Padcev (Enfortumab Vedotin-ejfv) FDA Approved for the Treatment of Metastatic Urothelial Carcinoma

Urothelial carcinoma, also known as transitional-cell carcinoma (TCC), is the most common subtype of bladder cancer.1 Based on data from 2016, more than 80,000 cases of bladder cancer were estimated to be diagnosed in the United States in 2019, and approximately 17,600 patients were expected to die from this disease.2

The prognosis associated with urothelial carcinoma is relatively favorable for patients with localized disease, with approximately 70% of patients still alive at 5 years, according to 2016 data.2 However, for patients with distant disease, the 5-year survival rate decreases to 5%, despite treatment with surgery, chemotherapy, and/or radiation.2

In recent years, the standard treatment options for patients with advanced urothelial carcinoma have expanded beyond traditional platinum-based chemotherapy. Before December 2019, a total of 5 immunotherapy agents were approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced urothelial carcinoma, including atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda). These therapies include the programmed-cell death receptor (PD)-1 and PD ligand 1 (PD-L1) inhibitors, the newer types of immunotherapy that are also collectively known as checkpoint inhibitors.3

In addition, patients with urothelial cancer and susceptible FGFR3 or FGFR2 genetic alterations now have a new treatment option, erdafitinib (Balversa), which was approved by the FDA in 2019.4 Nevertheless, patients with advanced or metastatic urothelial carcinoma who have received treatment with platinum-based chemotherapy and 1 or more of the 5 checkpoint inhibitors need additional treatment options in the relapse setting.5

Padcev Approved for Metastatic Bladder Cancer

On December 18, 2019, the FDA accelerated the approval of enfortumab vedotin-ejfv (Padcev; Astellas Pharma), a Nectin-4–directed antibody and microtubule inhibitor conjugate, for the treatment of adults with locally advanced or metastatic urothelial carcinoma after treatment with a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy.6 Enfortumab vedotin is the first antibody–drug conjugate approved for the treatment of this patient population.6

“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. Padcev is an antibody–drug conjugate that targets Nectin-4, a cell surface protein expressed on bladder cancer cells and [releases] a cell-killing agent, monomethyl auristatin E” (MMAE), said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.6

Further clinical trial results are needed to confirm the clinical benefit of enfortumab vedotin.6,7

Mechanism of Action

Enfortumab vedotin is a human immunoglobulin G1 antibody directed against Nectin-4, an adhesion protein located on the surface of cells.7 MMAE, the small molecule released by enfortumab vedotin, is a microtubule-disrupting agent. MMAE is attached to the antibody via a protease-cleavable linker. Based on nonclinical data, the anticancer activity of enfortumab vedotin results from its binding to Nectin-4–expressing cells, internalization of the antibody–drug conjugate-Nectin-4 complex, and the release of MMAE after proteolytic cleavage. When MMAE is released, it disrupts the cancer-cell microtubule network and induces cell-cycle arrest and apoptosis.7

Dosing and Administration

The recommended dose of enfortumab vedotin is 1.25 mg/kg. For patients who weigh ≥100 kg, the maximum total dose is 125 mg.7

Enfortumab vedotin is administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.7

Pivotal Clinical Trial: EV-201 Study

Enfortumab vedotin received FDA approval based on the overall response rate and duration of response data from the pivotal global phase 2, single-arm, multicenter EV-201 clinical trial.5,7 The efficacy of enfortumab vedotin was evaluated in 125 patients with locally advanced or metastatic urothelial carcinoma after treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.5 Patients were excluded from the study if they had active central nervous system metastases, grade ≥2 ongoing sensory or motor neuropathy, or uncontrolled diabetes.5

The dose of enfortumab vedotin was 1.25 mg/kg given intravenously for approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. The patient’s body weight was used to calculate the dosing, up to a maximum dose of 125 mg.5

Most (90%) of the 125 patients (median age, 69 years; range, 40-84 years) had visceral metastases, including 40% liver metastases.5 Approximately 67% of the patients had pure TCC histology, and the remaining 33% had TCC with other histologic variants. Patients received a median of 3 (range, 1-6) previous systemic therapies. All 120 patients with tumor tissue available had Nectin-4 expression.5

The major efficacy outcomes were confirmed objective response rate and duration of response.5 Among the 125 patients in the EV-201 study, the objective response rate to enfortumab vedotin was 44% (95% confidence interval [CI], 35.1%-53.2%), including 12% complete responses and 32% partial responses (Table).5,7 Enfortumab vedotin demonstrated a median duration of response of 7.6 months (95% CI, 6.3 months-not estimable).5,7

Table

Adverse Events

Based on a median exposure to enfortumab vedotin of 4.6 months (range, 0.5-15.6 months), the rate of serious adverse reactions was 46%; of these, the most common (≥3%) events were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%).7

Fatal adverse reactions, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%), were 3.2%.7

Adverse reactions leading to treatment discontinuation occurred in 16% of patients, with 6% resulting from peripheral neuropathy. Dose interruption because of adverse reactions occurred in 64% of patients, and included peripheral neuropathy (18%), rash (9%), and fatigue (6%).7 Adverse reactions leading to dose reduction occurred in 34% of patients, and included peripheral neuropathy (12%), rash (6%), and fatigue (4%).7

Enfortumab vedotin has no contraindications.

Drug Interactions

No clinical studies evaluating the drug–drug interaction potential of enfortumab vedotin have been conducted. However, when another antibody–drug conjugate that contains MMAE was coadministered with ketoconazole, a strong cytochrome (CY) P3A4 inhibitor, the maximum concentration (Cmax) of MMAE increased by 25% and the area under the curve (AUC) increased by 34%. Concomitant use of strong inhibitors of CYP3A4 with enfortumab vedotin would likely result in similar effects on free MMAE levels.7

When another antibody–drug conjugate that contains MMAE was coadministered with rifampin, a strong CYP3A4 inducer, the MMAE Cmax was decreased by 44% and the AUC decreased by 46%.7 Concomitant use of strong inducers of CYP3A4 with enfortumab vedotin would likely result in similar effects on free MMAE levels.7

Use in Specific Populations

Enfortumab vedotin can cause fetal harm. Women of reproductive potential should use effective contraception during treatment and for at least 2 months after the final dose. Men with female partners of reproductive potential should use effective contraception while taking enfortumab vedotin and for 4 months after the final dose. Based on animal studies, enfortumab vedotin may impair fertility in men.7

Women should not breastfeed during treatment with enfortumab vedotin and for at least 3 weeks after the final dose.7

Enfortumab vedotin was not studied in children.7

Among 310 total patients who received treatment with enfortumab vedotin, no overall differences in safety or effectiveness were observed between older and younger patients.7

Enfortumab vedotin should not be used in patients with moderate or severe hepatic impairment.7

Dose adjustment is not required in patients with mild, moderate, or severe renal or mild hepatic impairment.7

Warnings and Precautions

Hyperglycemia has been reported with enfortumab vedotin therapy. The incidence of severe hyperglycemia was greater in patients with larger body mass index and/or higher baseline A1c. Blood glucose levels should be closely monitored for signs of hyperglycemia.7

Peripheral neuropathy, mostly sensory, can occur with enfortumab vedotin therapy.7

Ocular disorders, including keratitis, blurred vision, limbal stem-cell deficiency, and other dry eye events, can occur with enfortumab vedotin. Ophthalmologic evaluation may be necessary.7

Skin reactions, including maculopapular rash and pruritus, as well as more severe reactions, can occur with enfortumab vedotin. Topical steroids and antihistamines may be appropriate treatments for these reactions.7

Adequate venous access should be ensured before starting enfortumab vedotin therapy. Patients should be monitored for extravasation during treatment.7

Conclusion

The FDA approval of enfortumab vedotin, a Nectin-4–directed antibody and microtubule inhibitor conjugate, provides a first-in-class treatment option for adults with locally advanced or metastatic urothelial carcinoma after treatment with a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy.

Based on data from a single-arm phase 2 study showing a 44% objective response rate, a 7.6-month duration of response, and acceptable safety, enfortumab vedotin is a novel and effective treatment option for patients with progressing urothelial carcinoma.

References

  1. American Cancer Society. What is bladder cancer? Revised January 30, 2019. www.cancer.org/cancer/bladder-cancer/about/what-is-bladder-cancer.html. Accessed January 30, 2020.
  2. National Cancer Institute SEER Program. Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed January 30, 2020.
  3. National Cancer Institute. Bladder cancer treatment (PDQ)–health professional version. Updated January 22, 2020. www.cancer.gov/types/bladder/hp/bladder-treatment-pdq#_156. Accessed January 31, 2020.
  4. US Food and Drug Administration. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. April 12, 2019. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma. Accessed February 4, 2020.
  5. 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;37:2592-2600.
  6. US Food and Drug Administration. FDA approves new type of therapy to treat advanced urothelial cancer. December 18, 2019. www.fda.gov/news-events/press-announcements/fda-approves-new-type-therapy-treat-advanced-urothelial-cancer. Accessed January 27, 2020.
  7. Padcev (enfortumab vedotin-ejfv) for injection, for intravenous use [prescribing information]. Northbrook, IL; Astellas Pharma US; Bothell, WA: Seattle Genetics; December 2019.

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