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TOKYO and BOTHELL, Wash., Feb. 14, 2022 /PRNewswire/ -- Astellas Pharma Inc. (TSE:4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq:SGEN) today announced the initial results from Cohort H of the EV-103 trial investigating PADCEV® (enfortumab vedotin-ejfv) as a monotherapy in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. Data from this late-breaking abstract will be included in an oral presentation (Abstract 435) at the 2022 ASCO Genitourinary Cancers Symposium (ASCO GU) on February 18.
MIBC is a stage of bladder cancer signified by the tumor spreading into the muscle of the bladder wall. Treatment for MIBC typically combines cisplatin-based chemotherapy with radical cystectomy, or removal of the bladder, as well as pelvic lymph node dissection. Cohort H of the phase 1b/2 EV-103 trial enrolled patients with MIBC who were eligible for surgical treatment but ineligible for cisplatin-based chemotherapy. Patients received three cycles of neoadjuvant (prior to surgery) enfortumab vedotin on days one and eight of every three-week cycle.
Results from the preliminary analysis of 22 patients showed 36.4% had a pathologic complete response, the primary endpoint, displaying no signs of cancer upon microscopic examination of tissue cells removed during surgery. Half (50%) of all patients had a pathological downstaging, or reduction in tumor size, a secondary endpoint of the trial. All patients underwent surgery, and no surgeries were delayed following treatment with enfortumab vedotin. The most common (≥20%) adverse events (AEs) related to treatment with enfortumab vedotin were fatigue (45.5%), alopecia (36.4%), dysgeusia (36.4%), diarrhea (27.3%), nausea (27.3%), peripheral sensory neuropathy (27.3%), dry eye (22.7%) and rash maculo-papular (22.7%), consistent with the known safety profile of enfortumab vedotin.
Please see Important Safety Information, including BOXED WARNING, at the end of this press release for further safety information regarding enfortumab vedotin.
"Neoadjuvant cisplatin-based chemotherapy, which is intended to shrink tumors prior to surgery, prolongs survival in patients with MIBC. However, up to half of these patients with MIBC are ineligible for cisplatin treatment and typically must undergo surgery without that treatment," said Ahsan Arozullah, M.D., M.P.H., Vice President, Medical Sciences-Oncology, Astellas.
"Results from EV-103 Cohort H showed that, when patients received enfortumab vedotin prior to surgery, more than one-third displayed no evidence of cancer when their bladder was removed and examined microscopically for residual tumors," said Daniel Petrylak, M.D., Yale School of Medicine Professor of Medicine (Medical Oncology) and of Urology; Co-Leader, Cancer Signaling Networks, Yale Cancer Center; and principal investigator for EV-103 Cohort H. "After treatment with enfortumab vedotin, all patients proceeded to surgery. Given there is no standard of care for neoadjuvant treatment in cisplatin-ineligible patients, these results are important and support further research."
"The initial findings from EV-103 Cohort H are encouraging, and we look forward to learning more from the Phase 3 studies evaluating enfortumab vedotin in muscle-invasive bladder cancer in combination with the anti-PD-1 therapy pembrolizumab," said Marjorie Green, M.D., Senior Vice President and Head of Late-Stage Development, Seagen.
In addition to this trial, enfortumab vedotin is being investigated as a monotherapy and in combination with other therapies in clinical trials across lines of treatment and stages of bladder cancer.
Astellas and Seagen will also present updates from the broader enfortumab vedotin program in four posters at ASCO GU 2022, including:
The abstract titles published in advance of the meeting can be found here.
About Muscle-Invasive Bladder Cancer Muscle-invasive bladder cancer, which makes up about 25% of bladder cancers, is a cancer that has spread into the muscle of the bladder wall and is more likely to spread to other parts of the body. 1,2 Each year in the U.S., there are more than 83,000 new cases of bladder cancer diagnosed in men and women.2 Survival rates are poor for muscle-invasive bladder cancer, with around 45% of patients surviving for five years regardless of the type of treatment.3
About the EV-103 Trial The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial of enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with locally advanced or metastatic urothelial cancer (la/mUC) and in patients with muscle-invasive bladder cancer.
About Enfortumab Vedotin Enfortumab vedotin is an antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.4 Nonclinical data suggest the anticancer activity of enfortumab vedotin 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).5
PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information
BOXED WARNING: SERIOUS SKIN REACTIONS
Indication
PADCEV® is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:
Important Safety Information
Warnings and Precautions
Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN, occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. Withhold PADCEV and refer for specialized care for suspected SJS or TEN or for severe (Grade 3) skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN, or for Grade 4 or recurrent Grade 3 skin reactions.
Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. 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.
Pneumonitis Severe, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. In clinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6). Monitor patients for signs and symptoms indicative of pneumonitis, such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis.
Peripheral neuropathy (PN) occurred in 52% of the 680 patients treated with PADCEV in clinical trials, including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.6 months (range: 0.1 to 15.8 months). Neuropathy led to treatment discontinuation in 5% of patients. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN.
Ocular disorders were reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months). 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.
Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 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. Two patients (0.3%) 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
Most Common Adverse Reactions, Including Laboratory Abnormalities (≥20%)
Rash, aspartate aminotransferase (AST) increased, glucose increased, creatinine increased, fatigue, PN, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase (ALT) increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.
EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy.
Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite and fatigue (3% each). Clinically relevant adverse reactions (
