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REVIEW OF ORAL ONCOLYTICSIrene Arias PharmD, MS, [email protected]
• I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation.
DISCLOSURES
• Review select oral chemotherapy agents approved in 2018• Describe pivotal trials resulting in their approval • Identify tips to help counsel oncology patients to overcome barriers
with oral chemotherapy• Review various adverse effects and monitoring parameters
OBJECTIVES
• Shift of chemotherapy administration from parenteral to oral• The rise of oral oncolytics places patients more in control of
their care• Adherence• Toxicities
• Patient follow-up and monitoring is important for improved outcomes and tolerability
ORAL CHEMOTHERAPY
Weingart S, et al: J Natl Compr Canc Netw, 2008
• Gilteritinib- AML 11/28/2018• Larotrectinib-Solid tumors with NTRK gene fusion 11/26/2018• Glasdegib- AML 11/21/2018• Lorlatinib- NSCLC 11/2/2018• Talazoparib- Metastatic Breast Cancer 10/16/2018• Dacomitinib-NSCLC 9/27/2018• Duvelisib- CLL/SLL 9/24/2018• Ivosidenib-AML 7/20/2018• Encorafenib and binimetinib- Melanoma 6/27/2018
NEW ORAL ONCOLYTIC APPROVALS IN 2018
ADVANCED BREAST CANCEROlaparibTalazoparib
• BRCA1/2 contribute to homologous recombination repair of double-stranded breaks in DNA repair
• About 1 in 400 people have a BRCA 1/2 mutation
• Poly (adenosine diphosphate-ribose) polymerase (PARP) plays a role in repair in response to single-stranded DNA breaks.
• PARP inhibitors interfere with repair of single-stranded DNA breaks
ROLE OF PARP INHIBITORS IN BREAST CANCER
= cell cycle arrest and apoptosis
Turk et al. 2018. CANCER 124: 2498-2506
Turk et al. 2018. CANCER 124: 2498-2506
OLAPARIBPoly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor
OLYMPIAD TRIAL:OLAPARIB FOR METASTATIC BREAST CANCER IN PATIENTS WITH A GERMLINE BRCAMUTATIONInternational, open-label randomized, phase III Study population
• gBRCAm HER2- negative metastatic breast cancer
• Received no more than 2 prior cytotoxic chemotherapy in this setting
• Received treatment with an anthracycline and/or taxane
• CNS metastases- completed definitive local therapy, stable
• Objective disease progression on prior platinum- Excluded
RANDOMIZE
N= 287Olaparib 300 mg po twice
daily
N= 144Physicians choice
(capecitabine, eribulin,, or vinorelbine)
2:1
Robson et al. 2017. NEJM 377: 523-533
OLYMPIAD TRIAL RESULTSProgression-free Survival
mPFS 7 mo vs 4.2 moHR 0.58; 95% CI 0.43-0.80, p< 0.001
mOS 19.3 mo vs 19.6 moHR 0.90; 95% CI 0.63-1.29, p= 0.57
Overall Survival
Robson et al. 2017. NEJM 377: 523-533
• Indication: gBRCAm, HER2-, metastatic breast cancer• Tablet formulation= 150 mg and 100 mg
• Dose of 300 mg po bid = 2 tablets in the am and 2 tablets in the pm
• Moderate-high emetogenic potential• Inform patients to avoid grapefruit, grapefruit juice, Seville
oranges, and Seville orange juice• Most common all grade adverse events (≥ 20%)
• Anemia, neutropenia, nausea, vomiting, diarrhea, fatigue, headache
• Most common grade 3 - 4 adverse events (≥ 5%)• Anemia, neutropenia
OLAPARIB PEARLS
Olaparib Prescribing Information 12/2018
• Monitoring• CBC at baseline and monthly or as clinically indicated
• For prolonged hematologic toxicity, monitor weekly until recovery
• Warnings• MDS/AML (<1.5%), pneumonitis (<1%), embryo-fetal toxicity
OLAPARIB PEARLS
Dose ModificationsStrong CYP3A4 inhibitors 100 mg po bidStrong CYP3A4 inducers No recommendationsCrCl 31 – 50 mL/min 200 mg po bidAdverse effects 250 mg po bid
Olaparib Prescribing Information 12/2018
TALAZOPARIBPoly (adenosine diphosphate-ribose) polymerase -(PARP)
International, open-label randomized, phase III Study population
• gBRCAm HER2- negative locally advanced or metastatic breast cancer
• Received no more than 3 prior cytotoxic chemotherapy in this setting
• Received treatment with an anthracycline and/or taxane
• CNS metastases- completed definitive local therapy, stable
• Objective disease progression on prior platinum- Excluded
EMBRACA TRIAL- TALAZOPARIB IN PATIENTS WITH ADVANCED BREAST CANCER AND A GERMLINE BRCA MUTATION
RANDOMIZE
N= 287Talazoparib 1 mg po daily
N= 144Physicians choice
(capecitabine, eribulin, gemcitabine, or vinorelbine)
2:1
Litton et al. 2018. NEJM 379: 753-763
EMBRACA TRIAL RESULTSInterim Analysis of Overall Survival
mOS 22.3 mo vs 19.5 moHR 0.76; 95% CI 0.55-1.06, p= 0.11
Progression-free Survival
mPFS 8.6 mo vs 5.6 moHR 0.54; 95% CI 0.41-0.71, p< 0.001
Litton et al. 2018. NEJM 379: 753-763
• Indication: gBRCAm, HER2-, metastatic breast cancer• Capsule formulation = 0.25 mg & 1 mg
• Starting dose 1 mg by mouth daily • Moderate-high emetogenic potential• Most common all grade adverse events (≥ 20%)
• Anemia, neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, fatigue, headache
• Most common grade 3 - 4 adverse events (≥ 5%)• Anemia, neutropenia, thrombocytopenia
TALAZOPARIB PEARLS
Talazoparib Prescribing Information Revised 10/2018
• Monitoring• CBC monthly and as clinically indicated
• Warnings• MDS/AML (0.3%), myelosuppression, embryo-fetal toxicity
TALAZPARIB PEARLS
Dose ModificationsP-gp inhibitors or BCRP inhibitors 0.75 mg po daily
CrCl 31 – 59 mL/min 0.75 mg po daily
Adverse effects 0.75 mg po daily
Talazoparib Prescribing Information Revised 10/2018
Medication Administration DDI Warnings and precautions
Olaparib Olaparib 300 mg (2 tabs)
BID with or without food;
renal adj
(pill burden= 4)
Avoid use of strong/mod CYP3A
inhibitors. If unavoidable, reduce
olaparib dose. Avoid grapefruit,
grapefruit juice, Seville oranges,
and Seville orange juice.
Avoid use of strong/mod CYP3A
inducers.
MDS/AML
Pneumonitis
Embryo-Fetal Toxicity
Talazoparib Talazoparib 1 mg (1 cap)
daily with or without food;
renal adj
(pill burden= 1)
Co-administration with P-gp or
BCRP inhibitors may increase
talazoparib exposure. Reduce the
dose to 0.75 mg once daily if
coadministration with P-gp inhibitor
is unavoidable.
MDS/AML
Myelosuppression
Embryo-Fetal Toxicity
Olaparib Prescribing Information 12/2018
Talazoparib Prescribing Information Revised 10/2018
• Which of the following grade 3/4 adverse effects were seen with both talazoparib and olaparib?
• A-Diarrhea• B-Anemia• C-Hair Loss• D-Electrolyte abnormalities
ASSESSMENT QUESTION
MELANOMAEncorafenib + binimetinib
• BRAF mutation ~ 35 – 50% of melanoma cases
MELANOMA
Dummer et al. 2018. Lancet Oncol 19: 603-615
ENCORAFENIB + BINIMETINIBBRAF kinase inhibitor + MEK kinase inhibitor
COLUMBUS: ENCORAFENIB PLUS BINIMETINIB VERSUS VEMURAFENIB IN PATIENTS WITH BRAF-MUTANT MELANOMAInternational, open-label randomized, phase III Study population
• Locally advanced, unresectable or metastatic cutaneous melanoma
• BRAFV600E and or BRAFV600K
• Treatment naïve or have progressed on or after 1st line immunotherapy
Dummer et al. 2018. Lancet Oncol 19: 603-615
RANDOMIZE
N= 192Encorafenib 450 mg daily +
binimetinib 45 mg twice daily
N= 191Vemurafenib 960 mg twice daily
1:1:1
N= 194Encorafenib 300 mg daily
COLUMBUS RESULTS
Dummer et al. 2018. Lancet Oncol 19: 603-615
Progression-free Survival Progression-free Survival
mPFS 14.9 mo vs 7.3 moHR 0.54; 95% CI 0.41-0.71, p< 0.0001
mPFS 14.9 mo vs 9.6 moHR 0.75; 95% CI 0.56-1.00, p< 0.051
• Indication: 1st line unresectable or metastatic melanoma + BRAF
V600E/K mutation
• Formulation
• Encorafenib: 50 mg and 75 mg capsules
• Binimetinib: 15 mg tablets
• Dose: encorafenib 450 mg (6 caps) daily binimetinib 45 mg (3 tab) BID
• Most common all grade adverse events (≥ 20%)
• Fatigue, nausea, diarrhea, vomiting, abdominal pain, constipation,
arthralgia, myopathy, hyperkeratosis, rash, headache, visual impairment,
serous retinopathy
• Most common grade 3/4 adverse events (≥ 5%)
• Hypertension
ENCORAFENIB + BINIMETINIB PEARLS
Encorafenib Prescribing Information 1/2019; Binimetinb Prescribing Information 1/2019
• Storage requirements• No refrigeration needed• Desiccant found in encorafenib should not be removed
• Encorafenib as a single agent• Grade 3/4 dermatologic reactions occurred in 21% compared to 2% with
combination therapy• If binimetinib is held, reduce encorafenib dose to 300 mg once daily
• Monitoring• Electrolytes; dermatologic evals baseline, every 2 months during therapy,
and for up to 6 months following d/c to assess for new cutaneous malignancies; signs/symptoms of uveitis, hemorrhage, and dermatologic toxicity, and for noncutaneous malignancies, CPK & creatinine at baseline and periodically, EF at baseline, 1 month, then every 2-3 months, thromboembolism
ENCORAFENIB + BINIMETINIB PEARLS
Encorafenib Prescribing Information 1/2019; Binimetinb Prescribing Information 1/2019
Medication Administration & Storage DDI Warnings and precautions
Vemurafenib/
Cobimetinib
Vemurafenib 960mg (4 tabs)
BID days 1-28
Cobimetinib 60 mg (3tabs) days
1-21 with or without food; RT
(pill burden= 11)
Strong CYP3A4 inhibitors
and inducers, drugs with a
narrow therapeutic window
predominantly
metabolized by CYP1A2,
use of P-gp substrates
with narrow therapeutic
indices
Hypersensitivity
reactions, QT prolongation, hepatotoxicity,
rhabodomyolysis,
Severe photosensitivity,
Radiation sensitization
and recall, Renal failure
Dabrafenib/
Trametinib
Dabrafenib 150 mg (2 caps) BID
Trametinib 2 mg (1 tab) daily
Without food; RT/RF (pill
burden= 5)
Strong CYP3A4 &
CYP2C8 inhibitors,
substrates of CYP3A4 and
CYP 2C9
Febrile drug reaction,
Hyperglycemia, G6PD
deficiency
Encorafenib/
Binimetinib
Encorafenib 450 mg (6 caps)
daily Binimetinib 45 mg (3 tab)
BID, with or without food; RT
binimetanib= hepatic adj
(pill burden=12)
Strong/mod CYP3A4
inhibitors and inducers,
CYP3A4 substrates,
medications known to
prolong QT/QTc interval
Hepatotoxicity,
Rhabdomyolysis, QTc prolongation
Vemurafenib Prescribing Information 11/2017; Cobimetinib Prescribing Information 1/2018; Dabrafenib Prescribing Information 5/2018; Trametinib
Prescribing Information 5/2018; Encorafenib Prescribing Information 1/2019; Binimetinb Prescribing Information 1/2019
• Which of the following is an important counseling point for encorafenib?
• A- Encorafenib should be stored in the refrigerator• B- Encorafenib should be kept in the original bottle with the desiccant
remaining in the bottle• C- If you miss a dose, you may take your medication regardless of
when your next dose is due• D- Your medication will not work if you do not take it with a high-fat
meal
ASSESSMENT QUESTION
NON SMALL CELL LUNG CANCERDacomitinibLorlatinib
Chan et al. 2015. Transl Lung Cancer Res 4: 36-54
DACOMITINIBIrreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
International, open-label, randomized, phase III Study population
• Newly diagnosed, stage IIIB/IV or recurrent NSCLC with an EGFR mutation
• Exclusions:• Prior therapy for locally
advance or metastatic NSCLC• CNS metastasis
ARCHER 1050: DACOMITINIB VERSUS GEFITINIB AS FIRST-LINE TREATMENT FOR PATIENTS WITH EGFR-M+ NSCLC
RANDOMIZE
N= 227Dacomitinib 45 mg po daily
1:1
Wu Y et al. 2017. Lancet Oncol 18: 1454-1466
ARCHER 1050 TRIAL RESULTS
Wu Y et al. 2017. Lancet Oncol 18: 1454-1466
ARCHER 1050- IMPROVEMENT IN OVERALL SURVIVAL IN A RANDOMIZED STUDY THAT COMPARED DACOMITINIB WITH GEFITINIB
Mok T et al. 2018. J Clin Oncol 36: 2244-2250
• Indication: 1st line treatment mNSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations
• Tablet formulation= 45, 30, and 15 mg• Dose of 45 mg po daily
• Drug interactions: PPI and CYP2D6 substrates• Take 6 hours before or 10 hours after taking an H2 antagonist• Avoid concomitant use with CYP2D6 substrates with narrow
therapeutic index
DACOMITINIB PEARLS
Dacomitinib Prescribing Information 11/2018
• Most common all grade adverse events (≥ 20%)• Diarrhea, paronychia, dermatitis acneiform, stomatitis, decreased
appetite, dry skin, decreased weight, alopecia, cough, pruritis
• Most common grade 3 - 4 adverse events (≥ 5%)• Diarrhea, paronychia, dermatitis acneiform
• Warnings• Interstitial lung disease
• Monitoring• Signs/symptoms of interstitial lung disease/pneumonitis, diarrhea,
and dermatologic toxicity
DACOMITINIB PEARLS
Dacomitinib Prescribing Information 11/2018
Medication Administration DDI Warnings and precautionsErlotinib 150 mg (1 tab) daily
without food; hepatic adj(pill burden= 1)
CYP3A4 inhibitors alone/in combo with CYP1A2 inhibitor ↓ by 50 mg; CYP3A4 & CYP1A2 inducers ↑ by 50 mg (max 450 mg); cigarette smoking ↑ by 50 mg (max 300 mg); meds affecting gastric pH
ILD, renal failure, hepatotoxicity, GI perforations, bullous and exfoliative skin disorders, CVA, microangiopathic hemolytic anemia, ocular disorders, hemorrhage (warfarin)
Gefitinib 250 mg (1 tab) daily with or without food; tablets may be dispersed in water (pill burden= 1)
Avoid CYP3A4 inducers ↑ to 500 mg daily, monitor patients on CYP3A4 inhibitors who are poor CYP2D6 metabolizers, monitor patients on warfarin, meds affecting gastric pH
ILD, hepatotoxicity, GI perforations, severe or persistent diarrhea, ocular toxicity, bullous and exfoliative skin disorders
Afatinib 40 mg (1 tab) daily without food; renal adj (pill burden=1)
P-gp inhibitors, reduce ↓ by 10 mg. P-gp inducers, ↑ by 10 mg
Diarrhea, bullous and exfoliative skin disorders, ILD, hepatotoxicity, keratitis
Osimertinib 80 mg (1 tab) daily with or without food; (pill burden=1)
Avoid CYP3A4 inducers, ↑ to 160 mg daily
ILD, QTc prolongation, cardiomyopathy, keratitis
Dacomitinib 45 mg (1 tab) daily with or without food; (pill burden=1)
Avoid CYP2D6 substrates; meds affecting gastric pH
ILD, diarrhea, dermatologic adverse reactions
Erlotinib Prescribing Information revised 10/2016; Gefitinib Prescribing Information revised 08/2018; Afatinib Prescribing Information Revised 01/2018; Osimertinib Prescribing Information revised 08/2018; Dacomitinib Prescribing Information 09/2018
• Patient JR has recently started therapy with dacomitinib. He explains that he has been experiencing heartburn lately and asks for your recommendation. Which is the best option for JR?
• A- Omeprazole 20 mg po 30 minutes before breakfast• B- Famotidine 10 mg to be taken at the same time as his dacomitinib• C- Ranitidine 150 mg by mouth 3 times per day• D- Famotidine 20 mg taken at least 6 hours after or 10 hours before
dacomitinib
ASSESSMENT QUESTION
LORLATINIBAnaplastic lymphoma kinase (ALK) inhibitor
LORLATINIB IN ALK+ PREVIOUSLY TREATED METASTATIC NSCLC: STUDY B7461001
Non-randomized, multicenter
N=215 previously treated with ≥ 1 ALK inhibitor
Lorlatinib 100 mg once daily
Major efficacy outcome:
• Overall response rate (ORR)
• Intracranial ORR
Solomon B et al. 2018. Lancet Oncol 19: 1654-1667
STUDY B7461001 RESULTSEfficacy Parameter N= 215
Independent Review Assessment
ORR (95%CI) 48% (28-49)
Complete response 4%
Partial response 44%
mDOR in months (95% CI) 12.5 (8.4, 23.7)
Efficacy Parameter CNS Measurable DiseaseN= 89
Intracranial response rate (95% CI) 60 % (49, 70)
Complete Response 21 %
Partial Response 38 %
CNS mDOR (95% CI) 19.5 (12.4, NR)
Solomon B et al. 2018. Lancet Oncol 19: 1654-1667
• Indication: ALK+ metastatic NSCLC whose disease progressed on• Crizotinib and at least one other ALK inhibitor for metastatic disease• Alectinib or ceritinib as the first ALK inhibitor for metastatic disease
• Formulation: 25 mg and 100 mg• Dose 100 mg orally once daily
• Most common all grade adverse events (≥ 20%)• Edema, peripheral neuropathy, cognitive effects, fatigue, weight gain,
arthralgia, mood effects and diarrhea
• Most common grade 3/4 adverse events (≥ 5%)• Dyspnea, hypercholesterolemia, hypertriglyceridemia, hyperglycemia
LORLATINIB PEARLS
Lorlatinib Prescribing Information Revised 11/2018
• Lab abnormalities (≥ 20%)• Hypercholesterolemia, hypertriglyceridemia, hyperglycemia, ↑ ALT,
↑ lipase, ↑ alk phos, ↑ amylase, hypophosphatemia, hyperkalemia, hypomagnesemia, anemia, thrombocytopenia, lymphopenia
• Contraindications• Strong CYP3A inducers, due to the potential for serious hepatotoxicity
• Monitoring • Cholesterol and triglycerides: at baseline, at 1 and 2 months after
lorlatinib initiation, then periodically; AST, ALT, and bilirubin: 48 hours after starting lorlatinib and at least 3 times during the first week after initiation*; ECG baseline and periodic; signs/symptoms of CNS adverse events and interstitial lung disease/pneumonitis
LORLATINIB PEARLS
* if concomitant use of moderate CYP3A inducers cannot be avoided
Lorlatinib Prescribing Information Revised 11/2018
Medication Administration DDI Warnings and precautionsCrizotinib 250 mg (1 tabs) BID
with/without food; renal & hepatic adj(pill burden= 2)
Avoid strong CYP3A4 inhibitors, ↓ to 250 mg daily
Hepatotoxicity, ILD/pneumonitis, QT prolongation, bradycardia, severe visual loss
Ceritinib 450 mg (3 caps) daily with food; hepatic adj(pill burden= 3)
Avoid strong CYP3A4 inhibitors/ inducers, ↓ to 300 mg daily; Avoid concurrent use of with CYP3A or CYP2C9 substrates with NT indices
GI adverse reaction, hepatotoxicity, ILD/pneumonitis, QT prolongation,hyperglycemia, bradycardia, pancreatitis
Alectinib 600 mg (4 caps) BID with food; hepatic adj(pill burden = 8)
No major interactions Hepatotoxicity, ILD/pneumonitis, renal impairment, bradycardia, severe myalgia and CPK elevation
Brigatinib 90 mg daily X 7; then 180 mg daily with/without food; renal &hepatic adj(pill burden= 1)
Avoid strong/mod CYP3A4 inhibitors, ↓ 50-40% respectively. Avoid mod CYP3A4 inducers, ↑ by 30 mg
ILD/Pneumonitis, hypertension, bradycardia, visual disturbance, CPK elevation, pancreatic enzymes elevation, hyperglycemia
Lorlatinib 100 mg daily with/without food; (pill burden = 1)
CI with strong CYP3A4 inducers. Avoid strong CYP3A4 inhibitors, ↓to 75 mg daily
Serious hepatotoxicity, CNS effects, hyperlipidemia, AV block ILD/Pneumonitis
Crizotinib Prescribing Information revised 01/2019; Certitinib Prescribing Information revised 12/2017; Alectinib Prescribing Information Revised 06/2018; Brigatinib Prescribing Information revised 12/2018; Lorlatinib Prescribing Information revised 11/2018
• Which of the following best describes the indicated use of lorlatinib?
• A- Patients with NSCLC that harbor a T790M mutation• B- As first line therapy for patients with ALK+ metastatic lung cancer• C- As treatment of patients with ALK+ metastatic NSCLC whose
disease progressed on crizotinib and at least one other ALK inhibitor for metastatic disease; or alectinib/ceritinib as the first ALK inhibitor therapy for metastatic disease
• D- In any line of therapy for patients with ALK + metastatic NSCLC
ASSESSMENT QUESTION
TRK FUSION–POSITIVE CANCERLarotrectinib
Alessio Amatu et al. ESMO Open 2016;1:e000023
LAROTRECTINIBTropomyosin receptor kinase (TRK) inhibitor
• Efficacy evaluated in a development program involving 3 clinical studies
• Phase 1 study involving adults• Phase 1-2 study involving children• Phase 2 “basket” study involving adolescents and adults
• BSA ≥ 1 m2 = 100 mg po bid• BSA < 1 m2 = 100 mg/m2 po bid
• TRK fusion mandated for phase 2 study• Non-CNS primary tumor
EFFICACY OF LAROTRECTINIB IN TRK FUSION-POSITIVE CANCERS IN ADULTS AND CHILDREN
Dose-escalation
Drilon A et al. 2018. N Engl J Med 378: 731-739
LAROTRECTINIB TRIAL RESULTS
11%
9%
2%
22%
56%
AGE<2 yr 2-5 yr 6-14 yr15-39 yr >40 yr
22%
20%
13%9%
7%
7%
7%5%
4%
2% 2% 2% Tumor Type
Salivary-glandOther STSInfantile fibrosarcomaThyroidColonLungMelanomaGISTCholangiocarcinomaAppendixBreastPancreatic
N=55
Drilon A et al. 2018. N Engl J Med 378: 731-739
Overall Response Rate, According to Investigato and Central Assessment
Response Investigator Assessment (N=55) (%)
Central Assessment (N=55) (%)
Overall response rate (95%CI) 80 (67-90) 75 (61- 85)
Best response
Partial response 64 62
Complete response 16 13
Stable disease 9 13
Progressive disease 11 9
Could not be evaluated 0 4
LAROTRECTINIB TRIAL RESULTS
Drilon A et al. 2018. N Engl J Med 378: 731-739
LAROTRECTINIB TRIAL RESULTS
Drilon A et al. 2018. N Engl J Med 378: 731-739
• Formulation• Capsules: 25 mg, 100 mg• Oral Solution: 20 mg/mL
• Oral solution • Glass bottle should be stored in the refrigerator• Discard any unused medication remaining after 90 days from first day the
bottle is opened• Should be dispensed with a bottle adaptor and five 1 mL or 5 mL oral
syringes, each of which can be used over a 7-day period (DO NOT use a household teaspoon)
• Dosing• Adult and Pediatrics with BSA ≥1 m2: 100 mg po bid with or without food• Pediatrics < 1 m2: 100 mg/m2 po bid
LAROTRECTINIB PEARLS
Can be interchanged
Larotrectinib Prescribing Information 11/2018
• Most common all grade adverse events• Increased LFT’s, anemia, fatigue, nausea, dizziness, cough,
vomiting, constipation, diarrhea• Monitoring
• LFT’s every 2 weeks during the first month, then monthly thereafter• Neurotoxicity
• Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity
LAROTRECTINIB PEARLS
Dose ModificationsStrong CYP3A4 inhibitors Reduce dose by 50%Strong CYP3A4 inducers Double the doseHepatic impairment Child-Pugh B or greater reduce starting dose by 50%
Larotrectinib Prescribing Information 11/2018
• The oral solution of larotrectinib should be dispensed with which of the following supplies
• A- A bottle adaptor and 5 oral syringes• B- A bottle adaptor and normal saline• C- Normal saline and loperamide• D- 3 oral syringes and St. John’s wort
ASSESSMENT QUESTION
• Rate of development of oral oncolytics has been rapid• Class options for certain targets are broadening
• Treatment selection is multifactorial• Pharmacist are in an ideal position to monitor and provide
education• Tips
• Patient calendars• Written education• Side effect management• Open-ended questions
FINAL THOUGHTS
• Weingart S. Brown E. BachPB, et al: NCCN Task Force Report: Oral Chemotherapy. J Natl ComprCanc Netw: 6S1-S14, 2008 (suppl 3)
• •Turk A, Wisinski K. PARP Inhibitoris in Breast Cancer: Bringing Synthetic Lethality to the Bedside. Cancer 2018; 124: 2498-2506
• Robson M, Seock-Ah I, Senkus E, et al: Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377:523-533
• Litton J, Rugo H, Ettl J, et al: Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 2018; 379: 753-763
• Talzenna® [package insert]. New York, NY: Pfizer Oncology October 2018• Smith M, Saad F, Chowdhury S, et al: Apalutamide Treatment and Metastasis-free Survival in Prostate
Cancer. N Engl J Med 2018; 378:1408-1418• Attar R, Takimoto C, Gottardis M. Castration-resistant Prostate Cancer: Locking Up the Molecular
Escape Routes. Clin Cancer Res 2009; 15(10) 3251- 3255• Erleda™ [package insert]. Janssen Pharmaceutical Companies, Horsham, PA 2018• Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or
encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5)603-615
• Braftovi® [package insert]. Boulder, CO: Array BioPharma Inc, 01/19
REFERENCES
• Mektovi® [package insert]. Boulder, CO: Array BioPharma Inc, 01/19• Chan B, Hughes B: Targeted therapy for non-small cell lung cancer: current standards and the
promise of the future. Transl Lung Cancer Res 2015; 4(1): 36-54 • Wu Y, Cheng Y, Zhou X et al. Dacomitinib versus gefitinib as first-line treatment for patients with
EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomized, open-label, phase 3 trial. Lancet Oncol 2017; 18: 1454-1466
• Mok TS, Cheng Y, Zhou X et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol 2018; 36(22): 2244-2250
• VIZIMPRO® [package insert] New York, NY: Pfizer Oncology, Inc.; September 2018• Solomon B, Besse B, Bauer T et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer:
results from a global phase 2 study. Lancet Oncol 2018; 19: 1654-1667• LORBRENA® ([package insert]. New York, NY: Pfizer Oncology, Inc.; November 2018• Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel tagets of cancer therapy across
multiple tumor types. ESMO Open 2016;1:e000023. doi:10.1136/esmoopen-2015-000023• Drilon A, Laetsch TW, Kummar S et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in
Adults and Children. N Engl J Med 2018; 378: 731-739• VITRAKVI® [package insert]. Stamford, CT: Loxo Oncology, Inc.; November 2018
REFERENCES
