FDA Approved Drugs

Purpose: Imlygic is a genetically modified live oncolytic herpes virus designed to replicate within cancer cells and produce an immunostimulatory protein called GM-CSF (granulocyte-macrophage colony-stimulating factor).

How it works: Imlygic is a weakened, generically modified form of the herpes virus, so that it does not cause a viral infection. It is injected into the tumor and after the injection the virus is able to divide only in tumor cells, causing their death. The activated immune system can then fight other tumors in the body that have not been injected.

Which patients: Imlygic is approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions, in patients with melanoma recurring after the initial surgery.

Important: Patients should not receive Imlygic if they are pregnant or have a weakened immune system (for example, an immune deficiency, blood or bone marrow cancer, steroid use, or HIV/AIDS).

How it is given: Imlygic is injected directly into your tumor(s). After the initial treatment, a second dose is given 3 weeks later with additional doses given every 2 weeks for at least six months, until there are no remaining injectable tumors to treat or other treatment is required.

Effectiveness: In a Phase III study, 16.3 percent of patients treated with Imlygic had a decrease in the size of their skin and lymph node lesions lasting for at least six months, compared to 2.1 percent of patients treated with GM-CSF). In the study, the median time to response was 4.1 months in the Imlygic arm. Imlygic has not been shown to improve overall survival or to have an effect on melanoma that has spread to the brain, bone, liver, lungs, or other internal organs.

Side effects: The most common side effects (≥ 25%) of Imlygic include:

• Tiredness
• Chills
• Fever
• Nausea
• Flu-like symptoms
• Pain at the injection site

Important: Tell your doctor immediately if you get any of these signs and symptoms of herpes infection:

• Pain, burning, or tingling in a blister around the mouth or genitals or on the fingers or ears
• Eye pain, light sensitivity, discharge from the eyes, or blurry vision
• Weakness in arms or legs
• Extreme drowsiness (feeling sleepy)
• Mental confusion

Financial Assistance: Click here

Purpose: Intron A is given to rev up the immune system in order to kill melanoma cells. Intron A is given to prevent the cancer from coming back after initial therapy, such as surgery. Note: Production of this drug is being discontinued.

How it works: Intron A is a naturally occurring protein that fights viral infections and other diseases. While the drug’s main function is to alert the immune system to kill the melanoma cells, its mechanism is not completely understood. It is possible that it also chokes the blood supply to the tumor (antiangiogenesis) and directly fights the tumor growth.

Which patients: Intron A was the previous standard of care for patients whose melanoma who had been surgically resected but had a high risk of recurrence. Newer agents are now more commonly used with resected Stage III melanoma. However, it is still the only approved drug for patients with late Stage IIB or Stage IIC melanoma (those with lesions of Breslow thickness > 4mm).

How it is given: Intron A can be given intravenously, intramuscularly, subcutaneously, or intralesionally.

In the United States, Intron A is usually given in a two phase process over a one year period. In the induction phase, Intron A is given intravenously in a hospital or an office setting at the maximum tolerated dose, which is five days a week for four weeks. Each injection takes about 20-30 minutes. During the maintenance phase, Intron A is given subcutaneously three times a week for the remainder of the year. Most often, patients can do these injections themselves.

There have also been studies using low-dose Intron A. In these studies, there was a subcutaneous induction phase for 1-3 weeks followed by a maintenance phase for 3 times a week for a period of 1-3 years.

Effectiveness: When compared with patients who had no adjuvant treatment (treatment following surgery), Intron A was effective at preventing melanoma relapse. It extended the relapse free period from 0.98 years to 1.72 years. Five year-survival was 46% for those who took the drug compared to 37% for those who did not.

Side effects: Intron A is associated with a variety of side effects:

• Acute flu-like symptoms occur typically within 4-8 hours of injection (fever, chills, muscle pain, headache, nausea, vomiting). These are often worst at the beginning of treatment but then improve with time.

Important: Stay hydrated during the acute phase, and you may want to take a fever-lowering drug to relieve some of the flu symptoms, if your doctor advises. Keep warm with plenty of warm blankets.

• Fatigue is also very common. It typically starts during week 2 or week 3 and increases throughout the therapy. See “Managing Side Effects” for a discussion of how to manage fatigue.

Important: Some techniques to fight fatigue include:

• Try to be active. Balance your activity with rest, and plan activity for times when you feel well.
• Get as much sleep as you can.
• Eat a balanced diet with lots of fruits and vegetables.
• Drink plenty of water.

Other side effects include:

• Low white blood cell and red blood cell counts (as recorded before, during, and at the completion of treatment).
• Liver damage (depending on severity, a potential signal to discontinue treatment).
• Depression. A common side effect, occurring in about 40% of patients in the main trial. A small percentage of patients, approximately 2%, attempt suicide or develop suicidal ideas.

Important: Be aware of the potential seriousness of depression and call 911 if you think you may harm yourself or anyone else. Your physician may screen you for depression at the beginning and throughout your treatment to determine if you need a dose reduction or need to be taken off treatment. If you have any history of depression or any psychiatric history, tell your physician.

• Loss of appetite (resulting in weight loss). This may result from nausea and vomiting or altered taste.

Important: Some techniques to help with appetite-related side effects

• • Eat smaller portions and have healthy snacks in between.
  • Avoid greasy and spicy foods.
  • Eat cold foods if cooking smells make you sick.
  • Drink tart liquids such as lemonade or orange juice if you have a metallic taste in your mouth Use plastic rather than metallic utensils. Eat fresh foods rather than canned foods.

• Lessened attention/memory. Note that this side effect may interfere with your ability to take the drug and perform certain tasks.

Other points about side effects:

As with any treatment, the side effects of Intron A therapy depend on the prescribed dose. Low-dose therapy is often well tolerated, while high-dose therapy tends to produce more severe and consistent side effects. Often, the most severe side effects occur during the first few weeks of therapy and then taper off significantly.

If the symptoms or signs are significantly abnormal, the treatment may be interrupted for a time and then resumed at a lower dose. Throughout the course of the therapy, treatment may be stopped and restarted at different dosages as needed.

If you are having severe side effects, talk to your doctor. Treatments are available to relieve symptoms such as nausea and fatigue. You will also receive careful and continuous monitoring for life-threatening side effects, including bone marrow suppression and liver damage. Many side effects are generally reversible when therapy is stopped.

Additional information/resources:

Patient assistance: ACT program. 1-866-363-6379 or visit http://www.merck.com/merckhelps/act-program/home.html

Purpose: Keytruda is a humanized monoclonal antibody. It is designed to block a cellular target known as PD-1, which restricts the body’s immune system from attacking melanoma cells.

How it works: Keytruda is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to fight advanced melanoma. Keytruda blocks the interaction between PD-1 and its lignds, PD-L1 and PD-L2, and may affect both tumor cells and healthy cells.

Which patients: Keytruda is approved for adult and pediatric patients (12 years of age and older) with Stage IIB and IIC melanoma following a complete resection, Stage III melanoma, and Stage IV melanoma.

How it is given: Keytruda is given intravenously. Keytruda can be given as a 200mg dose over a 30-minute period, usually every three weeks until there is disease progression or unacceptable side effects. It is given in an outpatient clinic and does not require hospitalization. In light of reduced clinic visits to protect patients with cancer due to the coronavirus disease 2019 (COVID-19) pandemic, the FDA approved a new dosage for Keytruda of 400 mg administered every 6 weeks across all adult indications.

Effectiveness: In a large Phase 3 clinical trial, comparing investigational therapy to standard of care for Stage IV melanoma patients, half of the participants received investigational Keytruda (pembrolizumab) at 10mg/kg or 3mg/kg every 3 weeks and the other half received four doses of Yervoy (ipilimumab) 3mg/kg every three weeks. At 5-year follow-up, Keytruda maintained overall and progression free-survival benefits over Yervoy in patients with advanced melanoma. At the time of follow-up, 67% of patients treated with Keytruda were alive compared to 40% of patients treated with Yervoy. The median overall survival was 32.7 months in the Keytruda group vs 15.9 months in the Yervoy group. Median progression-free survival for Keytruda was 8.4 months vs 3.4 compared to Yervoy. There was not significant difference found between the 10mg/kg or 3mg/kg every 3 week dosing arms.  The FDA approval for Stage IIB and C patients was based upon the results of a Phase 3 clinical trial involving 976 newly diagnosed patients in which Keytruda showed a statistically significant improvement in recurrence-free survival (RFS), reducing the risk of disease recurrence or death by 35% compared to placebo alone.

Side effects: Although it is not common, Keytruda can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening. It’s important to call or see your doctor right away if you develop any symptoms of the following problems or these symptoms get worse:

Lung problems (pneumonitis). Symptoms of pneumonitis may include:

• Shortness of breath
• Chest pain
• New or worse cough

Intestinal problems (colitis). These problems can lead to tears or holes in your intestine. Signs and symptoms of colitis may include:

• Diarrhea or more bowel movements than usual
• Stools that are black, tarry, sticky, or have blood or mucus
• Severe stomach-area (abdomen) pain or tenderness

Liver problems (hepatitis). Signs and symptoms of hepatitis may include:

• Yellowing of your skin or the whites of your eyes
• Dark urine
• Nausea or vomiting
• Feeling less hungry than usual
• Pain on the right side of your stomach area (abdomen)
• Bleeding or bruising more easily than normal

Often patients do not have symptoms and liver problems are detected on lab work alone

Hormone gland problems (especially the thyroid, pituitary, and adrenal glands). Signs and symptoms that your hormone glands are not working properly may include:

• Rapid heart beat
• Weight loss
• Increased sweating
• Weight gain
• Hair loss
• Feeling cold
• Constipation
• Your voice gets deeper
• Muscle aches
• Dizziness or fainting
• Headaches that will not go away or unusual headache

Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:

• Change in the amount or color of your urine.

Problems in other organs. These problems might include:

• Rash
• Changes in eyesight severe or persistent muscle or joint pains
• Severe muscle weakness

The following are the common side effects:

• Fatigue
• Cough
• Nausea
• Severe Itching
• Rash
• Decreased appetite
• Constipation
• Joint pain
• Diarrhea

Patient assistance: Patients can call 1-855-257-3932 or visit www.merckaccessprogram-keytruda.com

Purpose: Kimmtrak is a bispecific gp100 peptide-HLA-directed CD3 T cell engager.

How it works: KIMMTRAK attaches to the HLA-A*02:01/gp100 complex, a marker often found on uveal melanoma tumor cells. This helps your body’s T cells recognize, attack, and kill uveal melanoma tumor cells. Approximately half of all patients with metastatic uveal melanoma (mUM) test positive for HLA-A*02:01.

Which patients: Kimmtrak is approved for the treatment of adult patients with HLA-A*02:01-positive unresectable or metastatic uveal melanoma. Before beginning treatment, a patient should test positive for HLA-A*02:01.

How it is given: Kimmtrak is given intravenously. The recommended dosage is:

• 20 mcg intravenously on Day 1,
• 30 mcg intravenously on Day 8,
• 68 mcg intravenously on Day 15,
• 68 mcg once every week thereafter

Patients are treated until unacceptable side effects or disease progression occurs unless clinical benefit indicates treating past progression.

Administration of Kimmtrak takes 15 – 20 minutes.

Administration of the first three infusions of Kimmtrak are performed in an appropriate setting where they are monitored during the infusion and for at least 16 hours after the infusion is complete.

If a patient does not experience Grade 2 or worse hypotension (low blood pressure requiring medical intervention) during or after the third infusion, subsequent doses can be administered in an appropriate ambulatory care setting and patients are monitored for a minimum of 30 minutes following each of these infusions.

Effectiveness: In a Phase 3 clinical trial, Kimmtrak showed statistically and clinically meaningful overall survival benefit for mUM patients. A total of 378 previously untreated patients were randomly assigned to either the Kimmtrak group (252 patients) or the control group (126 patients). The control group received single-agent treatment with Keytruda (82% of control patients), Yervoy (13%), or DTIC (6%). Overall survival (OS) at one year was 73% in the tebentafusp group and 59% in the control group.

Side effects:

Kimmtrak can cause serious side effects that can be severe or life threatening and usually happen within the first three infusions, including:

Cytokine Release Syndrome (CRS): Symptoms of CRS may include:

• fever
• tiredness or weakness
• vomiting
• chills
• nausea
• low blood pressure dizziness and light- headedness
• headache
• wheezing and trouble breathing
• rash

Important: Tell your doctor immediately if any of these symptoms appear.

Skin reactions: In the clinical study, skin reactions occurred in 91% of patients treated with Kimmtrak. Skin reactions included:

• rash
• pruritus, (severe itching of the skin)
• cutaneous edema (swelling) that require treatment.

Important: Tell your doctor immediately if you get symptoms of skin reactions—such as rash, itching, or skin swelling—that are severe and do not go away.

Abnormal liver blood tests:  Before starting Kimmtrak and during treatment with Kimmtrak, your doctor will do blood tests to check your liver. In the clinical study, increases in alanine aminotransferase or aspartate aminotransferase were observed in 65% of patients treated with Kimmtrak.

Important: Tell your doctor immediately if you get symptoms of liver problems such as right-sided abdominal pain or yellowing of the skin or eyes.

The most common side effects of Kimmtrak include:

• cytokine release syndrome
• rash
• pyrexia
• pruritus
• fatigue
• nausea
• chills
• abdominal pain
• edema
• hypotension
• dry skin
• headache and vomiting

Embryo-Fetal Toxicity: Kimmtrak may cause fetal harm when administered to a pregnant woman.

Patient assistance (KIMMTRAKConnect): Patients can visit KIMMTRAKConnect.com or call 844-775-2273.

Purpose: Opdivo is a humanized monoclonal antibody. It is designed to block a cellular target known as PD-1, which results in an anti-tumor immune response.

How it works: Opdivo works by increasing the ability of the body’s immune system to fight advanced melanoma. Opdivo blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

Which patients: Opdivo is approved for the adjuvant treatment of completely resected Stage IIB and Stage IIC melanoma in patients 12 years and older, Stage III patients with lymph node involvement who have undergone a complete resection, and Stage IV melanoma patients.

How it is given: Stage IIB and Stage IIC patients are given Opdivo intravenously. For patients weighing 40 kg or greater, with each 240 mg dose given over a 30-minute period every 2 weeks or 480 mg dose given over a 60-minute period every 4 weeks until disease progression or unacceptable toxicity for up to 1 year. The recommended dose for pediatric patients weighing less than 40 kg is 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks until disease progression or unacceptable toxicity for up to 1 year. It is given in an outpatient clinic and does not require hospitalization.

Stage III patients are given Opdivo intravenously, with each 240mg dose given over a 30-minute period every two weeks or 480mg dose given over a 60-minute period every four weeks, until disease recurrence or unacceptable side effects for up to one year. It is given in an outpatient clinic and does not require hospitalization.

Stage IV patients are given Opdivo intravenously, with each 240mg dose given over a 30-minute period every two weeks or 480mg dose given over a 60-minute period every four weeks, until disease progression or unacceptable side effects. It is given in an outpatient clinic and does not require hospitalization.

Effectiveness: The FDA approval for Stage IIB and Stage IIC patients was based upon the results of a Phase 3 trial involving 790 newly diagnosed patients. In the trial, Opdivo reduced the risk of recurrence, new primary melanoma, or death in patients with completely resected Stage IIB or Stage IIC melanoma by 58% compared to placebo alone.

Stage III patients: In a phase III clinical trial, patients who were treated with Opdivo had a 58% reduction in the risk of recurrence or death in Stage IIIB and 43% in Stage IIIC versus those who received Yervoy.

Stage IV patients: In a phase III clinical trial, patients who were treated with Opdivo had a 45% reduction in the risk of disease progression versus those who received Yervoy. At the 5-year follow-up, the overall survival rate was 44%.

Side effects: Although it is not common, Opdivo can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening. It’s important to call or see your healthcare provider right away if you develop any symptoms of the following problems or these symptoms get worse:

Lung problems (pneumonitis). Symptoms of pneumonitis may include:

• New or worsening cough
• Chest pain
• Shortness of breath

Intestinal problems (colitis). These problems can lead to tears or holes in your intestine. Signs and symptoms of colitis may include:

• Diarrhea (loose stools) or more bowel movements than usual
• Blood in your stools or dark, tarry, sticky stools
• Severe stomach area (abdomen) pain or tenderness

Liver problems (hepatitis). Signs and symptoms of hepatitis may include:

• Yellowing of your skin or the whites of your eyes
• Severe nausea or vomiting
• Pain on the right side of your stomach-area (abdomen)
• Drowsiness
• Dark urine (tea colored)
• Bleeding or bruise more easily than normal
• Feeling less hungry than usual

Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:

• Decrease in the amount of urine
• Blood in your urine
• Swelling in your ankles
• Loss of appetite

Hormone gland problems (especially the thyroid, pituitary, and glands). Signs and symptoms that your hormone glands are not working properly may include:

• Headache that will not go away or unusual headaches
• Extreme tiredness
• Weight gain or weight loss
• Changes in mood or behavior, such as decreased sex drive, irritability or forgetfulness
• Dizziness or fainting
• Hair loss
• Feeling cold
• Constipation
• Voice gets deeper

Problems in other organs. Signs of these problems include:

• Rash
• Changes in eyesight
• Severe or persistent muscle or joint pains
• Severe muscle weakness
• The most common adverse reaction (reported in at least 20% of patients) was rash.

Patient assistance: 1-800-861-0048 (hours: 8 am – 8 pm est or visit www.bmsaccesssupport.com

Purpose: Proleukin/IL-2 (IL-2) is an immunotherapy that uses the body’s natural immune system to fight melanoma.

How it works: IL-2 is a recombinant form of interleukin-2 (IL-2), a cytokine which helps activate the immune system (including T cell and natural killer cells) to kill cancer cells.

Which patients: IL-2 is one of the earliest form of immunotherapy approved for the treatment of advanced metastatic melanoma. As newer agents have been approved for metastatic melanoma its use has decreased and it is not typically used in clinical trials in combination of other agents.

How it is given: It should be given in a hospital under the supervision of a qualified physician experienced in the use of IL-2. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available.

The drug is given via an IV line 3 times a day for 5 days (cycle 1), followed by 9 days of rest, followed by 5 days of treatment (cycle 2). This is considered one treatment course. You will typically get imaging done after the first treatment course and if you are responding, you will receive a second course of treatment and possibly a third course.

Effectiveness: IL-2 shrinks tumors in about 16% of patients. However, about 6% of patients get a complete response that can last 7 years or more.

Side effects: IL-2 can have very serious side effects, the most serious being a condition called “capillary leak” which occurs when fluids and proteins leak from the blood vessels, causing dangerously low blood pressure.

The most common side effects include:

• Nausea, vomiting, diarrhea, loss of appetite
• Weakness and fatigue
• Flu-like symptoms (fever, chills, headache and muscle aches)
• Low blood pressure
• General pain, chest pain (angina)
• Breathing problems due to fluid in the lungs
• Weight gain, fluid retention
• Mental effects (paranoia, hallucinations, insomnia)
• Itching, peeling skin
• Anemia (low red blood cell count)
• Low platelet count (increasing the risk of bleeding)
• Low white blood cell count
• Kidney damage
• Mouth sores

Reimbursement and Patient Assistance. Proleukin Patient Assistance Program 1-877-776-5385

Product Information: 1-877-378-4919

Purpose: Sylatron is given to rev up the immune system in order to kill melanoma cells. Sylatron is given to prevent the cancer from coming back after the initial therapy, such as surgery. Note: Production of this drug is discontinued.

How it works: Interferon is a naturally occurring protein that fights viral infections and other diseases. While Sylatron’s main function is to alert the immune system to kill the melanoma cells, its mechanism is not completely understood. It is possible that it also chokes the blood supply to the tumor (antiangiogenesis) and directly fights the tumor growth. Sylatron allows interferon to stay in the blood longer, so the drug can be given at a lower dose and for a longer period of time than Intron A.

Which patients: Sylatron is given to patients with microscopic or macroscopic nodal melanoma within 84 days of surgical resection that includes therapeutic lymph node dissection. As newer agents have been approved for metastatic melanoma, its use has decreased.

How it is given: Sylatron is given subcutaneously at a higher dose for eight doses followed by a lower dose (which can be given once a week) for up to five years. The dose is adjusted based on weight. Acetaminophen is given prior to the first dose and as needed thereafter.

Effectiveness: Sylatron is effective in delaying or preventing relapse of melanoma. The drug has not demonstrated a benefit on overall survival.

Side effects: Sylatron is better tolerated than Intron A. However, it still can cause acute flu-like symptoms within four to eight hours of injection including fever, chills, muscle pain, headache, nausea, vomiting, fatigue, low white blood cell and red blood cell counts, liver damage, depression, loss of appetite, and impaired cognitive function (diminished attention/memory).

Patient assistance: ACT program.
1-866-363-6379 or visit http://www.merck.com/merckhelps/act-program/home.html

Purpose: Yervoy is an anti-CTLA-4 monoclonal antibody. It is designed to restore and strengthen the immune system by supporting the activation and proliferation of T-cells, a critical component of the immune system. By supporting T-cells, Yervoy helps sustain an active immune response to fight the cancer cells. In Stage III patients, it helps lower the risk that the melanoma will return following surgery.

How it works: Yervoy is a human monoclonal antibody designed to block the activity of a molecule called CTLA-4, a protein that normally helps keep the immune system cells, called T cells, in check. When Yervoy blocks CTLA-4, the drug “takes the breaks off the immune system” and allows T cells to activate and proliferate in order to attack the melanoma cells.

Which patients: Yervoy is approved for adult patients with Stage III or Stage IV melanoma and pediatric patients 12 years and older with unresectable or metastatic melanoma.

How it is given: Yervoy is given intravenously. It is given in an outpatient clinic and does not require hospitalization. For adjuvant melanoma: 10 mg/kg is administered over 90 minutes every three weeks for four doses, followed by 10 mg/kg every 12 weeks for up to three years or until documented disease recurrence or unacceptable toxicity. Adjuvant use is less common with the FDA approval of Opdivo, Keytruda, and Tafinlar/Mekinist in this setting. For unresectable or metastatic melanoma: 3 mg/kg is administered intravenously over 90 minutes every three weeks for a total of four doses.

Effectiveness: In a large clinical trial, Stage IV patients who were treated with Yervoy plus GP100, a peptide vaccine, showed a significant improvement in overall survival versus those who received GP100 alone. Higher estimated survival rates were observed at one year (46% vs. 25%) and at two years (24% vs.14%). Yervoy improved overall median survival by four months.

In a 2013 analysis of data collected from 12 prospective and retrospective studies of 1861 patients, it was shown that the median overall survival for patients treated with Yervoy was 11.4 months. Among these patients, 22% were still alive after three years. There were no deaths among patients who survived beyond seven years, at which time the overall survival rate was 17%.

In a large clinical trial, patients with Stage III melanoma received either Yervoy or a placebo after complete surgical removal of their melanoma. At a median 5.3 years follow-up, the 5 year overall survival for patients receiving Yervoy was 65.4% compared to 54.4% for the patients receiving the placebo. Treatment with Yervoy reduced the risk of death by 28%.

Side effects: Because Yervoy makes T cells more responsive to many stimuli (not just cancer cells), the drug can cause powerful autoimmune reactions in which the immune system attacks normal cells in the body. 15% of patients reported autoimmune reactions that were classified as severe and some fatalities did occur in the studies of Yervoy. (Note: The statistics cited in this section are for the 3 mg/kg dosing.)

Colitis (inflammation of the colon), occurs in about 12% of patients. In 5% of the patients the symptoms are moderate, while in 7% of the patients the symptoms can be severe or life threatening, causing death in less than 1% of the cases. Signs and symptoms of colitis are:

• Diarrhea (loose stools) or more bowel movements than usual
• Blood in your stools or dark, tarry, sticky stools
• Stomach pain (abdominal pain) or tenderness

Important: If you develop diarrhea, you should call your doctor immediately. If you cannot reach your doctor go to the nearest emergency room. For the majority of patients, if found early, diarrhea can be controlled within a few days.

Hepatitis: An inflammation of the liver that occurs in less than 5%-10% of case but can lead to liver failure. Since it rarely has symptoms, it is Important that your liver function be tested before you start Yervoy and during treatment, to identify any elevation in liver enzymes. Signs and symptoms of hepatitis may include:

• Yellowing of your skin or the whites of your eyes
• Dark urine (tea colored)
• Nausea or vomiting
• Pain on the right side of your stomach
• Bleeding or bruising more easily than normal

Important: Before each dose of Yervoy, your blood should be checked for liver function.

Skin/Toxicity/Rash: Occurs in about 15% of patients. Typically, it is a rash that comes and goes without itch. However, it can present as a more severe skin reaction (toxic epidermolysis necrolysis). Signs and symptoms of a severe skin reaction are:

• Skin rash with or without itching
• Sores in your mouth
• Skin blisters and/or peels

Inflammation of Hormone Glands: Dysfunction of the pituitary, adrenal, or thyroid glands, which occurs less than 10% of the time. Signs and symptoms that your glands are not working properly include:

• Persistent or unusual headaches
• Unusual sluggishness, feeling cold all the time, or weight gain
• Changes in mood or behavior such as decreased sex drive, irritability, or forgetfulness
  dizziness or fainting

Important: The most common way inflammation of the hormone glands is determined is through blood work. Your physician should monitor this at regular intervals. If you have a preexisting thyroid problem before you start this medicine, it’s even more Important to watch your blood counts and to make your physician aware of this so that this can be safely monitored.

Other Side Effects:

Inflammation of the Nerves: This can lead to paralysis. Symptoms of nerve problems may include:

• Unusual weakness of legs, arms, or face
• Numbness or tingling in hands or feet

Inflammation of the Eyes: Symptoms may include:

• Blurry vision, double vision, or other vision problems
• Eye pain or redness

Most Common Side Effects:

The most common side effects of YERVOY include: tiredness, diarrhea, itching, rash, headache, weight loss and nausea.

Important: Women who are pregnant should not take Yervoy because it may cause harm to a developing fetus.

Financial Support: Click here

Risk Evaluation and Mitigation Strategy (REMS Program): Click here

Purpose: Tafinlar blocks a cellular pathway to stop the growth of melanoma tumors.

How it works: Tafinlar is a kinase inhibitor that blocks the activity of the V600E-mutated form of BRAF, a key protein that helps cancer cells grow. About half of patients with melanoma have this mutated form of the protein in their tumors.

Which patients: Tafinlar is FDA-approved for adult patients who carry the BRAF V600E or V600K mutation and who have unresectable Stage III melanoma (melanoma that cannot be removed by surgery) or Stage IV melanoma. Before receiving Tafinlar, patients must test positive for the BRAF mutation.

How it is given: Tafinlar is an oral drug. Patients receive 150 mg orally twice daily.

Effectiveness: In a large clinical trial, progression-free survival (the time a patient lives without cancer growing or spreading) was 6.9 months for patients on Talfinar versus 2.7 months for patients on standard chemotherapy.

In the phase III clinical trial, comparing Tafinlar to dacarbazine (chemotherapy), 52% of all patients treated with Tafinlar experienced tumor shrinkage compared to 17% who received dacarbazine.

In a phase II clinical trial, Taflinar was evaluated in patients with the BRAF V600E mutation whose melanoma had spread to the brain. In this trial, 18% of the patients, both those who had local treatment for brain metastases and those who did not have local treatment for brain metastases, showed a shrinkage in their brain metastases.

Side effects: Several side effects are common in the course of treatment. Most of these side effects are mild or moderate, although there have been some severe side effects. These side effects can usually be managed with either a decrease in the dosage or by briefly stopping the drug and then resuming its use after the symptoms improve. Sometimes, when the drug is resumed, it is at a lower dose.

New Skin Cancers

• Cutaneous Squamous Cell Carcinoma (cSCC) occurs in approximately 11% of patients. Of those who developed a cSCC, approximately 33% went on to develop one or more additional cSCC’s
• New primary melanomas occur in approximately 2% of patients

If these lesions appear they should be removed, but typically you can continue taking the drug without changing the dosage

Important: You should have a dermatologic examination before you start Tafinlar, every two months while you remain on the drug, and up to 6 months after you stop taking the drug.

Serious Fevers: 28% of all patients developed fevers. In 3.7% of patients these fevers were serious and were accompanied by one or more of the following symptoms:

• Low Blood Pressure
• Chills
• Dizziness
• Too much fluid loss (dehydration)
• Kidney problems

Important: Tell your doctor immediately if you get a fever.

Blood Sugar Problems (diabetes): Some people may develop high blood sugar or if they have diabetes it may get worse. Tell your doctor if you have any of the following symptoms:

• Increased thirst
• Urinating more than usual
• Your breath smells like fruit

Eye problems such as uveitis occurred in 1% of patients. Symptoms include eye pain, swelling or redness, blurred vision or other vision changes

Important: You should have your eyes examined before and while you are taking Tafinlar. Tell your doctor immediately if any eye symptoms appear.

The most common side effects include:

• Thickening of the outer layer of the skin
• Headache
• Joint pain
• Warts
• Hair loss
• Redness, swelling, peeling, or tenderness of the hands or feet

Patient assistance: Patients can call 1-800-282-7630

Purpose: Zelboraf blocks a cellular pathway to stop the growth of melanoma tumors.

How it works: Zelboraf is a kinase inhibitor that blocks the activity of the V600E-mutated form of BRAF, a key protein that helps cancer cells grow. About half of patients with melanoma have this mutated form of the protein in their tumors.

Which patients: Zelboraf is FDA-approved for patients who carry the BRAF V600E mutation and who have unresectable Stage III melanoma (melanoma that cannot be removed surgically) or Stage IV melanoma. Before receiving Zelboraf, patients must test positive for the BRAF mutation.

How it is given: Zelboraf is an oral drug. Patients receive 960mg orally twice daily.

Effectiveness: In a large clinical trial, comparing Zelboraf to dacarbazine almost 50% of all patients treated with Zelboraf experienced tumor shrinkage compared to 5% who received DTIC. It is not yet clear how long Zelboraf can increase overall survival, but at the time the trial was studied 77% of the people taking Zelboraf were still alive, compared to 64% of those taking DTIC.

In the phase III clinical trial, progression-free survival (the time a patient lives without cancer growing or spreading) was 13.6 months for patients on Zelboraf versus 9.7 months for patients on standard chemotherapy.
Side effects: Several side effects are common early in the course of treatment. Most of these side effects are mild or moderate in severity and, when severe, can be managed with either a decrease in the dosage or by briefly stopping the drug and then resuming its use.

Cutaneous Squamous Cell Carcinoma (cSCC) occurs in approximately 24% of patients and is by far the most common side effect.

• cSCC usually appears in the first seven to eight weeks of treatment.
• Squamous cell carcinoma is seen most often in older patients, those with a history of skin cancer, and those who have experienced chronic sun exposure

If these lesions appear, they should be removed, but typically you can continue taking the drug without changing the dosage.

Important: You should have a dermatologic examination before you start Zelboraf and every two months while you are on the drug.

Severe Allergic Reaction may cause:

• Blisters on the skin and blisters or sores in the mouth
• Peeling of the skin
• Fever
• Swelling of the face, hands, or soles of the feet

Skin Rash is also very common. The rash usually appears on the arms and legs but can also appear on the chest and back.

• It often appears over the course of several days and may cause itching.
• This is usually a reversible side effect, and once the drug is temporarily stopped the rash generally improves very quickly, and often does not return when the medication is restarted.
• In severe cases a patient may need to discontinue use of the drug.

Important: If the rash is uncomfortable and if it covers more than half of the body, you should call your doctor. The doctor will decide whether it is necessary to temporarily stop the therapy and also when to resume and at what dosage.

Increased Sensitivity to the Sun (photosensitivity) is also common. You should avoid going out in the sun as much as possible.

Important: When you do go outside, cover up with clothing that protects your skin, including head, face, hands, arms and lips. Use a sunscreen with an SPF of 30 or higher and use a lip balm.

Joint Discomfort is another relatively common side effect that usually occurs early in the course of treatment. Joint discomfort may involve one or multiple joints. The hands and feet are often painful, but the knees or shoulders can also be affected. On occasion swelling and redness around the joints will occur.

Important: Nonsteroidal antiinflammatories (aspirin-like medications) can be used to control the discomfort. In severe cases a dose interruption or reduction may be necessary.

Other Side Effects: These may include:

• Changes in the electrical activity of the heart (QT prolongation) that can cause irregular heartbeats that are potentially life-threatening. Symptoms include feeling faint, lightheaded, dizzy or irregular or fast heartbeat.
• Liver problems: symptoms include skin or the whites of the eyes turning yellow, feeling tired, dark or brown urine, nausea or vomiting, pain on the right side of the stomach
• Eye problems such as uveitis. Symptoms include eye pain, swelling or redness, blurred vision or other vision changes
• New primary malignant melanomas
• Hair loss
• Tiredness
• Nausea
• Warts

Financial assistance. Zelboraf Access Solutions: 1-888-249-4918

Purpose: Cotellic in combination with Zelboraf blocks a cellular pathway to inhibit the growth of melanoma tumors.

How it works: Zelboraf is a kinase inhibitor that blocks the activity of the V600E-mutated form of BRAF, a key protein that helps cancer cells grow. Cotellic is an inhibitor that blocks the activity of an enzyme known as MEK. About half of all patients with melanoma have a mutated form of the BRAF protein in their tumors.

Which patients: Cotellic in combination with Zelboraf is indicated for the treatment of adult patients with Stage IV melanoma who have the BRAF V600E or V600K mutation. Before starting treatment, the patient should test positive for the presence of a BRAF V600E or V600K mutation.

How it is given: Zelboraf is an oral drug. Patients receive 960mg orally twice daily. Cotellic is also an oral drug and patients receive 60 mg (three 20 mg tablets) once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

Effectiveness: In a phase III trial that compared, Cotellic in combination with Zelobraf to Zelboraf alone, progression-free survival (the time a patient lives without cancer growing or spreading) was 12.3 months for patients treated with the combination, versus 7.2 months for patients treated with Zelboraf alone. In addition, patients taking Cotellic plus Zelobraf lived longer (overall survival), with approximately 65 percent of patients alive 17 months after starting treatment as compared to half of those taking Zelobraf alone.

Side effects: The most common side effects of treatment with Cotellic in combination with Zelboraf are diarrhea, sensitivity to ultraviolet (UV) light (photosensitivity reaction), nausea, fever, and vomiting.

Side Effects of Cotellic:

Risk of skin cancers. Cotellic may cause skin cancers (cutaneous squamous cell carcinoma, keratoacanthoma, or basal cell carcinoma).

Important: You should check your skin and tell your doctor right away about any skin changes, including: a new wart, a skin sore or reddish bump that bleeds or does not heal, a change in size or color of a mole

Important: You should have a dermatologic examination prior to the start of therapy and every 2 months while on therapy, have suspicious skin lesions managed with excision and dermatopathologic evaluation, and continue to have your skin checked for 6 months following discontinuation of Cotellic.

Increased risk of bleeding. Cotellic may cause bleeding, including blood in the urine, rectal bleeding, unusual or excessive vaginal bleeding, bleeding of the gums and bleeding within the brain (cerebral hemorrhage).

Important: You should tell your doctor right away if you experience any of these symptoms: red or black stools that look like tar, blood in the urine, headache, dizziness or feeling weak, abdominal pain, or unusual vaginal bleeding.

Heart problems that can lead to inadequate pumping of the blood by the heart.

Important: Before taking Cotellic, your doctor should check the ability of your heart to pump blood. Signs and symptoms of a decrease in the amount of blood pumped include: persistent coughing or wheezing, shortness of breath, swelling of their ankles and feet, tiredness, or increased heart rate.

Rash. You should tell your doctor right away if you experience any of these symptoms:

• A rash that covers a large area of your body, blisters or peeling skin

Eye problems. You should tell your doctor right away if you experience any of these symptoms:

• Blurred vision
• Distorted vision
• Partly missing vision
• Halos
• Any other vision changes

Abnormal liver test or liver injury. You should have blood tests performed by your doctor before the start taking Cotellic, and during treatment.

Important: You should tell your doctor right away if you experience any of these symptoms: yellowing of their skin or the white of their eyes, dark or brown (tea color) urine, nausea or vomiting, feeling tired or weak, or loss of appetite.

Increased levels of an enzyme in the blood. Creatine phosphokinase (CPK) is an enzyme that is primarily found in the muscle, heart and brain. You should have your doctor perform a blood test.

Important: You should tell your doctor right away if you experience any of these symptoms: muscle aches, muscle spasms and weakness, or dark, or reddish urine.

Photosensitivity Your skin may become more sensitive to sunlight and cause you to burn more easily and get severe sunburns.

Important: You should tell your doctor right away if you notice any of the following symptoms: red, painful, itchy skin that is hot to touch, sun rash, skin irritation bumps or tiny papules, or thicken, dry, wrinkled skin.

Important: When you go outside, you should wear clothes that protect your skin, including your head, face, hands, arms, and legs. You should also use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.

Embro-Fetal Toxicity: Cotellic can cause fetal harm when administered to a pregnant woman.

Important: Patients should use effective methods of birth control during treatment, for at least two weeks after stopping Cotellic, and for at least two months after stopping Zelboraf.

Important: You should tell your doctor right away if you become pregnant or think you are pregnant during treatment with Cotellic.

Important: You should tell your doctor if are breastfeeding or plan to breastfeed. It is not known if Cotellic passes into breast milk, so patients should not breastfeed during treatment with Cotellic and for two weeks after the final dose. You should talk to your healthcare provider about the best way to feed their baby during this time.

Patients should tell their doctor if they have:

• Any previous or current skin problems other than melanoma
• Any medical conditions and/or are on any medications that increase your risk of bleeding
• Any heart problems
• Any eye problems
• Any liver problems
• Any muscle problems
• Any other medical conditions

Side Effects of Zelboraf:

Cutaneous Squamous Cell Carcinoma (cSCC) occurs in approximately 24% of patients when taken as a single agent and is by far the most common side effect.

• cSCC usually appears in the first seven to eight weeks of treatment.
• cSCC is seen most often in older patients, those with a history of skin cancer, and those who have experienced chronic sun exposure.
• If these lesions appear, they should be removed, but typically you can continue taking the drug without changing the dosage.

Important: You should have a dermatologic examination before you start Zelboraf and every two months while you are on the drug.

Severe Allergic Reaction may cause:

• Blisters on the skin and blisters or sores in the mouth
• Peeling of the skin
• Fever
• Swelling of the face, hands, or soles of the feet

Skin Rash is also very common. The rash usually appears on the arms and legs but can also appear on the chest and back.

• It often appears over the course of several days and may cause itching.
• This rash is usually a reversible side effect, and once the drug is temporarily stopped the rash generally improves very quickly, and often does not return when the medication is restarted.
• In severe cases a patient may need to discontinue use of the drug.

Important: If the rash is uncomfortable and if it covers more than half of the body, you should call your doctor. The doctor will decide whether it is necessary to temporarily stop the therapy and also when to resume and at what dosage.

Increased Sensitivity to the Sun (photosensitivity) is also common. You should avoid going out in the sun as much as possible.

Important: When you do go outside, cover up with clothing that protects your skin, including head, face, hands, arms, and lips. Use a sunscreen with an SPF of 30 or higher and use a lip balm.

Joint Discomfort is another relatively common side effect that usually occurs early in the course of treatment. Joint discomfort may involve one or multiple joints. The hands and feet are often painful, but the knees or shoulders can also be affected. On occasion swelling and redness around the joints will occur.

Important: Nonsteroidal anti-inflammatories (aspirin-like medications) can be used to control the discomfort. In severe cases a dose interruption or reduction may be necessary.

Other Side Effects. These may include:

• Changes in the electrical activity of the heart (QT prolongation) that can cause irregular heartbeats that are potentially life-threatening. Symptoms include feeling faint, lightheaded, or dizzy, and an irregular or fast heartbeat.
• Liver problems. Symptoms include skin or the whites of the eyes turning yellow, feeling tired, dark or brown urine, nausea or vomiting, pain on the right side of the stomach
• Eye problems such as uveitis. Symptoms include eye pain, swelling or redness, blurred vision, or other vision changes
• New primary malignant melanomas
• Hair loss
• Tiredness
• Nausea
• Warts

Financial assistance. http://www.genentech-access.com/cotellic patients or call 1-888-249-4918
Support: Call 1-855-692-6835

Purpose: Opdivo is a humanized monoclonal antibody designed to block a cellular target known as PD-1, which results in an anti-tumor immune response. Yervoy is an anti-CTLA-4 monoclonal antibody designed to restore and strengthen the immune system by supporting the activation and proliferation of T-cells.

How it works: Opdivo and Yervoy are both monoclonal antibodies and immune checkpoint inhibitors that target separate, distinct checkpoint pathways. Inhibition of these immune checkpoint pathways results in enhanced T cell function greater than the effects of either antibody alone.

Which patients: Opdivo+Yervoy is approved for patients with either unresectable Stage III melanoma (melanoma that cannot be completely removed surgically), or Stage IV melanoma.

How it is given: Opdivo+Yervoy are both given intravenously. Opdivo is given as a 1mg/kg dose, and Yervoy as a 3mg/kg dose every three weeks for a total of four doses. After that, Opdivo alone is given at 240mg every two weeks until disease progression or unacceptable side effects. Both are given in an outpatient clinic and do not require hospitalization.

Effectiveness: According to data from CheckMate-067, a Phase III clinical trial, 49% of patients who were treated with Opdivo+Yervoy combination were alive at 6.5 years. Of those patients who were still alive, 77% of those patients remained off treatment. The median overall survival (OS) rate for patients with Stage IV melanoma was 72.1 months with Opdivo+Yervoy, compared with 36.9 months for patients who received Opdivo alone and 19.9 months for Yervoy alone.

Side effects: The most common side effects, reported in at least 20% of patients, were rash, itching, headache, vomiting, and colitis.

Important: If you develop diarrhea, you should call your doctor immediately. If you cannot reach your doctor, go to the nearest emergency room. For the majority of patients, if found early, diarrhea can be controlled within a few days.

Other side effects include:

Hepatitis: An inflammation of the liver that occurs in less than 5%-10% of cases but can lead to liver failure. Since it rarely has symptoms, it is Important that your liver function be tested before you start Yervoy and during treatment, to identify any elevation in liver enzymes. Signs and symptoms of hepatitis may include:

• Yellowing of your skin or the whites of your eye
• Dark urine (tea colored)
• Nausea or vomiting
• Pain on the right side of your stomach
• Bleeding or bruising more easily than normal

Important: Before each dose of Yervoy, your blood should be checked for liver function.

Skin/Toxicity/Rash: Occurs in about 22.6% of patients. Typically, it is a rash that comes and goes without itch. However, it can present as a more severe skin reaction (toxic epidermolysis necrolysis). Signs and symptoms of a severe skin reaction are:

• Skin rash with or without itching
• Sores in your mouth
• Skin blisters and/or peels

Inflammation of Hormone Glands: Dysfunction of the pituitary, adrenal, or thyroid glands, which occurs less than 10% of the time. Signs and symptoms that your glands are not working properly include:

• Persistent or unusual headaches
• Unusual sluggishness, feeling cold all the time, or weight gain
• Changes in mood or behavior such as decreased sex drive, irritability, or forgetfulness
• Dizziness or fainting

Important: The most common way inflammation of the hormone glands is determined is through blood work. Your physician should monitor this at regular intervals. If you have a preexisting thyroid problem before you start this medicine, it’s even more Important to watch your blood counts and to make your physician aware of this so that this can be safely monitored.

Inflammation of the Nerves: This can lead to paralysis. Symptoms of nerve problems may include:

• Unusual weakness of legs, arms, or face
• Numbness or tingling in hands or feet

Inflammation of the Eyes: Symptoms may include:

• Blurry vision, double vision, or other vision problems
• Eye pain or redness

Patient assistance: 1-800-861-0048 (hours: 8 am – 8 pm est. or visit www.bmsaccesssupport.com

Purpose: Opdualag is a combination of nivolumab (Opdivo), a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab, a lymphocyte activation gene-3 (LAG-3) blocking antibody, indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable (melanoma that cannot be completely removed surgically), or metastatic melanoma.

How it works: Opdivo is a humanized monoclonal antibody designed to block a cellular target known as PD-1, which results in an anti-tumor immune response. Relatlimab helps attack the cancer by enhancing the Tcell activity by targeting a protein called LAG-3. The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone.

Which patients: Opdualag is approved for the treatment of adult and pediatric patients (12 years of age or older) who have Stage III melanoma that cannot be removed by surgery or Stage IV melanoma.

How it is given: Opdualag is a fixed-dose combination of nivolumab and relatlimab and is given intravenously as a single infusion over 30 minutes. The FDA approved dose for adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg is 480mg nivolumab and 160 mg relatlimab. It is administered every four weeks. The dosage for pediatric patients (12 years of age or older) who weigh less than 40kg has not been determined.

Effectiveness: According to data from RELATIVITY-047, a Phase 2/3 clinical trial, Opdualag showed a statistically and clinically meaningful progression-free survival benefit over the nivolumab alone. Opdualag more than doubled the median progression-free survival when compared to opdivo monotherapy.

Side effects: Opdualag can cause severe and fatal immune-mediated adverse reactions (IMARs) These are adverse drug reactions that may be severe or fatal and can occur in any tissue or organ. IMARs can occur at any time after starting treatment and can also continue after discontinuation of treatment.

Important: Early identification and management of IMARs are essential to ensure safe use. Any new symptoms or signs should be reported to your physician.

Immune-Mediated Pneumonitis (lung problems): Opdualag can cause immune-mediated pneumonitis, which may be fatal. Symptoms of pneumonitis may include:

• New or worsening cough
• Chest pain
• Shortness of breath

Immune-Mediated Colitis (intestinal problems): These problems can lead to tears or holes in your intestine. Signs and symptoms of colitis may include:

• Diarrhea (loose stools) or more bowel movements than usual
• Blood in your stools or dark, tarry, sticky stools
• Severe stomach area (abdomen) pain or tenderness

Immune-Mediated Hepatitis (liver problems): Signs and symptoms of hepatitis may include:

• Yellowing of your skin or the whites of your eyes
• Severe nausea or vomiting
• Pain on the right side of your stomach-area (abdomen)
• Drowsiness
• Dark urine (tea colored)
• Bleeding or bruise more easily than normal
• Feeling less hungry than usual

Immune-Mediated Endocrinopathies  (hormone gland problems), especially the thyroid, pituitary, and glands):  Signs and symptoms that your hormone glands are not working properly may include:

• Headache that will not go away or unusual headaches
• Extreme tiredness
• Weight gain or weight loss
• Changes in mood or behavior, such as decreased sex drive, irritability or forgetfulness
• Dizziness or fainting
• Hair loss
• Feeling cold
• Constipation
• Voice gets deeper

Immune-Mediated Nephritis with Renal Dysfunction (kidney problems, including nephritis and kidney failure): Signs of kidney problems may include:

• Decrease in the amount of urine
• Blood in your urine
• Swelling in your ankles
• Loss of appetite

Immune-Mediated Dermatologic Adverse Reactions (rash or dermatitis)

Immune-Mediated Myocarditis (inflammation of the heart muscle, and inflammation of the outer lining of the heart)

Other Immune-Mediated Adverse Reactions: These adverse reactions occur much less frequently.  Regardless, any new symptoms or signs should be reported to your physician.

Signs of these problems include:

• Cardiac/Vascular: pericarditis, vasculitis (chest pain, shortness of breath, racing heartbeat, or pain/swelling in an extremity or other body part)
• Nervous System: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy (confusion, difficulty with coordination, numbness, tingling, loss of muscle function, muscle weakness, difficulty walking)
• Ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur (foreign body sensation in eye, eye redness and itching, blurred vision or other changes in vision, sensitivity to light, blindness) Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur.
• Gastrointestinal: pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis (severe abdominal pain, nausea/vomiting, diarrhea, loss of appetite)
• Musculoskeletal and Connective Tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica (severe muscle pain or loss of muscular function)
• Endocrine: hypoparathyroidism (changes in calcium levels in blood, muscle aches/cramps, fatigue/weakness, spasms or twitching in hands/arms/around mouth, tingling/burning sensations in lips/toes/fingertips, dry skin, brittle nails)
• Other (Hematologic/Immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection (significant changes in blood counts, bruising, recurrent infections, fever without infection, enlarged lymph nodes)

Infusion-Related Reactions: 

This is a reaction that occurs during or immediately after the administration of medication. The symptoms of an infusion-related reaction can vary but can include the following: fever, increased heart rate, changes in blood pressure, shortness of breath, flushing, rash, pain, and cough. Any new symptoms during or immediately following infusion should be reported to your healthcare team.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): You may experience complications if you receive donor stem cells (allogeneic stem cell transplant) before or after treatment with opdualag.

Embryo-Fetal Toxicity: Opdualag can cause fetal harm when administered to a pregnant woman. Females of childbearing age should use effective contraception during treatment and at least 5 months after the last dose of opdualag.

Lactation: Opdualag may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, it is advised that patients not breastfeed during treatment and for at least 5 months after the last dose of Opdualag.

Patient assistance: 1-800-861-0048 (hours: 8 am – 8 pm EST or visit www.bmsaccesssupport.com

Purpose: Mekinist in combination with Tafinlar blocks a cellular pathway to inhibit the growth of melanoma metastases.

How it works: Tafinlar is an inhibitor of some mutated forms of BRAF kinases. Mekinist is an inhibitor of some MEK kinases. Both of these kinases are key proteins that help melanoma cells grow. About half of all patients with melanoma have a mutated form of the BRAF protein in their tumors.

Which patients: Mekinist in combination with Tafinlar is indicated for the treatment of Stage III patients with lymph node involvement who have undergone a complete resection and Stage IV patients, with BRAF V600 E or V600 K mutations. Before starting treatment, the patient should test positive for the presence of a BRAF V600E or V600K mutation.

How it is given: Tafinlar and Mekinist are both oral drugs.

Stage III: Patients receive 150mg of Taflinar orally twice daily and receive 2mg of Mekinist once daily until disease recurrence or unacceptable side effects for up to 1 year.

Stage IV: Patients receive 150mg of Taflinar orally twice daily and receive 2mg of Mekinist once daily until disease recurrence or unacceptable side effects.

Effectiveness:

Stage III: In a Phase III trial that compared the Mekinist and Taflinar combination to a placebo the three-year relapse-free survival rate in the combination arm was 58% vs 39% in the placebo arm. This represented a 53% reduced risk of disease recurrence or death.

Stage IV: In a Phase III trial that compared the Mekinist and Tafinlar combination to Zelboraf, at one year the overall survival in the combination arm was 73% versus 64% in the Zelboraf arm. After two years, 51% of patients taking Tafliinar plus Mekinist were alive compared to 38% taking Zelboraf alone.

Progression-free survival (the time a patient lives without cancer growing or spreading) was 12.6 months for patients treated with the Mekinist and Tafinlar combination, versus 7.3 months for patients treated with Zelboraf.

Side effects: Several side effects are common in the course of treatment. Most of these side effects are mild or moderate, although there have been some severe side effects. These side effects can usually be managed with either a decrease in the dosage or by briefly stopping one or both of the drugs and then resuming after the symptoms improve. Sometimes, when the drug or drugs are resumed, it is at a lower dosage.

New skin cancers

• For patients treated with Mekinist in combination with Tafinlar, the incidence of cutaneous squamous cell carcinoma was 7% compared with 19% in patients treated with Tafinlar alone. The incidence of basal cell carcinomas was higher (9% compared with 2%) for Mekinist in combination with Tafinlar.

New primary melanomas: they occur in approximately 2% of patients.

• If these lesions appear, they should be removed, but typically you can continue taking the drug without changing the dosage.

Important: You should have a dermatologic examination before you start these medicines, and every two-three months while you remain on the drugs, up to 6 months after you stop taking the drugs.

Serious fevers: 26% of all patients developed fevers when treated with Tafinlar alone. In 2% of these patients these fevers were serious and were accompanied by one or more additional symptoms. For patients treated with Mekinist in combination with Tafinlar, the incidence of fever was 71%, while 25% had other associated symptoms such as:

• Low Blood Pressure
• Chills
• Dizziness
• Too much fluid loss (dehydration)
• Kidney problems

Important: Tell your doctor immediately if you get a fever.

Skin rash is the most common side effect, occurring in 65% of all patients taking Mekinist in combination with Tafinlar. In some cases it can be severe enough to cause hospital admission. Tell your doctor if you get any of these symptoms:

• Skin rash
• Acne
• Blistering
• Redness, swelling, peeling, or tenderness of hands or feet
• Skin redness

Hemorrhage: 16% of all patients had a hemorrhagic event (including accumulation of blood within the brain) and in 4% of cases it was fatal.

Blood clots: 7% of all patients had a blood clot in a vein (deep vein thrombosis) or in the lung (pulmonary embolism). One patient died of a pulmonary embolism (2% of patients).

Important: Immediately seek medical attention if you experience any concerning symptoms, including but not limited to; shortness of breath, chest pain, leg swelling, bleeding or confusion.

Heart problems, including heart failure, occurred in approximately 9% of patients. Signs and symptoms of heart problems include:

• Feeling like your heart is pounding
• Shortness of breath
• Swelling of ankles or feet
• Feeling lightheaded

Important: You should have your heart function checked before you start taking Tafinlar in combination with Mekinist as well as during treatment.

Blood sugar problems (diabetes): Some people may develop high blood sugar, or if they have diabetes it may get worse. Tell your doctor if you have any of the following symptoms:

• Increased thirst
• Urinating more than usual
• Your breath smells like fruit

Eye problems such as uveitis, retinal vein occlusion, and Retinal Pigment Epithelial Detachment occurred very rarely in patients. Symptoms include eye pain, swelling or redness, blurred vision, floaters, or sudden loss of vision.

Important: You should have your eyes examined before and while you are taking these medicines. Tell your doctor immediately if any eye symptoms appear.

Patient assistance: Patients can call 1-800-282-7630

Purpose: Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 which restricts the body’s immune system from attacking melanoma cells. Cotellic in combination with Zelboraf blocks a cellular pathway to inhibit the growth of melanoma tumors.

How it works: Tecentriq is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to fight advanced melanoma. It 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. Tecentriq may enable the re-activation of T cells but also may affect normal cells. Zelboraf is a kinase inhibitor that blocks the activity of the V600E-mutated form of BRAF, a key protein that helps cancer cells grow. Cotellic is an inhibitor that blocks the activity of an enzyme known as MEK. About half of all patients with melanoma have a mutated form of the BRAF protein in their tumors. Inhibition of both the PD-1/PD-L1 and MPK pathways increases antigen presentation and T cell infiltration and activation compared to targeted therapy alone.

Which patients: Tecentriq in combination with Cotellic and Zelboraf is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable (melanoma that cannot be completely removed by surgery) or Stage IV melanoma. Before starting treatment, the patient should test positive for the presence of a BRAF V600E or V600K mutation.

How it is given: Prior to starting Tecentriq, patients should receive a 28-day treatment cycle of Cotellic 60 mg orally once daily (21 days on and 7 days off) and Zelboraf 960 mg orally twice daily from Days 1-21 and Zelboraf 720 mg orally twice daily from Days 22-28.

After the first 28-day treatment cycle, the recommended dose of Tecentriq is 840 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients continue to receive Cotellic 60 mg orally once daily (21 days on and 7 days off) and Zelboraf 720 mg orally twice daily.

If the first infusion of Tecentriq is tolerated, all subsequent infusions may be delivered over 30 minutes.

Please refer to Prescribing Information for Cotellic and Zelboraf prior to initiation.

Effectiveness: In a phase III trial that compared Tecentriq plus Cotellic and Zelboraf to a placebo plus Cotellic and Zelboraf, the median progression-free survival (the time a patient lives without cancer growing or spreading ) was 15.1 months for the patients treated with Tecentriq in combination of Cotellic and Zelboraf versus 10.6 months for the patients treated with the placebo arm with Cotellic and Zelboraf.

Side effects: Adverse reactions were consistent with the known safety profiles of Tecentriq and Cotellic + Zelboraf. The most common adverse reactions in patients who received Tecentriq plus Cotellic + Zelboraf were skin rash, joint, muscle, or bone pain, feeling tired or week, liver injury, fever, nausea, itching, swelling of legs or arms, mouth swelling (sometimes with sores), low thyroid hormone levels, and sunburn or sun sensitivity.

Side Effects of Tecentriq:

Tecentriq can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening.

Important: Call or see your healthcare provider right away if you develop any symptoms of the following problems or these symptoms get worse:

Lung problems (pneumonitis). Signs and symptoms of pneumonitis may include:

• New or worsening cough
• Shortness of breath
• Chest pain

Liver problems (hepatitis). Signs and symptoms of hepatitis may include:

• Yellowing of your skin or the whites of your eyes
• Severe nausea or vomiting
• Pain on the right side of your stomach area (abdomen)
• Drowsiness
• Dark urine (tea colored)
• Bleeding or bruising more easily than normal
• 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 mucus in your stools or dark, tarry, sticky stools
• Severe stomach area (abdomen) pain or tenderness

Hormone gland problems (especially the thyroid, adrenal glands, pancreas, and pituitary). Signs and symptoms that your 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
• Your voice gets deeper
• Urinating more often than usual
• Nausea or vomiting
• 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, 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 your face or lips
• Dizziness
• Fever
• Feeling like passing out
• Back or neck pain

Important: Before you receive Tecentriq, tell your healthcare provider about all of your medical conditions, including if you:

• 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 your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
• Are being treated for an infection
• Are pregnant or plan to become pregnant. Tecentriq can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Tecentriq. Females who are able to become pregnant:
  • Your healthcare provider should do a pregnancy test before you start treatment with Tecentriq.
  • You should use an effective method of birth control during your 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 your breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of Tecentriq.

Side Effects of Cotellic + Zelboraf:
Cotellic + Zelboraf may cause serious side effects including:

Risk of new skin cancers. Cotellic in combination with Zelboraf may cause new skin cancers (cutaneous squamous cell carcinoma, keratoacanthoma, or basal cell carcinoma). New melanoma lesions have occurred in people who take Zelboraf.

Purpose: Hepzato prevents the reproduction of uveal melanoma cells that has spread to the liver.

How it works: Hepzato is a chemotherapy drug that prevents cell replication. It works by attaching itself into tumor DNA which interferes with DNA synthesis that is needed for tumor cells to replicate.

Which patients: Hepzato is FDA-approved for adult patients with uveal melanoma with unresectable (melanoma that can’t be completely removed surgically) liver metastases affecting less than 50% of the liver and no extrahepatic (cancer that is located or occurring outside the liver) disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.

How it is given: Hepzato is administered as an infusion using a hepatic (liver) delivery system to inject the chemotherapy drug melphalan into the liver. This procedure is referred to as percutaneous hepatic perfusion (PHP). Percutaneous hepatic perfusion uses a series of catheters and balloons to isolate the liver from the body’s circulatory system, allowing for high-dose chemotherapy to be delivered directly to the liver only and avoiding the remainder of the body. The blood is collected as it exits the liver and filtered outside the body via a bypass circuit to remove any remaining chemo. The recommended dose is 3 mg/kg based on ideal body weight with a maximum absolute dose of 220 mg during a single Hepzato treatment. The drug is infused over 30 minutes followed by a 30-minute washout period. Treatments are delivered every six to eight weeks but can be delayed until recovery from toxicities and as per clinical judgement. Administration of the drug requires general anesthesia.

Effectiveness: In the FOCUS Study, 91 patients with metastatic uveal melanoma received Hepzato. Thirty-three (33) patients (36.3%) responded to therapy. Seven (7) patients (7.7%) patients achieved a complete response and twenty-six (26) patients (28.6%) had a partial response. The median duration of response was 14.0 months.

Side effects: Hepzato can cause side effects during the course of treatment. Side effects vary among patients, yet you will receive medications prior to and during the infusion to minimize side effects. A reduction in the dose of Hepzato may occur for subsequent infusions when your doctor recommends it.

Most common (≥20%) adverse reactions or laboratory abnormalities are: low platelet level, fatigue, anemia, nausea, musculoskeletal pain, reduction of white blood cells, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased alkaline phosphatase, and shortness of breath.

• Myelosuppression which is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. This can result in severe infection, bleeding, or symptomatic anemia
• An exaggerated allergic reaction from the immune system, such as anaphylaxis, skin rash, cough, itching, and increased heart rate
• Gastrointestinal reactions, such as nausea and vomiting, abdominal pain, and diarrhea
• Secondary cancers
• Lethal toxicity to a fetus
• Infertility

Serious adverse reactions are possible with Hepzato. Because of the risk of severe complications, it is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.

The risks of severe complications include ruptured blood vessels, injury of the liver cells, and blood clotting. Patients are monitored for these reactions during Hepzato infusion and for at least 72 hours following drug administration. The drug should be discontinued if patients have life-threatening or persistent drug toxicity that has not resolved after 8 weeks of treatment.

To report suspected adverse reactions: 1-833-632-0458