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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761137s000lbl.pdf

On December 18, 2019 the U.S. Food and Drug Administration granted accelerated approval to Enfortumab vedotin-ejfv (Padcev, Astellas Pharma US, Inc.), a Nectin-4-directed antibody and microtubule inhibitor conjugate, meaning the drug specifically targets cancer cells – in this case, the cell adhesion molecule Nectin-4, which is highly expressed in urothelial cancers. Padcev is indicated for the treatment of adult patients with locally advanced (when cancer has grown too large to be surgically removed) or metastatic (when cancer cells spread to other parts of the body) urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy. Platinum-containing chemotherapy, PD-1 and PD-L1 inhibitors are standard treatments for patients with bladder cancer, the sixth most common cancer in the U.S. Urothelial cancer, accounting for more than 90% of bladder cancers, begins in cells that line the bladder and nearby organs. Padcev represents a new type of therapy for patients with advanced urothelial cancer whose disease has progressed on chemotherapy and immunotherapy.

“Antibody-drug conjugates are strategic tools in the targeted treatment of cancer. These conjugates combine the ability of monoclonal antibodies to target specific receptors on cancer cells and then deliver a drug to the cancer cell,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Padcev is an antibody-drug conjugate that targets Nectin-4, a cell surface protein expressed on bladder cancer cells and a cell-killing agent, monomethyl auristantin E.”

Padcev was approved based on the results of a clinical trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. The overall response rate, reflecting the percentage of patients who had a certain amount of tumor shrinkage, was 44%, with 12% having a complete response and 32% having a partial response. The median duration of response was 7.6 months.

The most common side effects for patients taking Padcev were fatigue, peripheral neuropathy (nerve damage resulting in tingling or numbness), decreased appetite, rash, alopecia (hair loss), nausea, altered taste, diarrhea, dry eye, pruritis (itching) and dry skin. Patients may experience hyperglycemia (high blood sugar levels) regardless of whether they have diabetes or not, and blood sugar levels should be monitored closely in patients receiving Padcev. Patients should also be monitored for new or worsening peripheral neuropathy and have the dose of Padcev interrupted, reduced or discontinued if needed. Patients may experience eye disorders, including dry eyes and vision changes, while taking Padcev. Health care professionals may consider prophylactic artificial tears for dry eyes and referral to an ophthalmologist for any new symptoms related to the eye. Patients who experience infusion site extravasation (leakage of medications administered through veins into the surrounding tissue) may experience delayed extravasation site reactions with pain, blisters and peeling of skin. Adequate venous access should be ensured prior to starting Padcev.

The FDA advises health care professionals to tell patients of reproductive age to use effective contraception during treatment with Padcev, and for a period of time thereafter. Women who are pregnant or breastfeeding should not take Padcev because it may cause harm to a developing fetus or newborn baby, or cause delivery complications.

Padcev was granted Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need based on a result that is reasonably likely to predict a clinical benefit to patients. A further clinical trial is required to verify and describe Padcev’s clinical benefit.

View full prescribing information for Padcev.

The FDA granted this application Priority Review and Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Padcev received approval approximately three months before the goal date.

The FDA granted the approval of Padcev to Astellas Pharma US Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Pharmacist’s Application to Practice

Enfortumab vedotin-ejfv for the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Author: Jacquelyn Day, PharmD
PGY-1 Pharmacy Resident
Vanderbilt University Medical Center
Nashville, TN

What is the role of enfortumab in the treatment of locally advanced or metastatic urothelial cancer?

  • Enfortumab is an IgG1 antibody-drug conjugate (ADC) directed against nectin-4 fused with monomethyl auristatin E (MMAE) via a protease-cleavable linker.1
  • Nectin-4 is a transmembrane protein that is associated with oncogenesis and is overexpressed in urothelial carcinoma. MMAE is an anti-microtubule agent that causes the disruption of microtubules via tubulin polymerization during mitosis leading to cell cycle arrest. The ADC binds to cells expressing nectin-4 with a high affinity, is internalized, and subsequently leads to apoptosis.2,3
  • Currently, a platinum-based therapy is used first line for locally advanced or metastatic urothelial cancers and results in objective response rates (ORRs) of 41%–50%. Programmed cell death-1 (PD-1) inhibitors, such as nivolumab and pembrolizumab, or programmed death-ligand 1 (PD-L1) inhibitors, such as avelumab, durvalumab, and atezolizumab, used in the second-line setting have lower ORRs of 13%–21%. Until recently, single-agent chemotherapy agents were the only available therapy for the third-line setting. These agents, which include taxanes, have ORRs around 10%.4
  • Based on the EV-201 trial, the U.S. Food and Drug Administration (FDA) approved enfortumab for patients who have locally advanced or metastatic urothelial cancer and who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant or adjuvant setting.3
  • EV-201 was a phase 2 single-arm trial that assessed the safety and efficacy of enfortumab vedotin-ejfv 1.25 mg/kg (maximum 125 mg) on days 1, 8, and 15 of a 28-day cycle for patients with locally advanced or metastatic urothelial carcinoma who had been previously treated with platinum chemotherapy and anti–PD-1/PD-L1 therapy. Treatment was continued until radiographic progression, unacceptable toxicity, or withdrawal occurred. Inclusion criteria included an Eastern Cooperative Oncology Group performance status of 0–1 before enrollment and adequate baseline organ function. Patients with ongoing neuropathy grade >2, active central nervous system metastases, or uncontrolled diabetes were excluded. Uncontrolled diabetes was defined as a hemoglobin A1C >8% or >7%–8% and symptomatic. There was no limit to prior lines of therapy. The primary endpoint was ORR as assessed by blinded independent central review (BICR). Secondary endpoints were duration of response and progression-free survival (PFS) by BICR and investigator review, ORR by investigator review, overall survival (OS), safety, and tolerability. The confirmed ORR was 44% (95% confidence interval [CI] 35.1%–53.2%), as assessed by BICR; this included a 12% complete response rate. Median time to response was 1.84 months, and median duration of response was 7.6 months (range, 0.95–11.30+ months). Results were consistent across all subgroups, and objective responses occurred regardless of response to prior anti–PD-1/PD-L1 therapy (56% responders), presence of liver metastases (38%), and receipt of >3 prior lines of therapy (41%). Median PFS was 5.8 months (CI 4.9–7.5 months), and estimated median OS was 11.7 months (CI 9.1 months to not reached). The most frequent treatment-related adverse events were fatigue (50% all grade, 6% >grade 3), alopecia (49% all grade, none >grade 3), decreased appetite (44% all grade, 1% >grade 3), dysgeusia (40% all grade, none >grade 3) and peripheral neuropathy (40% all grade, 2% >grade 3).3
  • The National Comprehensive Cancer Network (NCCN) guidelines for the treatment of bladder cancer indicate enfortumab as category 2A third-line systemic therapy option and first-in-class nectin-4/MMAE ADC for locally advanced or metastatic disease. Similarly, erdafitinib is included as a category 2A third-line option, but only for patients with bladder cancer and an FGFR3 or FGFR2 genetic alteration.4
  • The most common adverse reactions to enfortumab are fatigue, peripheral neuropathy, decreased appetite, rash, alopecia, nausea, dysgeusia, diarrhea, dry eye, pruritus, and dry skin.1

What role can the pharmacist play in the management of patients on enfortumab?

  • Enfortumab is dosed at 1.25 mg/kg (maximum dose 125 mg) and is administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle until disease progresses or an unacceptable level of toxicity is reached.
  • Warnings and precautions related to enfortumab:1,3
    • Hyperglycemia: Diabetic ketoacidosis may occur in patients with and without a history of diabetes. Withhold agent until blood glucose < 250 mg/dL.
    • Peripheral neuropathy
      • Grade 2: Withhold until grade <1 and resume at same dose; in cases of recurrence, withhold until grade <1 and dose reduce by one dose level.
      • Grade 3: Permanently discontinue.
    • Ocular disorders: dry eye–associated disorders (e.g., keratitis, blurred vision, limbal stem cell deficiency). Consider prophylactic use of artificial tears. Consider treatment with topical steroids and dose interruption or reduction.
    • Skin reactions: time to onset of severe reactions was 0.8 months; consider treatment with topical steroids and/or antihistamines.
      • Grade 2: Withhold until grade <1 and resume at same dose; in cases of recurrence, withhold until grade <1 and dose reduce by one dose level.
      • Grade 4 or recurrent grade 3: Permanently discontinue.
    • Hematologic toxicity
      • Grade 2 or 3 thrombocytopenia: Withhold until grade <1 and resume at same dose; in cases of recurrence, withhold until grade <1 and dose reduce by one dose level.
      • Grade 4 or recurrent grade 3: withhold until grade <1 and resume at same dose; in cases of recurrence, withhold until grade <1 and dose reduce by one dose level or permanently discontinue.
    • Infusion site reactions: Extravasation reactions may be delayed 2–7 days and resolve within 1–4 weeks of peak. Ensure adequate venous access before beginning therapy.
  • Dose reduction schedule
    • Starting dose: 1.25 mg/kg; up to 125 mg
    • First dose reduction: 1.0 mg/kg; up to 100 mg
    • Second dose reduction: 0.75 mg/kg; up to 75 mg
    • Third dose reduction: 0.5 mg/kg; up to 50 mg
  • Patients should use effective contraception during treatment and for at least 2 months in women and 4 months in men after discontinuation because enfortumab may cause fetal harm.1
  • Enfortumab should be avoided in patients with moderate or severe hepatic impairment (Child-Pugh Class B and C). In patients taking other drugs containing MMAE, the frequency of adverse drug reactions and death was increased. No dose adjustments are necessary for renal impairment.1
  • Basic metabolic panel, complete blood count, and eye exam should be performed prior to initiation of enfortumab and throughout treatment because electrolyte abnormalities, cytopenias, and ocular disorders are side effects associated with this medication. Liver function tests should also be performed at baseline and throughout therapy; enfortumab should be avoided in patients with moderate-to-severe hepatic impairment.1,3
  • Patients’ baseline hemoglobin A1C should also be considered because patients with A1C >8% were not included in EV-201; 8% of patients developed grade 3–4 hyperglycemia.3
  • The most common >grade 3 adverse events were neutropenia (8%), anemia (7%), and fatigue (6%). Peripheral neuropathy was the most common reason for dose reduction (9%) and discontinuation (6%).3
  • Enfortumab is a substrate for CYP3A4 and P-gp based on the release of MMAE by proteolytic cleavage. Drug levels may be altered with concomitant CYP3A4 inducers or inhibitors, and these combinations should be used with caution.1

Clinical Pearls

  • Nectin-4 is not routinely tested for upon diagnosis because 97% of bladder cancer samples expressed nectin-4 via immunohistochemistry in preclinical models. Therefore, enfortumab remains an option for all patients in the third-line setting.2
  • According to NCCN guidelines, enfortumab is classified as a moderate emetic risk. Therefore, patients should receive an antiemetic prior to the start of chemotherapy and on days 2 and 3.5
  • Rash is a common side effect of enfortumab, which may be due to the presence of nectin-4 expression in cutaneous cells. In addition, other ADCs that include MMAE have cutaneous toxicities as a common side effect.6
  • Enfortumab is supplied as 20-mg and 30-mg lyophilized powder in a single-dose vial for reconstitution and should not be administered as a push or bolus or administered with other medications.1
  • Enfortumab vials should be stored in the refrigerator in the original carton, should not be frozen or shaken, and should be protected from light.1 
  • All patients receiving enfortumab should have previously received PD-1/PD-L1 and a platinum-containing chemotherapy.1,3
  • Padcev Support Solutions offers access and reimbursement support to patients who have been prescribed enfortumab (Padcev). The access service can be reached Monday–Friday 8:30 am–8:30 pm EST at 1.888.402.0627.7

References

  1. Padcev (enfortumab vedotin-ejfv) [package insert]. Northbrook, IL: Astellas Pharma US, Inc., and Bothell, WA: Seattle Genetics, Inc., 2019.
  2. Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76(10):3003-3013.
  3. Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol. 2019;37(29):2592-2600.
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer. Version 5.2020 (May 12, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed June 8, 2020.
  5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 2.2020 (April 23, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed May 7, 2020.
  6. Wu S, Adamson AS. Cutaneous toxicity associated with enfortumab vedotin treatment of metastatic urothelial carcinoma. Dermatol Online J. 2019;25(2)1-3.
  7. Padcev (enfortumab). Astellas Pharma US, Inc., and Seattle Genetics, Inc., 2020. Accessed at https://www.padcev.com/resources.
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