On October 9, 2018 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that new results from a number of studies across its industry-leading oncology portfolio of approved and investigational medicines will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress, taking place from October 19-23 in Munich, Germany (Press release, Genentech, OCT 9, 2018, View Source [SID1234529824]). These data include positive Phase III results from Genentech’s cancer immunotherapy development program across multiple tumor types, positive Alecensa (alectinib) data from the Phase III ALESIA study and new pivotal data for entrectinib, a tumor-agnostic investigational medicine that targets NTRK gene fusion-positive solid tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We look forward to presenting the first positive Phase III study of a cancer immunotherapy combination in breast cancer, which showed encouraging results for Tecentriq plus nab-paclitaxel in people with metastatic triple-negative breast cancer, specifically in the PD-L1-positive population," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "We will also share new data from our pivotal analysis of entrectinib for people with NTRK gene fusion-positive solid tumors, an example of our continued commitment to developing next-generation personalized treatments."

Follow Genentech on Twitter via @genentech and keep up to date with ESMO (Free ESMO Whitepaper) 2018 Congress news and updates by using the hashtag #ESMO18.

Key Presentations

Breast cancer:

Primary results will be presented from the positive, Phase III, randomized IMpassion130 study investigating Tecentriq plus chemotherapy (Abraxane [albumin-bound paclitaxel; nab-paclitaxel]) as an initial (first-line) treatment for people with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC), an aggressive type of the disease, which currently has limited treatment options. Abstract LBA1_PR (Presidential Symposium 1) – Saturday, October 20, 4:30 – 4:45 p.m. CEST: Hall A2 – Room 18

As reported earlier this year by Genentech, the combination of Tecentriq plus chemotherapy (nab-paclitaxel) significantly reduced the risk of disease worsening or death (progression-free survival, PFS) in the intention-to-treat and the PD-L1-positive populations, and showed an encouraging overall survival (OS) improvement at this interim analysis in people whose disease expresses the PD-L1 protein, a subgroup determined by PD-L1 biomarker testing.

Data from the IMpassion130 study will also be featured as part of ESMO (Free ESMO Whitepaper)’s press program on Saturday, October 20.

Tumor-agnostic:

Pivotal data from the positive Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA trials will be presented on entrectinib (RXDX-101) for the treatment of people with NTRK gene fusion-positive solid tumors. Abstract LBA17 (oral) – Sunday, October 21, 11:24 – 11:36 a.m. CEST: Hall B3 – Room 22

Molecular profiling and next-generation sequencing will play a critical role in identifying people most likely to benefit from entrectinib. Genentech is combining comprehensive genomic profiling with precision medicines, like entrectinib, in order to offer patients more personalized healthcare solutions.

Entrectinib has been granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) for the treatment of NTRK gene fusion-positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or have no acceptable standard therapies.

Lung cancer:

Key data to be presented at ESMO (Free ESMO Whitepaper) cover advances from Genentech’s lung cancer program, including a combination approach using the cancer immunotherapy Tecentriq with targeted therapies and a range of different chemotherapies.

OS and PFS data will be presented for the first time from the positive Phase III IMpower130 study, a multicenter, open-label, randomized study evaluating the efficacy and safety of Tecentriq in combination with chemotherapy (carboplatin and nab-paclitaxel) versus chemotherapy (carboplatin and nab-paclitaxel) alone for advanced non-squamous non-small cell lung cancer (NSCLC). Abstract LBA53 (oral) – Monday, October 22, 9:15 – 9:30 a.m. CEST: Hall A1 – Room 17

PFS data will also be presented for the first time from the positive Phase III ALESIA study, a randomized, multicenter, open-label study evaluating the efficacy and safety of Alecensa versus crizotinib in Asian patients with treatment-naive anaplastic lymphoma kinase (ALK)-positive advanced NSCLC. Abstract LBA10 (Presidential Symposium 3) – Monday, October 22, 5:30 – 5:45 p.m. CEST: Hall A2 – Room 18

Liver cancer:

Updated data will be presented from a Phase Ib study assessing the safety and clinical activity of the combination of Tecentriq and Avastin (bevacizumab) as treatment for patients with unresectable or advanced hepatocellular carcinoma (HCC). HCC is an aggressive cancer with limited treatment options and a major cause of cancer deaths worldwide. Earlier this summer the FDA granted BTD for Tecentriq in combination with Avastin as an initial (first-line) treatment for people with advanced or metastatic HCC. Data at ESMO (Free ESMO Whitepaper) include longer follow-up and data from patients with hepatitis B virus, a major driver of the disease. Abstract LBA26 (oral) – Sunday, October 21, 11:54 a.m. – 12:09 p.m. CEST: Hall A1 – Room 17

Overview of key data featuring Genentech medicines at ESMO (Free ESMO Whitepaper) 2018

Tumor Abstract title Abstract number
Breast IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC)
Abstract LBA1_PR (Presidential Symposium)
Saturday, October 20
4:30 – 4:45 p.m. CEST
Hall A2 – Room 18

Subcutaneous trastuzumab (H SC) with intravenous pertuzumab (P IV) and docetaxel (D IV) in HER2-positive advanced breast cancer (BC): MetaPHER second interim analysis
Abstract 323P (Poster)
Monday, October 22
12:45 – 1:45 p.m. CEST
Hall A3 – Poster Area

Tumor-agnostic Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001
Abstract LBA17 (Oral)
Sunday, October 21
11:24 – 11:36 a.m. CEST
Hall B3 – Room 22

Pan-cancer assessment of BRCA1/2 genomic alterations (GAs) by comprehensive genomic profiling (CGP) of tissue and circulating tumor DNA (ctDNA)

Abstract 51O (Oral)
Saturday, October 20
9:54 – 10:06 a.m. CEST
ICM – Room 14b

Clinical and analytical validation of an FDA approved comprehensive genomic profiling (CGP) assay incorporating multiple companion diagnostics for targeted and immunotherapies

Abstract 79P (Poster)
Saturday, October 20
12:30 – 1:30 p.m. CEST
Hall A3 – Poster Area

Lung IMpower130: Progression-free survival (PFS) and safety analysis from a randomised phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC
Abstract LBA53 (Oral)
Monday, October 22
9:15 – 9:30 a.m. CEST
Hall A1 – Room 17

Primary results of ALESIA: A randomised, phase III, open-label study of alectinib vs crizotinib in Asian patients with treatment-naïve ALK+ advanced NSCLC
Abstract LBA10 (Presidential Symposium)
Monday, October 22
5:30 – 5:45 p.m. CEST
Hall A2 – Room 18

IMpower132: efficacy of atezolizumab (atezo) + carboplatin (carbo)/cisplatin (cis) + pemetrexed (pem) as 1L treatment in key subgroups with stage IV non-squamous non-small cell lung cancer (NSCLC)
Abstract LBA54 (Oral)
Monday, October 22
9:30 – 9:45 a.m. CEST
Hall A1 – Room 17

IMpower131: Progression-free survival (PFS) and overall survival (OS) analysis of a randomised Phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel in 1L advanced squamous NSCLC
Abstract LBA65 (Poster Discussion)
Sunday, October 21
4:45 – 5:45 p.m. CEST
ICM – Room 13

IMpower150: clinical safety, tolerability and immune-related adverse events in a Phase III study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous NSCLC
Abstract 1386PD (Poster Discussion)
Sunday, October 21
4:45 – 5:45 p.m. CEST
ICM – Room 13

Analytic validation of tumor mutational burden as a companion diagnostic for combination immunotherapy in non-small cell lung cancer
Abstract 56PD (Poster Discussion)
Saturday, October 20
3:00 p.m. CEST
Hall B4 – Room 19

Kidney IMmotion151: molecular correlates differentiate response to atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC)
Abstract LBA31 (Oral)
Saturday, October 20
9:15 – 9:27 a.m. CEST
Hall A1 – Room 17

Safety and tolerability of atezolizumab (atezo) plus bevacizumab (bev) vs sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC): pooled analysis of IMmotion150 and IMmotion151
Abstract 873P (Poster)
Monday, October 22
12:45 – 1:45 p.m. CEST
Hall A3 – Poster Area

Liver Updated safety and clinical activity results from a Phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC)
Abstract LBA26 (Oral)
Sunday, October 21
11:54 a.m. – 12:09 p.m. CEST
Hall A1 – Room 17

Biomarkers Primary efficacy results from B-F1RST, a prospective Phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC)
Abstract LBA55 (Oral)
Monday, October 22
9:45 – 10:00 a.m. CEST
Hall A1 – Room 17

Colorectal Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): Findings from Cohort 2 of MODUL – a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy
Abstract LBA19 (Oral)
Monday, October 22
9:27 – 9:39 a.m. CEST
Hall A2 – Room 18

Bladder A phase II study investigating the safety and efficacy of neoadjuvent atezolizumab in muscle invasive bladder cancer (ABACUS)
(Investigator initiated study)

Abstract 899P (Poster)
Monday, October 22
12:45 – 1:45 p.m. CEST
Hall A3 – Poster Area

Biological features and clinical outcomes in atezolizumab (atezo)-treated patients (pts) with metastatic urothelial cancer (mUC) of the upper vs lower urinary tract (UTUC vs LTUC)
Abstract 902P (Poster)
Monday, October 22
12:45 – 1:45 p.m. CEST
Hall A3 – Poster Area

Abraxane is a registered trademark of Abraxis Bioscience, LLC, a wholly owned subsidiary of Celgene Corporation.

About triple negative breast cancer

Breast cancer is the second most common cancer among women in the United States. According to the American Cancer Society, it is estimated that about 266,000 American women will be diagnosed with invasive breast cancer in 2018, and nearly 41,000 will die from the disease. Approximately 10-20 percent of breast cancers are triple negative breast cancer (TNBC). TNBC is an aggressive form of the disease with a high unmet need. It can be more difficult to treat because it is not sensitive to hormone therapy or medicines that target HER2.

About NTRK gene fusions

Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TrKA/TrKB/TrKC) that can activate signaling pathways involved in proliferation of certain types of cancer. NTRK gene fusions are tumor-agnostic, meaning they are present in tumors irrespective of site of origin. These fusions have been identified in a broad range of solid tumor types, including lung, head and neck, salivary, pancreatic, breast and thyroid. There is a high unmet medical need for treatments for people with life-threatening and hard-to-treat NTRK fusion-positive tumors.

About lung cancer

According to the American Cancer Society, it is estimated that more than 234,000 Americans will be diagnosed with lung cancer in 2018. Lung cancer can be broadly divided into two major types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is the most prevalent type, accounting for around 85 percent of all lung cancer cases, and SCLC accounting for approximately 15 percent of all cases. It is estimated that approximately 60 percent of lung cancer diagnoses in the United States are made when the disease is in the advanced stages.

About hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for approximately 75 percent of all liver cancer cases diagnosed in the United States, with more than 20,000 men and more than 5,000 women diagnosed annually. HCC develops predominantly in people with cirrhosis due to chronic hepatitis B or C, and typically presents at an advanced stage where there are limited treatment options.

About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

Tecentriq U.S. Indication (pronounced ‘tē-SEN-trik’) Tecentriq is a prescription medicine used to treat:

A type of bladder and urinary tract cancer called urothelial carcinoma.

Tecentriq may be used when your bladder cancer:
has spread or cannot be removed by surgery, and if you have any one of the following conditions:
you are not able to take chemotherapy that contains a medicine called cisplatin, and your doctor has tested your cancer and found high levels of a specific protein on your cancer called programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test, or you are not able to take chemotherapy that contains any platinum regardless of PD-L1 status on your cancer, or
you have tried chemotherapy that contains platinum, and it did not work or is no longer working
The approval of Tecentriq in these patients is based on a study that measured response rate and duration of response. There is an ongoing study to confirm clinical benefit.

A type of lung cancer called non-small cell lung cancer (NSCLC).

Tecentriq may be used when your lung cancer:
has spread or grown, and
you have tried chemotherapy that contains platinum, and it did not work or is no longer working
If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.

It is not known if Tecentriq is safe and effective in children.

Important Safety Information

What is the most important information about Tecentriq?

Tecentriq can cause the immune system to attack normal organs and tissues and can affect the way they work. These problems can sometimes become serious or life threatening and can lead to death.

Patients should call or see their healthcare provider right away if they get any symptoms of the following problems or these symptoms get worse.

Tecentriq can cause serious side effects, including:

Lung problems (pneumonitis)–signs and symptoms may include new or worsening cough, shortness of breath, and chest pain
Liver problems (hepatitis)–signs and symptoms of hepatitis may include yellowing of the skin or the whites of the eyes, severe nausea or vomiting, pain on the right side of the stomach area (abdomen), drowsiness, dark urine (tea colored), bleeding or bruising more easily than normal, and feeling less hungry than usual
Intestinal problems (colitis)–signs and symptoms of colitis may include diarrhea (loose stools) or more bowel movements than usual, blood or mucous in the stools or dark, tarry, sticky stools, and severe stomach area (abdomen) pain or tenderness
Hormone gland problems (especially the thyroid, adrenal glands, pancreas, and pituitary)–signs and symptoms that the hormone glands are not working properly may include headaches that will not go away or unusual headaches, extreme tiredness, weight gain or weight loss, dizziness or fainting, feeling more hungry or thirsty than usual, hair loss, changes in mood or behavior (such as decreased sex drive, irritability, or forgetfulness), feeling cold, constipation, the voice gets deeper, urinating more often than usual, nausea or vomiting, and stomach area (abdomen) pain
Problems in other organs–signs and symptoms may include severe muscle weakness, numbness or tingling in hands or feet, confusion, blurry vision, double vision, or other vision problems, changes in mood or behavior, extreme sensitivity to light, neck stiffness, eye pain or redness, skin blisters or peeling, chest pain, irregular heartbeat, shortness of breath, or swelling of the ankles
Severe infections–signs and symptoms of infection may include fever, cough, flu-like symptoms, pain when urinating, and frequent urination or back pain
Severe infusion reactions–signs and symptoms of infusion reactions may include chills or shaking, itching or rash, flushing, shortness of breath or wheezing, swelling of the face or lips, dizziness, fever, feeling like passing out, and back or neck pain
Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider may treat patients with corticosteroid or hormone replacement medicines. A healthcare provider may delay or completely stop treatment with Tecentriq if patients have severe side effects.

Before receiving Tecentriq, patients should tell their healthcare provider about all of their medical conditions, including if they:

have immune system problems (such as Crohn’s disease, ulcerative colitis, or lupus); have had an organ transplant; have lung or breathing problems; have liver problems; have a condition that affects the nervous system (such as myasthenia gravis or Guillain-Barre syndrome); or are being treated for an infection
are pregnant or plan to become pregnant. Tecentriq can harm an unborn baby. Patients should tell their healthcare provider right away if they become pregnant or think they may be pregnant during treatment with Tecentriq. If patients are able to become pregnant: o A healthcare provider should do a pregnancy test before they start treatment with Tecentriq.
They should use an effective method of birth control during their treatment and for at least 5 months after the last dose of Tecentriq.
are breastfeeding or plan to breastfeed. It is not known if Tecentriq passes into the breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of Tecentriq
Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Tecentriq in people with urothelial carcinoma include:

feeling tired
decreased appetite
nausea
constipation
urinary tract infection
diarrhea
fever
The most common side effects of Tecentriq in people with non-small cell lung cancer include:

feeling tired
decreased appetite
muscle pain
cough
shortness of breath
Tecentriq may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information. Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at 1-800-FDA-1088 or View Source Report side effects to Genentech at 1-888-8352555.

Please visit View Source for the Tecentriq full Prescribing Information for additional Important Safety Information.

About Avastin (bevacizumab)

Avastin is a prescription-only medicine that is a solution for intravenous infusion. It is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF) that plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin is designed to interfere with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize).

Avastin Indications:

Metastatic colorectal cancer (mCRC) for first- or second-line treatment in combination with intravenous 5-fluorouracil–based chemotherapy. It is also approved to treat mCRC for second-line treatment, when used with fluoropyrimidine-based (combined with irinotecan or oxaliplatin) chemotherapy, after cancer progresses following a first-line treatment that includes Avastin.
Avastin is not approved for use after the primary treatment of colon cancer that has not spread to other parts of the body
Advanced nonsquamous non–small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel, in people who have not received chemotherapy for their advanced disease
Metastatic kidney cancer (mRCC) when used with interferon alfa
Glioblastoma (GBM) in adult patients whose cancer has progressed after prior treatment (recurrent or rGBM)
Advanced cervical cancer (CC) in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is approved to treat persistent, recurrent, or metastatic cancer of the cervix
Ovarian cancer (OC). Avastin, in combination with carboplatin and paclitaxel, followed by Avastin alone, is used for the treatment of patients with advanced (Stage III or IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgery.
Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan, is approved to treat platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) in women who received no more than two prior chemotherapy treatments.

Avastin, either in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine, followed by Avastin alone, is approved for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC)

Possible serious side effects

Everyone reacts differently to Avastin therapy. So, it’s important to know what the side effects are. Although some people may have a life-threatening side effect, most do not. Their doctor will stop treatment if any serious side effects occur. Patients should contact their health care team if there are any signs of these side effects.

Most serious side effects (not common, but sometimes fatal):

GI perforation. A hole that develops in the stomach or intestine. Symptoms include pain in the abdomen, nausea, vomiting, constipation, or fever
Wounds that don’t heal. A cut made during surgery can be slow to heal or may not fully heal. Avastin should not be used for at least 28 days before or after surgery and until surgical wounds are fully healed
Serious bleeding. This includes vomiting or coughing up blood; bleeding in the stomach, brain, or spinal cord; nosebleeds; and vaginal bleeding. If a patient has recently coughed up blood or had serious bleeding, they should be sure to tell their doctor
Other possible serious side effects

Abnormal passage in the body. This type of passage—known as a fistula—is an irregular connection from one part of the body to another and can sometimes be fatal
Severe high blood pressure. Blood pressure that severely spikes or shows signs of affecting the brain. Blood pressure should be monitored every 2 to 3 weeks while on Avastin and after stopping treatment
Kidney problems. These may be caused by too much protein in the urine and can sometimes be fatal
Infusion reactions. These were uncommon with the first dose (less than 3% of patients). 0.2% of patients had severe reactions. Infusion reactions include high blood pressure or severe high blood pressure that may lead to stroke, trouble breathing, decreased oxygen in red blood cells, a serious allergic reaction, chest pain, headache, tremors, and excessive sweating. The patient’s doctor or nurse will monitor for signs of infusion reactions
Severe stroke or heart problems. These may include blood clots, mini-stroke, heart attack, chest pain, and the heart may become too weak to pump blood to other parts of the body (congestive heart failure). These can sometimes be fatal
Nervous system and vision problems. Signs include headache, seizure, high blood pressure, sluggishness, confusion, and blindness
Side effects seen most often

In clinical studies across different types of cancer, some patients experienced the following side effects:

High blood pressure
Too much protein in the urine
Nosebleeds
Rectal bleeding
Back pain
Headache
Taste change
Dry skin
Inflammation of the skin
Inflammation of the nose
Watery eyes
Avastin is not for everyone

Patients should talk to their doctor if they are:

Undergoing surgery. Avastin should not be used for 28 days before or after surgery and until surgical wounds are fully healed
Pregnant or think they are pregnant. Data have shown that Avastin may harm a woman’s unborn baby. Birth control should be used while patients are on Avastin. If Avastin is stopped, patients should keep using birth control for 6 months before trying to become pregnant
Planning to become pregnant. Taking Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children
Breastfeeding. Breastfeeding while on Avastin may harm the baby and is therefore not recommended during and for 6 months after taking Avastin
Patients should talk with their doctor if they have any questions about their condition or treatment.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

For full Prescribing Information and Boxed WARNINGS on Avastin please visit View Source

About Alecensa (alectinib)

Alecensa is a kinase inhibitor approved for the treatment of people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

Alecensa U.S. Indication

Alecensa is a kinase inhibitor approved for the treatment of people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

Important Safety Information

Everyone reacts differently to treatment with Alecensa. It’s important to know the most serious and most common side effects with Alecensa.

A doctor may lower the dose or stop treatment with Alecensa if any serious side effects occur. Patients taking Alecensa should contact their doctor right away if they have any of the following side effects.

Alecensa may cause serious side effects, including:

Liver problems (hepatotoxicity). Alecensa may cause liver injury. A doctor will do blood tests at least every 2 weeks for the first 3 months and as needed during treatment with Alecensa. Patients taking Alecensa should tell their doctor right away if they experience any of the following signs and symptoms:

Feeling tired
Feeling less hungry than usual
Yellowing of the skin or whites of the eyes
Dark urine
Itchy skin
Nausea or vomiting
Pain on the right side of stomach area
Bleeding or bruising more easily than normal
Lung problems. Alecensa may cause severe or life-threatening swelling (inflammation) of the lungs during treatment. Symptoms may be similar to those symptoms from lung cancer. Patients taking Alecensa should tell their doctor right away if they have any new or worsening symptoms, including:

Trouble breathing
Shortness of breath
Fever
Cough
Kidney problems. Alecensa may cause severe or life-threatening kidney problems. Tell your healthcare provider right away if you have a change in the amount or color of your urine, or if you get new or worsening swelling in your legs or feet.

Slow heartbeat (bradycardia). Alecensa may cause very slow heartbeats that can be severe. A doctor will check a patient’s heart rate and blood pressure during treatment with Alecensa. Patients taking Alecensa should tell their doctor right away if they feel dizzy, lightheaded, or faint during treatment with Alecensa. Patients taking Alecensa should tell their doctor if they take any heart or blood pressure medicines.

Muscle pain, tenderness, and weakness (myalgia). Muscle problems are common with Alecensa and can be severe. A doctor will do blood tests at least every 2 weeks for the first month and as needed during treatment with Alecensa. Patients taking Alecensa should tell their doctor right away if they have any new or worsening signs and symptoms of muscle problems, including unexplained muscle pain or muscle pain that does not go away, tenderness, or weakness.

Before taking Alecensa, patients should tell their doctor about all medical conditions, including if they:

Have liver problems
Have lung or breathing problems
Have a slow heartbeat
Are pregnant or plan to become pregnant. Alecensa can harm an unborn baby. Patients taking Alecensa should tell their doctor right away if they become pregnant during treatment with Alecensa or think they may be pregnant
Women who are able to become pregnant should use effective birth control during treatment with Alecensa and for one week after the final dose of Alecensa
Men who have female partners that are able to become pregnant should use effective birth control during treatment with Alecensa and for three months after the final dose of Alecensa
Are breastfeeding or plan to breastfeed. It is not known if Alecensa passes into breast milk. A patient should not breastfeed during treatment with Alecensa and for one week after the final dose of Alecensa. Patients should talk with their doctor about the best way to feed their baby during this time.
Patients taking Alecensa should tell their doctor about all the medicines they take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements.

Patients taking Alecensa should avoid spending time in the sunlight during treatment with Alecensa and for seven days after the final dose of Alecensa. Patients taking Alecensa may burn more easily and get severe sunburns. Patients taking Alecensa should use sunscreen and lip balm with a SPF 50 or greater to help protect against sunburn.

The most common side effects of Alecensa include:

Tiredness
Constipation
Swelling in hands, feet, ankles, and eyelids
Low red blood cell count
These are not all of the possible side effects of Alecensa. For more information, patients should ask their doctor or pharmacist. Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at (800) FDA-1088 or View Source Patients and caregivers may also report side effects to Genentech at (888) 835-2555.

About entrectinib

Entrectinib (RXDX-101) is an investigational oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TrKA/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK fusions. Entrectinib is being investigated across a range of solid tumor types, including NSCLC, pancreatic cancer, sarcomas, thyroid cancer, salivary cancer, gastrointestinal stromal tumors (GIST) and cancers of unknown primary (CUP).

On October 9, 2018 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that new data from Merck’s broad oncology portfolio and robust early pipeline will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany from October 19-23 (Press release, Merck & Co, OCT 9, 2018, View Source [SID1234529820]). More than 100 abstracts involving Merck medicines – including eight late-breaking abstracts – across more than 15 tumor types have been accepted. Additionally, pivotal Phase 3 data evaluating anti-PD-1 therapy KEYTRUDA as a first-line treatment in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the KEYNOTE-048 trial (Abstract #LBA8_PR) and the PARP inhibitor LYNPARZA(in collaboration with AstraZeneca) as maintenance therapy in newly diagnosed patients with BRCA-mutated (BRCAm) advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy from the SOLO-1 trial (Abstract #LBA7_PR) are to be presented in the ESMO (Free ESMO Whitepaper) Presidential Symposium and featured in the official ESMO (Free ESMO Whitepaper) Press Program.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"At Merck, our unwavering commitment to R&D has permitted us to establish an extraordinarily broad discovery research program in oncology," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "The data at ESMO (Free ESMO Whitepaper) are reflective of our focus on discovering important new targets and developing novel medicines – including KEYTRUDA and LYNPARZA– with the potential to set new treatment standards across multiple tumor types."

Key abstracts from Merck’s broad pipeline to be presented at ESMO (Free ESMO Whitepaper) include:

First presentation of overall survival (OS) data from the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA for the first-line treatment of recurrent or metastatic HNSCC (Abstract #LBA8_PR).
First-time findings from the Phase 2 KEYNOTE-057 trial evaluating KEYTRUDA monotherapy in the treatment of advanced non-muscle invasive bladder cancer (NMIBC) (Abstract 864O).
First-time data from the pivotal Phase 3 SOLO-1 trial investigating LYNPARZA as maintenance therapy in newly diagnosed patients with BRCAm advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy (Abstract LBA7_PR). As previously announced, SOLO-1 met its primary endpoint, showing a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to placebo in these patients.
First presentation of Phase 1 clinical data for MK-1454, Merck’s investigational stimulator of interferon genes (STING) agonist, as monotherapy and in combination with KEYTRUDA, for the treatment of patients with advanced solid tumors or lymphomas (Abstract #LBA15).
Additional details and other select late breaker abstracts, proffered papers, and poster discussions to be presented from Merck’s portfolio and early pipeline at ESMO (Free ESMO Whitepaper) are below.

KEYTRUDA

Abstract #LBA8_PR, Presidential Symposium: First-Line Pembrolizumab for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC): Interim Results From the Phase 3 KEYNOTE-048 Study. B. Burtness. Monday, October 22, 4:30-4:45 p.m. CEST. Location: Hall A2.
Abstract #864O, Proffered Paper Session: Pembrolizumab for High-Risk (HR) Non–Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guérin (BCG): Phase 2 KEYNOTE-057 Trial. R de Wit, Saturday, October 20, 9:54-10:06 a.m. CEST. Location: Hall A1 – Room 17.
Abstract #1244O, Proffered Paper Session: KEYNOTE-022 Part 3: Phase 2 Randomized Study of 1L Dabrafenib (D) and Trametinib (T) Plus Pembrolizumab (Pembro) or Placebo (PBO) for BRAF-Mutant Advanced Melanoma. P A Ascierto. Monday, October 22, 10:23-10:35 a.m. CEST. Location: ICM – Room 1.
Abstract #LBA62, Poster Discussion Session: Health-related Quality of Life (HRQoL) for Pembrolizumab/Placebo plus Carboplatin and Paclitaxel/Nab-paclitaxel in Patients with Metastatic Squamous NSCLC: Data from KEYNOTE-407. J Mazieres. Sunday, October 21, Poster: 4:45-5:45 p.m. CEST. Discussion: 4:45-5:05 p.m. CEST. Location: ICM – Room 13.
Abstract #LBA63, Poster Discussion Session: Long-term Survival in Patients (pts) with Advanced NSCLC in the KEYNOTE-010 Study Overall and in Pts who Completed 2 Years of Pembrolizumab (pembro). R S Herbst. Sunday, October 21, Poster: 4:45-5:45 p.m. CEST. Discussion: 4:45-5:05 p.m. CEST. Location: ICM – Room 13.
Abstract #LBA36, Poster Discussion Session: Association of PD-L1 expression and Gene Expression Profiling with Clinical Response to Pembrolizumab in Patients with Advanced Recurrent Ovarian Cancer: Results from the Phase 2 KEYNOTE-100 Study. J A Ledermann. Saturday, October 20, Poster: 9:15-10:45 a.m. CEST. Discussion: 9:37-9:49 a.m. CEST. Location: ICM – Room 13.
Abstract #LBA45, Poster Discussion Session: Phase 1b/2, Open Label, Multicenter, Study of the Combination of SD-101 and Pembrolizumab in Patients with Advanced Melanoma who are Naïve to Anti-PD-1 Therapy. G V Long. Saturday, October 20, Poster: 2:45-4:05 p.m. CEST. Discussion: 2:45-3:05 p.m. CEST. Location: ICM – Room 14b.
Abstract #1248PD, Poster Discussion Session: Efficacy of Pembrolizumab (Pembro) in Patients (Pts) With Advanced Melanoma with Stable Brain Metastases (BM) at Baseline: A Pooled Retrospective Analysis O. Hamid. Saturday, October 20, Poster: 2:45-4:05 p.m. CEST. Discussion: 3:35 – 3:45 p.m. CEST. Location: ICM – Room 14b.
LYNPARZA (in collaboration with AstraZeneca)

Abstract #LBA7_PR, Presidential Symposium: Maintenance Olaparib Following Platinum-Based Chemotherapy in Newly Diagnosed Patients (pts) with Advanced Ovarian Cancer (OC) and a BRCA1/2 Mutation (BRCAm): Phase III SOLO1 Trial. K N Moore. Sunday, October 21, 5:45-6:00 p.m. CEST. Location: Hall A2 – Room 18.
LENVIMA (lenvatinib) (in collaboration with Eisai)

Abstract #59PD, Proffered Paper Session: Final Analysis of Serum Biomarkers in Patients from the Phase 3 Study of Lenvatinib vs Sorafenib in Unresectable Hepatocellular Carcinoma [REFLECT]. R. Finn, Saturday, October 20, Poster: 15:00-16:00 CEST. Discussion: 15:30-16:00 CEST. Location: Hall B4 – Room 19.
Abstract #1819O, Proffered Paper Session: Tumor Growth Rate and Lenvatinib Efficacy in Radioiodine-refractory Differentiated Thyroid Cancer. S. Leboulleux, Monday, October 22, 3:09-3:21 p.m. CEST. Location: Hall A1 – Room 16.
Merck Early Oncology Pipeline

Abstract #LBA15, Poster Discussion Session: Preliminary Results of the First-in-Human (FIH) Study of MK-1454, an Agonist of Stimulator of Interferon Genes (STING), Administered Intratumorally as Monotherapy or in Combination with Pembrolizumab (P) in Patients (pts) with Advanced Solid Tumors or Lymphomas. K J Harrington. Saturday, October 20, Poster: 3:00-4:15 p.m. CEST. Discussion: 3:00-3:20 p.m. CEST. Location: Hall B3 – Room 22.
Abstract #LBA16, Poster Discussion Session: Phase 1/2, Multicenter, Open-Label Study of Intratumoral/Intralesional Administration of the Retinoic Acid–Inducible Gene I (RIG-I) Activator MK-4621 in Patients With Advanced or Recurrent Tumors. M R Middleton. Saturday, October 20, Poster: 3:00-4:15 p.m. CEST. Discussion: 3:00-3:20 p.m. CEST. Location: Hall B3 – Room 22.
Abstract #LBA40, Poster Discussion Session: Phase 1b KEYNOTE-200. A Study of an Intravenously Delivered Oncolytic Virus, Coxsackievirus A21 in Combination with Pembrolizumab in Advanced NSCLC and Bladder Cancer Patients. C M Rudin. Saturday, October 20, Poster: 4:45-5:45 p.m. Discussion: 5:15-5:35 p.m. CEST. Location: ICM – Room 14b.
Abstract #414PD, Poster Discussion Session: Phase 1 Study of the CTLA-4 Inhibitor MK-1308 in Combination With Pembrolizumab in Patients With Advanced Solid Tumors. B C Cho. Saturday, October 20, Poster: 3:00-4:15 p.m. CEST. Discussion: 3:30-3:45 p.m. CEST. Location: Hall B3 – Room 22.
For more information, including a complete list of abstract titles and presentation dates and times for Merck’s oncology portfolio and early pipeline, please visit the ESMO (Free ESMO Whitepaper) website at View Source

About KEYTRUDA (pembrolizumab) Injection 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 800 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALKgenomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin or cisplatin, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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 the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue for Grade 4 colitis.

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1 fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients with Multiple Myeloma

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Lactation

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

About LYNPARZA (olaparib) 100 mg tablets

LYNPARZAis the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death. LYNPARZA is being tested in a range of DDR-deficient tumor types.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, is approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients worldwide. LYNPARZAhas a broad and advanced clinical trial development program and AstraZeneca and Merck are working together to deliver it as quickly as possible to more patients across multiple cancer types.

Important Safety Information for LYNPARZA

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals,

LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of

LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Indications

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm,human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

About LENVIMA (lenvatinib) capsules 10 mg and 4 mg

LENVIMA (lenvatinib) is a kinase inhibitor that is indicated in the U.S.:

For the treatment of patients with locally recurrent or metastatic, progressive radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
LENVIMA, discovered and developed by Eisai, is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

Important Safety Information for LENVIMA

Warnings and Precautions

Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC, hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3).

Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction.

Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Fistulas and gastrointestinal perforations have also been reported in other lenvatinib clinical trials and in post-marketing experience. Pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula, and pneumothorax occurred in association with tumor regression or necrosis. In most cases of fistula formation or gastrointestinal perforation, risk factors such as prior surgery or radiotherapy were present.

Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients.

Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome. Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events.

Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications. Wound healing complications, including fistula formation and wound dehiscence, can occur with LENVIMA. Withhold for at least 6 days prior to scheduled surgery. Resume after surgery based on clinical judgment of adequate wound healing. Permanently discontinue in patients with wound healing complications.

Embryo-fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions

In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

Use in Specific Populations

Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with RCC or DTC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

No dose adjustment is recommended for patients with DTC or RCC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe hepatic impairment. Reduce the dose for patients with DTC or RCC and severe hepatic impairment.

On October 9, 2018 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, reported that investigators will present data from the larotrectinib and LOXO-292 programs at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress to be held October 19-23, 2018, in Munich, Germany (Press release, Loxo Oncology, OCT 9, 2018, View Source [SID1234529819]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The larotrectinib oral presentation will provide updated follow-up on the primary analysis set of 55 patients enrolled across the larotrectinib pivotal program, as well as details on the clinical activity of larotrectinib in additional TRK fusion patients subsequently enrolled. The submitted abstract utilized a February 2018 data cut-off date, and the presentation will utilize a July 2018 data cut-off date.

Additionally, an updated analysis of patients’ plasma cell free DNA during treatment with LOXO-292 will be presented in a separate poster presentation.

The schedule for the presentations is as follows:

Oral Presentation Session Date & Time: October 21, 2018, 11:00 a.m. – 12:30 p.m. CET
Title: Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach
Presentation Number: 4090
Session Title: Proffered paper session – Developmental therapeutics
Location: Hall B3 – Room 22
Presenter: Ulrik Lassen, M.D., Ph.D.

Poster Presentation Session Date & Time: October 20, 2018, 12:30 p.m. – 1:30 p.m. CET
Title: Detection and clearance of RET variants in plasma cell free DNA (cfDNA) from patients (pts) treated with LOXO-292
Presentation Number: 105P
Session Title: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC – early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Location: Hall A3 – Poster Area Networking Hub
Presenter: Benjamin Besse, M.D.

About Larotrectinib
Larotrectinib is an oral and selective investigational tropomyosin receptor kinase (TRK) inhibitor in clinical development for the treatment of patients with cancers that harbor a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In clinical trials, larotrectinib demonstrated anti-tumor activity in patients with tumors harboring NTRK gene fusions, regardless of patient age or tumor type. In an analysis of 55 RECIST-evaluable adult and pediatric patients with NTRK gene fusions, using a July 17, 2017 data cutoff, larotrectinib demonstrated a 75 percent centrally-assessed confirmed overall response rate (ORR) and an 80 percent investigator-assessed confirmed ORR, across many different types of solid tumors. The majority (93 percent) of all adverse events were grade 1 or 2.

Larotrectinib has been granted Priority Review, Breakthrough Therapy Designation, Rare Pediatric Disease Designation and Orphan Drug Designation by the U.S. FDA.

In November 2017, Loxo Oncology and Bayer entered into an exclusive global collaboration for the development and commercialization of larotrectinib and LOXO-195, a next-generation TRK inhibitor. Bayer and Loxo Oncology are jointly developing the two products with Loxo Oncology leading the ongoing clinical studies as well as the filing in the U.S., and Bayer leading ex-U.S. regulatory activities and worldwide commercial activities. In the U.S., Loxo Oncology and Bayer will co-promote the products.

For additional information about the larotrectinib clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123 or visit www.loxooncologytrials.com/trk-trials.

About TRK Fusion Cancer
TRK fusion cancer occurs when a neurotrophic tyrosine receptor kinase (NTRK) gene fuses with another unrelated gene, producing an altered tropomyosin receptor kinase (TRK) protein. The altered protein, or TRK fusion protein, is constantly active, triggering a permanent signal cascade. These proteins become the primary driver of the spread and growth of tumors in patients with TRK fusion cancer. TRK fusion cancer is not limited to certain types of cells or tissues and can occur in any part of the body. NTRK gene fusions occur in various adult and pediatric solid tumors with varying prevalence, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, GIST, infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas. Only sensitive and specific tests can reliably detect TRK fusion cancer. Next-generation sequencing (NGS) can provide a comprehensive view of genomic alterations across a large number of genes. Fluorescence in situ hybridization (FISH) can also be used to test for TRK fusion cancer, and immunohistochemistry (IHC) can be used to detect the presence of TRK protein.

About LOXO-292
LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. LOXO-292 has been granted Breakthrough Therapy Designation by the U.S. FDA.

LOXO-292 is currently being studied in the global LIBRETTO-001 Phase 1/2 trial. For additional information about the LOXO-292 clinical trial, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient RET Clinical Trial Hotline at 1-855-RET-4-292 or email [email protected].

About RET-Altered Cancers
Genomic alterations in the RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2% of non-small cell lung cancer, 10-20% of papillary and other thyroid cancers, and a subset of other cancers. Activating RET point mutations account for approximately 60% of medullary thyroid cancer (MTC). Both RET fusion cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as "oncogene addiction," renders such tumors highly susceptible to small molecule inhibitors targeting RET.

On October 9, 2018 Incyte (Nasdaq:INCY) reported that interim Phase 2 data on its investigational, selective FGFR1/2/3 inhibitor, pemigatinib (INCB54828), will be presented at the upcoming European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress taking place in Munich, Germany from October 19-23, 2018 (Press release, Incyte, OCT 9, 2018, View Source [SID1234529818]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Data at ESMO (Free ESMO Whitepaper) 2018 will include poster presentations on the FIGHT-202 study of pemigatinib in patients with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (bile duct cancer) with fibroblast growth factor (FGF)/FGFR genetic alterations, as well as the FIGHT-201 study of pemigatinib in patients with metastatic or surgically unresectable urothelial carcinoma (bladder cancer) harboring FGF/FGFR genetic alterations.

"We are pleased that data on pemigatinib – part of our targeted therapy portfolio – have been selected for presentation at this year’s ESMO (Free ESMO Whitepaper) Congress," stated Steven Stein, M.D., Chief Medical Officer, Incyte. "We look forward to sharing updated interim data from the ongoing FIGHT-202 trial of pemigatinib in patients with cholangiocarcinoma, which continue to support our plan for a 2019 NDA submission in this indication, as well as updated data from the FIGHT-201 study of pemigatinib in patients with urothelial carcinoma, which support recruitment into the continuous dosing cohort of this study."

Abstracts were made available today on the ESMO (Free ESMO Whitepaper) Congress website at View Source

Poster details:

Interim Results of FIGHT-202, a Phase 2, Open-Label, Multicenter Study of INCB054828 in Patients (pts) with Previously Treated Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma (CCA) with/without Fibroblast Growth Factor (FGF)/FGF Receptor (FGFR) Genetic Alterations (Abstract #756P, poster display session)

Sunday, 21 October 2018 from 12:45 p.m. CEST to 1:45 p.m. CEST (6:45 a.m. ET to 7:45 a.m. ET) in Hall A3 – Poster Area Networking Hub
Interim Results of FIGHT-201, a Phase 2, Open-Label, Multicenter Study of INCB054828 in Patients (pts) with Metastatic or Surgically Unresectable Urothelial Carcinoma (UC) Harboring Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) Genetic Alterations (GA) (Abstract #900P, poster display session)

Monday, 22 October 2018 from 12:45 p.m. CEST to 1:45 p.m. CEST (6:45 a.m. ET to 7:45 a.m. ET) in Hall A3 – Poster Area Networking Hub
Full session details and data presentation listings for ESMO (Free ESMO Whitepaper) 2018 can be found at:
View Source

About FGFR and Pemigatinib (INCB54828)

Fibroblast growth factor receptors (FGFRs) play an important role in tumor cell proliferation and survival, migration and angiogenesis (the formation of new blood vessels). Activating mutations, translocations and gene amplifications in FGFRs are closely correlated with the development of various cancers.

Pemigatinib is a potent, selective, oral inhibitor of FGFR isoforms 1, 2 and 3 which, in preclinical studies, has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations. Phase 2 studies investigating the safety and efficacy of pemigatinib monotherapy across several FGFR-driven malignancies are ongoing—the FIGHT (FIbroblast Growth factor receptor in oncology and Hematology Trials) clinical trial program currently comprises FIGHT-201 in patients with metastatic or surgically unresectable bladder cancer, including with activating FGFR3 alterations; FIGHT-202 in patients with metastatic or surgically unresectable cholangiocarcinoma who have failed previous therapy, including with activating FGFR2 translocations; and FIGHT-203 in patients with myeloproliferative neoplasms with activating FGFR1 translocations.

On October 9, 2018 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a clinical stage biotechnology company focused on developing targeted cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that its PCT patent application covering a targeted therapy to treat solid cancerous tumors was published on September 27, 2018 (Publication No. WO 2018/175576) (Press release, PharmaCyte Biotech, OCT 9, 2018, View Source [SID1234529817]). It was titled "Encapsulated Cells Producing Cytochrome P450 and Methods of Use Thereof." This PCT application allows PharmaCyte to file patent applications and seek protection in most major market countries throughout the world. These patent applications, if granted, will provide protection for PharmaCyte’s technology for 20 years without a gap in patent protection – until March 2038.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Kenneth L. Waggoner, PharmaCyte Biotech’s Chief Executive Officer, commented "The publication of this PCT patent application is a significant step in being able to protect our unique cancer therapy for many years to come. It is particularly important now as we get closer to beginning our clinical trial in patients with locally advanced pancreatic cancer (LAPC). However, in addition to pancreatic cancer, the Cell-in-a-Box live cell encapsulation technology also gives us opportunities to develop unique therapies for other forms of cancer where new treatment modalities are needed."

The PCT application also specifically includes methods of treating other cancerous tumors, such as those of the liver, breast and colon, using the live-cell encapsulation of genetically modified human cells that overexpress a form of the cytochrome P450 enzyme system normally found in the liver. These cells are encapsulated using the proprietary Cell-in-a-Box technology. Together with low doses of a drug of the oxazaphosphorine class, ifosfamide, the encapsulated cells comprise PharmaCyte’s therapy for pancreatic cancer. The patent application also includes using PharmaCyte’s platform technology with cyclophosphamide, another chemotherapy drug of the oxazaphosphorine class that is activated by the cytochrome P450 enzyme system. In the case of pancreatic cancer, it is hoped that the Cell-in-a-Box plus low dose ifosfamide combination will be beneficial to patients whose pancreatic tumors become resistant to standard chemotherapies such as the combination of the anticancer drugs gemcitabine and Abraxane or FOLFIRINOX. The use of Cell-in-a-Box encapsulation with other drugs against other forms of cancer remains to be investigated.

The PCT patent application originated from a provisional patent application by the same title that was filed with the U.S. Patent and Trademark Office (USPTO) on March 21, 2017 and a patent application by the same title that was filed with the USPTO on March 21, 2018.