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Educational Affairs
New Oral Oncolytics of 2017: Key Points for a Counseling Pharmacist

by Janna Afanasjeva, PharmD, BCPSa; Chloe Majkowski, PharmD Candidate 2018a; Christopher Campbell, PharmD, BCPS, BCOPb; Institutional affiliations: aUniversity of Illinois Chicago; bNorthwestern Memorial Hospital

The research in oncology has been increasing over the past few years, and the availability of oral oncolytic agents has also surged.^1,2 Oral formulations comprise about 25% to 35% of oncology medications in the pipeline. For the year 2017, the Food and Drug Administration (FDA) approved 8 oral oncolytics that are new molecular entities.³

As more oral oncolytics become available on the market, more opportunities exist for pharmacists to provide direct patient care to patients with cancer.^2,4 One of the key services that pharmacists can provide is patient education. In fact, patient education is extremely important for oral oncolytics because patients take these medications at home without direct supervision of a treating physician. Oral oncolytics have similar benefits and drawbacks as intravenous medications, and therefore, patients must completely understand proper drug administration, importance of adherence, and possible adverse events. This article reviews new oral oncolytics that have been approved by the FDA in the year 2017. The goal of the article is to briefly introduce and describe new agents and their efficacy and safety data so that practicing pharmacists in a variety of settings can counsel on these agents if the need arises.

This article also mentions the cost of agents (see Table 1). The affordability is a particular concern with oral oncolytics as copays tend to be higher for them compared to intravenous medications that are administered in infusion clinics.⁵ Prescription drug benefits typically cover the cost of oral oncolytics while medical insurance for physician office visits covers intravenous medications resulting in lower costs to patients. Although some states are working on legislation to ensure comparable coverage between oral and intravenous oncolytics, a federal law in this area is lacking. Pharmacists may need to work with patients, oncology providers, and prescription drug benefits to confirm that patients are able to afford and adhere to new oncolytics.

Abemaciclib (Verzenio)

Abemaciclib inhibits cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are responsible for phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

Indication

Abemaciclib is approved for use as a monotherapy or in combination with fulvestrant for hormone-receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer after patients have progressed on endocrine therapy.⁶ Abemaciclib is also approved as initial therapy in combination with an aromatase inhibitor for postmenopausal women with HR-positive, HER-2 negative advanced or metastatic breast cancer. The monotherapy approval requires prior chemotherapy but is unique that it is the only drug in class to be used as stand-alone therapy.

Efficacy

The approval of abemaciclib was based on 3 clinical trials: MONARCH1, MONARCH2, and MONARCH3.⁶ MONARCH1 was an open-label phase 2 study of abemaciclib monotherapy (200 mg every 12 hours until disease progression or unacceptable toxicity) in 132 women with HR-positive HER2-negative metastatic breast cancer who have progressed on endocrine therapy.⁷ The objective response rate (ORR), which was the primary endpoint, was 19.7% (95% CI, 13.3% to 27.5%). Median progression-free survival (PFS) was 6 months, and overall survival (OS) was 17.7 months.

MONARCH2 was a double-blind, phase 3 study of abemaciclib (150 mg twice daily) with fulvestrant versus fulvestrant alone in 669 women with HR-positive HER2-negative advanced breast cancer, who have progressed on endocrine therapy.⁸ Median PFS, the primary endpoint, was 16.4 months in the combination group versus 9.3 months in the fulvestrant group (hazard ratio, 0.55; 95% confidence interval (CI), 0.45 to 0.68; p<0.001). The ORR was 48.1% (95% CI, 42.6% to 53.6%) in the combination group and 21.3% (95% CI, 15.1% to 27.6%) in the fulvestrant group. At the time of the publication, OS results were not mature.

The approval for abemaciclib in combination with an aromatase inhibitor as initial therapy for postmenopausal women with advanced or metastatic breast cancer was based on results from the MONARCH3 trial.⁹ This was a double-blind, phase 3 study of 493 patients with no prior systemic therapy in the advanced setting. Patients were randomized to receive abemaciclib 150 mg or placebo twice daily in addition to physician’s choice of letrozole (80% of patients) or anastrozole (20% of patients). Median PFS was prolonged in the abemaciclib group with a hazard ratio of 0.54 (95% CI, 0.41 to 0.72; p = 0.000021). The median was not reached in the abemaciclib arm, and the median PFS in the placebo group was 14.7 months. The ORR was 48.2% (95% CI, 42.8% to 53.6%) in the abemaciclib group versus 34.5% (95% CI, 27.3% to 41.8%) in the placebo group.

Safety

In MONARCH 1, the most common grade 3 adverse events with abemaciclib were diarrhea (19.7%), fatigue (12.9%), and nausea (4.5%).⁷ The only grade 4 event in MONARCH1 was decreased neutrophil count (4.6%). Adverse events led to discontinuation of treatment in 7.6% of patients. In MONARCH2, the most common grade 3 or 4 adverse events with abemaciclib were neutropenia (26.5%), diarrhea (13.4%), and leukopenia (8.8%).⁸ The most common grade 3 or 4 adverse events in the MONARCH3 with the abemaciclib group were neutropenia (21.1%), diarrhea (9.5%), and leukopenia (7.6%).⁹ Guidelines

Per National Comprehensive Cancer Network (NCCN) Breast Cancer guidelines, abemaciclib plus an aromatase inhibitor is recommended as a preferred regimen for HR-positive, HER2-negative recurrent or metastatic breast cancer in postmenopausal women and may be considered as a first-line option for patients without previous systemic therapy.¹⁰ Abemaciclib plus fulvestrant is also listed as a preferred regimen for postmenopausal patients with advanced or metastatic HR-positive, HER2-negative breast cancer but is only indicated after progression on prior endocrine therapy. Abemaciclib monotherapy is listed as useful in certain circumstances for this population.

Acalabrutinib (Calquence)

Acalabrutinib inhibits Bruton tyrosine kinase (BTK) more selectively than first-generation BTK inhibitors. These kinases are involved in downstream signaling pathways vital to malignant B-cell proliferation and survival.

Indication

Acalabrutinib received accelerated approval for use as monotherapy for mantle cell lymphoma (MCL) after patients have progressed on at least 1 prior therapy.¹¹

Efficacy

The accelerated approval of acalabrutinib was based on ORR in Trial LY-004, an open-label, phase 2 study.¹¹ Acalabrutinib was administered (100 mg twice daily until disease progression or unacceptable toxicity) in 124 relapsed or refractory (r/r) MCL patients, who had at least 1 prior therapy.¹² The primary endpoint, ORR, was 81 % 80% (95% CI, 73% 72% to 87%). The trial reported a complete response (CR) in 40% of patients and partial response in 41% of patients, with a median time to best response of 1.9 months. After 15.2 months of follow-up, the median duration of response (DOR) had not been reached.

Safety

In Trial LY-004, the most common non-hematologic adverse effects (AEs) of acalabrutinib were headache, diarrhea, fatigue, myalgia, and bruising. Decreased hemoglobin (46%), platelets (44%), and neutrophils (36%) were very common. The most common Grade 3 or greater toxicities were diarrhea, neutropenia, thrombocytopenia, and anemia. Dose reductions or discontinuations due to any AE were reported in 1.6% and 6.5% patients, respectively.¹² Similar to first-generation BTK inhibitor, ibrutinib, the package insert for acalabrutinib carries warnings for hemorrhage, infection, cytopenias, second primary malignancies, and atrial arrhythmias.^11,13 Transient lymphocytosis may also occur with a median time to onset of 1.1 weeks and median duration of 6.7 weeks.

Guidelines

Per NCCN B-Cell Lymphomas guideline, acalabrutinib is recommended as a second-line single-agent therapy for patients with stage I or II disease, aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV disease to achieve a CR after partial response to induction therapy or for relapsed, refractory, or progressive disease.¹⁴ The NCCN chronic lymphocytic leukemia (CLL) guideline provides a category 2A recommendation for acalabrutinib as a single agent therapy for relapsed or refractory disease with or without del(17p)/TP53 mutation.¹⁵ Of note, acalabrutinib should not be used for ibrutinib-refractory CLL or small lymphocytic lymphoma in patients with BTK C481S mutations.

Brigatinib (Alunbrig)

Brigatinib is a tyrosine kinase inhibitor with broad activity against multiple kinases including ALK, c-ros oncogene 1 (ROS1), insulin-like growth factor-1 receptor (IGF-1R), and fetal liver tyrosine kinase 3 (FLT-3) including epidermal growth factor receptor (EGFR) deletion and point mutations. Brigatinib inhibits ALK and blocks a signaling cascade with downstream effects on proteins STAT3, AKT, ERK1/2, and S6. Brigatinib’s mechanism of action allows for activity despite ALK-inhibitor resistance due to EML4-ALK and 17 other mutant forms, even after progression on crizotinib.

Indication

Brigatinib received accelerated approval for use in non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK)-positive metastatic disease after crizotinib.¹⁶

Efficacy

The accelerated approval of brigatinib was based on clinically significant and durable ORR in the ALTA trial, an open-label, two-arm, phase 2 study. Brigatinib was administered (either 90 mg once daily or 180 mg once daily with an initial 7-day lead-in of 90 mg daily) in 222 patients with locally advanced or metastatic ALK-positive NSCLC and who were previously treated with crizotinib.¹⁷ The primary endpoint, ORR, was 48 % (95% CI, 39% to 58%) and 53% (95% CI, 43% to 62%) in the 90 mg and 180 mg arms, respectively. Brigatinib showed clinically meaningful improvement in measurable brain metastases in both arms. Most of the intracranial responses were durable for at least 4 months. The trial reported a total of 3.6% or 4.5% CRs and 45% or 48% partial responses, in the 90 mg and 180 arms, respectively. The median DOR was 13.8 months. The PFS was 12.9 months in the 180 mg group and 9.2 months in the 90 mg group.

Safety

In the published abstract of the ALTA trial, the most common AEs in the 90 mg and 180 mg groups were nausea (33% and 40%), diarrhea (19% and 38%), headache (28 and 27%), and cough (18% and 34%), while less than 10% of patients experienced grade 3 events including hypertension, increased blood creatine phosphokinase (CPK), pneumonia, and increased lipase.¹⁷ Notably, pulmonary AEs were more common among patients (6%) in the lead-in phase. The abstract reports no increase in serious pulmonary events after escalation to 180 mg. According to the package insert, brigatinib commonly led to increases in liver and pancreatic enzymes and has a warning for amylase, lipase, CPK, and glucose elevations. Caution is advised regarding the development of hypertension and bradycardia.¹⁶

Guidelines

The NCCN NSCLC guideline recommends brigatinib as monotherapy for ALK-positive recurrent or metastatic disease for patients, who are refractory or intolerant to crizotinib, except in cases of symptomatic systemic disease with an isolated lesion.¹⁸ The NCCN Central Nervous System Cancers recommends brigatinib as a single-agent treatment for recurrent brain metastases in patients with ALK-positive NSCLC.¹⁹

Enasidenib (Idhifa)

Enasidenib works by inhibiting the mutated IDH2 enzyme, leading to decreased 2-hydroxyglutarate levels, reduced blast counts, and increased myeloid differentiation and mature myeloid cells.

Indication

Enasidenib is approved for the treatment of relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation.²⁰

Efficacy

Results from study AG221-C-001, a phase 1/2, open-label, single-arm trial, led to the approval of enasidenib for AML.²⁰ Enasidenib 100 mg daily was selected for the expansion phase of the study, which assessed efficacy in 199 patients response rate was 40.3%, and median DOR was 5.8 months. Median OS was 9.3 months (95% CI, 8.2 to 10.9 months), and 19.3% of patients attained a CR with a median overall survival of 19.7 months (95% CI, 11.6 months to not reached).

Safety

The most common adverse events seen with enasidenib in the AG221-C-001 study were hyperbilirubinemia and nausea.²¹ Hyperbilirubinemia, IDH differentiation syndrome, hematologic events, and infections were the most common grade 3 or 4 events.

Guidelines

The NCCN AML guideline recommends enasidenib for patients with relapsed or refractory AML with IDH2 mutation that are not candidates for intensive remission induction therapy.²² Patients with a response to therapy, which may take 3 to 5 months, should continue enasidenib therapy until progression occurs. The guideline also warns about the increased risk of IDH differentiation syndrome and hyperleukocytosis that may require treatment with hydroxyurea and steroids during treatment with enasidenib.

Midostaurin (Rydapt)

Midostaurin inhibits several receptor tyrosine kinases such as FLT3 mutant kinases, KIT, PDGFRα/β, VEGFR2, and PKC.²³ The inhibition of FLT3 promotes apoptosis of leukemic cells expressing FLT3 mutant kinases such as internal tandem duplication (ITD) and tyrosine kinase domain (TKD) and leukemic cells overexpressing wild type FLT3 and platelet-derived growth factor (PDGF) receptors.

Indication

Midostaurin is indicated for newly diagnosed AML in patients who are positive for FLT3 mutation.²³ The medication is administered in combination with cytarabine and daunorubicin induction and cytarabine consolidation. Midostaurin is also approved for aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia.

Efficacy

Midostaurin was studied in a phase 3 trial that enrolled 717 patients with newly diagnosed AML and FLT3 mutation.²⁴ Patients received induction therapy with daunorubicin and cytarabine, consolidation therapy with high-dose cytarabine, and midostaurin or placebo. From enrolled patients, 214 had high ITD mutation, 341 low ITD mutation, and 162 point mutations in TKD. Median OS, the primary endpoint, was prolonged in the midostaurin (74.7 months) group versus in the placebo (25.6 months) group (hazard ratio for death, 0.78; 95% CI, 0.63 to 0.96; p=0.009).

Midostaurin was also studied in an open-label study in 116 patients, who had ASM, SM-AHN, or mast cell leukemia.²⁵ Patients received midostaurin 100 mg twice daily. The median OS was 28.7 months, and the median PFS was 14.1 months.

Safety

In the trial exploring midostaurin versus placebo use in patients with newly diagnosed AML and FLT3 mutation, both groups displayed similar adverse events except for higher rate of anemia and rash in the midostaurin group and higher rate of nausea in the placebo group.²⁴ From the trial of midostaurin in patients with ASM, SM-AHN, or mast cell leukemia, the most common adverse events were nausea, vomiting, and diarrhea.²⁵ About 24% of patients developed grade 3 or 4 neutropenia, 41% grade 3 or 4 anemia, and 29% grade 3 or 4 thrombocytopenia.

Guidelines

Per the NCCN AML guideline, midostaurin is recommended as induction therapy for FLT3 mutation-positive disease in combination with standard dose cytarabine and daunorubicin as induction therapy. It is also recommended as post-induction therapy or post-remission therapy in combination with cytarabine.²² The US guidelines are lacking for treatment of systemic mastocytosis.

Niraparib (Zejula)

Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor.²⁶ PARP-1 and PARP-2 are enzymes involved in DNA repair. Inhibition of PARP 1/2 increases formation of PARP-DNA complexes, leading to DNA damage, apoptosis, and cell death.

Indication

Niraparib is approved as maintenance therapy for adults with primary peritoneal cancer, recurrent epithelial ovarian cancer, or fallopian tube cancer who have experienced CR or partial response to platinum-based chemotherapy.²⁶

Efficacy

Niraparib was approved based on the phase 3 NOVA trial.²⁶ NOVA was a randomized, double-blind trial comparing niraparib 300 mg daily versus placebo in 553 patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.²⁷ All patients had previously received at least 2 platinum-based regimens and had shown sensitivity to platinum-based treatment. Study treatment was started within 8 weeks after the last dose of platinum-based therapy and was continued until disease progression. Patients were categorized based on the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort). In the gBRCA cohort, median PFS was 21.0 months in the niraparib group versus 5.5 months in the placebo group (hazard ratio, 0.27 0.26; 95% CI, 0.17 to 0.41). The non-gBRCA cohort had a median PFS of 9.3 months with niraparib versus 3.9 months with placebo (hazard ratio, 0.45; 95% CI, 0.34 to 0.61).

Safety

The most common grade 3 or 4 adverse events reported in the NOVA trial for patients taking niraparib were thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%).²⁷ Treatment discontinuation due to an adverse event of any grade occurred in 14.7% of the niraparib group compared to only 2.2% of the placebo group.

Guidelines

The NCCN Ovarian Cancer guideline recommends niraparib as maintenance therapy for patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who had previously received 2 or more platinum-based regimens and demonstrated a CR or partial response.²⁸

Neratinib (Nerlynx)

Neratinib inhibits EGFR and HER2, demonstrating antitumor activity in cell lines expressing these kinases.

Indication

Neratinib is approved for use as extended adjuvant treatment following trastuzumab-based therapy in patients with early-stage HER2-positive breast cancer.²⁹

Efficacy

Neratinib was approved for HER2-positive breast cancer based on results from the ExteNET trial.²⁹ ExteNET was a randomized, double-blind, phase 3 study assessing the safety and efficacy of neratinib therapy versus placebo over 1 year in 2,840 women who previously completed trastuzumab-based adjuvant therapy for early-stage HER2-positive breast cancer.³⁰ The invasive disease-free survival rate was 93.9% 94.2% in the neratinib group versus 91.6% 91.9% in the placebo group at 2 years after randomization, with 5% of neratinib patients experiencing invasive disease recurrence or death versus 8% of patients in the placebo group (hazard ratio, 0.67 0.66; 95% CI, 0.50 0.49 to 0.91 0.90, p=0.0091 p=0.008).

Safety

The most common grade 3 and 4 adverse events with neratinib in the ExteNET trial were diarrhea, nausea, and vomiting.³⁰ Rates of QT prolongation were similar in the neratinib group (3%) and placebo group (7%), and decreases in left ventricular ejection fraction occurred in only 1% of each group. Four deaths occurred in the neratinib group and 3 in the placebo group after study drug discontinuation, none of which were attributed to study treatment.

Guidelines

The NCCN breast cancer guideline recommends neratinib as extended adjuvant therapy for HER2-positive patients after completion of adjuvant trastuzumab-based therapy when there is a high risk of recurrence.¹⁰

Ribociclib (Kisqali)

Ribociclib is a CDK4 and CDK6 inhibitor.³¹ Enzymes CDK4 and 6 phosphorylate Rb leading to cell cycle progression and cell proliferation. Ribociclib decreases phosphorylation of the Rb and results in cell cycle arrest in the G1 phase.

Indication

Ribociclib is indicated in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy in combination with an aromatase inhibitor.³¹

Efficacy

Ribociclib gained approval based on the results of the MONALEESA-2 trial.³¹ MONALEESA-2 was a phase 3, double-blind, placebo-controlled trial.³² A total of 668 patients with HR-positive, HER2-negative advanced breast cancer who had not received any previous systemic therapy were enrolled in the trial. Patients were randomized to receive either ribociclib 600 mg daily for 21 days on and 7 days off plus letrozole 2.5 mg daily continuously, or placebo plus letrozole. Median PFS was not reached in the ribociclib plus letrozole group, as compared to 14.7 months in the placebo plus letrozole group. At 18 months, the estimated PFS was 63.0% (95% CI, 54.6 to 70.3) in the ribociclib group versus 42.2% (95% CI, 34.8 to 49.5) in the placebo group.

Safety

The most common grade 3 or 4 adverse events in the MONALEESA-2 trial were neutropenia (59.3% in the ribociclib group versus 0.9% in the placebo group), leukopenia (21% versus 0.6%), and hypertension (9.9% versus 10.9%).³² Discontinuation of study drug due to adverse events occurred in 7.5% of the ribociclib group versus 2.1% of the placebo group.

Guidelines

The NCCN Breast Cancer guideline recommends a CDK4/6 inhibitor (ribociclib or palbociclib) in combination with an aromatase inhibitor as first-line treatment option for postmenopausal patients with HR-positive, HER2-negative metastatic breast cancer.¹⁰ Ribociclib in addition to tamoxifen is another recommended therapy for this population.

Table 1. Key properties of newly approved oral oncology agents in 2017.^{6,11,16,20,23,26,29,31,33}

Drug name (Brand)

Dosage form,

strength(s)

Dosing

Cost^a

Abemaciclib

(Verzenio™)

Tablet; 50 mg, 100 mg, 150 mg, 200 mg

200 mg twice daily as monotherapy; 150 mg twice daily in combination with fulvestrant 500 mg on Days 1, 15, 29, and then once monthly

$3,284

(14 tablets)

Acalabrutinib (Calquence™)

Capsule; 100 mg

100 mg twice daily

$16,877

(60 capsules)

Brigatinib

(Alunbrig™)

Tablet; 30 mg, 90 mg, 180 mg

90 mg daily for 7 days, and then 180 mg daily if tolerated

$1,995

(21 tablets)

Enasidenib

(Idhifa™)

Tablet; 50 mg, 100 mg

100 mg daily

$29,846

(30 tablets)

Midostaurin

(Rydapt™)

Capsule; 25 mg

50 mg twice daily for AML; 100 mg twice daily for ASM, SM-AHN, or mast cell leukemia

$4,497

(28 capsules)

Niraparib

(Zejula™)

Capsule; 100 mg

300 mg daily

$17,700

(90 capsules)

Neratinib

(Nerlynx™)

Tablet; 40 mg

240 mg daily

$12,600

(180 tablets)

Ribociclib

(Kisqali™)

Tablet; 200 mg

600 mg daily for 21 days, followed by 7 days off in combination with continuous letrozole

$13,140

(63 tablets)

^aPricing is based on average wholesale price.

Conclusion

In 2017, the FDA approved 8 new oral oncolytics with indications for AML, MCL, ASM, SM-AHN, mast cell leukemia, NSCLC, breast cancer, peritoneal cancer, epithelial ovarian cancer, or fallopian tube cancer. Pharmacists must be familiar with the efficacy and safety data for these agents as a comprehensive counseling is imperative for patients taking oral oncolytics. Patients may inquire about the costs of these newly approved agents because higher copays are more typical with oral oncolytics compared to intravenous oncology medications.

References:

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