with advanced NSCLC
Author: Kanda
Abstract #P2.07-011
Session: P2.07
Tuesday, October 17, 9:30 AM – 4:00 PM, Hall B and C

•
First-line nivolumab plus platinum-based doublet chemotherapy for advanced NSCLC: CheckMate -012 3-year update
Author: Juergens
Abstract #OA 17.03
Oral Abstract Session: Immunotherapy II
Wednesday, October 18, 2:30–4:15 PM, Rooms 301 and 302
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

Pelican Therapeutics Announces Manufacturing Agreement with KBI Biopharma
to Advance Cancer-targeting Immunotherapies

On September 27, 2017 Pelican Therapeutics ("Pelican"), a subsidiary of Heat Biologics, Inc. ("Heat") (Nasdaq: HTBX), entered into a manufacturing agreement with KBI Biopharma, Inc., a global biopharmaceutical contract development and manufacturing organization, for cGMP production of its PTX-35 antibody and PTX-15 fusion protein (Press release, Heat Biologics, SEP 27, 2017, View Source [SID1234520664]). PTX-35 and PTX-15 have the potential to improve clinical response in combination with Heat’s ImPACT therapeutic platform and other immunotherapy drugs by simulating the production of antigen-specific T-cells.

"We selected KBI as our manufacturing partner because, based on our assessment, they have strong development capabilities, and possess the agility and flexibility to help Pelican prepare for early development of both our Phase 1 and 2 clinical trials," said Rahul Jasuja, CEO of Pelican.

Under the agreement, KBI Biopharma will offer comprehensive development and manufacturing services, which Pelican expects will offer advantages such as speed, productivity, stability and flexibility over traditional approaches to cell line development.

In May 2016, Pelican was awarded a $15.2 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT) to support these manufacturing efforts, as well as to complete a 70-patient, Phase 1 clinical trial incorporating one or more of these compounds.

Celsion Provides Update on ThermoDox® in the Phase III OPTIMA Study of Primary Liver Cancer

On September 27, 2017 (GLOBE NEWSWIRE) — Celsion Corporation (NASDAQ:CLSN), an oncology drug development company, reported a detailed update for the Company’s 550 patient, multinational, double-blind, placebo-controlled, pivotal Phase III clinical study of ThermoDox in combination with radiofrequency ablation (RFA) for primary liver cancer (the OPTIMA Study) which include recent investigators meetings in Bangkok, Thailand and Shanghai, China (Press release, Celsion, SEP 27, 2017, View Source [SID1234520660]). With the growing incidence of primary liver cancer in China and Asia-Pacific, representing approximately 75% of the estimated 850,000 cases diagnosed annually, this region represents a strategically important element of the Company’s global registration and commercialization strategy for ThermoDox.

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The Company announced that enrollment in the OPTIMA Study is now approaching 70% of the 550 patients necessary to ensure that its primary end point, overall survival, can be evaluated with statistical significance. The statistical plan for the OPTIMA Study calls for two interim efficacy analyses by the independent Data Monitoring Committee (DMC). The Company currently projects full patient enrollment by mid-2018 and the first pre-planned efficacy analysis after 118 overall survival events by the first quarter of 2019.

"With independent confirmation by the NIH of the relationship between RFA heating time and the significant impact that it has on overall survival when combined with ThermoDox, OPTIMA Study investigators fully recognize the value of the findings from the HEAT Study, reinforcing their interest and support for our highly de-risked, ongoing global Phase III OPTIMA Study," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "The previously announced unanimous recommendation for study continuation by the independent Data Monitoring Committee was based on their review of all available clinical data from 275 patients, and is further evidence of ThermoDox’s recognized potential to provide a new and important first line therapeutic option for patients with primary liver cancer."

The design of the OPTIMA Study is supported by a retrospective analysis of a large subgroup of 285 patients in the Company’s previous 701 patient HEAT Study in primary liver cancer. This subgroup of patients who received ThermoDox plus standardized RFA demonstrated a statistically significant improvement in survival of over two years compared to standardized RFA alone. The median overall survival in the ThermoDox plus standardized RFA arm was approximately 80 months (6 ½ years), which is considered a curative treatment for primary liver cancer.

On November 29, 2016, the Company announced results from an independent retrospective analysis conducted by the National Institutes of Health (NIH) on the intent-to-treat population of the 701 patient HEAT Study of ThermoDox plus optimized RFA for the treatment of primary liver cancer. The NIH analysis, which sought to evaluate the correlation between RFA burn time per tumor volume (min/ml) and clinical outcome, concluded that increased RFA "burn time" per tumor volume significantly improved overall survival (OS) in patients with solitary lesions treated with RFA + ThermoDox compared to patients treated with RFA alone. The NIH analysis included 437 patients with a single lesion from the Company’s HEAT Study, the same patient population being treated in the Company’s ongoing Phase III OPTIMA study. The NIH findings are consistent with Celsion’s own analysis of the HEAT Study data, which demonstrated that over a 3.5 year period, there was a statistically significant survival benefit consistent with the HEAT Study in patients treated with ThermoDox plus optimized RFA over the optimized RFA only group.

In August 2017, the Company’s Data Monitoring Committee, comprised of an independent group of medical and scientific experts who are responsible for reviewing and evaluating patient safety and efficacy data, completed a planned interim analysis of the first 50% of patients randomized in the trial as of April 2017 and unanimously recommended that the OPTIMA Study continue as planned based on the risk to benefit analysis by the Committee. The OPTIMA Study to date has accumulated data within acceptable safety parameters.

"There is clear evidence that the duration of the RFA regimen is critical when treating patients with ThermoDox, and the totality of the data presented to date demonstrate that ThermoDox plus optimized RFA has a strong potential to serve as a curative therapy for patients with liver cancer," said Professor Won Young Tak, M.D., Ph.D., Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea and lead investigator in South Korea for the Company’s HEAT and OPTIMA studies. "The OPTIMA Study is designed to validate this approach in an indication where there exists a strong unmet need for effective treatment options."

Regulatory Strategy for ThermoDox. ThermoDox has received U.S. FDA Fast Track Designation and has been granted orphan drug designation for primary liver cancer in both the U.S. and Europe. Further, the U.S. FDA has provided ThermoDox with a 505(b)(2) registration pathway. Subject to a successful trial, the OPTIMA Study has been designed to support registration in all key primary liver cancer markets. Celsion fully expects to submit registrational applications in the USA, Europe and China. The Company believes that applications will be accepted in South Korea, Taiwan and Vietnam, three other large and important markets for ThermoDox subject to approval in Europe, China or the USA.

"The Company’s optimism for Chinese registration is based on our multiple interactions with the China Food and Drug Administration," said Nicholas Borys, MD, Celsion’s senior vice president and chief medical officer. "During our December 2016 meeting with the Deputy Director of the Center for Drug Evaluation, Celsion presented the final overall survival data from the Chinese patient cohort from the prior HEAT Study, which demonstrated a survival benefit in patients treated with ThermoDox plus optimized RFA versus optimized RFA alone. The China only cohort was found to be consistent with the overall HEAT Study findings. We were informed that if the ongoing Phase III OPTIMA trial is successful, the trial could serve as the basis for a direct regulatory filing in China without the need to file for prior approval in the U.S. or the European Union. This would allow the Company to accelerate its plans for a regulatory filing in China and, if approved, provide for a significantly earlier launch date in China than originally expected," noted Dr. Borys.

Takeda to Feature ALUNBRIGTM (brigatinib) Data from Pivotal Phase 2 ALTA Trial at 18th World Conference on Lung Cancer

On September 27, 2017 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that the company will present four company-sponsored abstracts, including one oral presentation, at the 18th World Conference on Lung Cancer (WCLC) of the International Association for the Study of Lung Cancer (IASLC), October 15-18, in Yokohama, Japan (Press release, Takeda, SEP 27, 2017, View Source [SID1234520682]). Presentations at this year’s meeting will highlight Takeda’s progress in developing ALUNBRIGTM (brigatinib), an anaplastic lymphoma kinase (ALK) inhibitor in non-small cell lung cancer (NSCLC). As part of a deep commitment to advancing research and serving the needs of patients, Takeda aspires to develop best-in-class treatments for people living with NSCLC.
“The presentations at this year’s meeting support the role of ALUNBRIG as a targeted therapy for patients with advanced ALK-positive NSCLC,” said Jesus Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “Updated data being presented at WCLC from the pivotal ALTA trial reinforces, with longer follow-up, the clinical findings previously reported. We are committed to continuing research and development in NSCLC to improve the lives of the more than 30,000 patients diagnosed with ALK+ NSCLC worldwide each year.”
During the oral presentation, Takeda will feature updated data from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial, highlighting the efficacy and safety of ALUNBRIG at two separate dosing regimens in patients with advanced ALK+ NSCLC who have progressed on crizotinib. Additional efficacy and safety sub-analyses from the trial will also be presented.
The four Takeda-sponsored abstracts accepted for presentation during WCLC 2017 include:
Note: all times listed are in Japan Standard Time.
Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial. Abstract 8027. Oral presentation. Monday, October 16, 4:30 – 4:40 p.m., Room 301 & 302.
Hypertension With Brigatinib: Experience in ALTA, a Randomized Phase 2 Trial in Crizotinib-Refractory ALK+ NSCLC. Abstract 8346. Monday, October 16, 9:30 a.m.- 4:00 p.m., Exhibit Hall (Hall B + C).
Depth of Target Lesion Response to Brigatinib and Its Association With Outcomes in Patients With ALK+ NSCLC in the ALTA Trial. Abstract 8035. Monday, October 16, 9:30 a.m.- 4:00 p.m., Exhibit Hall (Hall B + C).
Overall Survival (OS) After Disease Progression on Brigatinib in Patients With Crizotinib-Refractory ALK+ NSCLC in ALTA. Abstract 8546. Monday, October 16, 9:30 a.m.- 4:00 p.m., Exhibit Hall (Hall B + C).

About the ALTA Trial
The Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial of brigatinib in adults is an ongoing, two-arm, open-label, multicenter trial, which enrolled 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib. Patients received either 90 mg of ALUNBRIG once daily (n=112) or 180 mg once daily following a seven-day lead-in of 90 mg once daily (n=110). The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR.
About ALK+ NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 222,500 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately two to eight percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.
The central nervous system (CNS) is a frequent site for progression in ALK+ NSCLC, with brain metastases present in up to 70 percent of patients after treatment with crizotinib.
About ALUNBRIG (brigatinib)
ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. ALUNBRIG recently received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALK+ NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ALUNBRIG 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, ROS1+ and EGFR+ NSCLC. A Marketing Authorization Application (MAA) for ALUNBRIG was submitted to the European Medicines Agency (EMA) in February 2017.
In the US, the recommended dosing regimen for ALUNBRIG is:
90 mg orally once daily for the first 7 days;
if 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.
The ALTA clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. In addition to the ongoing Phase 1/2 and Phase 2 ALTA trial, brigatinib is also being studied in the Phase 3 ALTA 1L trial to assess its efficacy and safety in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor.
To learn more about ALUNBRIG, please visit www.ALUNBRIG.com or call 1-844-A1POINT (1-844-217-6468). For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.
Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.
Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.
Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.
Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.
Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.
Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.
ADVERSE REACTIONS
Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).
The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).
DRUG INTERACTIONS
CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.
USE IN SPECIFIC POPULATIONS
Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.
Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.
Females and Males of Reproductive Potential:
Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.
Infertility: ALUNBRIG may cause reduced fertility in males.
Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.
Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.
Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.
Please see the full Prescribing Information for ALUNBRIG at www.ALUNBRIG.com