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IMPROVING ADHERENCE AND OPTIMIZING

OUTCOMES WITH OUR NEWEST DRUGS

Ferowsi Pecoraro, PharmD, BCOP Oncology Pharmacist Specialist CHI Franciscan Health March 11, 2016

LEARNING OBJECTIVES

1.  Discuss new agents, including administration and monitoring considerations

2.  Describe new indications for current therapies, including administration and monitoring considerations

3.  Identify treatment-specific challenges to adherence and achieving optimal outcomes and discuss strategies to overcome poor adherence and suboptimal outcomes

WHAT’S NEW?

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IV MEDICATIONS

 Elotuzumab (Empliciti™) **New Mechanism**

 Necitumumab (Portrazza™)

 Daratumumab (Darzalex™)

 Irinotecan liposome (Onivyde™)

 Trabectedin (Yondelis®)

ORAL MEDICATIONS

 Alectinib (Alecensa®)

 Ixazomib (Ninlaro®) **1st oral proteasome inhibitor**

 Osimertinib (Tagrisso™)

 Cobimetinib (Cotellic™)

 Trifluridine/tipiracil (Lonsurf®)

 Sonidegib (Odomzo®)

 Panobinostat (Farydak®)

INDICATIONS

 Multiple myeloma – 4

 Pancreatic cancer

 Non-small cell lung cancer – 3

 Melanoma

 Basal cell carcinoma

 Sarcoma – soft tissue sarcoma, liposarcoma, leiomyosarcoma

 Colorectal cancer

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ALECTINIB (ALECENSA®)  Class: Kinase inhibitor

 Indication: ALK(+) metastatic NSCLC who have progressed on or did not tolerate Crizotinib

 Dose/Administration: 600mg PO BID with food until disease progression or unacceptable toxicity

 Common side effects: Fatigue, constipation, edema, myalgia, vomiting

 Monitoring: ­  LFTs (hepatic panel) every 2 weeks during the first 2 months, then periodically ­  CPK every 2 weeks during the first 1 month, then as clinically indicated if patient reports muscle pain,

tenderness, weakness ­  HR (assess for bradycardia) ­  Dyspnea or chest pain that may indicate PE, interstitial lung disease, pneumonitis

ALECTINIB (ALECENSA®)

 Improving adherence: ­  Education on taking medication with food ­ Appropriate antiemetics if patient experiences nausea +/- vomiting ­  Education on avoiding excessive exposure to sunlight and skin protection

 Optimizing outcomes: Education on importance of recommended lab monitoring

ELOTUZUMAB (EMPLICITI™)

 Class: Monoclonal antibody targeting Signaling Lymphocyte Activation Molecule Family 7 (SLAMF7) – New mechanism

 Indication: Multiple myeloma who have received 1-3 prior therapies; in combination with Lenalidomide and Dexamethasone

 Dose/Administration: 10mg/kg IV weekly for Cycle 1 and 2, then every 2 weeks until disease progression or unacceptable toxicity; infusions are titrated – Cycle 1 Doses 1 and 2, Cycle 4 up to max 5mL/min ­  Pre-medications: Dexamethasone, Diphenhydramine 25-50mg IV, Ranitidine 50mg IV or equivalent,

Acetaminophen 650-1000mg PO 45-90 min prior to infusion ­ Dexamethasone: 8mg IV 45-90 min prior to infusion and 28mg PO 3-24 hr prior on weeks with

Elotuzumab; 40mg PO on weeks without Elotuzumab ­  Lenalidomide: 25mg PO daily on Days 1-21

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ELOTUZUMAB (EMPLICITI™)

ELOTUZUMAB (EMPLICITI™)  Common side effects: Fatigue, diarrhea, constipation, pyrexia, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia

 Monitoring: ­  Infusion reactions ­  Temperature, signs of infection ­  LFTs ­  Providers – potential for new primary malignancy, appropriate assessment of lab results that indicate

response (interfere with assays to monitor M protein)

 Improving adherence: ­  Barriers – complicated regimen ­  Reinforce and provide tools to keep track of treatment schedule – detailed calendar

 Optimizing outcomes: Follow pre-medication recommendations

NECITUMUMAB (PORTRAZZA™)  Class: EGFR inhibitor

 Indication: 1st-line in metastatic squamous NSCLC; in combination with Cisplatin and Gemcitabine

 Dose/Administration: 800mg IV over 60 min on Days 1 and 8 of each 21-day cycle; continue until disease progression or unacceptable toxicity (max 6 cycles of Cisplatin/Gemcitabine) ­  Pre-medications: Diphenhydramine or equivalent if experienced Grade 1 or 2 infusion-related

reaction. After 2nd Grade 1 or 2 reaction, pre-medicate with Diphenhydramine, Acetaminophen, Dexamethasone (or equivalents) prior to each treatment.

 Common side effects: Rash, hypomagnesemia

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NECITUMUMAB (PORTRAZZA™)  Monitoring: ­  Electrolytes (Mg, K, Ca), symptoms indicating low Mg; low Mg may be increased when combined with

Cisplatin ­  Replace when appropriate ­  Continue monitoring for at least 8 weeks after Necitumumab

­  Rash ­  Infusion related reactions ­  DVT/PE

 Improving adherence: ­  Education on limiting sun exposure; addressing dermatologic toxicities ­  Appropriate antiemetics during concurrent Cisplatin/Gemcitabine

 Optimizing outcomes: ­  Education on importance of electrolyte monitoring and replacement ­  Initiating pre-medications if infusion-related reactions occur

IXAZOMIB (NINLARO®)  Class: Proteasome inhibitor – 1st oral in class

 Indication: Multiple myeloma who have received at least 1 prior therapy; in combination with Lenalidomide and Dexamethasone

 Dose/Administration: 4mg PO on Days 1, 8, and 15 of 28-day cycle on an empty stomach; continue until disease progression or unacceptable toxicity ­  Lenalidomide: 25mg PO on Days 1-21 ­ Dexamethasone: 40mg PO on Days 1, 8, 15, and 22 of 28-day cycle

 Common side effects: Diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, vomiting, peripheral edema, back pain

IXAZOMIB (NINLARO®)  Monitoring: ­  Platelets, LFTs ­ GI symptoms ­  Peripheral neuropathy ­  Rash ­  Fluid retention

 Improving adherence: ­  Appropriate antiemetics if patient experiences nausea +/- vomiting ­  Ensure appropriate doses in patients with renal or hepatic impairment

­ Optimizing outcomes:

­  Education on taking medication on empty stomach

­  Request pharmacist review for potential drug interactions

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DARATUMUMAB (DARZALEX™)  Class: Monoclonal antibody – targets CD38

 Indication: Multiple myeloma who have received at least 3 prior therapies, including proteasome inhibitor and immunomodulatory agent, or who are refractory to both

 Dose/Administration: 16mg/kg IV weekly, then every 2 weeks for 16 weeks, then every 4 weeks until disease progression; infusions are titrated ­  Pre-medications: Methylprednisolone 100mg IV or equivalent, Acetaminophen 650-1000mg PO,

Diphenhydramine 25-50mg IV/PO or equivalent 1 hr prior to treatment. Corticosteroid dose may be reduced (Methylprednisolone 60mg IV) after 2nd infusion.

­  Post-infusion medication: Methylprednisolone 20mg PO or equivalent daily for 2 days following Daratumumab

­  For history of obstructive pulmonary disorder: Recommend short- and long-acting bronchodilators and inhaled corticosteroids; may be discontinued if no reactions during first 4 treatments

DARATUMUMAB (DARZALEX™)  Prophylaxis for herpes zoster reactivation: Initiate within 1 week of starting Daratumumab; continue for 3 months following treatment

 Special consideration: Type and cross patient for possible transfusion needs PRIOR to initiating Daratumumab; drug interferes with Indirect Antiglobulin Tests (Coombs)

 Common side effects: Infusion reactions, fatigue, nausea, back pain, pyrexia, cough, upper respiratory tract infection

 Monitoring: ­  Infusion-related reactions ­  Temperature, signs of infection

 Improving adherence: ­  Educate on importance of scheduled appointments; duration of treatment may be long due to titration and reactions – important to

start on time to allow for this ­  Appropriate antiemetics if patient experiences nausea

 Optimizing outcomes: Follow pre- and post-medication recommendations; educate patients on importance of these medications

OSIMERTINIB (TAGRISSO™)

 Class: Kinase inhibitor

 Indication: Metastatic EGFR T790M mutation (+) NSCLC who have progressed on or after TKI therapy; mutation must be confirmed

 Dose/Administration: 80mg PO daily until disease progression or unacceptable toxicity; with or without food

 Common side effects: Diarrhea, rash, dry skin, nail toxicity, eye disorders, nausea, decreased appetite, constipation

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OSIMERTINIB (TAGRISSO™)

 Monitoring: ­ QTc prolongation – ECG, electrolytes especially in patients with history or on concurrent medications

known to prolong QTc interval ­  Baseline ECHO, then every 3 months ­  Symptoms of interstitial lung disease (ILD), pneumonitis

 Improving adherence: ­ An oral solution can be made for those with swallowing difficulty ­  Education on avoiding sun exposure and proper protection; addressing dermatologic toxicities ­  Recommend taking medication with food or appropriate antiemetics if patient experiences nausea

 Optimizing outcomes: Request pharmacist review for potential drug interactions

COBIMETINIB (COTELLIC™)

 Class: Kinase inhibitor

 Indication: Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation; in combination with Vemurafenib

 Dose/Administration: 60mg PO daily on Day 1-21 of 28-day cycle until disease progression or unacceptable toxicity; with or without food

 Common side effects: Diarrhea, photosensitivity reaction, nausea, pyrexia, vomiting

COBIMETINIB (COTELLIC™)

 Monitoring: ­ Dermatologic toxicities ­  Signs, symptoms of bleeding ­ Visual disturbances ­  LFTs – baseline and at least monthly, CPK – baseline, then periodically ­  ECHO – baseline, after 1st month of treatment, then every 3 months ­  Providers – New primary malignancies (up to 6 months following last dose)

 Improving adherence: ­  Education on avoiding sun exposure and proper protection; addressing dermatologic toxicities ­ Appropriate antiemetics if patient experiences nausea +/- vomiting

 Optimizing outcomes: Request pharmacist review for potential drug interactions

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IRINOTECAN LIPOSOME (ONIVYDE™)  Class: Topoisomerase inhibitor

 Indication: Metastatic pancreatic adenocarcinoma with disease progression following gemcitabine-based therapy; in combination with Fluorouracil and Leucovorin

 Dose/Administration: 70mg/m2 IV over 90 min every 2 weeks ­  For patients with UGT1A1*28 allele, start at 50mg/m2 and can be increased as tolerated in

subsequent treatments ­ Do not substitute with conventional Irinotecan

­  Pre-medications: Corticosteroid, antiemetic 30 min prior ­ Do not give if ANC < 1500

IRINOTECAN LIPOSOME (ONIVYDE™)  Common side effects: Diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, pyrexia

 Monitoring: ­  CBC w/ differential on Days 1 and 8 of every cycle, more frequently if indicated ­ GI symptoms ­  Respiratory symptoms ­  Temperature, signs of infection

 Improving adherence: ­  Atropine, Loperamide if appropriate for diarrhea ­  Appropriate antiemetics if patient experiences nausea +/- vomiting

 Optimizing outcomes: ­  Request pharmacist review for potential drug interactions ­ Observe ANC criteria for treatment

TRIFLURIDINE/TIPIRACIL (LONSURF®)  Class: Nucleoside metabolic inhibitor/Thymidine phosphorylase inhibitor

 Indication: Metastatic colorectal cancer with prior treatment with fluoropyrimidine-, oxaliplatin-, irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (if RAS wild-type)

 Dose/Administration: 35mg/m2 PO BID on Days 1-5, Days 8-12 of each 28-day cycle until disease progression or unacceptable toxicity; take within 1 hr of morning and evening meals ­ Dose can be titrated up to max 80mg/m2 BID

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TRIFLURIDINE/TIPIRACIL (LONSURF®)  Common side effects: Anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, pyrexia

 Monitoring: ­ CBC with differential – prior to and on Day 15 of each cycle ­  Temperature, signs of infection ­  Signs, symptoms of bleeding ­ GI symptoms

 Improving adherence: Appropriate antiemetics if patient experiences nausea +/- vomiting

 Optimizing outcomes: ­  Education on taking medication within 1 hr of meal ­  Education on importance of lab monitoring

TRABECTEDIN (YONDELIS®)

 Class: Alkylating agent

 Indication: Advanced soft tissue sarcoma (STS), liposarcoma, leiomyosarcoma subtypes who have received prior chemotherapy, including anthracycline-based regimen

 Dose/Administration: 1.5mg/m2 IV over 24 hr every 3 weeks until disease progression or unacceptable toxicity ­  Pre-medication: Dexamethasone 20mg IV or equivalent 30 min prior to Trabectedin ­ Administration via central line recommended

TRABECTEDIN (YONDELIS®)  Common side effects: Nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, fever, cough, neutropenia, anemia

 Monitoring: ­  CBC with differential ­  LFTs ­  Cardiac function evaluation – baseline and every 2-3 months until discontinuation ­ GI symptoms ­  Respiratory symptoms ­  Temperature, signs of infection

 Improving adherence: Appropriate antiemetics if patient experiences nausea +/- vomiting

 Optimizing outcomes: ­  Follow pre-medication recommendation ­  Request pharmacist review for potential drug interactions

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SONIDEGIB (ODOMZO®)

 Class: Hedgehog pathway inhibitor

 Indication: Locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation, or those who are not candidates for surgery or radiation

 Dose/Administration: 200mg PO daily on an empty stomach until disease progression or unacceptable toxicity

 Boxed warning: Embryo-fetal toxicity

SONIDEGIB (ODOMZO®)  Common side effects: Muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, headache, myalgia, abdominal pain, pain, vomiting, pruritis

 Monitoring: ­  Baseline CK, SCr then periodically; musculoskeletal symptoms ­ GI symptoms

 Improving adherence: Appropriate antiemetics if patient experiences nausea +/- vomiting

 Optimizing outcomes: ­  Education on taking medication on empty stomach ­  Request pharmacist review for potential drug interactions ­  Education on importance of recommended lab monitoring

PANOBINOSTAT (FARYDAK®)

 Class: Histone deacetylase inhibitor

 Indication: Multiple myeloma who have received at least 2 prior regimens, including Bortezomib and an immunomodulatory agent; in combination with Bortezomib and Dexamethasone

 Dose/Administration: 20mg PO once daily 3 times per week for 2 weeks per 3-week cycle; with or without food ­ Additional 8 cycles for patients with clinical benefit, unless unresolved or significant toxicities

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PANOBINOSTAT (FARYDAK®)

 Cycles 1-8

 Cycles 9-16 ­  Panobinostat – same days ­  Bortezomib – Days 1, 8 ­ Dexamethasone – Days 1, 2, 8, 9

Days 1-7 Days 8-14 Days 15-21

Panobinostat 1 3 5 8 10

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Rest period

Bortezomib 1 4 8 11

Rest period

Dexamethasone 1 2 4 5 8 9 11

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Rest period

PANOBINOSTAT (FARYDAK®)  Common side effects: Diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, vomiting

 Monitoring: ­  GI symptoms ­  Temperature, signs of infection ­  Cardiac changes, ECG and electrolytes – baseline and periodically ­  CBC with differential, signs of bleeding ­  LFTs

 Improving adherence: ­  Barriers – complicated regimen ­  Reinforce and provide tools to keep track of treatment schedule – detailed calendar ­  Antidiarrheal agents and antiemetics as appropriate

 Optimizing outcomes: ­  Educate on importance of electrolyte monitoring and replacement ­  Request pharmacist review for potential drug interactions

EXPANDED INDICATIONS

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NIVOLUMAB (OPDIVO®) Indication Dosing/Administration Common Side Effects Other

Unresectable or metastatic melanoma

Monotherapy: 3mg/kg IV over 60 min every 2 weeks

Monotherapy: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea

Potential for increased side effects/toxicities in combination with Ipilimumab

With Ipilimumab: 1mg/kg IV over 60 min weekly for 4 weeks, the 3mg/kg every 2 weeks

With Ipilimumab: Fatigue, rash, diarrhea, nausea, vomiting, pyrexia, dyspnea

Metastatic non-small cell lung cancer (NSCLC)- progression on platinum-based therapy

3mg/kg IV over 60 min every 2 weeks

Fatigue, musculoskeletal pain, decreased appetite, cough, constipation

If EGFR or ALK , must have had prior treatment

Advanced renal cell carcinoma who received prior anti-angiogenic agents

3mg/kg/IV over 60 min every 2 weeks

Asthenic conditions, cough, nausea, rash, dyspnea, constipation, diarrhea, decreased appetite, back pain, arthralgia

NIVOLUMAB (OPDIVO®)

 Monitoring: ­  Infusion-related reactions ­  Potential side effects – there are many which can be serious

 Optimizing outcomes: Closely monitor for side effects. It may be helpful to develop a standard list of questions to ask your patients – ­  Lung symptoms, GI symptoms – indicating colitis or liver problems, gland problems, kidney symptoms,

skin symptoms, symptoms of brain inflammation ­ Can specific complex assessment be incorporated into your system for patients on Nivolumab?

PEMBROLIZUMAB (KEYTRUDA®) Indication Dose/Administration Common Side Effects Other

Unresectable or metastatic melanoma

2mg/kg IV over 30 min every 3 weeks

Fatigue, rash, pruritis, diarrhea, nausea, constipation, decreased appetite

Metastatic NSCLC – progression on platinum-based therapy

2mg/kg IV over 30 min every 3 weeks

Fatigue, decreased appetite, dyspnea, cough

If EGFR or ALK , must have had prior treatment

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PEMBROLIZUMAB (KEYTRUDA®)  Monitoring: ­  Infusion-related reactions ­ Multiple potential side effects/toxicities

 Optimizing outcomes: Closely monitor for side effects. It may be helpful to develop a standard list of questions to ask your patients – ­  Lung symptoms, GI symptoms – indicating colitis or liver problems, gland problems, kidney symptoms,

skin symptoms ­ Can specific complex assessment be incorporated into your system for patients on Pembrolizumab? Or

PD-1 inhibitors?

QUESTIONS?

RESOURCE: DERMATOLOGIC TOXICITIES  N Tang, D Ratner. Managing Cutaneous Side Effects From Targeted Molecular Inhibitors for Melanoma and Nonmelanoma Skin Cancer. Dermatol Surg. 2016 Jan;42 Suppl 1:S40-8.