On February 10, 2020 Seattle Genetics, Inc. (Nasdaq: SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported updated results from the phase 1b/2 clinical trial EV-103 in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for treatment with cisplatin-based chemotherapy (Press release, Astellas, FEB 10, 2020, View Source [SID1234554081]). Forty-five patients were treated with the combination of PADCEV (enfortumab vedotin-ejfv) and pembrolizumab and were evaluated for safety and efficacy. After a median follow-up of 11.5 months, the study results continue to meet outcome measures for safety and demonstrate encouraging clinical activity for this platinum-free combination in a first-line setting. Updated results will be presented during an oral session on Friday, February 14 at the 2020 Genitourinary Cancers Symposium in San Francisco (Abstract #441). Initial results from the study were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in September 2019.
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PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.1,2
"Cisplatin-based chemotherapy is the standard treatment for first-line advanced urothelial cancer; however, it isn’t an option for many patients," said Jonathan E. Rosenberg, M.D., Medical Oncologist and Chief, Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York. "I’m encouraged by these interim results, including a median progression-free survival of a year for patients who received the platinum-free combination of PADCEV and pembrolizumab in the first-line setting."
In the study, 58 percent (26/45) of patients had a treatment-related adverse event greater than or equal to Grade 3: increase in lipase (18 percent; 8/45), rash (13 percent; 6/45), hyperglycemia (13 percent; 6/45) and peripheral neuropathy (4 percent; 2/45); these rates were similar to those observed with PADCEV monotherapy.3 Eighteen percent (8/45) of patients had treatment-related immune-mediated adverse events of clinical interest greater than or equal to Grade 3 that required the use of systemic steroids (arthralgia, dermatitis bullous, pneumonitis, lipase increased, rash erythematous, rash maculo-papular, tubulointerstitial nephritis, myasthenia gravis). None of the adverse events of clinical interest were Grade 5 events. Six patients (13 percent) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy. As previously reported, there was one death deemed to be treatment-related by the investigator attributed to multiple organ dysfunction syndrome.
The data demonstrated the combination of PADCEV plus pembrolizumab shrank tumors in the majority of patients, resulting in a confirmed objective response rate (ORR) of 73.3 percent (33/45; 95% Confidence Interval (CI): 58.1, 85.4) after a median follow-up of 11.5 months (range, 0.7 to 19.2). Responses included 15.6 percent (7/45) of patients who had a complete response (CR) and 57.8 percent (26/45) of patients who had a partial response. Median duration of response has not yet been reached (range 1.2 to 12.9+ months). Eighteen (55%) of 33 responses were ongoing at the time of analysis, with 83.9% of responses lasting at least 6 months and 53.7% of responses lasting at least 12 months (Kaplan-Meier estimate). The median progression-free survival was 12.3 months (95% CI: 7.98, -) and the 12-month overall survival (OS) rate was 81.6 percent (95% CI: 62 to 91.8 percent); median OS has not been reached.
"These updated data are encouraging and provide support for the recently initiated phase 3 trial EV-302 that includes an arm evaluating PADCEV in this platinum-free combination in the first-line setting," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.
"These additional results support continued evaluation of PADCEV in combination with other agents and at earlier stages of treatment for patients with urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.
About the EV-103 Trial
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial of PADCEV alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer.
The dose-escalation cohort and expansion cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of this initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.
The primary outcome measure of the cohorts included in this analysis is safety. Key secondary objectives related to efficacy include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression free survival (PFS) and overall survival (OS). DoR, PFS and OS are not yet mature.
Additional cohorts in the EV-103 study will evaluate enfortumab vedotin:
as monotherapy or in combination with pembrolizumab or a platinum chemotherapy in a first-line setting for metastatic disease;
in combination with pembrolizumab and carboplatin or cisplatin in first-line metastatic disease;
as a monotherapy or in combination with pembrolizumab in muscle invasive disease;
with pembrolizumab in second-line metastatic disease; and
with gemcitabine in first- or second-line metastatic disease.4
More information about PADCEV clinical trials can be found at clinicaltrials.gov.
About Bladder and Urothelial Cancer
It is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020.5 Urothelial cancer accounts for 90 percent of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.6 Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide.7
The recommended first-line treatment for patients with advanced urothelial cancer is a cisplatin-based chemotherapy. For patients who are ineligible for cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens.8
About PADCEV
PADCEV (enfortumab vedotin-ejfv) was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic 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 before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA’s Accelerated Approval Program based on tumor response rate. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.9
PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.2,9 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).9 PADCEV is co-developed by Astellas and Seattle Genetics.
Important Safety Information
Warnings and Precautions
Hyperglycemia occurred in patients treated with PADCEV, including death and diabetic ketoacidosis (DKA), in those with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C ≥8% were excluded. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.
Peripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with PADCEV in clinical trials; 2% experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients that develop Grade ≥3 peripheral neuropathy.
Ocular disorders occurred in 46% of the 310 patients treated with PADCEV. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.
Skin reactions occurred in 54% of the 310 patients treated with PADCEV in clinical trials. Twenty-six percent (26%) of patients had maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3). Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement. Monitor patients for skin reactions. Consider appropriate treatment, such as topical corticosteroids and antihistamines for skin reactions, as clinically indicated. For severe (Grade 3) skin reactions, withhold PADCEV until improvement or resolution and administer appropriate medical treatment. Permanently discontinue PADCEV in patients that develop Grade 4 or recurrent Grade 3 skin reactions.
Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.
Adverse Reactions
Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).
Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).
The most common adverse reactions (≥20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade ≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and fatigue (6%).
Lab Abnormalities
In one clinical trial, Grade 3-4 laboratory abnormalities reported in ≥5% were: lymphocytes decreased, hemoglobin decreased, phosphate decreased, lipase increased, sodium decreased, glucose increased, urate increased, neutrophils decreased.
Drug Interactions
Effects of other drugs on PADCEV Concomitant use with a strong CYP3A4 inhibitor may increase free MMAE exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with strong CYP3A4 inhibitors.
Specific Populations
Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.
Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.