On September 14, 2018 EpimAb Biotherapeutics, an emerging Shanghai-based biopharmaceutical company specializing in bispecific antibodies, reported that it has filed an IND for its most advanced therapeutic development candidate EMB01 (Press release, EpimAb Biotherapeutics, SEP 14, 2018, View Source [SID1234529512]). The applications were simultaneously submitted to the U.S. Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA) in China to investigate the treatment of solid tumors with EpimAb’s novel bispecific antibody.

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"Advancing our first compound into the clinic just three years after founding the company is a significant and transformational milestone for EpimAb," commented Chengbin Wu, PhD, CEO and founder of EpimAb Biotherapeutics. "This achievement proves that our FIT-Ig technology delivers bispecific antibodies with drug-like properties and manufacturing efficiency that can rapidly be advanced into clinical trials. We are now eager to learn how these novel drug candidates can impact patients’ lives."

EMB01 is a bispecific antibody based on EpimAb’s proprietary FIT-Ig (Fabs-In-Tandem Immunoglobulin) technology to generate bispecific molecules with superior properties. EMB01 simultaneously targets two receptors, which are widely expressed on cancer cells, EGFR and cMET, with a unique and synergistic mechanism and has shown significant and long-lasting activity in multiple preclinical solid tumor models. EpimAb initiated formal preclinical development in May 2017 and since then successfully completed all requirements for IND filing.

While EMB01 is progressing towards the clinic, EpimAb is advancing several biologics creating a proprietary pipeline based on its FIT-Ig platform. These earlier-stage assets are focused on immuno-oncology approaches in areas of high medical need in cancer.

On September 14, 2018 AstraZeneca and MedImmune, its global biologics research and development arm, reported that the US Food and Drug Administration (FDA) has approved Lumoxiti (moxetumomab pasudotox-tdfk) for the treatment of adult patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog (Press release, AstraZeneca, SEPT 14, 2018, View Source [SID1234529431]). Lumoxiti is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min).2 The Phase III trial results demonstrated 75% (95% confidence interval [CI]: 64, 84) of patients receiving Lumoxiti achieved an overall response; 30% (95% CI: 20, 41) had a durable complete response.2,3

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Dave Fredrickson, Executive Vice-President, Global Head Oncology Business Unit, said: "Today’s FDA approval of Lumoxiti represents a significant milestone for people living with hairy cell leukaemia, a rare blood cancer that can result in serious and life-threatening conditions. For patients, this approval provides the first FDA-approved medicine for this condition in more than 20 years."

Robert J. Kreitman, MD, Senior Investigator, Head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, and Principal Investigator of the Phase III clinical trial, said: "While many patients with hairy cell leukaemia experience a remission with current treatments, 30% to 40% will relapse five to ten years after their first treatment.4 With subsequent treatments, durations of response diminish and toxicities accumulate, and few approved treatment options exist.5,6 Moxetumomab pasudotox represents a promising non-chemotherapeutic agent for HCL, addressing an unmet medical need for physicians and their patients."

Lumoxiti was approved under FDA Priority Review.7 The approval is based on data from the Phase III single-arm, open-label ‘1053’ trial of Lumoxiti monotherapy in 80 patients who have received at least two prior therapies, including a purine nucleoside analog.3 The primary endpoint of the trial was durable complete response.3 Summary of key results from the trial, as determined by a blinded independent central review:2

Efficacy measure

Result %, (95% CI)

Durable complete response ratea,b

30% (20, 41)

Overall response ratec

75% (64, 84)

Complete response rated

41% (30, 53)

Partial response ratee

34% (24, 45)

Haematologic remission rateb

80%

a Durable complete response is defined as patients who achieved complete response with haematologic remission for a duration of more than 180 days

b Haematologic remission is defined as haemoglobin > 11g/dL, neutrophils > 1500/mm3, platelets > 100,000/mm3 without transfusions or growth factor for at least 4 weeks

c Overall response rate is defined as best overall response of complete response or partial response

d Complete response is defined as clearing of the bone marrow of hairy cells by routine haematoxylin and eosin stain, radiologic resolution of pre-existing lymphadenopathy and/or organomegaly, and haematologic remission

e Partial response is defined as ≥ 50% decrease or normalisation (< 500/mm3) in peripheral blood lymphocyte count, reduction of pre-existing lymphadenopathy and/or organomegaly, and haematologic remission

The median time to haematologic remission was 1.1 months (range: 0.2 to 13).2 At data cut-off, the median duration of complete response was not yet reached after a median 16.7 months of follow-up.2

Capillary leak syndrome (CLS) and haemolytic uraemic syndrome (HUS), including life-threatening cases of each, have been reported among patients treated with Lumoxiti. In the combined safety database of 129 HCL patients treated with Lumoxiti, Grade 3 or 4 CLS occurred in 1.6% and 2% of patients, respectively. Grade 3 or 4 HUS occurred in 3% and 0.8% of patients, respectively.2

In the ‘1053’ trial of 80 patients, the most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS. HUS was the most common adverse reaction leading to discontinuation (5%). The most common adverse reactions (≥ 20%) of any grade were infusion related reactions (50%), oedema (39%), nausea (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation (23%), anaemia (21%), and diarrhoea (21%). The most common laboratory abnormalities (≥ 20%) of any grade were creatinine increased, ALT increased, hypoalbuminaemia, AST increased, hypocalcaemia, hypophosphataemia, haemoglobin decreased, neutrophil count decreased, hyponatreamia, blood bilirubin increased, hypokalaemia, GGT increased, hypomagnesaemia, platelet count decreased, hyperuricaemia, and alkaline phosphate increased.2

The recommended dose of Lumoxiti is 0.04 mg/kg administered as an intravenous infusion over 30 minutes on days 1, 3, and 5 of each 28-day cycle up to 6 cycles, disease progression, or unacceptable toxicity.2

Notes to Editors
About hairy cell leukaemia

Hairy cell leukaemia (HCL) is a rare, chronic, and slow-growing leukaemia in which the bone marrow overproduces abnormal B cell lymphocytes.8,9 HCL can result in serious and life-threatening conditions, including infections, bleeding and anaemia.10 Approximately 1,000 people are diagnosed with HCL in the US each year.11 While many patients initially respond to treatment, 30% to 40% will relapse five to ten years after their first treatment.4 With no established standard of care and very few treatments available, there remains significant unmet medical need for people with relapsed or refractory HCL.4,8

About Lumoxiti

Lumoxiti (moxetumomab pasudotox, formerly CAT8015 or HA22) is a CD22-directed cytotoxin and a first-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min).2 It comprises the CD22 binding portion of an antibody fused to a truncated bacterial toxin; the toxin inhibits protein synthesis and ultimately triggers apoptotic cell death.2 Lumoxiti has been granted Orphan Drug Designation by the FDA for the treatment of HCL.

About the ‘1053’ Phase III trial

The ‘1053’ trial is a single-arm, multicentre Phase III clinical trial assessing the efficacy, safety, immunogenicity and pharmacokinetics of moxetumomab pasudotox monotherapy in patients with relapsed or refractory HCL who have received at least two prior therapies, including one purine nucleoside analog. The trial was conducted in 80 patients across 34 sites in 14 countries. The primary endpoint was durable complete response (CR), defined as CR with haematologic remission (blood count normalisation) for >180 days. Secondary outcome measures included overall response rate, relapse free survival, progression-free survival, time to response, safety, pharmacokinetic and immunogenic potential.7

Early discovery of moxetumomab pasudotox was led by the National Cancer Institute (NCI). The collaboration between NCI and MedImmune, AstraZeneca’s global biologics research and development arm, is an example of how scientific partnerships can lead to important advances for cancer patients.

On September 14, 2018 INSYS Therapeutics, Inc. (NASDAQ: INSY), a leader in the development, manufacture and commercialization of pharmaceutical cannabinoids and spray technology, reported that Saeed Motahari, president and chief executive officer, will present at the upcoming Janney Montgomery Scott 2018 Healthcare Conference as follows (Press release, Insys Therapeutics, SEPT 14, 2018, View Source [SID1234529432]):

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Date: Tuesday, Sept. 18, 2018
Time: 9:05 a.m. Eastern Time
Location: New York, N.Y.
The presentation will be webcast live at the aforementioned time, and archived for 90 days thereafter, via the Investors section of company’s website at View Source, under Presentations & Events. Accessible at the same webpage, the presentation slides will be available during and after the conference.

On September 13, 2018 Moleculin Biotech, Inc., (Nasdaq: MBRX) reported that it has initiated a Phase 1 clinical trial of a new first-in-class cancer drug candidate, a small molecule compound discovered by Prof. Waldemar Priebe at The University of Texas MD Anderson Cancer Center and known as WP1066 (Press release, Moleculin, SEPT 13, 2018, View Source [SID1234529417]). The compound has been shown in animal models to both inhibit an important cell signaling protein STAT3 that is involved in cell growth and proliferation and considered critical to tumor development, while also stimulating an immune response. The first glioblastoma patient has received the initial doses of WP1066, which were apparently well tolerated, in the physician-sponsored IND (investigational new drug) study at MD Anderson Cancer Center.

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Built from the chemical backbone of the active ingredient in propolis, a natural product of honey bees, WP1066 is the first anticancer agent with drug-like properties that consistently inhibits the activated form of STAT3 within cancer cells, a target that has been long-sought because of its broad range of tumor promoting effects.

Importantly, activated STAT3 supports the survival and proliferation of tumor cells, evasion of the immune response and metastasis to distant organs, as well as angiogenesis (growth of blood vessels) essential for tumor growth. Activated STAT3 is not only connected with directly supporting tumor activity, but also suppressing the immune system, making this target even more important to cancer therapy.

With the support of extensive preclinical studies demonstrating high antitumor activity and the critically important ability to cross the blood-brain barrier, WP1066 in this Phase 1 clinical trial will focus on treating aggressive brain tumors which all share a grim prognosis. The intent is to eventually treat up to 15 relapsed brain cancer patients over the next six to eight months. Phase 1 clinical trials typically focus on exploring safe and well tolerated doses, as well as evaluating initial signals of effectiveness. Each treatment is completed over three weeks.

"Treating the first brain tumor patient with WP1066 is the start of a very exciting and encouraging program for doctors treating the worst types of brain cancers. There has been very little progress in recent years toward improved therapies for glioblastoma and other aggressive primary or metastatic brain tumors. WP1066 has shown extremely promising results based on animal studies where we have seen inhibition of tumor growth and improvements in survival," said Dr. Sandra Silberman, a world-renowned oncologist and Moleculin’s Chief Medical Officer. "This is based on the fact that although STAT3 has long been identified as an important target for treating tumors, for years most efforts have focused on attempts to indirectly inhibit STAT3 from upstream signaling, not from within the cancer cell itself. WP1066 appears to be unique in its ability in vitro and in animal models to consistently and directly inhibit the activated form of STAT3 and produce significant anticancer effects, including tumor growth inhibition and increased life span of treated animals."

"This represents a major milestone for Moleculin," commented Walter Klemp, Chairman and CEO. "There has been tremendous enthusiasm within the oncology community for targeting STAT3, a key molecular hub of multiple pathways promoting tumor growth. Although the industry has been struggling to find a way to target STAT3, we at Moleculin believe that most of these efforts have been mechanistically misguided and ended in failure because their approach would ultimately be ineffective at adequately blocking the activation of STAT3 and lack the necessary drug-like properties to succeed. The opportunity to test a unique STAT3 therapy in these patients is significant in supporting Moleculin’s mission to provide benefit for those who need new and better treatments."

How WP1066 Works in Tumor Cells

WP1066 is a small molecule compound that can not only directly kill tumor cells, but also has the ability to overcome the tumor’s ability to evade the natural immune response, which would otherwise be working to eliminate the cancerous activity. This compound is a first in class drug candidate capable of down-regulating the activated form of STAT3, a target that has been long-sought because of its role in supporting the survival and growth of tumor cells.

The compound has been shown to prevent tumor progression and increase survival in a wide range of animal models by directly attacking tumors and blocking the cell signaling by STAT3 that supports tumor development and simultaneously suppressing regulatory T cells (Tregs), which then allows stimulation of an enhanced natural anti-tumor immune response. The compound’s dual functions have been shown to increase survival in a wide range of animal models, which have been documented in more than 50 peer-reviewed articles.

On September 13 Array BioPharma Inc. (NASDAQ: ARRY) reported the publication of detailed overall survival (OS) results from the COLUMBUS trial in The Lancet Oncology (Press release, Array BioPharma, SEP 13, 2018, View Source [SID1234529437]). The pivotal Phase 3 trial evaluated the efficacy and safety of the combination of BRAFTOVI+ MEKTOVI compared to vemurafenib monotherapy in patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation. BRAFTOVI + MEKTOVI reduced the risk of death compared to treatment with vemurafenib [hazard ratio (HR) of 0.61, (95% CI 0.47-0.79, p <0.0001)] in the planned analysis of OS. Median OS was 33.6 months for patients treated with the combination, compared to 16.9 months for patients treated with vemurafenib as a monotherapy. The analysis of OS and updated efficacy and safety data extend findings of previously announced results.

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Based on data from the previously reported primary analysis of the COLUMBUS trial, the U.S. Food and Drug Administration (FDA) approved BRAFTOVI capsules in combination with MEKTOVI tablets on June 27, 2018 for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma. Further, on July 16, 2018, Array submitted supplementary New Drug Applications to seek inclusion of OS data from the COLUMBUS trial in the BRAFTOVI and MEKTOVI labels.

Mature median progression-free survival (mPFS) for BRAFTOVI + MEKTOVI was 14.9 months (95% CI 11.0–20.2) compared to vemurafenib with 7.3 months (5.6–7.9), [HR 0.51, (95% CI 0.39–0.67; two-sided p<0.0001)].

"The publication of updated findings from the COLUMBUS trial in The Lancet Oncology underscores the value that BRAFTOVI + MEKTOVI bring to patients with BRAF-mutant melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "Based on the observed efficacy and tolerability, this targeted combination is an important new treatment option for patients with this life-threatening form of melanoma."

Use of post-trial immunotherapy was limited and consistent with other published pivotal trials of BRAF + MEK inhibitors in advanced BRAF-mutant melanoma. The manuscript also noted that the performance of vemurafenib, the control arm, was consistent across efficacy endpoints with its performance in other trials of BRAF + MEK inhibitor combinations where it also served as a control. Finally, the authors conclude the data represent a new benchmark for BRAF + MEK inhibitors in metastatic or unresectable BRAF-mutant melanoma.

With 18 months of additional follow-up relative to the initial publication of COLUMBUS results, the safety profile of the combination remained generally consistent with the prior report. Observed grade 3 or 4 adverse events in more than 5% of patients with BRAFTOVI + MEKTOVI were increased gamma-glutamyltransferase (9%), increased blood creatine phosphokinase (7%) and hypertension (6%). Additional safety information can be found in the manuscript and in the Important Safety Information below.

About BRAF-mutant Metastatic Melanoma
Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumors. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [1, 2] There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma. [1, 3, 4, 5]

About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.

Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical Co, Ltd. exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia (excluding Japan and South Korea) and Latin America.

BRAFTOVI and MEKTOVI are not approved outside of the U.S. The European Medicines Agency (EMA), the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA), are currently reviewing the Marketing Authorization Applications submitted by Pierre Fabre, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) is currently reviewing the Manufacturing and Marketing Approval Applications for submitted by Ono Pharmaceutical Co, Ltd.

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib) compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. The primary endpoint of the trial was mPFS; all secondary efficacy analyses, including the prospectively planned analysis of overall survival, are descriptive in nature. Over 200 sites across North America, Europe, South America, Asia and Australia participated in the trial.

BRAFTOVI + MEKTOVI Indications and Usage
BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.

BRAFTOVI + MEKTOVI Important Safety Information
The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted.

Warnings and Precautions
New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or BRAFV600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy: In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis, was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmic evaluation at regular intervals and for any visual disturbances.

Interstitial Lung Disease (ILD): ILD, including pneumonitis, occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST). Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK periodically and as clinically indicated.

QTc Prolongation: In the COLUMBUS trial, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Adverse Reactions
The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial) were: fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS Trial, the most common laboratory abnormalities (≥20%, all Grades) included: increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

Drug interactions
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information [6,7]. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).