Recent updates in oncology

Mechanism of Action:
Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.

At clinically achievable concentrations (= 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.

INDICATIONS AND USAGE:
ALUNBRIG is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. (1)

DOSAGE AND ADMINISTRATION:
90 mg orally once daily for the first 7 days; if tolerated, increase to 180 mg orally once daily. May be taken with or without food.
See package insert for additional instructions - PDF

HOW SUPPLIED:
Tablets: 30 mg and 90 mg

Initial U.S. Approval:  2017

Mechanism of Action:
PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the immune response resulting in the restoration of immune responses, including anti-tumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

INDICATIONS AND USAGE:
BAVENCIO is a programmed death ligand-1 (PD-L1) blocking antibody indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). (1)

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION:
PDF

HOW SUPPLIED:
Injection: 200 mg/10 mL (20 mg/mL) solution in single-dose vial.

Initial U.S. Approval:  2017

Mechanism of Action:
Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.

Durvalumab is a human immunoglobulin G1 kappa (IgG1?) monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC).

PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

INDICATIONS AND USAGE:
IMFINZI is a programmed death-ligand 1 (PD-L1) blocking antibody indicated for the treatment of patients with:

•Locally advanced or metastatic urothelial carcinoma who:
•have disease progression during or following platinum-containing chemotherapy. ( 1)
•have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. ( 1)
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION:
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HOW SUPPLIED:
Injection: 500 mg/10mL (50 mg/mL) solution in a single-dose vial.
Injection: 120 mg/2.4mL (50 mg/mL) solution in a single-dose vial.

Initial U.S. Approval:  2017

Mechanism of Action:
Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).

In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single agent ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of ribociclib and antiestrogen (e.g. letrozole) resulted in increased tumor growth inhibition compared to each drug alone.

INDICATIONS AND USAGE:
KISQALI is a kinase inhibitor indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

DOSAGE AND ADMINISTRATION:
See package insert for additional instructions - PDF
KISQALI tablets are taken orally with or without food in combination with letrozole. (2)

Recommended starting dose: 600 mg orally (three 200 mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment. (2.1)
Dose interruption, reduction, and/or discontinuation may be required based on individual safety and tolerability. (2.2)

HOW SUPPLIED:
Tablets: 200 mg

Initial U.S. Approval:  2016

Mechanism of Action: Olaratumab is a human IgG1 antibody that binds platelet-derived growth factor receptor alpha (PDGFR-a). PDGFR-a is a receptor tyrosine kinase expressed on cells of mesenchymal origin. Signaling through this receptor plays a role in cell growth, chemotaxis, and mesenchymal stem cell differentiation. The receptor has also been detected on some tumor and stromal cells, including sarcomas, where signaling can contribute to cancer cell proliferation, metastasis, and maintenance of the tumor microenvironment. The interaction between olaratumab and PDGFR-a prevents binding of the receptor by the PDGF-AA and -BB ligands as well as PDGF-AA, -BB, and -CC-induced receptor activation and downstream PDGFR-a pathway signaling. Olaratumab exhibits in vitro and in vivo anti-tumor activity against selected sarcoma cell lines and disrupted the PDGFR-a signaling pathway in in vivo tumor implant models.

INDICATIONS AND USAGE:  LARTRUVO™ is a platelet-derived growth factor receptor alpha (PDGFR-a) blocking antibody indicated, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. (1)
This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

DOSAGE AND ADMINISTRATION:
Administer LARTRUVO at 15 mg/kg as an intravenous infusion over 60 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. (2.1)
For the first 8 cycles, LARTRUVO is administered with doxorubicin. (2.1)
Premedicate with diphenhydramine and dexamethasone intravenously, prior to LARTRUVO on Day 1 of cycle 1. (2.2)
For intravenous infusion only. Do not administer as an intravenous push or bolus. (2.4)

HOW SUPPLIED:
Injection: 500 mg/50 mL (10 mg/mL) solution in a single-dose vial

Initial U.S. Approval:  2017

Mechanism of Action:
Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFRa/ß, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family.

Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.

INDICATIONS AND USAGE:
RYDAPT is a kinase inhibitor indicated for the treatment of adult patients with:
Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation (1.1).

Limitations of Use:
RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.
Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). (1.2)

DOSAGE AND ADMINISTRATION:
PDF

HOW SUPPLIED:
Capsules: 25 mg

Initial U.S. Approval:  2016

Mechanism of Action: Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased rucaparib-induced cytotoxicity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.

INDICATIONS AND USAGE:  RUBRACA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION:
Recommended Dose
The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.

Continue treatment until disease progression or unacceptable toxicity.

If a patient misses a dose of Rubraca, instruct the patient to take the next dose at its scheduled time. Vomited doses should not be replaced.

Dose Modifications for Adverse Reactions
To manage adverse reactions, consider interruption of treatment or dose reduction. Recommended dose reductions are indicated in Table 1.
Table 1.
Starting Dose 600 mg twice daily (two 300 mg tablets)
First Dose Reduction 500 mg twice daily (one 300 mg tablet and one 200 mg tablet)
Second Dose Reduction 400 mg twice daily (two 200 mg tablets)
Third Dose Reduction 300 mg twice daily (one 300 mg tablet)

HOW SUPPLIED:
Tablets (200 mg): blue, round, immediate-release, film-coated, debossed with “C2”.
Tablets (300 mg): yellow, oval, immediate-release, film-coated, debossed with “C3”.

Initial U.S. Approval:  2017

Mechanism of Action:
Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2.

INDICATIONS AND USAGE:
ZEJULA is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

DOSAGE AND ADMINISTRATION:
PDF
2.1 Recommended Dosage
The recommended dose of ZEJULA as monotherapy is 300 mg (three 100 mg capsules) taken orally once daily.

Instruct patients to take their dose of ZEJULA at approximately the same time each day. Each capsule should be swallowed whole. ZEJULA may be taken with or without food. Bedtime administration may be a potential method for managing nausea.

Patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen.

ZEJULA treatment should be continued until disease progression or unacceptable toxicity.

In the case of a missed dose of ZEJULA, instruct patients to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of ZEJULA, an additional dose should not be taken.

2.2 Dose Adjustments for Adverse Reactions
To manage adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. The recommended dose modifications for adverse reactions are listed in Tables 1, 2 and 3.

Table 1: Recommended dose modifications for adverse reactions
Dose level -   Dose
* If further dose reduction below 100 mg/day is required, discontinue ZEJULA.
Starting dose 300 mg/day (three 100 mg capsules)
First dose reduction 200 mg/day (two 100 mg capsules)
Second dose reduction 100 mg/day* (one 100 mg capsule)

See package insert for additional comments - PDF

HOW SUPPLIED:
Capsules: 100 mg