On September 19, 2019 Pfizer Inc. (NYSE: PFE) is presenting data across its industry-leading oncology portfolio, including company-sponsored and collaborative research studies, spanning 11 therapies in 22 types of cancer, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress to be held in Barcelona, Spain, September 27 – October 1, 2019 (Press release, Pfizer, SEP 19, 2019, View Source [SID1234539642]). Data from nearly 50 abstracts involving Pfizer cancer medicines will illustrate the diversity of the portfolio and the company’s cutting-edge scientific approach. For the first time, this will include data presentations on compounds from the acquisition of Array Biopharma Inc.
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"At this year’s ESMO (Free ESMO Whitepaper) Congress, we’re looking forward to showcasing how we’re embodying ESMO (Free ESMO Whitepaper)’s theme of translating science into better patient care," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "Whether it’s studying patient populations such as those affected by BRAF-mutant metastatic colorectal cancer who are in need of new treatment options, utilizing new techniques like real-world evidence to understand further the impact of our medicines in the non-clinical trial setting, or studying a different way to administer a treatment that may be more convenient for patients, Pfizer is leading the way in taking innovative approaches to meeting the needs of people living with cancer."
Clinical data can be complex and often difficult to understand if a person is not a scientist. To help interested non-scientists better understand the latest research, Pfizer developed summaries in non-technical language for research results being presented at this year’s ESMO (Free ESMO Whitepaper) Congress. These informational materials, called "abstract plain language summaries (APLS)," will be made available for non-scientists to learn more about Pfizer’s latest scientific developments.
Key Pfizer-sponsored abstracts leveraging the depth of Pfizer’s scientific advances include:
A late-breaking oral presentation of expanded results from the Phase 3 BEACON CRC study of BRAFTOVI (encorafenib) plus cetuximab with or without MEKTOVI (binimetinib) in BRAFV600E-mutant metastatic colorectal cancer (LBA32).
A poster presentation on real-world clinical practices of IBRANCE (palbociclib) plus letrozole vs. letrozole for metastatic breast cancer (329P).
A poster presentation on early safety and clinical activity data of RN888 (PF-06801591) in metastatic non-small cell lung cancer and urothelial carcinoma (1275P).
A poster discussion on a subgroup analysis from JAVELIN Renal 101 of BAVENCIO (avelumab) plus INLYTA (axitinib) in renal cell carcinoma patients who did not undergo nephrectomy (908PD).
A poster discussion on a subgroup analysis from JAVELIN Renal 101 of BAVENCIO (avelumab) plus INLYTA (axitinib) in renal cell carcinoma patients with sarcomatoid histology (910PD).
A poster discussion on the efficacy of LORBRENA (lorlatinib) in the post second-generation ALK tyrosine kinase inhibitor setting (1487PD).
A poster presentation on the efficacy of XTANDI (enzalutamide) with androgen deprivation therapy in high and low disease volume and risk groups in patients with metastatic hormone-sensitive prostate cancer (853P).
Details for key Pfizer-sponsored oral presentations, poster discussions and poster presentations are below:
Title/Abstract Number
Date/Time (CEST)
Location
(LBA32)
Encorafenib plus Cetuximab With or Without Binimetinib for BRAF V600E–Mutant Metastatic Colorectal Cancer: Expanded Results from a Randomized, 3-Arm, Phase III Study vs. the Choice of Either Irinotecan or FOLFIRI plus Cetuximab (BEACON CRC)
Tabernero J
Monday, September 30
8:30 AM – 8:45 AM
Barcelona Auditorium
(908PD)
Primary renal tumour shrinkage in patients (pts) who did not undergo upfront cytoreductive nephrectomy (uCN): subgroup analysis from the phase 3 JAVELIN Renal 101 trial of first-line avelumab + axitinib (A + Ax) vs sunitinib (S) for advanced renal cell carcinoma (aRCC)
Albiges L
Sunday, September 29
3:00 PM – 4:15 PM
Pamplona Auditorium
(910PD)
Efficacy and biomarker analysis of patients (pts) with advanced renal cell carcinoma (aRCC) with sarcomatoid histology (sRCC): subgroup analysis from the phase 3 JAVELIN Renal 101 trial of first-line avelumab plus axitinib (A + Ax) vs sunitinib (S)
Choueiri TK
Sunday, September 29
3:00 PM – 4:15 PM
Pamplona Auditorium
(329P)
Comparative effectiveness of palbociclib plus letrozole vs letrozole for metastatic breast cancer in US real-world clinical practices
Layman RM
Sunday, September 29
12:00 PM – 1:00 PM
Hall 4
(1487PD)
Intracranial and extracranial efficacy of lorlatinib in the post second-generation ALK tyrosine kinase inhibitor (TKI) setting
Camidge DR
Sunday, September 29
4:30 PM – 5:45 PM
Cordoba Auditorium
(853P)
ARCHES – the role of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analyses of high and low disease volume and risk groups
Stenzl A
Monday, September 30
12:00 PM – 1:00 PM
Hall 4
(1275P)
Safety and clinical activity of subcutaneously (SC) administered anti-PD-1 antibody PF-06801591 in phase I dose-expansion cohorts of locally advanced or metastatic non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC)
Cho BC
Monday, September 30
12:00 PM – 1:00 PM
Hall 4
(1360P)
Intracranial anti-tumor activity in melanoma brain metastases with encorafenib plus binimetinib: a multicenter, retrospective analysis
Lutzky J
Monday, September 30
12:00 PM – 1:00 PM
Hall 4
(1379TiP)
A phase 2, open-label, randomized, multicenter trial of encorafenib + binimetinib evaluating a standard-dose and a high-dose regimen in patients with BRAFV600-mutant melanoma brain metastasis (MBM) (POLARIS)
Davies MA
Monday, September 30
12:00 PM – 1:00 PM
Hall 4
Please see a complete list of Pfizer-sponsored abstracts featuring data on our broad pipeline of biologics and small molecules at View Source
About BAVENCIO (avelumab)
In Europe, BAVENCIO (avelumab)is indicated as monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (MCC).
In the U.S., BAVENCIO is indicated for:
Adults and pediatric patients 12 years and older with metastatic MCC.
Patients with locally advanced or metastatic urothelial carcinoma (UC)who:
Have disease progression during or following platinum-containing chemotherapy.
Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
First-line treatment, in combination with axitinib of patients with advanced renal cell carcinoma.
BAVENCIO Important Safety Information from the U.S. FDA-Approved Label
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.
BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.
BAVENCIO in combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold BAVENCIO and axitinib for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed. In patients treated with BAVENCIO in combination with axitinib, Grades 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4.
BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% of patients, including seven (0.4%) with Grade 3.
BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.
Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% of patients, including one (0.1%) with Grade 3.
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3.
Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia.
BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% of patients.
BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with axitinib: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.
BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.
BAVENCIO in combination with axitinib can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).
BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.
Please see full U.S. Prescribing Information and Medication Guide for BAVENCIO available at www.Bavencio.com.
About INLYTA (axitinib)
In Europe, INLYTA (axitinib) is indicated for the treatment of adult patients with advanced renal-cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine.
In the U.S., INLYTA is indicated for the treatment of advanced RCC after failure of one prior systemic therapy.
INLYTA Important Safety Information from the U.S. FDA-Approved Label
Hypertension including hypertensive crisis has been observed with axitinib. Blood pressure should be well controlled prior to initiating axitinib. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue axitinib if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of axitinib, and discontinuation should be considered if there is evidence of hypertensive crisis.
Arterial and venous thrombotic events have been observed with axitinib and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events.
Hemorrhagic events, including fatal events, have been reported with axitinib. Axitinib has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the axitinib dose.
Cardiac failure has been observed with axitinib and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with axitinib. Management of cardiac failure may require permanent discontinuation of axitinib.
Gastrointestinal perforation and fistula, including death, have occurred with axitinib. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.
Hypothyroidism requiring thyroid hormone replacement has been reported with axitinib. Monitor thyroid function before initiation of, and periodically throughout, treatment.
No formal studies of the effect of axitinib on wound healing have been conducted. Stop axitinib at least 24 hours prior to scheduled surgery.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed with axitinib. If signs or symptoms occur, permanently discontinue treatment.
Proteinuria has been observed with axitinib. Monitor for proteinuria before initiation of, and periodically throughout, treatment with axitinib. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.
Liver enzyme elevation has been observed during treatment with axitinib. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment.
For patients with moderate hepatic impairment, the starting dose should be decreased. axitinib has not been studied in patients with severe hepatic impairment.
Axitinib can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception during treatment.
Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided.
Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.
Please see full U.S. Prescribing Information for INLYTA at www.Inlyta.com.
About IBRANCE (palbociclib)
In Europe, IBRANCE (palbociclib) is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor; in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone releasing hormone agonist.
In the U.S., IBRANCE (palbociclib) 125 mg capsules is indicated for the treatment of adult patients with HR+/HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or fulvestrant in patients with disease progression following endocrine therapy.
IBRANCE Important Safety Information from the U.S. FDA-Approved Label
Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.
Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with CDK4/6 inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis.
Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients to consider sperm preservation before taking IBRANCE. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.
The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).
The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).
Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).
The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).
The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).
Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).
Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.
For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis.
Please see full U.S. Prescribing Information for IBRANCE at www.Ibrance.com.
About XTANDI (enzalutamide)
In Europe, XTANDI (enzalutamide) is indicated for the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC); the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated; the treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.
In the U.S., XTANDI is indicated for the treatment of patients with CRPC.
XTANDI Important Safety Information from the U.S. FDA-Approved Label
Warnings and Precautions
Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES) In post-approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.
Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.
Ischemic Heart Disease In the placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus 0.5% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.
Falls and Fractures In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.
Embryo-Fetal Toxicity Safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. XTANDI should not be handled by females who are or may become pregnant.
Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI patients from the randomized placebo-controlled trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.
In the placebo-controlled study of metastatic CRPC (mCRPC) patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.
Lab Abnormalities: In the two placebo-controlled trials in patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the placebo-controlled trial in patients with nmCRPC, Grade 1-4 neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4) and in 5% of patients receiving placebo (0.2% Grade 3-4).
Hypertension: In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in <1% of patients in each arm. In the placebo-controlled trial in patients with nmCRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.
Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.
Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.
Please see full U.S. Prescribing Information for XTANDI at www.Xtandi.com.
About LORBRENA (lorlatinib)
In Europe, LORBRENA (lorlatinib) is marketed as LORVIQUA and is indicated as monotherapy for the treatment of adult patients with ALK-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI.
In the U.S., LORBRENA is indicated for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease; or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
LORBRENA Important Safety Information from the U.S. FDA-Approved Label
Contraindications: LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity.
Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers: Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORBRENA with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 ALT or AST elevations occurred in 50% of subjects, Grade 3 in 33% of subjects, and Grade 2 in 8% of subjects. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA. Avoid concomitant use of LORBRENA with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin 48 hours after initiating LORBRENA and at least 3 times during the first week after initiating LORBRENA. Depending upon the relative importance of each drug, discontinue LORBRENA or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity.
Central Nervous System (CNS) Effects: A broad spectrum of CNS effects can occur. These include seizures, hallucinations, and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Withhold and resume at the same or reduced dose or permanently discontinue based on severity.
Hyperlipidemia: Increases in serum cholesterol and triglycerides can occur. Grade 3 or 4 elevations in total cholesterol occurred in 17% and Grade 3 or 4 elevations in triglycerides occurred in 17% of the 332 patients who received LORBRENA. Eighty percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 21 days. Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter. Withhold and resume at same dose for the first occurrence; resume at same or reduced dose of LORBRENA for recurrence based on severity.
Atrioventricular (AV) Block: PR interval prolongation and AV block can occur. In 295 patients who received LORBRENA at a dose of 100 mg orally once daily and who had a baseline electrocardiography (ECG), 1% experienced AV block and 0.3% experienced Grade 3 AV block and underwent pacemaker placement. Monitor ECG prior to initiating LORBRENA and periodically thereafter. Withhold and resume at reduced or same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker.
Interstitial Lung Disease (ILD)/Pneumonitis: Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur. ILD/pneumonitis occurred in 1.5% of patients, including Grade 3 or 4 ILD/pneumonitis in 1.2% of patients. Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis. Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity.
Embryo-fetal Toxicity: LORBRENA can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since LORBRENA can render hormonal contraceptives ineffective, during treatment with LORBRENA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for 3 months after the final dose.
Adverse Reactions: Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). The most common (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea; the most common (≥20%) laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.
Drug Interactions: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Avoid concomitant use with moderate CYP3A inducers and strong CYP3A inhibitors. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor ALT, AST, and bilirubin as recommended. If concomitant use with a strong CYP3A inhibitor cannot be avoided, reduce the LORBRENA dose as recommended. Concomitant use of LORBRENA decreases the concentration of CYP3A substrates.
Lactation: Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.
Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment. The recommended dose of LORBRENA has not been established for patients with moderate or severe hepatic impairment.
Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. The recommended dose of LORBRENA has not been established for patients with severe renal impairment.
Please see full U.S. Prescribing Information for LORBRENA at www.Lorbrena.com.
About BRAFTOVI (encorafenib) and MEKTOVI (binimetinib)
In Europe, BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation.
In the U.S., BRAFTOVI and MEKTOVI are indicated 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 and MEKTOVI Important Safety Information from the U.S. FDA-Approved Label
WARNINGS AND PRECAUTIONS
New Primary Malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Median time to first occurrence of cuSCC/KA was 5.8 months. Perform dermatologic 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. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.
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, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients. 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). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Hemorrhage: Hemorrhage can occur when BRAFTOVI is administered in combination with MEKTOVI. In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 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. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
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. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months. Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI (n=690), 1 patient experienced RVO (0.1%). 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. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients treated with MEKTOVI in combination with BRAFTOVI. 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.
Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% (2 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Hepatotoxicity: Hepatotoxicity can occur when MEKTOVI is administered in combination with BRAFTOVI. In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Rhabdomyolysis: Rhabdomyolysis can occur when MEKTOVI is administered in combination with BRAFTOVI. In the COLUMBUS trial, elevation of laboratory values of serum CPK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% (1 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI. Monitor 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.
QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with MEKTOVI. 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.
Embryo-Fetal Toxicity: BRAFTOVI and MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI and MEKTOVI.
Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% in patients treated with BRAFTOVI in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.
ADVERSE REACTIONS
The most common adverse reactions (≥ 20%, all Grades, in the COLUMBUS trial) for BRAFTOVI and 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/RFED (20% vs. 2). Other clinically important adverse reactions occurring in <10% of patients in the COLUMBUS trial were facial paresis, pancreatitis, panniculitis, drug hypersensitivity, and colitis.
In the COLUMBUS trial, the most common laboratory abnormalities (all grades) (≥ 20%) for BRAFTOVI and MEKTOVI compared to vemurafenib included increased creatinine (93% vs. 92%), increased creatine phosphokinase (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%).
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. Avoid coadministration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.
Please see full U.S. Prescribing Information for BRAFTOVI and MEKTOVI at www.BraftoviMektovi.com.
Pfizer has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Ono Pharmaceutical Co. Ltd. has exclusive rights to commercialize both products in Japan and South Korea, Medison has exclusive rights to commercialize both products in Israel and Pierre Fabre has exclusive rights to commercialize both products in all other countries, including Europe, Latin American and Asia (excluding Japan and South Korea).