Seagen, Astellas and Merck Announce Results of Clinical Trial Investigating PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) and PADCEV as Monotherapy in First-Line Advanced Urothelial Cancer

– Results demonstrated a 64.5% confirmed objective response rate in patients treated with investigational combination of enfortumab vedotin and pembrolizumab –

– Data highlighted in late-breaking presentation at the European Society for Medical Oncology (ESMO) Congress 2022 –

BOTHELL, Wash. & TOKYO & RAHWAY, N.J.--(BUSINESS WIRE)--Seagen Inc. (Nasdaq:SGEN), Astellas Pharma Inc. (TSE:4503, President and CEO: Kenji Yasukawa, Ph.D., “Astellas”) and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from the phase 1b/2 EV-103 clinical trial (also known as KEYNOTE-869) Cohort K investigating PADCEV^® (enfortumab vedotin-ejfv) in combination with Merck’s anti-PD-1 therapy KEYTRUDA^® (pembrolizumab) and PADCEV alone as first-line treatment in patients with unresectable locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible to receive cisplatin-based chemotherapy. The findings were presented today at the European Society for Medical Oncology (ESMO) Congress as part of a late-breaking abstract presentation (Abstract #LBA73).

In patients treated with enfortumab vedotin and pembrolizumab (n=76), results demonstrated a 64.5% confirmed objective response rate (ORR) (95% CI: 52.7 to 75.1) per RECIST v1.1 by blinded independent central review (BICR), the primary endpoint of Cohort K, with 10.5% of patients experiencing a complete response and 53.9% of patients experiencing a partial response. The median duration of response (DOR) per BICR was not reached (95% CI: 10.25 months to NR). All-grade treatment-related adverse events (TRAEs) of special interest for enfortumab vedotin in combination with pembrolizumab were skin reactions (67.1%), peripheral neuropathy (60.5%), ocular disorders (dry eye, blurred vision, and corneal disorders) (26.3%), hyperglycemia (14.5%), and infusion-related reactions (3.9%). Pembrolizumab adverse events of special interest were consistent with previously observed safety data from monotherapy with the exception of severe skin reactions. Overall, the results were generally consistent with previously reported efficacy and safety results of the EV-103/KEYNOTE-869 dose-escalation cohort and expansion Cohort A.¹

Please see Important Safety Information at the end of this press release for both drugs, including BOXED WARNING for enfortumab vedotin and immune-mediated adverse reactions for pembrolizumab.

Cohort K also included a monotherapy arm in which patients were treated with enfortumab vedotin alone (n=73), though this study was not designed to support a formal comparison between the two arms. Results showed a 45.2% confirmed ORR (95% CI: 33.5 to 57.3) per RECIST v1.1 by BICR, with 4.1% of patients experiencing a complete response and 41.1% of patients experiencing a partial response. The median DOR was 13.2 months (95% CI: 6.14 to 15.97) per RECIST v1.1 by BICR. All-grade TRAEs of special interest for enfortumab vedotin were peripheral neuropathy (54.8%), skin reactions (45.2%), ocular disorders (dry eye, blurred vision, and corneal disorders) (28.8%), hyperglycemia (11.0%), and infusion-related reactions (5.5%).

Additional secondary endpoints in the EV-103 Cohort K trial included progression-free survival (PFS) and overall survival (OS). Among patients treated with enfortumab vedotin and pembrolizumab, median PFS was not reached (95% CI: 8.31 months to NR). Median OS was 22.3 months (95% CI: 19.09 to NR). Among patients treated with enfortumab vedotin, median PFS was 8.0 months (95% CI: 6.05 to 10.35) and median OS was 21.7 months (95% CI: 15.21 to NR).

TRAEs of any grade that occurred in more than 20% of patients treated with enfortumab vedotin alone or in combination with pembrolizumab were fatigue, peripheral sensory neuropathy, alopecia, rash maculo-papular, pruritus, dysgeusia, weight decreased, diarrhea, decreased appetite, nausea, and dry eye.

“Results from EV-103/KEYNOTE-869 Cohort K support the ongoing investigation of enfortumab vedotin and pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who are in need of treatment options, and this combination may be an important therapeutic option for these patients,” said Jonathan E. Rosenberg, M.D., Chief, Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, and Enno W. Ercklentz Chair, Memorial Sloan Kettering Cancer Center and EV-103/KEYNOTE-869 Cohort K ​primary investigator. Dr. Rosenberg has consulting relationships with Seagen, Astellas and Merck.

“Nearly sixty-five percent of patients who were treated with enfortumab vedotin and pembrolizumab responded to the combination, with almost eleven percent showing no detectable cancer following treatment. These study results represent an encouraging finding for people with advanced urothelial cancer who are not eligible for cisplatin treatment,” said Marjorie Green, Senior Vice President and Head of Late-Stage Development, Seagen.

“We're encouraged by these positive findings from the combination of enfortumab vedotin and pembrolizumab in people with advanced urothelial cancer who historically have had limited treatment options in the first-line setting, and we intend to discuss these results with regulatory authorities,” said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas.

“We’re pleased that this combination provided a meaningful benefit to this group of advanced bladder cancer patients in this study, and we will continue to investigate enfortumab vedotin plus pembrolizumab through our collaboration,” said Dr. Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, Merck Research Laboratories.

In February 2020, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for enfortumab vedotin in combination with pembrolizumab for patients with unresectable la/mUC who are ineligible to receive cisplatin-based chemotherapy in the first-line setting. The designation is based on results from the dose-escalation cohort and expansion Cohort A of the phase 1b/2 trial, EV-103/KEYNOTE-869 (NCT03288545), evaluating patients with la/mUC who are ineligible to receive cisplatin-based chemotherapy treated in the first-line setting with enfortumab vedotin in combination with pembrolizumab.

Seagen, Astellas and Merck are further investigating enfortumab vedotin plus pembrolizumab in Phase 3 studies, including EV-302/KEYNOTE-A39 (NCT04223856), which is intended to confirm these results for the investigational treatment combination in previously untreated la/mUC and in muscle-invasive bladder cancer in EV-304/KEYNOTE-B15 (NCT04700124) and EV-303/KEYNOTE-905 (NCT03924895).

About Bladder and Urothelial Cancer

It is estimated that approximately 83,730 people in the U.S. were diagnosed with bladder cancer in 2021.² Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.³ Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.⁴

About the EV-103/KEYNOTE-869 Trial (Cohort K)

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.

Cohort K of the EV-103/KEYNOTE-869 trial is a randomized 1:1 cohort investigating enfortumab vedotin alone (n=73) or in combination with pembrolizumab (n=76) in adult patients with unresectable la/mUC who are ineligible for cisplatin-based chemotherapy and have received no prior treatment for la/mUC. The enfortumab vedotin monotherapy study arm is intended to characterize the activity of enfortumab vedotin alone in this patient population. The key outcome measure of EV-103/KEYNOTE-869 Cohort K is objective response rate (ORR) per blinded independent central review (BICR) using RECIST 1.1. Secondary endpoints include ORR per investigator assessment; duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) per BICR and investigator assessment; overall survival (OS); and assessment of safety.

About PADCEV

PADCEV (enfortumab vedotin-ejfv) 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.⁵ 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).⁶

PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

BOXED WARNING: SERIOUS SKIN REACTIONS

• PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
• Closely monitor patients for skin reactions.
• Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
• Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Indication

PADCEV^® is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:

• have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
• are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.⁶

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 pre-existing 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 (<15%) include vomiting (14%), AST increased (12%), hyperglycemia (10%), ALT increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for platinum-based chemotherapy.

Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), AST increased and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%) and fatigue (7%). Clinically relevant adverse reactions (<15%) include vomiting (13%), AST increased (12%), lipase increased (11%), ALT increased (10%), pneumonitis (4%) and infusion site extravasation (1%).

Drug Interactions

Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)

Concomitant use with a dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and 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.

For more information, please see the full Prescribing Information including BOXED WARNING for PADCEV here.

About KEYTRUDA^® (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA^® (pembrolizumab) Indications in the U.S.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

• who are not eligible for any platinum-containing chemotherapy, or
• who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis.

Seagen Contacts:
For Media
David Caouette
(310) 430-3476
dcaouette@seagen.com

For Investors
Peggy Pinkston
(425) 527-4160
ppinkston@seagen.com

Astellas Contacts:
For Media
Cassie Hogenkamp
(847) 942-0980
cassie.hogenkamp@astellas.com

For Investors
Astellas Pharma Inc.
Corporate Advocacy & Relations
+81-3-3244-3202

Merck Contacts:
For Media
Melissa Moody
(215) 407-3536

Chrissy Trank
(640) 650-0694

For Investors
Peter Dannenbaum
(908) 740-1037

Damini Chokshi
(908) 740-1807