– Risk of death was reduced by 53% in patients treated with enfortumab vedotin plus pembrolizumab compared to chemotherapy –

– Enfortumab vedotin plus pembrolizumab improved median overall survival by more than 15 months vs. chemotherapy –

– Results will form the basis of global regulatory submissions –

BOTHELL, Wash. & TOKYO--(BUSINESS WIRE)--Seagen Inc. (Nasdaq: SGEN) and Astellas Pharma Inc. (TSE:4503 “Astellas”) today announced results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) for PADCEV^® (enfortumab vedotin-ejfv) in combination with KEYTRUDA^® (pembrolizumab) versus chemotherapy. The combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). The findings were presented at the European Society for Medical Oncology (ESMO) Congress 2023 as part of the Presidential Session (Abstract #LBA6).

The EV-302 study met its dual primary endpoints of OS and PFS, compared to platinum and gemcitabine chemotherapy. Patients treated with enfortumab vedotin and pembrolizumab experienced:

• Median OS of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) in the chemotherapy arm.​
  • Significantly prolonged OS, reducing the risk of death by 53% compared to treatment with chemotherapy (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001).
• An Independent Data Monitoring Committee determined that OS crossed the pre-specified efficacy boundary at interim analysis.
• Median PFS of 12.5 months (95% CI: 10.4-16.6) compared to 6.3 months (95% CI: 6.2-6.5) in the chemotherapy arm.
  • 55% reduction in the risk of cancer progression or death compared to treatment with chemotherapy (HR=0.45; 95% CI: (0.38-0.54); P<0.00001).
• Consistent OS results across all pre-defined subgroups, including cisplatin eligibility and PD-L1 expression level.

The most common (≥3%) Grade 3 or higher adverse events (AEs) related to treatment with enfortumab vedotin and pembrolizumab were rash maculo-papular, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. The safety results in EV-302 are consistent with those previously reported with this combination in EV-103 in cisplatin-ineligible patients with la/mUC. No new safety issues were identified.

Please see Important Safety Information at the end of this press release, including BOXED WARNING for PADCEV (enfortumab vedotin-ejfv).

Roger Dansey, M.D.​, President, Research and Development, Seagen​

“The combination of enfortumab vedotin and pembrolizumab, if approved, represents a potential paradigm shift in the treatment of metastatic urothelial cancer. The results of this historic trial presented today show improvements in overall survival and progression free survival not previously achieved in a broad population of patients.”

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas​

“The remarkable findings presented today demonstrate that the combination of enfortumab vedotin and pembrolizumab could offer longer survival and more time without disease progression for patients with advanced urothelial cancer. The presentation of this data is an important milestone for this patient population, and we look forward to continued discussions with regulatory authorities as we work to expedite bringing this therapy to those who need it most.”

Thomas Powles, M.R.C.P., M.D., Professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London; EV-302 Primary Investigator​

“An advanced urothelial cancer diagnosis is difficult for patients and their families, and physicians have limited treatment options for these patients. The results of this Phase 3 trial are unlike any we have seen so far and open a new chapter in advanced urothelial cancer treatment. This presents a great opportunity for this medicine to make a meaningful impact on advanced urothelial cancer patients, who face an urgent need for new therapies.”

Among secondary endpoints, results demonstrated a 68% confirmed objective response rate (ORR) (95% CI: 63.1-72.1, P<0.00001) in patients treated with enfortumab vedotin plus pembrolizumab, versus an ORR of 44% (95% CI: 39.7-49.2) in patients treated with chemotherapy. In the enfortumab vedotin plus pembrolizumab arm, 29.1% of patients experienced a complete response, and 38.7% of patients experienced a partial response, compared with 12.5% and 32.0% in the chemotherapy arm, respectively. The median duration of response (DOR) was not reached in the enfortumab vedotin plus pembrolizumab arm, versus 7 months (95% CI: 6.2-10.2, P<0.00001) in the chemotherapy arm.

The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.

The EV-302 trial is intended to serve as the basis for global submissions and as the confirmatory trial for the U.S. accelerated approval of this combination. In April 2023, the U.S. Food and Drug Administration (FDA) granted an accelerated approval to PADCEV in combination with KEYTRUDA for the treatment of adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy based on tumor response rate and durability of response from the EV-103 trial. The EV-302 trial is part of an extensive program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Topline results of the EV-302 trial were announced in September 2023.

About Bladder and Urothelial Cancer

• Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.¹
• If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease. ²
• Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.³
• It is estimated that approximately 82,290 people in the U.S. will be diagnosed with bladder cancer in 2023.⁴
• It is estimated that approximately 200,000 people in Europe and 24,000 people in Japan are diagnosed with bladder cancer annually. ^5,6
• Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. ²
• Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.⁷

Ongoing Investigational Trials

The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating the impact of treatment with enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC).

Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and in MIBC has not been proven safe or effective.

The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma.

About PADCEV^® (enfortumab vedotin-ejfv)

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.⁸ 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 (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^®, as a single agent, 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.¹

PADCEV, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin-containing chemotherapy.¹

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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 56% (all grades) of the 753 patients treated with PADCEV as a single agent in clinical trials. Twenty-four percent (24%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 12% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.7 months (range: 0.1 to 6 months). 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.

When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate. Skin reactions occurred in 72% (all grades) of the 121 patients treated with PADCEV in combination with pembrolizumab in clinical trials. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 20% of patients (Grade 3: 19%, Grade 4: 0.8%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.8%). The median time to onset of severe skin reactions was 2.6 months (range: 0.3 to 16 months). Skin reactions led to discontinuation of PADCEV in 6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia and diabetic ketoacidosis (DKA). 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 of PADCEV as a single agent, 14% of the 753 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. Fatal events of hyperglycemia and diabetic ketoacidosis occurred in one patient each (0.1%). 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 months). Hyperglycemia led to discontinuation of PADCEV in 0.4% 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/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. In clinical trials of PADCEV as a single agent, 2.9% of the 753 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of pneumonitis/ILD was 2.7 months (range: 0.6 to 6 months). The incidence of pneumonitis/ILD, including severe events occurred at a higher rate when PADCEV was given in combination with pembrolizumab. When PADCEV was given in combination with pembrolizumab, 9% of the 121 patients treated with combination therapy had pneumonitis/ILD of any grade and 3.3% had Grade 3. A fatal event of pneumonitis occurred in one patient (0.8%). The median time to onset of pneumonitis/ILD was 6 months (range: 0.6 to 26 months). Monitor patients for signs and symptoms indicative of pneumonitis/ILD 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 Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD.

Peripheral neuropathy (PN) Peripheral neuropathy occurred in 53% of the 753 patients treated with PADCEV as a single agent in clinical trials including 40% with sensory neuropathy, 7% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. Peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥2 peripheral neuropathy was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 7% of patients. Of the patients who experienced neuropathy who had data regarding resolution (N = 319), 14% had complete resolution, 46% had partial improvement, and 40% had no improvement at the time of their last evaluation. Of the 86% of patients with residual neuropathy at last evaluation, 51% had Grade 2 or greater neuropathy at the time of their last evaluation. The incidence of peripheral neuropathy occurred at a higher rate when PADCEV was given in combination with pembrolizumab. When PADCEV was given in combination with pembrolizumab, 65% of the 121 patients treated with combination therapy had peripheral neuropathy of any grade, 45% had Grade 2 neuropathy, and 3.3% had Grade 3 neuropathy. The median time to onset of Grade ≥2 peripheral neuropathy was 6 months (range: 0.3 to 25 months). 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 who develop Grade ≥3 peripheral neuropathy.

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent 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 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 753 patients treated with PADCEV as a single agent in clinical trials, 1.5% 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%) (PADCEV monotherapy)

Rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase 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 cisplatin-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%).

EV-103 Study: 121 patients with previously untreated locally advanced or metastatic urothelial cancer who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab)

The most common adverse reactions, including laboratory abnormalities (≥20%), of PADCEV in combination with pembrolizumab were glucose increased, aspartate aminotransferase increased, rash, hemoglobin decreased, creatinine increased, peripheral neuropathy, lymphocytes decreased, fatigue, alanine aminotransferase increased, sodium decreased, lipase increased, albumin decreased, alopecia, phosphate decreased, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, potassium decreased, neutrophils decreased, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.

Contacts

Seagen Contacts:
For Media
David Caouette

Vice President, Corporate Communications

(310) 430-3476

[email protected]

For Investors
Douglas Maffei, Ph.D.

Vice President, Investor Relations & ESG

(425) 527-4881

[email protected]

Astellas Contacts:
For Media
Elysia Wood

(703) 722-4656

[email protected]

For Investors
Astellas Pharma Inc.

Corporate Communications

+81-3-3244-3202

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