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Pharmacy Forum

This monthly column focuses on noteworthy treatments and provides important information to assist oncologists in their day-to-day practice. Janelle E. Mann, PharmD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. Oncology Times Clinical Advisory Editor Ramaswamy Govindan, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology and Director, Section of Medical Oncology, Washington University School of Medicine, St. Louis, Mo., is the Pharmacy Forum column physician advisor.

Wednesday, September 22, 2021

By Cassandra Perkey, PharmD, BCOP​

What is pertuzumab/trastuzumab/hyaluronidase-zzxf?

Pertuzumab/trastuzumab/hyaluronidase-zzxf is a subcutaneous injection combining human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab and pertuzumab.

How does it work?

Trastuzumab and pertuzumab are humanized monoclonal antibodies that bind distinct portions of the extracellular domain of HER2 to promote receptor degradation and block HER2 dimerization, thus inhibiting downstream signaling and cell proliferation. Both also mediate antibody-dependent cellular cytotoxicity on HER2-positive cells.

Hyaluronidase acts in subcutaneous tissue to depolymerize hyaluronan and increase permeability and absorption of pertuzumab/trastuzumab/hyaluronidase-zzxf.

What is this approved for?

This subcutaneous injection is approved for neoadjuvant and adjuvant treatment of adults with HER2-positive, early-stage breast cancer at high risk of recurrence, in combination with chemotherapy. It may also be used first line for HER2-positive metastatic disease in combination with docetaxel.

What is the basis for this approval?

The approval of pertuzumab/trastuzumab/hyaluronidase-zzxf was based on the FeDeriCa trial (Lancet Oncol 2021; doi: 10.1016/S1470-2045(20)30536-2), a randomized, open-label, non-inferiority, Phase III trial comparing pharmacokinetics, safety, and efficacy of subcutaneous trastuzumab/pertuzumab versus intravenous (IV) trastuzumab and pertuzumab among early-stage HER2-positive breast cancer patients. The primary endpoint was non-inferiority of cycle 7 pertuzumab serum trough concentration.

All patients received neoadjuvant chemotherapy with 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of paclitaxel or docetaxel. Patients were randomized 1:1 to receive pertuzumab/trastuzumab/hyaluronidase-zzxf or IV combination of trastuzumab and pertuzumab every 3 weeks starting with taxane therapy and continuing for 1 year.

Geometric mean pertuzumab trough concentration was 72.4 mcg/mL in the IV combination group versus 88.7 mcg/mL in the pertuzumab/trastuzumab/hyaluronidase-zzxf group, with geometric mean ratio (GMR) of 1.22, meeting the prespecified non-inferiority margin. Importantly, pathological complete response rate was similar between groups (59.5% vs. 59.7%). Overall incidence of adverse events was similar between groups.

The FeDeriCa trial demonstrated that pertuzumab/trastuzumab/hyaluronidase-zzxf has comparable pharmacokinetics, safety, and efficacy outcomes to IV pertuzumab and trastuzumab.

How do you administer this drug?

Pertuzumab/trastuzumab/hyaluronidase-zzxf is administered subcutaneously in the thigh over approximately 8 minutes for the loading dose and 5 minutes for maintenance doses, once every 3 weeks.

Are there any premedications needed?

No premedications are required for pertuzumab/trastuzumab/hyaluronidase-zzxf. If a patient develops a low-grade administration-related reaction to it, prescribing information recommends adding an antipyretic and/or antihistamine premedication to subsequent doses. If pertuzumab/trastuzumab/hyaluronidase-zzxf is given in combination with chemotherapy, administer premedications according to the standard for each agent.

What are the common side effects (≥10%)?

  • Gastrointestinal: nausea (60%), diarrhea (60%), stomatitis (25%), constipation (22%), vomiting (20%), decreased appetite (17%), mucosal inflammation (15%), dyspepsia (14%)
  • Increased lab values: serum creatinine (84%), alanine aminotransferase (58%), aspartate aminotransferase (50%), potassium (13%)
  • Decreased lab values: potassium (17%), albumin (16%), sodium (13%)
  • Hematologic: anemia (36-90%), lymphocytopenia (89%), neutropenia (22%-68%), thrombocytopenia (27%)
  • Dermatologic: alopecia (77%), rash (16%), dry skin (15%)
  • Neuromuscular/skeletal: asthenia (31%), fatigue (29%), myalgia (25%), arthralgia (24%)
  • Central nervous system: dysgeusia (17%), peripheral neuropathy (12-16%), headache (17%), insomnia (17%), dizziness (13%)
  • Local: injection site reactions (15%), injection site pain (13%)
  • Respiratory: cough (15%), epistaxis (12%), upper respiratory tract infection (11%), dyspnea (10%)
  • Miscellaneous: pyrexia (13%), hot flashes (12%), weight loss (11%)

What are the uncommon side effects (5-10%)?

  • Metabolic: hyperbilirubinemia, hypoglycemia, hypernatremia
  • Gastrointestinal: abdominal pain, hemorrhoids
  • Dermatologic: nail changes, palmar-plantar erythrodysesthesia
  • Peripheral edema
  • Febrile neutropenia
  • Urinary tract infection
  • Rhinorrhea
  • Muscle spasms
  • Increased lacrimation/dry eye

Are there any important drug interactions I should be aware of?

Avoid concurrent administration of anthracycline therapy with pertuzumab/trastuzumab/hyaluronidase-zzxf due to increased risk of cardiotoxicity.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no recommended dose adjustments for renal or hepatic impairment, due to lack of data.  

What should my patients know about pertuzumab/trastuzumab/hyaluronidase-zzxf?

Important counseling points include education on diarrhea, fatigue, rash and dry skin, injection reactions, and risk of cardiomyopathy and fetal toxicity. Heart function will be monitored prior to initiation of treatment and at least every 3 months while on therapy with echocardiograms. Women of reproductive age should use effective contraception while receiving pertuzumab/trastuzumab/hyaluronidase-zzxf and for at least 7 months after treatment completion.

What else should I know about this drug?

Pertuzumab/trastuzumab/hyaluronidase-zzxf carries a boxed warning for cardiomyopathy. Incidence of cardiac failure with it in the FeDeriCa trial was 0.8 percent, similar to the comparator.

Although pertuzumab/trastuzumab/hyaluronidase-zzxf has a warning for hypersensitivity reactions and 13 percent of patients experienced administration-related reactions in FeDeriCa, all were Grade 1-2 severity, most commonly reporting injection site pain or erythema.

What useful links are available?

  • FDA Approval: https://bit.ly/3yglj4p
  • Prescribing Information: https://bit.ly/38fv8F8

Any ongoing clinical trials related to this drug?

A trial evaluating at-home administration of pertuzumab/trastuzumab/hyaluronidase-zzxf amidst the COVID-19 pandemic is ongoing. It is also being evaluated in the neoadjuvant setting alone, followed by randomization to adjuvant pertuzumab/trastuzumab/hyaluronidase-zzxf, or ado-trastuzumab emtansine with or without chemotherapy, depending on pathologic response status at surgery. More information is available about these clinical trials at https://clinicaltrials.gov.

Cassandra Perkey, PHARMD, BCOP, is Oncology Clinical Pharmacist at UK HealthCare, Markey Cancer Center, Lexington, Ky. 

Tuesday, August 24, 2021

By Michelle Sproat, PharmD

What is tivozanib?
Tivozanib is an oral small-molecule tyrosine kinase inhibitor which targets vascular endothelial growth factor receptors (VEGFR) and other kinases. It is a tyrosine kinase inhibitor that inhibits phosphorylation of VEGFR-1, VEGFR-2, and VEGFR-3. Tivozanib also inhibits other kinases, including c-kit and PDGFR-β. In mice and rats, tivozanib inhibited angiogenesis, vascular permeability, and tumor growth of various tumor cell types, including human renal cell carcinoma. 

What is this approved for? 
Tivozanib is currently approved for adults with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Tivozanib was approved for relapsed or refractory advanced RCC based on the results from the TIVO-3 study (Lancet Oncol 2020;21(1):95-104). This was an international, randomized, open-label, Phase III study comparing tivozanib 1.34 mg by mouth once daily for 21 days followed by 7 days off (n=175) versus sorafenib 400 mg by mouth twice daily continuously (n=175). This study included adult patients with confirmed metastatic RCC with a clear cell component; previous unsuccessful treatment with two or three systemic regimens, including at least one VEGFR tyrosine kinase inhibitor; a performance status of 0 or 1; and a life expectancy of 3 months or longer.

After a median follow-up of 19 months, the primary endpoint of median progression-free survival (PFS) assessed by blind independent review committee was found to be significantly longer with tivozanib (5.6 months) than with sorafenib (3.9 months) (HR 0.73, p=0.016). Partial response was achieved for 18 percent of the tivozanib group and 8 percent of the sorafenib group; no patients achieved a complete response. Median duration of response was not yet reached with tivozanib compared to 5.7 months with sorafenib. Median overall survival (OS) with tivozanib was 16.4 months and 19.7 months with sorafenib (p=0.95). Treatment-related adverse events were reported in 84 percent of patients receiving tivozanib and 94 percent of patients receiving sorafenib. 

How do you administer this drug? 
Tivozanib starting dose is administered as one 1.34 mg capsule taken by mouth with a glass of water daily for 21 days followed by 7 days off for a 28-day cycle, continued until disease progression or unacceptable toxicity. Capsules can be taken with or without food and should be swallowed whole and not crushed or opened. 
No premedication is required for tivozanib. Tivozanib is currently listed as minimal or low (<30%) emetic potential. 

What are the common side effects associated with tivozanib (< or =10%)?
The following side effects are reported for tivozanib:

  • Cardiovascular: hypertension (44-45%)
  • Dermatologic: palmar-plantar erythrodysesthesia (16%), skin rash (18%)
  • Gastrointestinal: decreased appetite (39%), diarrhea (43%), nausea (30%), stomatitis (21%), vomiting (18%)
  • Decreased lab values: magnesium (26%), phosphate (38%), sodium (36%)
  • Increased lab values: amylase (23%), lipase (32%), calcium (15%), glucose (50%), potassium (26%)
  • Hepatic: increased aspartate aminotransferase (AST) (28%), increased alanine aminotransferase (ALT) (30%), increased alkaline phosphatase (30%), increased bilirubin (11%)
  • Neuromuscular & skeletal: back pain (19%), osteonecrosis (less than 15%)
  • Respiratory: cough (22%), dyspnea (15%)
  • Other: weight loss (17%), thyroid dysfunction (11%), hypothyroidism (8-24%), fatigue (67%), voice disorder (27%), delirium (less than 15%)

What are the uncommon side effects associated with tivozanib (less than 10%)?
Uncommon side effects reported in the package labeling include proteinuria (8%), alopecia (3%), arterial thromboembolism (2%), cardiac failure (2%), ischemic heart disease (3%), hepatobiliary disorders (2.3%), venous thromboembolism (2%), and hyperthyroidism (1%).

Are there any important drug interactions I should be aware of?
Tivozanib is a major substrate of CYP3A4. Use with strong CYP3A4 inducers will decrease tivozanib concentration and effectiveness and should be avoided.

How do I adjust the dose in the setting of renal or hepatic insufficiency?
At treatment initiation, there are no dose adjustments for patients with mild-to-severe renal impairment (creatinine clearance 15-89 mL/min, estimated by Cockcroft-Gault) and/or mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1-1.5 times ULN with any AST).
For patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST) dose reduction to 0.89 mg once daily for 21 days of a 28-day cycle is recommended in the product labeling. Tivozanib has not been studied in patients with end-stage renal disease or severe hepatic impairment (total bilirubin >3-10 times ULN with any AST).

See table below for dosing recommendations for renal toxicity occurring during treatment.

Renal ToxicityDose Modification
Proteinuria (≥2 g per 24 hours)Hold tivozanib until < 2 g per 24 hours, then resume at a reduced dose.
Nephrotic syndrome Permanently discontinue

 

Tivozanib dose reduction levels
Usual (initial) dose1.34 mg on days 1 to 21 of a 28-day cycle
First dose reduction0.89 mg on days 1 to 21 of a 28-day cycle

 
What should my patients know about tivozanib? 

  • Routine blood pressure monitoring is recommended given the risk of hypertension with tivozanib therapy.
  • Tivozanib has significant drug interactions, inform health care providers of all concomitant medication and ask before starting any new medication, including prescription medications, over-the-counter, and herbal supplements.
  • Patients of child-bearing age should be educated on use of effective contraception throughout treatment and for at least 1 month after the last dose due to risk of fetal harm. Additionally, based on findings in animal studies, tivozanib can impair fertility in females and males of reproductive potential and appropriate resources should be offered and discussed prior to initiation.

What else should I know about tivozanib?
There are currently no black box warnings or contraindications for tivozanib included in the package insert. Current warnings and precautions to note and monitor for include the following:

  • Hypertension/hypertensive crisis: Median time to onset was 2 weeks. Tivozanib has not been studied in patients with systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg. Control blood pressure prior to treatment and monitor after 2 weeks and at least monthly thereafter.
  • Cardiac failure, cardiac ischemia, thromboembolic events, and hemorrhagic events: Tivozanib can cause serious, sometimes fatal, cardiac failure, thromboembolic events, as well as hemorrhage. Patients should be periodically monitored for symptoms throughout treatment.
  • Proteinuria: Proteinuria occurred in 8 percent, with 2 percent of events Grade 3. Patients should be monitored for proteinuria before initiation of, and periodically throughout, treatment with tivozanib.
  • Risk of impaired wound healing: Impaired wound healing can occur in patients who receive VEGF inhibitors such as tivozanib. Current recommendations state to withhold tivozanib for at least 24 days prior to elective surgery and to not administer for at least 2 weeks following major surgery and until adequate wound healing.
  • Allergic reactions to tartrazine (FD&C Yellow No. 5): Tivozanib 0.89 capsules contain FD&C Yellow No. 5, which may cause allergic-type reactions in certain patients. Overall incidence in the general population is low and is frequently seen in patients who also have aspirin hypersensitivity.

What useful links are available regarding tivozanib?

Any ongoing clinical trials related to tivozanib?
Trials are ongoing for tivozanib in combination with other agents, including nivolumab for RCC. There are also ongoing studies looking at tivozanib for other conditions such as cholangiocarcinoma, hepatocellular carcinoma, glioblastoma, prostate, and gynecologic malignancies. More information is available about these clinical trials at https://clinicaltrials.gov.

Michelle Sproat PharmD, is Clinical Oncology Pharmacist at Washington University School of Medicine, St. Louis, Mo.

Wednesday, August 11, 2021

By Janelle E. Mann, PharmD, BCOP

What is sotorasib?

Sotorasib is an oral molecule which specifically and irreversibly inhibits KRAS G12C, a mutant-oncogenic form of the RAS GTPase, KRAS. Sotorasib is a RAS inhibitor which irreversibly and covalently binds to KRAS G12C. In the inactive state of mutant KRAS G12C, the mutant cysteine resides next to a narrow surface pocket, the P2 pocket. Sotorasib binds with the unique cysteine of KRAS G12C through an interaction with the P2 pocket, locking the protein in an inactive state which prevents downstream signaling, leading to inhibition of cell growth and promoting apoptosis only in KRAS G12C tumor cell lines.

What is this approved for?

Sotorasib is approved for adults with non-small cell lung cancer (NSCLC) whose tumors have a KRAS G12C mutation and have received at least one prior systemic therapy. This is the first approved targeted therapy for KRAS-mutant cancers. Of all KRAS mutations, KRAS G12C is the most common in lung adenocarcinoma. KRAS G12C accounts for 13 percent of mutations seen in lung adenocarcinoma. Sotorasib is specific for KRAS G12C mutant lung cancer. Sotorasib received FDA approval through the accelerated approval pathway and was granted fast track, priority review, breakthrough therapy, and orphan drug designation.

What is the basis for this approval?

Sotorasib was approved for previously treated KRAS G12C-mutated NSCLC patients based on results from the CodeBreaK 100 trial (N Engl J Med 2021;384(25):2371-81). The trial was a multicenter, single-group, open-label, Phase II trial of sotorasib at 960 mg by mouth daily as monotherapy in patients with locally advanced or metastatic KRAS G12C-mutated NSCLC. A total of 124 patients had measurable disease at baseline and were evaluated for response. The primary endpoint was objective response (complete or partial response). The observed objective response was 37.1 percent [95%CI, 28.6-46.2], with 3.2 percent complete response and 33.9 percent partial response. Key secondary endpoints observed were median duration of response, which was 11.1 months, a median progression-free survival of 6.8 months, and median overall survival 12.5 months. Treatment-related adverse events occurred in 69.8 percent patients, including Grade 3 at 19.8 percent and Grade 4 at 0.8 percent.

How do you administer this drug?

Sotorasib starting dose of 960 mg and is administered as 8 x 120 mg tablets taken by mouth daily with or without food. Tablets should be swallowed whole and not crushed.

Are there any premedications needed for sotorasib?

No premedications are required for sotorasib. It is listed as minimal or low (<30%) emetic potential.

What are the common side effects associated with sotorasib (> or = 10%)?

The following side effects are reported for sotorasib:

  • Gastrointestinal: diarrhea (42%), nausea (26%), vomiting (17%), abdominal pain (15%), decreased appetite (13%)
  • Increased lab values: aspartate aminotransferase (AST) (39%), alanine aminotransferase (ALT) (38%)
  • Hepatic: hepatotoxicity (25%)
  • Neuromuscular & Skeletal: musculoskeletal pain (35%), arthralgia (12%)
  • Hematologic: lymphocytopenia (48%), anemia (43%), prolonged PTT (23%)
  • Respiratory: cough (20%), dyspnea (16%), pneumonia (12%)
  • Decreased lab values: calcium (35%), sodium (28%), albumin (22%)
  • Cardiovascular: edema (15%)
  • Dermatologic: rash (12%)
  • Other: increased urinary output (29%), fatigue (26%)

What are the uncommon side effects associated with sotorasib (less than 10%)?

Interstitial pulmonary disease, pneumonitis, respiratory failure, cardiac failure, and gastric ulcer were observed in less than 1 percent.

Are there any important drug interactions I should be aware of?

Sotorasib is a major substrate of CYP3A4 and use with strong CYP3A4 or moderate inducers will decrease sotorasib concentration and effectiveness and should be avoided. Use with strong CYP3A4 inhibitors will increase risk of toxicities with sotorasib and should be avoided.

Sotorasib is also a moderate inducer of CYP3A4 and may decrease concentrations of drugs metabolized via these pathways. Additionally, co-administration with P-gp substrates with a narrow therapeutic index should be avoided.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no recommended dose adjustments for renal impairment, due to lack of patients of these populations in the primary literature.

At treatment initiation, there are no recommended dose adjustments for hepatic impairment. See table below for dosing recommendations in case of hepatotoxicity occurring during treatment. ​

Hepatotoxicity SeverityManagement

Grade 2 AST or ALT elevation (>3-5x ULN with symptoms) or

Grade 3 AST or ALT elevation (>5-20x ULN) or

Grade 4 AST or ALT elevation (>20x ULN)

Hold until ≤ Grade 1, then resume at next lower dose level
ALT or AST >3x ULN and bilirubin >2x ULNPermanently discontinue

ULN = upper limit of normal

 

Sotorasib Dose Reduction Levels
Initial dose960 mg daily
First dose reduction480 mg daily
Second dose reduction240 mg daily
Permanently discontinue if further dose reduction is indicated from 240 mg daily

 

What should my patients know about sotorasib?

  • Avoid proton pump inhibitors and H2 receptor antagonists while taking sotorasib. If treatment with an acid-reducing agent can't be avoided, sotorasib should be taken 4 hours before or 10 hours after use of a local acting antacid.
  • Contact your provider for new or worsening respiratory symptoms (difficulty breathing, cough, or fever) or liver dysfunction (dark or tea-colored urine, jaundice, nausea/vomiting).

What else should I know about sotorasib?

A comprehensive medication review is recommended at the start of treatment. If a patient is started on new medications it is recommended to evaluate for drug-drug interactions as sotorasib has significant drug interactions with one of the most common CYP pathways, CYP3A4. Additionally, it is recommended to avoid P-gp substrates (ie, digoxin) where minimal concentration changes may lead to serious toxicities.

Hepatotoxicity has been reported with sotorasib and may result in drug-induced liver injury and hepatitis. The median time to first onset of elevate ALT and/or AST was 9 weeks (range: 0.3–42 weeks). Monitor LFTs every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated.

Pulmonary toxicity including interstitial lung disease/pneumonitis occurred rarely on clinical trial. All cases were Grade 3 or 4 at onset and one fatality did occur. The median time to onset was 2 weeks (range: 2-18 weeks).

What useful links are available regarding sotorasib?

Any ongoing clinical trials related to sotorasib?

Trials are ongoing for use of sotorasib in combination with other agents for KRAS-mutated advanced NSCLC following initial first line treatment as well as first line monotherapy use for KRAS-mutated NSCLC patients. More information is available about these clinical trials at https://clinicaltrials.gov.


JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

Friday, June 25, 2021

By Kendall C. Shultes, PharmD, BCOP

What is melphalan flufenamide?

Melphalan flufenamide (melflufen) is a first-in-class anticancer peptide-drug conjugate for adults with refractory or relapsed multiple myeloma (RRMM). The unique peptide carrier increases the lipophilicity of the drug allowing for passive distribution into cells.

Melflufen, as a peptide-drug conjugate, is a peptide carrier combined with the alkylating payload, melphalan. The peptide-drug conjugate is passively distributed into the cells where the peptide carrier is released through enzymatic hydrolysis allowing for melphalan to exert its irreversible crosslinking of DNA.

What is this approved for?

Melflufen was granted accelerated approval for adults with RRMM who have received at least four lines of therapy, including at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.

What is the basis for this approval?

Melflufen was approved based on the results the HORIZON study, a Phase II, single-arm, multicenter study in patients with RRMM. Patients had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody, had an ECOG performance status of 0-2, and measurable disease. Patients received melphalan flufenamide 40 mg intravenously on Day 1 in combination with dexamethasone 40 mg orally (20 mg for age greater than or equal to 75 years) once weekly on Day 1, 8, 15, and 22 of a 28-day cycle. Overall response rate (ORR) was the primary endpoint assessed by International Myeloma Work Group response criteria. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Median lines of prior therapy was five. ORR was 29 percent (95% CI: 22,37) with one stringent complete response, 17 very good partial response (VGPR), and 28 partial responses (PR). In patients who were triple-class refractory (TCR), ORR was 26 percent (95% CI: 18,35) with 13 VGPR and 18 PR. In all patients, PFS was 4.2 months (95% CI: 3.4,4.9) compared to 3.9 months (95% CI: 3.0,4.6) for TCR patients. Among responders, PR or greater, median PFS was 8.5 months for both all patients and TCR groups, median OS was 17.6 months (95% CI: 13.2,28.9) and 16.5 months (95% CI: 11.5,18.5), and DOR was 5.5 months (95% CI: 3.9,7.6) and 4.4 months (95% CI: 3.4, 7.6) for all patients and triple-class refractory, respectively.

All patients experienced at least one treatment-emergent adverse event, including neutropenia (79%), thrombocytopenia (76%), and anemia (43%) being most common. Common nonhematologic adverse events were nausea (32%), diarrhea (27%), and constipation (15%). Grade 3 neutropenia with concurrent infection occurred in 11 percent of patients (J Clin Oncol 2020;39:757-767).

How do you administer this drug?

Melflufen is given as a 40 mg intravenously infusion over 30 minutes on Day 1 of a 28-day cycle in combination with either oral/intravenous dexamethasone.

Are there any premedications needed for melphalan flufenamide?

No required premedications but an anti-emetic may be considered as needed.

What are the common side effects associated with melphalan flufenamide (> or =10%)?

  • Hematologic: anemia, thrombocytopenia, neutropenia
  • Cardiovascular: edema
  • Central nervous system: headache, dizziness
  • GI: diarrhea, nausea, constipation, vomiting
  • General: fatigue, decreased appetite
  • Endocrine & Metabolic: hypokalemia, hypocalcemia
  • Neuromuscular & Skeletal: myalgia, arthralgia, pain
  • Respiratory: dyspnea, cough
  • Infectious: respiratory tract, pneumonia​

What are the uncommon side effects associated with melphalan flufenamide (less than 10%?

Additional side effects included hypersensitivity reaction (7%), febrile neutropenia (6), sepsis (3.8%), Grade 3 or 4 hemorrhage (3.8%).

Are there any important drug interactions I should be aware of?

There are no metabolism or transport effects associated with melflufen, but other drugs causing immunosuppression should be avoided.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no known renal or hepatic dose adjustments. It hasn't been studied in patients with creatinine clearance less than 45mL/min or moderate-severe hepatic dysfunction.

Practical tips

  • Ensure platelets are greater than 50,000 and absolute neutrophil count is greater than 1,000 prior to each dose of melflufen. Hold and monitor counts weekly until resolution then resume at same or reduced dose based on duration of interruption.
  • Melflufen degrades rapidly at room temperature. The infusion of diluted solution must start within 60 minutes of reconstitution.

What should my patients know about melphalan flufenamide?

Patients should contact their health care provider if they experience any of the following:

  • Any signs or symptoms of bleeding or infection
  • This drug may cause embryo-fetal harm. Effective birth control should be utilized during and after treatment.

What else should I know about melphalan flufenamide?

  • Secondary cancers such as myelodysplastic syndrome or acute leukemia have occurred. Patients should be aware and monitored for development of secondary malignancies.
  • Any grade infections were reported in 58 percent of patients—consider use of antimicrobials as clinically appropriate.

What useful links are available regarding melphalan flufenamide?

  • Prescribing Information: https://bit.ly/34Chvy5
  • Drug Information: https://bit.ly/3fUZMqY

Any ongoing clinical trials related to melphalan flufenamide?

Clinical trials with melflufen are investigating its role in the treatment of patients with amyloidosis, as well as in combination with other agents such as daratumumab, bortezomib, or pomalidomide for RRMM. More information is available about the clinical trials at https://clinicaltrials.gov. 

Friday, June 4, 2021

By Adam Robinson, PharmD

What is idecabtagene vicleucel?

Idecabtagene vicleucel is a chimeric antigen receptor (CAR)-positive T-cell therapy targeting B-cell maturation antigen (BCMA). The CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T-cell activation domain, and a 4-1BB costimulatory domain.

How does idecabtagene vicleucel work?

BCMA is expressed on the surface of normal and malignant plasma cells. Antigen-specific activation of idecabtagene vicleucel results in CAR-positive T-cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

What is this approved for?

Idecabtagene vicleucel was granted approval by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

What is the basis for this approval?

Idecabtagene vicleucel was studied in a multicenter, open-label, single-group, Phase II study designed to evaluate efficacy in patients with advanced and heavily pretreated multiple myeloma. Patients were assigned to receive idecabtagene vicleucel target doses of 150 x 106 to 450 x 106 CAR-positive T cells. After a median follow-up of over 13 months, the overall response rate was 73 percent for patients, including a 33 percent complete response (CR) or stringent complete response (sCR). The median progression-free survival was 8.8 months in the overall patient population and 20.2 months in patients achieving a CR/sCR. Median overall survival was 19.4 months. Adverse reactions were common, though rates of high-grade (grade ≥3) cytokine release syndrome (CRS) and neurotoxicity were low at 5 percent and 3 percent, respectively (N Engl J Med 2021; doi: 10.1056/NEJMoa2024850).

How do you administer this drug?

Idecabtagene vicleucel is administered as a single-dose infusion given on Day 0 following lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 daily for 3 days (D-5 to D-3).

Are there any pre-medications needed?

Idecabtagene vicleucel has low emetic risk and does not require antiemetic medications. Premedication with acetaminophen and diphenhydramine are recommended approximately 30-60 minutes before infusion of idecabtagene vicleucel. Prophylactic use of dexamethasone or other systemic corticosteroids should be avoided.

What are the common side effects associated with idecabtagene vicleucel (> or =20%)?

The most common adverse events were cytopenias (neutropenia, anemia, thrombocytopenia, lymphopenia) following lymphodepletion chemotherapy, infection (all grade neutropenia: 91%; grade 3 or 4: 89%), gastrointestinal adverse events (diarrhea, nausea), and laboratory abnormalities. All-grade CRS was common (84%), though incidence of high-grade (according to Lee et al. 2014 criteria) CRS and neurotoxicity were low.

What are the uncommon side effects associated with idecabtagene vicleucel (less than 20%)?

Coagulopathy, cardiac disorders, gastrointestinal hemorrhage, hemophagocytic lymphohistiocytosis, fungal infections, psychiatric disorders, respiratory, and thrombosis occurred in <10 percent of patients treated with idecabtagene vicleucel.

Are there any important drug interactions I should be aware of?

No known clinically significant drug interactions exist.

How do I adjust the dose in the setting of renal or hepatic insufficiency?

Hepatic and renal impairment studies were not conducted, and there are no dosage adjustments per the prescribing information. However, dose adjustments for cyclophosphamide and fludarabine may be necessary.

What should my patients know about idecabtagene vicleucel?

  • Manufacture and shipment of product may take 4 weeks or longer following blood collection (apheresis).
  • Idecabtagene vicleucel may cause side effects that are severe or life-threatening. Patients should notify their provider if they have difficulty breathing, fever, confusion, dizziness, word-finding difficulties, or other unusual side effects following infusion.
  • Patients should not drive or operate machinery for at least 8 weeks following infusion.
  • Patients should plan to stay within 2 hours of the health care facility where CAR T cell was received for at least 4 weeks after infusion.
  • Treatment can lower one or more types of blood cells, which can make patients feel weak or tired or increase risk of infection or bleeding.
  • Patients will be provided with a Patient Wallet Card and instructed to remain within 2 hours of the certified health care facility for at least 4 weeks following infusion.

What else should I know about idecabtagene vicleucel?

All relevant staff involved in prescribing, dispensing, or administering idecabtagene vicleucel are required to be enrolled in the REMS program and adhere to the REMS requirements, including availability of tocilizumab on-site for immediate administration.

What useful links are available regarding idecabtagene vicleucel?

  • New England Journal of Medicine Research: https://bit.ly/2RiFHCh
  • FDA Approval: https://bwnews.pr/3nT1WLh
  • Patient Information: https://www.abecma.com/
  • Risk Evaluation and Mitigation Strategy: https://www.abecmarems.com/

Any ongoing clinical trials related to idecabtagene vicleucel?

Idecabtagene vicleucel is being investigated in various ongoing trials for treatment of multiple myeloma and other B-cell lymphomas. More information is available about these trials at clinicaltrials.gov.

Adam Robinson, PharmD, is PGY2 Oncology Pharmacy Resident at Barnes-Jewish Hospital, St. Louis, Mo.