On October 12, 2023 EpimAb Biotherapeutics, a clinical stage biopharmaceutical company specializing in the development of multispecific antibodies, and Almirall, a global biopharmaceutical company focused on medical dermatology, reported a license agreement on the development of bispecific antibodies for up to three undisclosed target pairs (Press release, EpimAb Biotherapeutics, OCT 12, 2023, View Source [SID1234635919]).

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Under the terms of this agreement, Almirall will gain a license to utilize EpimAb’s proprietary Fabs-In-Tandem Immunoglobulin (FIT-Ig) platform technology to generate, develop and commercialize bispecific antibodies, for which Almirall will have exclusive global rights. In exchange, EpimAb is eligible to receive milestone payments totaling up to $210 million contingent upon launch and commercial success of multiple products, plus royalties on net sales for any commercialized product. Further financial details were not disclosed.

"We are pleased to partner with Almirall to expand the application of our FIT-Ig technology beyond the oncology space," said Dr. Chengbin Wu, CEO and founder of EpimAb. "While we have made significant progress in utilizing our platform technology to develop a differentiated portfolio of bispecific antibodies in oncology, the potential of our platform in other areas such as immunology remains untapped. We believe Almirall is the partner of choice for this endeavor and look forward to exploring the use of our novel bispecific platform to offer additional treatment options for patients with immune-related disorders."

Karl Ziegelbauer, Executive Vice President R&D and Chief Scientific Officer of Almirall, commented that "This agreement with EpimAb is an important step forward and a great example of our ambition to develop new biologics in the dermatology field to ultimately bring innovation to patients."

FIT-Ig, EpimAb’s proprietary technology platform, generates bispecific antibodies solely utilizing the basic structural parts of monoclonal antibodies without adding any complex changes, and is patented in all major markets of the world. With four bispecific molecules advanced into the clinic using this technology, EpimAb has also demonstrated the potential of this novel platform to rapidly advance drug candidates from idea to development.

On October 12, 2023 Pfizer Inc. (NYSE: PFE) reported that the U.S. Food and Drug Administration (FDA) has approved BRAFTOVI (encorafenib) + MEKTOVI (binimetinib) for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test (Press release, Pfizer, OCT 12, 2023, View Source [SID1234635918]). BRAF V600E mutations can be assessed from either plasma or tumor tissue using the FoundationOne Liquid CDx or the FoundationOne CDx FDA-approved companion diagnostic tests, respectively.

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"Today’s approval builds on our long-standing commitment to deliver innovative, personalized medicines to patients with lung cancer. By pursuing precision medicines that target a patient’s specific type of cancer, we are leveraging our deep understanding of tumor biology to help address the underlying cause of disease"

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"Today’s approval builds on our long-standing commitment to deliver innovative, personalized medicines to patients with lung cancer. By pursuing precision medicines that target a patient’s specific type of cancer, we are leveraging our deep understanding of tumor biology to help address the underlying cause of disease," said Chris Boshoff, M.D., Ph.D., Chief Oncology Research and Development Officer and Executive Vice President at Pfizer. "Since its initial FDA approval in 2018, BRAFTOVI + MEKTOVI combination therapy has helped thousands of people living with BRAF V600E- or V600K-mutant unresectable or metastatic melanoma.2 We look forward to helping even more patients with our BRAFTOVI + MEKTOVI targeted combination therapy."

The FDA’s approval is based on data from the ongoing Phase 2 PHAROS clinical trial (NCT03915951), an open-label, multicenter, single‑arm study examining BRAFTOVI + MEKTOVI combination therapy in both treatment-naïve and previously treated patients with BRAF V600E-mutant metastatic NSCLC.

"BRAF V600E mutations identify a unique subtype of metastatic non-small cell lung cancer that presents an actionable biomarker that precision medicines like BRAFTOVI + MEKTOVI combination therapy can help address," said Gregory Riely, M.D., Ph.D., Vice Chair, Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSK) and PHAROS investigator. "The PHAROS trial demonstrated that these patients could benefit from BRAFTOVI + MEKTOVI targeted therapy regardless of their prior treatment history. Given the specific efficacy and safety profile, patients and providers now have another option to help personalize treatment plans based on individual risk factors and preferences."

The PHAROS study met its major efficacy outcome measures of objective response rate (ORR), as assessed by independent review committee (IRC), and duration of response (DOR) in both treatment groups. For treatment-naïve patients (n=59), ORR was 75% (95% CI: 62, 85), and 59% of the patients responded for at least 12 months. Median DOR was not estimable (NE) for this group at the time of data cutoff. For previously treated patients (n=39), ORR was 46% (95% CI: 30, 63), and 33% of the patients responded for at least 12 months. Median DOR was 16.7 months (95% CI: 7.4, NE). These data were presented earlier this year at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and simultaneously published in the Journal of Clinical Oncology (JCO).3

The most common (≥25%) all-causality adverse reactions observed in the PHAROS trial were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough. A total of 17% of patients experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI and 16% experienced an adverse event that resulted in permanent discontinuation of BRAFTOVI. Serious adverse reactions occurred in 38% of patients. Serious adverse reactions occurring in ≥2% of patients included hemorrhage (6%), diarrhea (4.1%), anemia, dyspnea, pneumonia (3.1% each), arrhythmia, device-related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients, including intracranial hemorrhage and myocardial infarction (1% each).

BRAFTOVI + MEKTOVI is also FDA-approved for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. BRAFTOVI is FDA-approved, in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

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

The PHAROS trial is conducted with support from Pierre Fabre.

About BRAF V600E-mutant Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the second most common type of cancer and the number one cause of cancer-related death around the world.4 NSCLC accounts for approximately 80-85% of all lung cancers.5

Certain lung cancers are linked to acquired genetic abnormalities like a BRAF V600E mutation. By using biomarkers to identify a person’s particular tumor type, treatment can become more personalized and effective, since the molecular makeup of a person’s cancer often determines how they respond to different therapies.

A BRAF V600E mutation occurs in approximately 2% of NSCLC cases.6 It stimulates tumor cell growth and proliferation by altering the MAP kinase (MAPK) signaling pathway. Targeting components of this pathway could potentially help inhibit tumor growth and proliferation caused by BRAF mutations.7

Precision medicine is increasingly being developed for NSCLC patients with genetic changes, such as BRAF mutations, that can be detected using biomarker tests.8,9 In recent years, more widespread use of biomarker testing and targeted therapies have been associated with improvements in population-level NSCLC mortality.10

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 BRAF V600E or V600K mutation, as detected by an FDA-approved test.

BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

BRAFTOVI and MEKTOVI are kinase inhibitors indicated for use in combination for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC.

IMPORTANT SAFETY INFORMATION

This information applies to the safety of BRAFTOVI when used in combination with either MEKTOVI or cetuximab.

WARNINGS AND PRECAUTIONS

New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Perform dermatopathologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non- cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment.

BRAF-mutant type (BRAF-mt) metastatic melanoma (COLUMBUS study): Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients receiving BRAFTOVI with MEKTOVI. Median time to first occurrence of cuSCC/KA was 5.8 months.
BRAF-mt metastatic CRC (BEACON CRC study): cuSCC, including KA, occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI with cetuximab.
BRAF-mt metastatic NSCLC (PHAROS study): cuSCC and skin papilloma (SP), each occurred in 2% of patients.
Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI.

Cardiomyopathy: Cardiomyopathy manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported. Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (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 (LLN).
BRAF-mt metastatic melanoma (COLUMBUS study): Evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients receiving BRAFTOVI with MEKTOVI. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients.
BRAF-mt metastatic NSCLC (PHAROS study): Evidence of cardiomyopathy occurred in 11% and Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients.
Hepatotoxicity: Hepatotoxicity can occur. Monitor liver laboratory tests before initiation, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

BRAF-mt metastatic melanoma (COLUMBUS study): The incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI with BRAFTOVI was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase.
BRAF-mt metastatic NSCLC (PHAROS study): The incidence of Grade 3 or 4 increases in liver function laboratory tests was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.
Hemorrhage: Hemorrhage can occur when BRAFTOVI is administered in combination with MEKTOVI or cetuximab. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

BRAF-mt metastatic melanoma (COLUMBUS study): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with MEKTOVI and Grade 3 or higher hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.
BRAF-mt metastatic CRC (BEACON CRC study): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%).
BRAF-mt metastatic NSCLC (PHAROS study): Hemorrhage occurred in 12% of patients including fatal intracranial hemorrhage (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).
Uveitis: Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI with MEKTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

BRAF-mt metastatic melanoma (COLUMBUS study): The incidence of uveitis among patients treated with BRAFTOVI with MEKTOVI was 4%.
BRAF-mt metastatic NSCLC (PHAROS study): The incidence of uveitis among patients treated with BRAFTOVI with MEKTOVI was 1%.
QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.

BRAF-mt metastatic melanoma (COLUMBUS study): An increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI with MEKTOVI.
BRAF-mt metastatic NSCLC (PHAROS study): An increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI with MEKTOVI.
Embryo-Fetal Toxicity: Both BRAFTOVI and MEKTOVI can cause fetal harm when administered to a pregnant woman. BRAFTOVI can render hormonal contraceptives ineffective.

BRAF-mt metastatic melanoma (COLUMBUS study) and BRAF-mt metastatic NSCLC (PHAROS study): Effective, non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI with MEKTOVI.
BRAF-mt metastatic CRC (BEACON CRC study): Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.
BRAFTOVI as a Single Agent is associated with increased risk of certain adverse reactions compared to when BRAFTOVI is used with MEKTOVI.

BRAF-mt metastatic melanoma (COLUMBUS study): Grades 3 or 4 dermatologic reactions occurred in 21% of patients receiving BRAFTOVI as a single agent compared to 2% in patients receiving the combination of BRAFTOVI with MEKTOVI.
If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.
Risks Associated with Combination Treatment

In BRAF-mt metastatic melanoma (COLUMBUS study), BRAFTOVI is used in combination with MEKTOVI so refer to the prescribing information for MEKTOVI for additional risk information.
In BRAF-mt metastatic CRC (BEACON CRC study), BRAFTOVI is used in combination with cetuximab so refer to the prescribing information for cetuximab for additional risk information.
In BRAF-mt metastatic NSCLC (PHAROS study), BRAFTOVI is indicated for use as part of a regimen in combination with MEKTOVI, so refer to the prescribing information for MEKTOVI for additional risk information.
Additional WARNINGS AND PRECAUTIONS for MEKTOVI When Used With BRAFTOVI

Venous Thromboembolism (VTE): VTE occurred in 6% of patients with BRAF-mt metastatic melanoma (COLUMBUS study), including 3.1% of patients who developed pulmonary embolism. VTE occurred in 7% of patients with BRAF-mt metastatic NSCLC (PHAROS study), including 1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Other Ocular Toxicities

Serous retinopathy
Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
BRAF-mt metastatic melanoma (COLUMBUS study): serious retinopathy occurred in 20% of patients receiving MEKTOVI with BRAFTOVI; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months.
BRAF-mt metastatic NSCLC (PHAROS study): serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness.
Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients receiving MEKTOVI with BRAFTOVI. In BRAF-mt metastatic melanoma (COLUMBUS study), 1 patient experienced RVO (0.1%) in the MEKTOVI with BRAFTOVI group (n=690).
The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO, including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes.
Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO.
Interstitial Lung Disease (ILD): ILD, including pneumonitis, occurred in 0.3% (2 of 690 patients) with BRAF-mt metastatic melanoma (COLUMBUS study) receiving MEKTOVI with BRAFTOVI. One patient (1%) with BRAF-mt metastatic NSCLC (PHAROS study) receiving MEKTOVI with BRAFTOVI developed pneumonitis. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Rhabdomyolysis: Rhabdomyolysis can occur when MEKTOVI is taken with BRAFTOVI. Monitor creatine phosphokinase (CPK) and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

BRAF-mt metastatic melanoma (COLUMBUS study): Elevation of laboratory values of serum CPK occurred in 58% of patients receiving MEKTOVI with BRAFTOVI. Rhabdomyolysis was reported in 0.1% (1 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI.
BRAF-mt metastatic NSCLC (PHAROS study): Elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients. No patient experienced rhabdomyolysis.
ADVERSE REACTIONS

BRAF-mt Metastatic Melanoma (COLUMBUS study)

Most common adverse reactions (≥20%, all grades) for patients receiving BRAFTOVI with MEKTOVI compared to vemurafenib were fatigue (43% vs 46%), nausea (41% vs 34%), diarrhea (36% vs 34%), vomiting (30% vs 16%), abdominal pain (28% vs 16%), arthralgia (26% vs 46%), myopathy (23% vs 22%), hyperkeratosis (23% vs 49%), rash (22% vs 53%), headache (22% vs 20%), constipation (22% vs 6%), visual impairment (20% vs 4%), serous retinopathy/RPED (20% vs 2%).
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI were facial paresis, pancreatitis, panniculitis, drug hypersensitivity, and colitis
Most common laboratory abnormalities (≥20%, all grades) for BRAFTOVI with MEKTOVI compared to vemurafenib included increased creatinine (93% vs 92%), increased CPK (58% vs 3.8%), increased gamma glutamyl transferase (GGT) (45% vs 34%), anemia (36% vs 34%), increased ALT (29% vs 27%), hyperglycemia (28% vs 20%), increased AST (27% vs 24%), and increased alkaline phosphatase (21% vs 35%).
BRAF-mt Metastatic CRC (BEACON CRC study)

Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with cetuximab compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%).
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with cetuximab was pancreatitis.
Most common laboratory abnormalities (≥20%, all grades) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: anemia (34% vs 48%) and lymphopenia (24% vs 35%).
BRAF-mt Metastatic NSCLC (PHAROS study)

Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with MEKTOVI were fatigue (61%), nausea (58%), diarrhea (52%), musculoskeletal pain (48%), vomiting (37%), abdominal pain (32%), visual impairment (29%), constipation (27%), dyspnea (27%), rash (27%), and cough (26%).
Serious adverse reactions occurred in 38% of patients receiving BRAFTOVI with MEKTOVI. Serious adverse reactions occurring in ≥2% of patients were hemorrhage (6%), diarrhea (4.1%), anemia (3.1%), dyspnea (3.1%), pneumonia (3.1%), arrhythmia (2%), device related infection (2%), edema (2%), myocardial infarction (2%), and pleural effusion (2%).
Fatal adverse reactions occurred in 2% of patients, including intracranial hemorrhage (1%) and myocardial infarction (1%).
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI were peripheral neuropathy, dysgeusia, facial paresis, pancreatitis, hyperkeratosis, erythema, and drug hypersensitivity.
Most common laboratory abnormalities (≥20%, all grades) for BRAFTOVI and MEKTOVI included increased creatinine (91%), hyperglycemia (48%), anemia (47%), increased creatine kinase (41%), lipase increased (40%), increased ALT (34%), hypoalbuminemia (32%), increased alkaline phosphatase (31%), increased AST (31%), hyperkalemia (31%), hyponatremia (26%), lymphopenia (24%), serum amylase increased (22%), and thrombocytopenia (20%).
DRUG INTERACTIONS With BRAFTOVI When Used in Combination With Either MEKTOVI or Cetuximab

Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors (including grapefruit juice) or CYP3A4 inducers and use caution with sensitive CYP3A4 substrates. Avoid coadministration of BRAFTOVI with hormonal contraceptives
Modify BRAFTOVI dose if coadministration with a strong or moderate CYP3A4 inhibitor cannot be avoided
Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval
Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI
Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and MEKTOVI and for 2 weeks after the final dose.

Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility.

For BRAF-mt metastatic melanoma and for BRAF-mt metastatic NSCLC, see full Prescribing Information and Medication Guide for BRAFTOVI and full Prescribing Information and Medication Guide for MEKTOVI. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions. There may be a delay as the documents are updated with the latest information. They will be available as soon as possible. Please check back for the updated full information shortly.

For BRAF-mt metastatic CRC, see full Prescribing Information and Medication Guide for BRAFTOVI. See full Prescribing Information for BRAFTOVI for dose modifications for adverse reactions. Refer to cetuximab prescribing information for recommended dosing and safety information.

On October 12, 2023 FORE Biotherapeutics reported the acceptance of an abstract on new nonclinical data related to plixorafenib (FORE8394), the company’s novel, investigational, small-molecule, next-generation, orally available selective inhibitor of BRAF alterations at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC International Conference, taking place October 11-14, 2023, in Boston and virtually (Press release, Fore Biotherapeutics, OCT 12, 2023, View Source [SID1234635916]). The data set presented in the poster shows improved drug activity for both V600 and non-V600 BRAF alternations from other pan-RAF and BRAF inhibitors.

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Poster
Abstract number: A095
Title: The paradox-breaker BRAF inhibitor plixorafenib (FORE8394) efficiently inhibits non-V600 mutations and fusions
Presentation Session Date/Time: Oct 12, 2023, 12:30-4 p.m. Poster Session

About plixorafenib (FORE8394)

Plixorafenib is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF mutations while sparing wild-type forms of RAF. Preclinical studies and clinical trials have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAFV600 monomers targeted by first-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class 2 mutants, fusions, splice variants and others. Unlike first-generation RAF inhibitors, plixorafenib does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a "paradox breaker," plixorafenib could therefore treat acquired resistance to current RAF inhibitors and, more generally, yield improved safety and more durable efficacy than first-generation RAF inhibitors. The company previously announced interim data from the ongoing Phase 1/2a clinical trial evaluating plixorafenib in patients with advanced solid tumors (including brain and spinal cord tumors) with activating BRAF alterations, providing evidence of durable anti-tumor activity in patients with BRAF-mutated cancers. The data were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO) (Free ESMO Whitepaper) in September 2022 and ASCO (Free ASCO Whitepaper) 2023.

On October 12, 2023 Novocure (NASDAQ: NVCR) reported that it has entered into an agreement with Stanford University to establish the Stanford School of Medicine Tumor Treating Fields (TTFields) Research Program (Press release, NovoCure, OCT 12, 2023, View Source [SID1234635915]). The program is intended to support both preclinical studies and clinical trials with TTFields, electric fields that exert physical forces to kill cancer cells via a variety of mechanisms.

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"We look forward to collaborating with Stanford Medicine to establish a research framework for preclinical and clinical development of TTFields," said Moshe Giladi, Ph.D., Novocure’s Chief Science Officer. "Together, we will enable new discoveries into the mechanisms and treatment possibilities of TTFields, including new indications and uses of TTFields along with other therapies. We will pursue our mission to extend survival in some of the most aggressive forms of cancer while enhancing the education and scholarship of future clinicians and scientists."

To enable novel preclinical research, Novocure will provide Stanford Medicine investigators with its portfolio of proprietary inovitro, inovitro Live and inovivo TTFields preclinical systems which allows for exploring a vast range of research questions, starting from the fundamental physical mode of action all the way to most complex systemic biological outcomes. In addition, Novocure will provide devices for clinical studies.

At present, Stanford Medicine is a site for four clinical studies of TTFields therapy. This includes TRIDENT, a Novocure-sponsored multi-center study of TTFields therapy given concomitantly with radiation therapy and temozolomide in newly diagnosed glioblastoma (GBM) patients, in which Stanford University Cancer Institute is one of 132 participating study centers. Investigator-sponsored trials at Stanford include multiple investigational uses, including a study of TTFields therapy for children with high-grade glioma or ependymoma and TTFields therapy for children with diffuse intrinsic pontine glioma, a study of TTFields therapy with hypofractionated chemoradiotherapy in newly diagnosed GBM, and a study of TTFields therapy with bevacizumab in treating patients with recurrent or progressive Grade 2 or 3 meningioma.

In addition, Stanford is home to a preclinical study of the efficacy of TTFields in medulloblastoma.

"With this initiative, we will establish a research infrastructure for preclinical and clinical development of TTFields and of potential new indications and combination therapies using TTFields," said Michael Lim, M.D., Chair of the Department of Neurosurgery at Stanford Medicine. "We hope that this collaboration will educate, bring together, and inspire a diverse group of leaders in medicine and science who will help further our mission to deliver outstanding patient-centered care and improve human health through discovery, innovation, and education."

About Tumor Treating Fields Therapy

Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. The multiple, distinct mechanisms of TTFields therapy work together to selectively target and kill cancer cells. Due to its multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or targeted therapies in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors. To learn more about Tumor Treating Fields therapy and its multifaceted effect on cancer cells, visit tumortreatingfields.com.

On October 12, 2023 Bayer reported that it will present new data from across its oncology portfolio at the upcoming European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress taking place in Madrid, Spain from October 20-24, 2023 (Press release, Bayer, OCT 12, 2023, View Source [SID1234635914]). The breadth of new data showcases Bayer’s ongoing commitment to supporting patients living with cancer.

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NUBEQA (darolutamide) data includes further analyses from the Phase III ARASENS trial which evaluates prostate-specific antigen (PSA) outcomes of NUBEQA plus androgen deprivation therapy (ADT) and docetaxel, compared to ADT and docetaxel by disease volume in metastatic hormone-sensitive prostate cancer (mHSPC). In addition, Bayer will present new data on health-related quality of life (HRQoL) deterioration-free survival (DetFS) by PSA decline in the Phase III ARAMIS trial in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). NUBEQA is currently indicated in the U.S. in combination with docetaxel for the treatment of adult patients with mHSPC and for the treatment of adult patients with nmCRPC.1

Bayer will also present new data from the REASSURE observational study, evaluating the clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) who received combined treatment with Xofigo (radium Ra 223 dichloride) and enzalutamide. Xofigo is indicated for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease.2

Bayer remains committed to gastrointestinal (GI) cancer care. New real-world data featuring Stivarga (regorafenib) explores the clinical outcomes of Stivarga-treated patients when administered prior to trifluridine/tipiracil ± bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Additionally, Bayer will highlight data from the REFINE study, evaluating the safety and effectiveness of Stivarga in patients with unresectable hepatocellular carcinoma (uHCC) and prior liver transplantation (PLT). Stivarga is 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. Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.3

Bayer will highlight the latest efficacy and safety data of Vitrakvi (larotrectinib), including data from a post-hoc pooled analysis of three clinical trials evaluating Vitrakvi in the treatment of patients with treatment-naïve non-primary central nervous system (CNS) TRK fusion cancer, and updated data from a pooled analysis from three clinical trials of patients with longer follow-up. Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Patients should be selected for therapy based on a FDA-approved test. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.4

Bayer will highlight the latest data from its precision oncology pipeline, including the first disclosure of investigational clinical data from a first-in-human, Phase I trial of BAY 2927088, an oral tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC).

Details on presentations from Bayer for the 2023 ESMO (Free ESMO Whitepaper) Congress are listed below:

Darolutamide

Prostate-specific antigen (PSA) outcomes with darolutamide (DARO), androgen-deprivation therapy (ADT) and docetaxel (DOC) in patients (pts) with high- and low-volume metastatic hormone-sensitive prostate cancer (mHSPC) in ARASENS
E-Poster: 1784P; October 22
Health-related quality of life (HRQoL) deterioration-free survival (DetFS) by prostate-specific antigen (PSA) decline in darolutamide (DARO)-treated patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from ARAMIS
E-Poster: 1781P; October 22
Radium-223 dichloride (Ra-223)

Combination treatment with radium-223 (223Ra) and enzalutamide (enza) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) in the REASSURE study
E-Poster: 1816P; October 22
Regorafenib

Sequential treatment with regorafenib (REG) and trifluridine/tipiracil (TAS) +/- bevacizumab (Bev) in refractory metastatic colorectal cancer (mCRC) in community clinical practice in the USA
E-Poster: 616P; October 22
Regorafenib (REG) in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in real-world (RW) practice: Final analysis of the prospective, observational REFINE study by prior liver transplantation (PLT)
E-Poster: 994P; October 23
Larotrectinib

Efficacy and safety of larotrectinib (laro) as first-line treatment for patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer
E-Poster: 667P; October 23
Efficacy and Safety of Larotrectinib in a Pooled Analysis of Patients (Pts) with Tropomyosin Receptor Kinase (TRK) Fusion Cancer
E-Poster: 668P; October 23
Precision Oncology Pipeline

Early evidence of efficacy in patients (pts) with non-small cell lung cancer (NSCLC) with HER2 exon20 insertion (ex20ins) mutations treated in a Phase I study with BAY 2927088
Oral Presentation: 1320MO; October 23
About NUBEQA (darolutamide)1

NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.

On July 30, 2019, the FDA approved NUBEQA (darolutamide) based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study, which evaluated the safety and efficacy of oral NUBEQA in patients with non-metastatic castration-resistant prostate cancer (nmCRPC).

Based on results from the ARASENS trial, a randomized, Phase III, multi-center, double-blind, placebo-controlled trial, NUBEQA plus androgen deprivation therapy (ADT) and docetaxel was approved on August 5, 2022 for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC).

NUBEQA is also being investigated in additional studies across various stages of prostate cancer, including in the ARANOTE Phase III trial evaluating NUBEQA plus ADT versus ADT alone for mHSPC, as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at www.clinicaltrials.gov.

Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of adults with nmCRPC or with mHSPC in combination with docetaxel.1 Filings in other regions are underway or planned.

INDICATIONS

NUBEQA (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with:

Non-metastatic castration-resistant prostate cancer (nmCRPC)
Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel
IMPORTANT SAFETY INFORMATION

Warnings & Precautions

Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 2.9% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease.

Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.

Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.

Adverse Reactions

In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure.

In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury.

Drug Interactions

Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use.

Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed.

Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate.

NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.

Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.

For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information.

About Xofigo (radium Ra 223 dichloride) Injection2

Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Important Safety Information for Xofigo (radium Ra 223 dichloride) Injection

Warnings and Precautions:

Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care

Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established

Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo
Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia

Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo

Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial

Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy

Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

Please see the full Prescribing Information for Xofigo (radium Ra 223 dichloride).

About Stivarga (regorafenib)3

In April 2017, Stivarga was approved for use in patients with hepatocellular carcinoma who have been previously treated with sorafenib. In the United States, Stivarga is also indicated for the treatment of patients with metastatic colorectal cancer (CRC) 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 gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

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.

Indication

Stivarga is indicated for the treatment of patients with metastatic colorectal cancer (CRC) 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.

Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Important Safety Information for STIVARGA (regorafenib)

WARNING: HEPATOTOXICITY

Severe and sometimes fatal hepatotoxicity has occurred in clinical trials.
Monitor hepatic function prior to and during treatment.
Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

Infections: STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials. The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.

Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 25.5% of patients in the placebo arm including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES) and severe rash, requiring dose modification. In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3:18%). Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity.

Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo-controlled trials). Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension.

Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristics finding on MRI occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion, or altered mental function. Discontinue STIVARGA in patients who develop RPLS.

Wound Healing Complications: Impaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, STIVARGA has the potential to adversely affect wound healing. Withhold STIVARGA for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose.

Nursing Mothers: Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose.

Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients 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%).

Please see full Prescribing Information, including Boxed Warning for Stivarga (regorafenib).

About Vitrakvi (larotrectinib)4

Vitrakvi (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.

Select patients for therapy based on an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information for Vitrakvi (larotrectinib)

Warnings and Precautions

Central Nervous System Effects: Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances.

In patients who received VITRAKVI, all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 42% with Grades 3-4 in 3.9% of patients.

Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 5.6 months (range: 2 days to 41 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (3.6%), confusional state (2.9%), disturbance in attention (2.9%), delirium (2.2%), cognitive disorders (1.4%), and Grade 3 cognitive adverse reactions occurred in 2.5% of patients. Among the 30 patients with cognitive impairment, 7% required a dose modification and 20% required dose interruption.

Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.9 months (range: 1 day to 40.5 months). Mood disorders occurring in ≥1% of patients included anxiety (5%), depression (3.9%), agitation (2.9%), and irritability (2.9%). Grade 3 mood disorders occurred in 0.4% of patients.

Dizziness occurred in 27% of patients, and Grade 3 dizziness occurred in 1.1% of patients. Among the 74 patients who experienced dizziness, 5% of patients required a dose modification and 5% required dose interruption.

Sleep disturbances occurred in 10% of patients. Sleep disturbances included insomnia (7%), somnolence (2.5%), and sleep disorder (0.4%). There were no Grade 3-4 sleep disturbances. Among the 28 patients who experienced sleep disturbances, 1 patient each (3.6%) required a dose modification or dose interruption.

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Skeletal Fractures: Among 187 adult patients who received VITRAKVI across clinical trials, fractures were reported in 7% and among 92 pediatric patients, fractures were reported in 9% (N=279; 8%). Median time to fracture was 11.6 months (range 0.9 to 45.8 months) in patients followed per fracture. Fractures of the femur, hip or acetabulum were reported in 4 patients (3 adult, 1 pediatric). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients.

Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures.

Hepatotoxicity: In patients who received VITRAKVI, increased AST of any grade occurred in 52% of patients and increased ALT of any grade occurred in 45%. Grade 3-4 increased AST or ALT occurred in 3.1% and 2.5% of patients, respectively. The median time to onset of increased AST was 2.1 months (range: 1 day to 4.3 years). The median time to onset of increased ALT was 2.3 months (range: 1 day to 4.2 years). Increased AST and ALT leading to dose modifications occurred in 1.4% and 2.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 3 (1.1%) patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. VITRAKVI resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.
Adverse Reactions

The most common adverse reactions (≥20%), including laboratory abnormalities, were: increased AST (52%), increased ALT (45%), anemia (42%), musculoskeletal pain (42%), fatigue (36%), hypoalbuminemia (36%), neutropenia (36%), increased alkaline phosphatase (34%), cough (32%), leukopenia (28%), constipation (27%), diarrhea (27%), dizziness (27%), hypocalcemia (25%), nausea (25%), vomiting (25%), pyrexia (24%), lymphopenia (22%) and abdominal pain (21%).
Drug Interactions

Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs. For coadministration with moderate CYP3A4 inhibitors, monitor for adverse reactions more frequently and reduce the dosage based on severity. For coadministration with moderate CYP3A4 inducers, modify dose as recommended.
Use in Specific Populations

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.
Please see the full Prescribing Information for VITRAKVI (larotrectinib).