On April 28, 2017 Celyad (Euronext Brussels and Paris, and NASDAQ:CYAD), a leader in the discovery and development of engineered cell therapies, reported the dosing of the first patient of the second dose in the solid tumor arm of its THINK trial (THerapeutic Immunotherapy with NKR-2) (Press release, Celyad, APR 28, 2017, View Source [SID1234518722]). This first ovarian cancer patient has been dosed at Roswell Park Cancer Institute (Buffalo, New York).

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At the first solid tumor dose-level, one pancreatic and two colorectal cancer patients were successfully dosed. None of these patients experienced dose limiting adverse events.

THINK is a multinational open-label Phase I study to assess the safety and clinical activity of multiple administrations of autologous NKR-2 T-cells in seven refractory cancers including five solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and two hematological tumors (acute myeloid leukemia and multiple myeloma). These cancer indications were selected based on strong preclinical evidence and NKG2D ligand expression.

The THINK trial is being conducted in the US and in Europe. It contains a dose escalation and an extension stage. The dose escalation is conducted in parallel in the solid and liquid cancer groups, while the extension phase will evaluate in parallel each tumor independently.

The dose escalation design includes three dose levels adjusted to body weight: up to 3×108, 1×109 and 3×109 NKR-2 T-cells. At each dose, the patients receive three successive administrations, two weeks apart, of NKR-2 T-cells at the specified dose.

"The opening of the first U.S. arm of the THINK study is an exciting milestone, and one we are very proud to contribute to", said Kunle Odunsi, MD, PhD, FRCOG, FACOG, Deputy Director of Roswell Park Cancer Institute and the co-Principal Investigator leading Roswell Park’s involvement in the international basket trial. "NKR-2 represents a unique approach to CAR T- cell therapy, and we hope that our efforts help to establish a new treatment option that will benefit many people with cancer". Dr. Odunsi is also Chair of Gynecologic Oncology, M. Steven Piver Professor of Gynecologic Oncology and Executive Director of the Center for Immunotherapy at the Buffalo, N.Y., comprehensive cancer center.


Dr. Frédéric Lehmann, VP Clinical Development and Medical Affairs at Celyad added: "Preliminary results from the first dose-level are encouraging, further reinforcing the favorable safety profile of NKR-2. The THINK study is progressing very well and we look forward to the completion of the dose-escalation stage of the trial and the initiation of the expansion segments to confirm the encouraging clinical signal seen in our previous Phase I study. The active participation of a first key cancer institute in U.S. with the NKR-2 manufacturing in Europe demonstrates the ability of Celyad to conduct a global clinical development."

On April 28, 2017 OncoCyte Corporation (NYSE MKT:OCX), a developer of novel, non-invasive blood based tests to aid in the early detection of cancer, reported its financial results for the quarter ended March 31, 2017(Press release, BioTime, APR 28, 2017, View Source [SID1234518721]). In addition, OncoCyte announced it will conduct an investor call on May 22, 2017 at 4:30pm ET/1:30 pm PT after its lead investigator Dr. Anil Vachani presents data from the 300 patient R&D Validation study at the American Thoracic Society 2017 International Conference (ATS) in Washington D.C.

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"We made significant progress during the first quarter towards the commercialization of our lung cancer diagnostic product, including initiating a search for a head of our sales organization as well as beginning the expansion of our sales, marketing and market access teams," commented William Annett, Chief Executive Officer. "We believe the data on our lung cancer test being presented in May demonstrates the robustness of our science and strengthens our market position."

"We plan to provide investors with an overview of the results from the 300 patient R&D Validation study on our conference call following the presentation. We believe the total addressable market for our lung cancer diagnostic test could be over $4 billion, and that we are positioned to be the first company to provide a highly accurate non-invasive confirmatory blood test to address this market. Our focus over the next few months is to complete the development process, obtain CLIA certification of our laboratory, and prepare for our anticipated commercial launch in the second half of the year."

Significant First Quarter Accomplishments

Reported the successful results of the R&D Validation study for its lung cancer diagnostic test. The results, based on the analysis of samples from approximately 300 patients, confirmed previously reported data presented by The Wistar Institute at the CHEST 2016 Annual Meeting in October. The data from the study exceed levels OncoCyte believes necessary for a commercially successful test.

Reported that it locked its prediction algorithm and intends to move to the Clinical Validation phase of development—the last phase before commercial launch.

Submitted the application for CLIA certification of OncoCyte’s laboratory where the assay will be run.

Announced that its breast cancer test is developing ahead of schedule, and began a follow-up, multi-center study to further develop and verify the results of the earlier studies.
Near-term Milestones

OncoCyte is continuing to make progress and has several upcoming events and milestones related to the development of its lung cancer diagnostic:

Poster presentation of lung cancer diagnostic R&D Validation study at the (ATS) International Conference. The data will be presented by Dr. Anil Vachani, an Associate Professor of Medicine at the Hospital of the University of Pennsylvania and the Veteran’s Administration Medical Center, at 2:15 p.m. ET on May 22, 2017.

Conference call to report on 300-patient R&D Validation study, to be held at 4:30pm ET on May 22, 2017.

Establishment of a medical advisory committee (MAC), headed by top lung cancer specialists. The MAC will advise OncoCyte on clinical unmet needs and future development strategy.

CLIA certification and California state clinical laboratory license, which OncoCyte expects to receive during the second quarter of 2017.

Clinical Validation study to confirm and replicate OncoCyte’s findings in a commercial CLIA lab setting.

Expansion of OncoCyte’s commercial capabilities in sales and marketing, revenue cycle management and reimbursement.

Launch of lung cancer test during second half of 2017 assuming successful completion of the Clinical Validation and CLIA certification.
First Quarter 2017 Financial Results

For the quarter ended March 31, 2017, OncoCyte incurred a net loss of $4.7 million, or $0.16 per share, compared to a net loss of $2.9 million, or $0.12 per share, in 2016. The $4.7 million net loss includes a $1.1 million noncash expense, or $0.04 per share, related to issuance of warrants to certain shareholders as an inducement to exercise warrants. During the first quarter OncoCyte used $3.3 million in operating activities compared to $2.2 million from the comparative prior quarter.

Research and development expenses for the quarter ended March 31, 2017 were $1.8 million compared to $1.7 million for the same period in 2016. Overall the slight increase in research and development expenses was due to increased staffing and laboratory expenses.

General and administrative expenses increased to $2.0 million from $1.0 million for the same period in 2016. Sales and marketing expenses increased to $0.7 million from $0.2 million. The increases were attributable to a $1.1 million noncash expense for the issuance of warrants as well as increased staffing for the expected commercial launch of OncoCyte’s lung cancer diagnostic during second half of 2017.

At March 31, 2017, OncoCyte had liquid assets of $13 million, including $11.4 million of cash and cash equivalents, and available-for-sale securities valued at $1.6 million.

On April 28, 2017 Bayer reported that the U.S. Food and Drug Administration (FDA) approved Stivarga (regorafenib) tablets for the second-line treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Nexavar (sorafenib) (Press release, Bayer, APR 28, 2017, View Source [SID1234518717]).

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Stivarga is the first and only treatment to demonstrate significant improvement in overall survival in second-line HCC patients. In the RESORCE trial, Stivarga was shown to provide a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo; the median OS was 10.6 [(n=379) (CI 9.1, 12.1)] vs 7.8 [(n=194) (CI 6.3, 8.8)] months, respectively (HR 0.63, 95% CI 0.50-0.79; p<0.0001). This translates to a 37% reduction in the risk of death. The number of deaths in each arm included 233 of 379 (62%) with Stivarga and 140 of 194 (72%) with placebo. Today’s FDA approval expands Bayer’s leadership in liver cancer with a treatment plan in HCC involving use of Stivarga directly after progression on Nexavar.

Stivarga is an oral inhibitor of multiple kinases involved in normal cellular functioning and in pathological processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. The FDA’s approval is based on data from the international, multicenter, placebo-controlled Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma; NCT 01774344] trial, which investigated patients with HCC whose disease had progressed during treatment with Nexavar. The most frequently observed adverse drug reactions (≥30%) in patients treated with regorafenib vs. placebo-treated patients in HCC, respectively, were: pain (55% vs. 44%), HFSR/PPE (51% vs. 7%), asthenia/fatigue (42% vs. 33%), diarrhea (41% vs. 15%), hypertension (31% vs. 6%), infection (31% vs. 18%), decreased appetite and food intake (31% vs. 15%).

"Hepatocellular carcinoma is very hard to treat, and with no new treatments in nearly a decade, options have been very limited for physicians and patients," said Dr Jordi Bruix, lead investigator for the RESORCE trial, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Spain. "The U.S. approval of Stivarga for hepatocellular carcinoma therefore provides a significant step forward in addressing the high unmet need in this patient population."

The incidence of liver cancer is increasing worldwide and it is already the sixth most common cancer in the world and the second leading cause of cancer-related deaths globally.

"Bayer is proud to have played a significant role in the treatment of hepatocellular carcinoma," said Robert LaCaze, executive vice president and head of the Oncology Strategic Business Unit at Bayer. "We first embarked on our scientific research in this area 20 years ago. We could not have done it alone: we would like to thank the patients, caregivers and investigators for their participation and engagement in the RESORCE trial."

The approval of Stivarga in liver cancer marks the third time that this therapy has been granted FDA approval on a priority basis. The FDA granted Fast Track designation to Stivarga in HCC, which is an expedited program designed to facilitate development and review of drugs to address an unmet medical need in the treatment of a serious or life-threatening condition. The FDA also granted Orphan Drug Designation (ODD) to Stivarga in HCC. The ODD program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases and disorders. Additional regulatory filings for Stivarga in HCC are under review in countries around the world, including the EU, Japan and China. Decisions in the EU and Japan regions are expected later this year.

About Hepatocellular Carcinoma
Hepatocellular carcinoma, or HCC, is the most common form of liver cancer and represents approximately 70-85 percent of liver cancer worldwide. More than 780,000 cases of liver cancer are diagnosed worldwide each year (52,000 in the European Union, 501,000 in the Western Pacific region and 30,000 in the United States). In 2012, approximately 746,000 people died of liver cancer including approximately 48,000 in the European Union, 477,000 in the Western Pacific region and 24,000 in the United States.

About Regorafenib (Stivarga)
Regorafenib is an oral multi-kinase inhibitor that potently blocks multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumor immunity (CSF1R).

Regorafenib is already approved under the brand name Stivarga in more than 90 countries worldwide, including the U.S., countries of the EU, China and Japan for the treatment of mCRC. The product is also approved in over 80 countries, including the U.S., countries of the EU, China and Japan, for the treatment of metastatic GIST. In April 2017, Stivarga was approved in the U.S. for use in patients with HCC who have been previously treated with sorafenib. In the U.S., Stivarga is already indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy. It is also indicated for the treatment of patients with locally advanced, unresectable or metastatic GIST who have been previously treated with imatinib mesylate and sunitinib malate. In the EU, Stivarga is indicated for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, as well as for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib.

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.

On April 28, 2017 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that ALUNBRIG (brigatinib) has received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib (Press release, Ariad, APR 28, 2017, View Source [SID1234518734]). 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, which previously received Breakthrough Therapy Designation from the FDA, is a once-daily oral therapy that may be taken with or without food.

"In recent years, small molecule ALK inhibitors have revolutionized the treatment options for those with advanced ALK+ non-small cell lung cancer. Nevertheless, there is still a need for additional ALK inhibitors like brigatinib (ALUNBRIG), which have a manageable safety profile and may address mechanisms of clinical resistance to crizotinib, including progression in the central nervous system," said D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the University of Colorado. "The ALTA trial showed that brigatinib (ALUNBRIG) was highly effective post-crizotinib with the majority of patients who received 180 mg once daily with a seven-day lead in at 90 mg once daily achieving an overall response and a median duration of response greater than one year. Importantly, the extent of activity among those with brain metastases was also notable."

"For patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib, who are facing the uncertainty of disease progression and the potentially devastating impact of brain metastases, the approval of ALUNBRIG offers a new hope," said Bonnie Addario, founder and chair of the Addario Lung Cancer Foundation (ALCF).

"The rapiddevelopment of ALUNBRIG is a tribute to the dedication of many research scientists and clinicians who carefully designed and developed this new medicine to address unmet medical needs in the ALK+ NSCLC patient population. Most importantly, we would like to thank the patients and families who participated in the clinical trials," said Andy Plump, M.D., Ph.D., Takeda Chief Medical and Scientific Officer.

"Today’s FDA approval of ALUNBRIG is an important milestone in the treatment of patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib," said Christophe Bianchi, M.D., President, Takeda Oncology. "Takeda is committed to the continued development of ALUNBRIG around the globe and to bringing this important therapy to more patients in need."

About the ALTA Trial

The FDA approval of ALUNBRIG was primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial of brigatinib in adults. This ongoing, two-arm, open-label, multicenter trial 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.

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.

With a median follow-up of 8 months (range 0.1 – 20.2), results demonstrated that of the patients who received the recommended dosing regimen (90→180 mg), 53 percent achieved a confirmed overall response (OR) as assessed by IRC and 54 percent as assessed by Investigator. At the recommended dosing regimen, the median duration of response was 13.8 months as assessed by IRC and 11.1 months by Investigator assessment. Additionally, at the recommended dosing regimen, 67 percent of patients with measurable brain metastases (n=18) achieved a confirmed intracranial OR by IRC assessment.

Efficacy data are as follows:

ALTA Efficacy Results

Efficacy parameter

IRC Assessment

Investigator Assessment

90 mg once daily
(N=112)

90→180 mg
once daily
(N=110)

90 mg once daily
(N=112)

90→180 mg
once daily
(N=110)

Overall Response Rate (95% CI)

48% (39-58)

53% (43-62)

45% (35-54)

54% (44-63)

Complete Response, n (%)

4 (3.6%)

5 (4.5%)

1 (0.9%)

4 (3.6%)

Partial Response, n (%)

50 (45%)

53 (48%)

49 (44%)

55 (50%)

Duration of Response, median in months
(95% CI)

13.8
(7.4-NE)

13.8
(9.3-NE)

13.8
(5.6-13.8)

11.1
(9.2-13.8)











CI = Confidence Interval; NE = Not Estimable

IRC assessment of intracranial efficacy is shown below:

Intracranial Overall Response in Patients with Measurable Brain Metastases in ALTA

Efficacy parameter

IRC Assessment

90 mg once daily
(N=26)

90→180 mg once daily
(N=18)

Intracranial Overall Response Rate, (95 % CI)

42% (23-63)

67% (41-87)

Complete Response, n (%)

2 (7.7%)

0

Partial Response, n (%)

9 (35%)

12 (67%)

Duration of Intracranial Response, median (months)
(range)

NE
(1.9+ – 9.2+)

5.6
(1.9+ – 9.2+)

CI = Confidence Interval; NE = Not Estimable

Among the 23 patients who exhibited an intracranial response, 78% of patients in the 90 mg arm and 68% of patients in the 90→180 mg group maintained a response for at least four months.

The warnings and precautions for ALUNBRIG are: interstitial lung disease (ILD)/pneumonitis, hypertension, bradycardia, visual disturbance, creatine phosphokinase (CPK) elevation, pancreatic enzyme elevation, hyperglycemia and embryo-fetal toxicity.

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).

At the recommended dosing regimen, the most common adverse reactions (≥25%) with ALUNBRIG were nausea, diarrhea, fatigue, cough, and headache.

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 as well. Approximately two to eight percent of patients with NSCLC have a rearrangement in the ALK gene.

The central nervous system (CNS) is a frequent site for ALK+ NSCLC progression, with up to 70 percent of patients with ALK+ NSCLC who have been treated with a first-line ALK inhibitor facing brain metastases.

About ALUNBRIG (brigatinib)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. 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.

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 A1Point: 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: Advise lactating women not to breastfeed during treatment with ALUNBRIG and for 1 week following the final dose.
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