Category: 3. Business

• First and only combination regimen to improve survival when used before and after surgical cystectomy in cisplatin-ineligible patients with muscle-invasive bladder cancer
• Unprecedented survival results from pivotal Phase 3 EV-303 trial show potential for PADCEV plus KEYTRUDA to redefine standard of care

TOKYO and NEW YORK, Oct. 18, 2025 /PRNewswire/ — Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, “Astellas”) and Pfizer Inc. (NYSE: PFE) today announced positive results from the pivotal Phase 3 EV-303 clinical trial (also known as KEYNOTE-905) for PADCEV^™ (enfortumab vedotin), a Nectin-4 directed antibody-drug conjugate, in combination with KEYTRUDA^™ (pembrolizumab), a PD-1 inhibitor. The study evaluated the combination in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or declined cisplatin-based chemotherapy. PADCEV plus KEYTRUDA significantly improved event-free survival (EFS) and overall survival (OS) when used as a neoadjuvant and adjuvant treatment (before and after surgery) versus the current standard of care—surgery alone. Results from the EV-303 trial will be presented today in a Presidential Symposium (Abstract #LBA2) at the 2025 European Society of Medical Oncology (ESMO) Congress in Berlin, Germany.

At the first interim efficacy analysis, results from the primary endpoint of EFS showed a 60% reduction in the risk of tumor recurrence, progression or death for patients treated with neoadjuvant and adjuvant PADCEV plus KEYTRUDA as compared to surgery alone (Hazard Ratio (HR) of 0.40; 95% Confidence Interval (CI), 0.28-0.57; p<0.0001). The estimated median EFS has not yet been reached for the combination arm versus 15.7 months for the surgery alone arm. An estimated 74.7% of patients treated with the combination were event free at two years, relative to 39.4% of patients who received surgery only.

Results from the key secondary endpoint of OS showed a 50% reduction in the risk of death for neoadjuvant and adjuvant PADCEV plus KEYTRUDA as compared to surgery alone (HR of 0.50; 95% CI, 0.33-0.74; p<0.0002). The estimated median OS has not yet been reached for the combination arm versus 41.7 months for the surgery arm. An estimated 79.7% of patients were alive at two years relative to 63.1% of patients who received surgery only.

Consistent EFS and OS benefits were seen across all pre-defined subgroups, including age, gender, smoking status and PD-L1 status as well as protocol-defined stratification groups based on cisplatin ineligibility (ineligible vs eligible but declined), clinical stage and geographic region.

The safety results in EV-303 were consistent with those previously reported for this combination. The most common (≥30%) adverse events (AEs) reported in the neoadjuvant and adjuvant PADCEV plus KEYTRUDA arm were pruritus (itching), alopecia, diarrhea, fatigue and anemia. Grade ≥ 3 AEs due to any cause occurred in 71.3% of patients treated in the combination arm and 45.9% of patients who received surgery only.

Christof Vulsteke, M.D., Ph.D., Head of Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent and EV-303 Principal Investigator
“For decades, patients with muscle-invasive bladder cancer who are ineligible for cisplatin treatment have faced limited treatment options, often relying on surgery alone. The groundbreaking benefits seen in the KEYNOTE-905/EV-303 trial at this early interim analysis position the pembrolizumab and enfortumab vedotin combination to fundamentally change the way we approach the treatment of patients with this disease.”

For the secondary endpoint of pathologic complete response (pCR), treatment with neoadjuvant PADCEV plus KEYTRUDA demonstrated a 57.1% pCR rate versus an 8.6% pCR rate for patients who received surgery only (estimated difference 48.3%; 95% CI 39.5-56.5; p<0.000001).

Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Head of Oncology Development, Astellas
“The compelling EV-303 results may establish a new efficacy benchmark in muscle-invasive bladder cancer. For the first time, a systemic treatment approach used before and after surgery has improved survival over standard surgery in cisplatin-ineligible patients. These data underscore the transformative potential of PADCEV plus KEYTRUDA as we continue to explore this combination in a broad population of patients with muscle-invasive bladder cancer.”

Jeff Legos, Ph.D., M.B.A., Chief Oncology Officer, Pfizer
“The ability of PADCEV plus KEYTRUDA to reduce the risk of death by half in this setting is a remarkable advancement for patients who have seen limited treatment options and often face poor prognosis. These unprecedented results suggest that the transformational efficacy of this combination in advanced bladder cancer may extend into an earlier disease setting, potentially providing a life-changing impact for patients.”

Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 patients each year globally.¹ MIBC represents approximately 30% of all bladder cancer cases.² The standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which has been shown to prolong survival.³ However, up to half of patients with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery without any systemic treatment.³

PADCEV plus KEYTRUDA is not currently approved for use as neoadjuvant and adjuvant treatment in cisplatin-ineligible patients with MIBC. These results will be discussed with global health authorities for potential regulatory filings. Neoadjuvant and adjuvant PADCEV plus KEYTRUDA is also being evaluated in cisplatin-eligible patients with MIBC in the EV-304 Phase 3 clinical trial (also known as KEYNOTE-B15).

The EV-303 trial is continuing to evaluate the secondary EFS, OS and pCR rate endpoints for neoadjuvant and adjuvant KEYTRUDA monotherapy versus surgery alone as they continue to mature.

About the EV-303/KEYNOTE-905 Trial
The EV-303 trial (also known as KEYNOTE-905) is an ongoing, open-label, randomized, three-arm, controlled, Phase 3 study evaluating neoadjuvant and adjuvant PADCEV plus KEYTRUDA or neoadjuvant and adjuvant KEYTRUDA versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. Patients were randomized to receive either neoadjuvant and adjuvant KEYTRUDA (arm A), surgery alone (arm B) or neoadjuvant and adjuvant PADCEV plus KEYTRUDA (arm C).⁴

The primary endpoint of this trial is EFS between arm C and arm B, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) surgery or failure to undergo RC surgery in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy or death due to any cause. Key secondary endpoints include OS and pCR rate between arm C and arm B, as well as EFS, OS and pCR rate between arm A and arm B.⁴

For more information on the global EV-303 trial, go to clinicaltrials.gov.

About PADCEV^™ (enfortumab vedotin)
PADCEV^™ (enfortumab vedotin) 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 plus KEYTRUDA is approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) regardless of cisplatin eligibility in the United States, Japan, and a number of other countries around the world. In the European Union, the combination is approved for the treatment of adult patients with la/mUC who are eligible for platinum-containing chemotherapy. PADCEV is also approved as a single agent for the treatment of adult patients with la/mUC who have previously received a PD-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

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^®, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).

PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or 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.

PADCEV 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 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. 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 17% of patients (Grade 3: 16%, Grade 4: 1%), 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 (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients.

Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% 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 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% 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), 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, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA 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. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. 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. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months).

In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 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) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months).

PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% 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 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients.

Monitor patients for symptoms of new or worsening PN 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 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 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 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 720 patients treated with PADCEV as a single agent in clinical trials, 1% 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 in combination with pembrolizumab)
Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets.

Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy)
Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin.

EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab)
Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%).

EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab)
Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%). Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%). Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%) were PN (20%) and rash (6%). Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%) were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%).

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy (PADCEV monotherapy)
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%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, 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).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy)
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/ILD (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%), increased AST, 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%).

DRUG INTERACTIONS
Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)
Concomitant use with 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 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 U.S. full Prescribing Information including BOXED WARNING for PADCEV here .

About Astellas
Astellas is a global life sciences company committed to turning innovative science into VALUE for patients. We provide transformative therapies in disease areas that include oncology, ophthalmology, urology, immunology and women’s health. Through our research and development programs, we are pioneering new healthcare solutions for diseases with high unmet medical need. Learn more at www.astellas.com.

About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and multispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives.

About the Pfizer, Astellas and Merck Collaboration
Seagen and Astellas previously entered a clinical collaboration agreement with Merck to evaluate the combination of Seagen’s and Astellas’ PADCEV^™ (enfortumab vedotin) and Merck’s KEYTRUDA^™ (pembrolizumab) in patients with muscle-invasive bladder cancer (MIBC) who are not eligible for or declined cisplatin-based chemotherapy. Pfizer Inc. successfully completed its acquisition of Seagen on December 14, 2023. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada).

Astellas Cautionary Notes
In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management’s current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas’ intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice.

Pfizer Disclosure Notice
The information contained in this release is as of October 18, 2025. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or fu ture events or developments.

This release contains forward-looking information about Pfizer Oncology and PADCEV^™ (enfortumab vedotin) in combination with pembrolizumab in cisplatin-ineligible patients with muscle-invasive bladder cancer, including their potential benefits and plans to present the Phase 3 EV-303 clinical trial results at the 2025 European Society of Medical Oncology Congress and discuss the Phase 3 EV-303 clinical trial results with global health authorities for potential regulatory filings that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risk and uncertainties include, among other things, uncertainties regarding the commercial  success of enfortumab vedotin; the uncertainties inherent in research and development, including the a bility to meet anticipated clinical endpoints (and continuing evaluation of endpoints), commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; risks associated with interim data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory autho rities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when any applications may be filed with regulatory authorities in particular jurisdictions for any potential indication for enfortumab vedotin with pembrolizumab or as a single agent ; whether and when any applications that may be pending or filed for enfortumab vedotin with pembrolizumab or as a single agent  may be approved by regulatory authorities, which will depend on myriad factors, inclu ding making a determination as to whether the product’s benefits outweigh its known risks and determination of the product’s efficacy and, if approved, whether enfortumab vedotin with pembrolizumab or as a single agent will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of enfortumab vedotin with pembrolizumab or as a single agent; whether the collaboration between Pfizer, Astellas and Merck will be successful; risks and uncertainties related to issued or future executive orders or other new, or changes in, laws or regulations; uncertainties regarding the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2024, and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov  and www.pfizer.com .

SOURCE Astellas Pharma Inc.

The combination of datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) and rilvegostomig demonstrated potent antitumor activity as first-line therapy in cisplatin-ineligible and second-line therapy in platinum-pretreated patients with locally advanced or metastatic urothelial cancer, according to data from cohort 6B of the phase 2 TROPION-PanTumor03 trial (NCT05489211) presented at the 2025 ESMO Congress.¹

In the first-line cohort (n = 22), the confirmed objective response rate (ORR) was 68.2% (95% CI, 45.1%-86.1%), and the 12-week disease control rate (DCR) was 95.5% (95% CI, 83.4%-99.5%). The median time to response was 1.4 months (range, 1.2-3.9), and the median duration of response (DOR) was not calculable ([NC] 95% CI, 9.4 months to NC). In the second-line cohort (n = 18), the confirmed ORR was 38.9% (95% CI, 17.3%-64.3%), and the 12-week DCR was 83.3% (95% CI, 66.6%-93.7%). The median time to response was 1.3 months (range, 1.2-8.4), and the median DOR was NC (95% CI, 6.9 months to NC).

“The combination of Dato-DXd plus rilvegostomig demonstrated promising efficacy in patients with locally advanced or metastatic urothelial cancer who were cisplatin-ineligible and patients who had progressed on prior platinum-based chemotherapy,” lead study author Sun Young Rha, MD, PhD, professor of medical oncology in the Department of Internal Medicine and the director of Songdang Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System in Seoul, Korea, stated in the presentation.

Main Findings From Cohort 6B of the TROPION-PanTumor03 Trial

• Cisplatin-ineligible patients experienced an ORR of 68.2% and median PFS that was not calculable.

• Platinum-pretreated patients experienced an ORR of 38.9% and median PFS of 12.5 months.

• Adverse effects of special interest for dato-DXd included oral mucositis/stomatitis, ocular surface events, and adjudicated drug-related interstitial lung disease/pneumonitis.

What Was TROPION-PanTumor03 Designed to Answer?

Despite the evolution in first- and second-line treatments for patients with locally advanced or metastatic urothelial cancer, a clinical need remains for effective therapy. Dato-DXd is a TROP2-directed antibody-drug conjugate (ADC) and rilvegostomig is an Fc-reduced, monovalent, bispecific IgG1 antibody directed against PD-1 and TIGIT receptors.

TROPION-PanTumor03 is an open-label trial evaluating dato-DXd as monotherapy or in combination with anticancer agents in patients with advanced or metastatic solid tumors.²

Investigators enrolled patients with histologically confirmed, unresectable, locally advanced or metastatic urothelial cancer who had not received prior PD-(L)1, CTLA-4, or TIGIT inhibitors, enfortumab vedotin-ejfv (Padcev), or TROP2-directed or deruxtecan-based ADCs.¹ Patients had to be cisplatin-ineligible in the first-line setting or platinum-treated in the second line. Patients in the former cohort also had to have either an ECOG performance status between 0 and 2, creatinine clearance of at least 30 mL/min but less than 60 mL/min, NCI CTCAE 5.0 grade 2 or greater hearing loss, or NCI CTCAE 5.0 grade 2 or greater peripheral neuropathy. Patients in the latter cohort had to also have an ECOG performance status of 0 or 1.

Forty patients received 6 mg/kg of intravenous dato-DXd every 3 weeks plus 750 mg of rilvegostomig every 3 weeks in the first- and second-line cohorts. In the first-line cohort, the median age was 71 years (range, 53-85). Most patients were male (77.3%), had an ECOG performance status of 0 (77.3%), and had AJCC stage IV disease (86.4%). Most patients were untreated (86.4%), although some had received neo(adjuvant) cisplatin therapy (13.6%). In the second-line cohort, the median age was 66 years (range, 56-78). Most patients were male (83.3%), had an ECOG performance status of 0 (72.2%), and had AJCC stage IV disease (88.9%). Most patients had received 1 prior line of therapy (61.1%), with cisplatin (88.9%) being the most common.

The primary end points were investigator assessed ORR per RECIST 1.1 criteria, safety, and tolerability. Secondary end points were DCR, DOR, and investigator assessed progression-free survival (PFS) per RECIST 1.1 criteria.

How Durable Were the Responses?

In the first-line cohort, the median PFS was NC (95% CI, 10.8 months to NC) at median follow-up of 10.8 months (range, 2.6-19.4); the 6- and 12-month PFS rates were 85.9% (95% CI, 62.4%-95.2%) and 73.5% (95% CI, 46.5%-88.4%), respectively. In the second-line cohort, the median PFS was 12.5 months (95% CI, 4.2-NC) at median follow-up of 9.7 months (range, 8.1-17.8); the 6- and 12-month PFS rates were 72.2% (95% CI, 45.6%-87.4%) and 60.0% (95% CI, 33.7%-78.7%), respectively.

Was the Regimen Well Tolerated?

In the first- and second-line cohorts, respectively, treatment-related adverse effects (TRAEs) led to dose reduction (63.6% vs 22.2%), interruption (45.5% vs 33.3%), and discontinuation (9.1% vs 16.7%).

“The safety profile of Data-DXd plus rilvegostomig was consistent with previous reports of this combination. No new safety signals were identified,” Rha stated.

Adverse effects of special interest (AESIs) for Dato-DXd in the first-line cohort included oral mucositis/stomatitis (any grade, 40.9%; grade ≥3, 0%), ocular surface events (any grade, 18.2%; grade ≥3, 0%), and adjudicated drug-related interstitial lung disease (ILD)/pneumonitis (any grade, 4.5%; grade ≥3, 0%). AESIs for rilvegostomig included hepatic events (any grade, 13.6%; grade ≥3, 0%), diarrhea/colitis (any grade, 4.5%; grade ≥3, 0%), dermatitis/rash (any grade, 50.0%; grade ≥3, 0%), and infusion-related reaction/hypersensitivity reaction (any grade, 9.1%; grade ≥3, 0%).

AESIs for Dato-DXd in the second-line cohort included oral mucositis/stomatitis (any grade, 61.1%; grade ≥3, 5.6%), ocular surface events (any grade, 22.2%; grade ≥3, 0%), and adjudicated drug-related ILD/pneumonitis (any grade, 11.1%; grade ≥3, 0%). AESIs for rilvegostomig included hepatic events (any grade, 5.6%; grade ≥3, 5.6%), diarrhea/colitis (any grade, 5.6%; grade ≥3, 0%), and dermatitis/rash (any grade, 44.4%; grade ≥3, 0%).

The most common TRAEs that occurred in at least 10% of patients in the first- and second-line cohorts, respectively, were stomatitis (40.9% vs 50.0%), nausea (18.2% vs 44.4%), asthenia (40.9% vs 5.6%), fatigue (13.6% vs 33.3%), rash (31.8% vs 0%), amylase increase (22.7% vs 56.7%), decreased appetite (22.7% vs 16.7%), constipation (22.7% vs 11.1%), pruritus (13.6% vs 22.2%), decreased neutrophil count/neutropenia (4.5% vs 22.2%), alopecia (18.2% vs 16.7%), anemia (9.1% vs 16.7%), dry eye (13.6% vs 5.6%), aspartate aminotransferase increase (13.6% vs 0%), and dry mouth (0% vs 11.1%).

“These results warrant further exploration of Dato-DXd plus rilvegostomig in the first-line locally advanced or metastatic setting,” Rha concluded.

Disclosures: Rha reported being a consultant or advisor for Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Eisai, Jazz, Daiichi Sankyo, Gilead, Indivumed, LG Chem, MSD Oncology, Ono Pharmaceutical, and Toray Inc; speaker for Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb/Ono, Daiichi Sankyo, Eisai, BeOne, and MSD Oncology; and research funding from Amgen (inst), ASLAN Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BeOne, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Indivumed, Eli Lilly, Gilead, MSD Oncology, Roche/Genentech, Sillajen, and Jazz.

References

1. Young Rha S, Lim SH, Zhou F, et al. Datopotamab deruxtecan (Dato-DXd) + rilvegostomig (rilve) in patients (pts) with locally advanced or metastatic urothelial cancer (a/mUC): results from the phase 2 TROPION-PanTumor03 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 3072MO.
2. Study of dato-DXd as monotherapy and in combination with anti-cancer agents in patients with advanced solid tumors (TROPION-PanTumor03). ClinicalTrials.gov. Updated July 11, 2025. Accessed October 18, 2025. https://www.clinicaltrials.gov/study/NCT05489211

Paramount Skydance will begin mass layoffs the week of 27 October, eliminating about 2,000 US jobs as part of a $2bn cost-cutting plan under new chief executive David Ellison, Variety reported on Saturday.

The layoffs follow the $8.4bn merger between Skydance Media and Paramount Global, which closed in August.

Additional international job cuts are expected, with the company aiming to disclose full details in its third quarter earnings report on 10 November, the report added.

Variety had reported on 22 August that Paramount was looking to cut between 2,000 and 3,000 jobs by early November.

As of December 2024, Paramount had nearly 18,600 full- and part-time employees, and 3,500 project-based staff.

Paramount Skydance did not immediately respond to a Reuters request for comment.

By Mark Hulbert

Fed plans to end its ‘quantitative tightening’ – but stocks do better under those conditions

Federal Reserve Chair Jerome Powell said the central bank will end its bond purchases soon.

The economy and the stock market may eventually respond favorably to the change of policy, but if history is any guide, things will get worse before they get better.

U.S. Federal Reserve Chair Jerome Powell has announced that the Fed will soon end its balance sheet reduction program, known as quantitative tightening, or QT. But this policy shift isn’t the bullish stock-market driver most investors believe it is.

Of course, the Fed’s decision is meaningful; the central bank has been draining a large amount of liquidity from the financial system. Since some of that liquidity otherwise would have found its way into equities, QT presumably has been a significant headwind for the stock market: Since June 2022 the Fed has shrunk its balance sheet by $2.2 trillion. It seems plausible that ending it should provide a big boost for the stock market.

Yet history suggests just the opposite. Over the past two decades, the stock market has done better during QT periods than when the Fed was injecting liquidity into the markets – quantitative easing (QE).

Just take the most recent QT phase since June 2022. During this period in which the Fed drained $2.2 trillion from the financial market, the S&P 500’s SPX total return index has risen at the annualized rate of 20.9%, about twice its historical average.

This recent experience is the rule rather than the exception. Since 2003, the S&P 500’s average gain has been 16.9% during 12-month periods in which the Fed’s balance sheet was shrinking. That compares to an average gain of 10.3% during 12-month periods in which the Fed’s balance sheet was expanding.

What is the source of this inverse correlation between Fed balance sheet growth and the stock market? It has to do with what’s going on in the U.S. economy when the Fed decides to expand or shrink its balance sheet. When the economy is slumping, the Fed will flood the markets with liquidity in hopes of turning the ship around. Since that takes time, the economy typically will weaken while the Fed is expanding its balance sheet.

Notice from the chart above that the Fed hugely boosted its balance sheet during the 2008 Global Financial Crisis and during the recession that accompanied the Covid-19 pandemic lockdown. The stock market suffered severe bear markets during those times of QE.

The same story in reverse applies to the past couple of years. It was precisely because the economy was so strong that the Fed felt comfortable draining liquidity from it.

This puts a surprisingly bearish spin on Powell’s announcement this week that the central bank was ending the three-plus year period of QT. This suggests we’re entering a period of economic weakness. The economy and the stock market may eventually respond favorably to the change of policy, but if history is any guide, things will get worse before they get better.

Mark Hulbert is a regular contributor to MarketWatch. His Hulbert Ratings tracks investment newsletters that pay a flat fee to be audited. He can be reached at mark@hulbertratings.com

Also read: Not every dip is a buying opportunity. Here’s how to think about future stock-market pullbacks.

More: Bitcoin just lost more than stocks did in the 1929 market crash. It won’t be the last time.

-Mark Hulbert

This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

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  10-18-25 0958ET
Copyright (c) 2025 Dow Jones & Company, Inc.

By Jurica Dujmovic

Tokenization is unlikely to make you rich overnight. But it could make your portfolio more transparent, liquid and efficient.

Tokenized blockchain assets surged to more than $30 billion in 2025 from under $10 billion in 2023, according to on-chain data.

For individual investors, safe, accessible choices are narrower than the headlines suggest.

For years, blockchain boosters have promised that everything of value will move “on-chain.” In 2025, that futuristic vision is starting to look less like a slogan and more like a market trend. From tokenized U.S. Treasury bills to private-equity feeder funds, real-world assets (RWAs) are now being tokenized, traded and settled on blockchains, and slowly being made available to ordinary investors.

So, what does “tokenizing” an asset actually mean? Think of it as turning the investment ownership rights – for example, shares in a money-market fund or a slice of a private-equity vehicle – into a digital token that lives on a blockchain. Instead of relying on old-school paperwork, transfer agents, or settlement systems that take days, the token itself acts as the proof of ownership and can move instantly between approved investors.

In short: It’s the same underlying asset, but with a new digital wrapper that should make it easier to buy, sell and track in real time.

A market that has quietly hit tens of billions of dollars

Tokenized blockchain assets surged to more than $30 billion in 2025 from under $10 billion in 2023, according to on-chain data. Treasury-backed tokens alone accounted for $5.5 billion in April 2025, making them one of the largest and fastest-growing categories.

Who’s actually delivering products? Several financial firms have moved beyond pilot projects:

— Franklin Templeton BEN records shares of its U.S. Government Money Fund on blockchains including Polygon and Stellar. Retail investors in select markets can buy through its Benji app. The firm also launched a tokenized UCITS fund in Luxembourg.

— WisdomTree WT has built a blockchain-enabled transfer agent, WisdomTree Transfers, and offers digital funds through its WisdomTree Prime app, available in certain U.S. states.

— J.P. Morgan’s JPM Onyx unit operates the Tokenized Collateral Network, which enables institutions to move collateral more efficiently. It also took part in a cross-chain pilot with the DTCC to publish fund net asset values on-chain.

— Ondo Finance, a startup, issues tokenized Treasuries (OUSG) and yield products that have drawn over a billion dollars.

— Superstate, founded by Compound’s Robert Leshner, runs a tokenized short-term Treasury fund (USTB) and a new on-chain issuance venue for securities.

— Backed Finance issues tokenized tracker certificates on ethereum ETHUSD and Base, including tokens that mirror U.S. Treasury ETFs.

— Hamilton Lane, through Securitize, now offers tokenized feeder funds into private equity with minimums as low as $20,000 – down from the multimillion thresholds institutions typically face.

For investors, these initiatives span the spectrum: Some are strictly institutional, some are open to accredited investors, and a few – like Franklin’s Benji or WisdomTree Prime – are starting to reach the mass market.

Where tokenization works best today

The most obvious success story is short-term government debt. Tokenized money-market style funds can settle almost instantly, move 24/7, and publish holdings or NAV on-chain in real time. DTCC’s 2024 pilot with Chainlink demonstrated how fund data could be broadcast across multiple blockchains, paving the way for broader use in brokerage and retirement accounts.

Private-market funds have also seen momentum: By fractionalizing feeder vehicles, managers can broaden their investor base. But those products remain limited to accredited or qualified buyers.

Real estate has been a tougher category. For example, a company called RealT had promised investors fractional ownership of Detroit rental homes, with rental income streamed on-chain. However, a series of property management and compliance issues soon emerged, showing that tokenization can change the wrapper, but it can’t fix the off-chain realities of property management and landlord responsibilities.

What this means for you

The promise of tokenization – fractional access, faster settlement, and transparent record-keeping – is real. But for individual investors, safe, accessible choices are narrower than the headlines suggest.

— If you want tokenized cash or T-bill exposure, check whether you can access apps like WisdomTree Prime or Franklin’s Benji. These sit within regulated fund frameworks but use blockchains under the hood.

— If you are comfortable with KYC’d crypto rails, projects like Ondo Finance or Backed offer tokenized Treasury exposure. Keep in mind these tokens often restrict transfers to whitelisted wallets and can be frozen to meet securities rules.

— If you are an accredited investor, tokenized private-equity feeders may offer lower minimums but come with the usual long lockups and risk profile.

— If you are curious about real-estate tokens, diligence matters more than the tech. You’re still dependent on property managers to collect rent, fix boilers and pay taxes.

In other words, tokenization doesn’t change the fundamental question: What exactly are you buying, and who stands behind it?

Why it matters

Behind the jargon, tokenization addresses real frictions in finance. Traditional settlement is T+2 for equities and T+1 for many funds and bonds. Tokenized assets can settle nearly instantly, eliminating many “failed” trades and cutting collateral needs. J.P. Morgan’s blockchain unit Kinexys has shown how atomic settlement of cash and tokenized assets can work in repo and collateral markets. And in Singapore, the central bank’s Project Guardian has expanded from pilots to broader industry collaborations.

Programmable smart contracts also allow for continuous accrual of interest, automatic fee distribution, and even real-time auditability. Some issuers now publish funds’ net asset value (NAV) directly to blockchains on a near-continuous basis.

The speed bumps

Regulation remains the main constraint. In Europe, the new Markets in Crypto-Assets (MiCA) law is fully in force, but excludes tokenized securities, which still fall under MiFID II. Hong Kong’s Securities and Futures Commission has issued circulars on tokenized products. Singapore’s Monetary Authority is moving pilots toward real frameworks. Translation: these products are governed by securities law first, crypto second.

Standardization is another challenge. Citigroup (C), Deutsche Bank (DB) and others have called for global frameworks to avoid fragmentation as tokenized funds proliferate.

And finally, risk doesn’t vanish. Smart contracts can be buggy; custodial wallets can fail; and the underlying asset – whether a Treasury bill or a rental house – still carries its traditional risks.

Read: Some of the largest exchanges and financial institutions are embracing betting platforms and crypto. Is it just for the fees?

What to watch next

For retail investors, the next few years may bring more mainstream wrappers: brokerages tapping into tokenized money-market funds, ETFs recording shares on-chain, and possibly retirement products with tokenized back-ends. The underlying technology is being laid now.

Tokenization is unlikely to make you rich overnight. But it could make your portfolio more transparent, liquid and efficient. For now, the smartest approach is to treat tokenized assets the way you would any new product: Read the disclosures, know the legal wrapper and understand the risks. The tech may be new; the investor’s homework is the same as ever.

More: ‘We’re in a market bubble based on AI exuberance’: I’m moving my $200K IRA to a money-market account. Is that wise?

Also read: AI isn’t the solution to financial fraud – it actually might be the biggest problem

-Jurica Dujmovic

This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

  (END) Dow Jones Newswires

  10-18-25 0958ET
Copyright (c) 2025 Dow Jones & Company, Inc.

Treatment with belzutifan (Welireg) plus pembrolizumab (Keytruda) and lenvatinib (Lenvima) improved efficacy outcomes compared with multiple other pembrolizumab-based triplet regimens in patients with advanced clear cell renal cell carcinoma (ccRCC), according to findings from substudy 3A of the phase 1/2 KEYMAKER-U03 trial (NCT04626479) presented at the 2025 ESMO Congress.

Providing the background for the study, Cristina Suarez Rodriguez, MD, PhD, of Vall d’Hebron University Hospital, Barcelona, Spain, said, “First-line triplet regimens adding novel mechanisms of action to standard doublet therapy may be a promising approach for advanced clear cell renal cell carcinoma…The potent and selective HIF-2α inhibitor belzutifan is a treatment for advanced RCC following prior anti-PD-(L1) and VEGFR-TKI therapy, and may be a highly suitable candidate for novel triplet therapy in the first-line setting.”

For substudy 3A (NCT04626479) of the umbrella phase 1/2 KEYMAKER-U03 trial, investigators sought to evaluate novel pembrolizumab-based regimens as first-line treatment for advanced ccRCC.

“The study employed an adaptive design in which experimental arms were added and/or inactivated on a rolling basis with a continuous enrolling reference arm. Experimental arms each had a safety lead-in phase of 10 patients,” Suarez Rodriguez explained.

Patients with histologically confirmed locally advanced or metastatic ccRCC as measurable by RECIST v1.1, no prior systemic therapy for advanced RCC, and a KPS score of at least 70% were eligible for the study. Following the safety lead-in phase, the study entered the randomized phase. In this phase, patients were randomly assigned to 2:1 to 1 of 5 arms. Arm 1 included coformulated favezelimab/pembrolizumab 800mg/200 mg intravenously every 3 weeks, and lenvatinib 20 mg orally once daily. Arm 2 included coformulated vibostolimab/pembrolizumab 200/200 mg IV every 3 weeks plus belzutifan 120 mg orally once daily. Arm 3 included coformulated quavonlimab/pembrolizumab 25 mg/400 mg IV every 6 weeks plus lenvatinib 20 mg orally once daily. Arm 4 included belzutifan 120 mg orally once daily plus pembrolizumab 400 mg IV every 6 weeks, plus lenvatinib 20 mg orally once daily. A concurrent reference arm included pembrolizumab 400 IV every 6 weeks plus lenvatinib 20 mg orally once daily.

Primary end points were overall responsive rate (ORR) as measured by RECIST v1.1 by blinded independent central review (BICR), as well as safety. Secondary end points included duration of response (DOR) and progression-free survival by RECIST v1.1 by BICR, as well as overall survival (OS).

Suarez Rodriguez reported ORR for the arms as follows:

• Arm 1: At a median follow-up of 39.2 months (range, 28.8-44.6 months), ORR was 62.7% (95% CI: 48.1-75.9).

• Arm 2: At a median follow-up of 16.4 months (range, 11.8-23.4 months), ORR was 42.5% (95% CI: 31.5-54.1).

• Arm 3: At a median follow-up of 22.1 months (range, 13.5-40.6 months), ORR was 71.3% (95% CI: 60.0-80.8).

• Arm 4: At a median follow-up of 23.4 months (range, 14.1-41.0 months), ORR was 77.5% (95% CI: 66.8-86.1).

• Reference arm: At a median follow-up of 21.2 months (range, 11.9-44.4 months), ORR was 80.6% (95% CI: 68.6-89.6).

Complete response was observed in 5 (9.8%), 4 (5.0%), 5 (6.3%), 10 (12.5%), and 4 (6.5%) patients across the respective arms.

In arm 1, DOR and PFS were found to be numerically similar to the reference arm, Suarez Rodriguez reported. The treatment regimen of arm 2 was found to be not superior to the reference arm. For arm 3, median DOR was 25.0 months (range, 2.4-37.1+ months) in arm 3 and 25.6 months (range, 1.4+-27.6 months) in the reference arm.

Arm 4 “showed a median duration of response of 33 months vs 26 months in the reference arm,” Suarez Rodriguez said. Median PFS was 31.8 months (95% CI: 26.3-NR) in arm 4 vs 20.8 months (95% CI: 12.4-29.0) in the reference arm (HR, 0.45, 95% CI: 0.25-0.83). OS was not reached in either arm.

Suarez Rodriguez also discussed safety across the regimens. Arm 1 had the highest incidence of grade 3 or higher adverse events (AEs) (86.9%), followed by arm 3 (73.3%), the reference arm (71.0%), arm 4 (70.0%), and arm 2 (68.9%). Arm 1 had the highest rate of treatment-related AEs (37.7%), followed by arm 3 (34.4%), arm 2 (31.1%), the reference arm (30.6%), and arm 4 (24.4%). Serious treatment-related AEs were highest in arm 1 (36.1%) followed by arm 3 (34.4%), the reference arm (30.6%), arm 2 (27.8%), and arm 4 (22.2%).

“As expected, the most common adverse event observed in the combination arms containing lenvatinib was hypertension. The most common adverse event in the combinations containing belzutifan was anemia,” Suarez Rodriguez said.

“In conclusion, observed efficacy of pembrolizumab plus lenvatinib were confirmatory of prior observations for this combination. Belzutifan/pembrolizumab plus lenvatinib and the anti-CTLA-4 combination had similar overall response rate compared to pembrolizumab/lenvatinib as first-line therapy in patients with previously untreated advanced clear cell renal cell carcinoma. Responses were potentially less favorable in the anti-LAG-3 and anti-TIGIT arms. Belzutifan plus pembrolizumab plus lenvatinib, but not the other investigative arms, may have been associated with a higher proportion of complete response, prolonged duration of response, and prolonged progression-free survival compared to pembrolizumab plus lenvatinib,” Suarez Rodriguez said in her concluding remarks.

Suarez Rodriguez also noted that belzutifan plus pembrolizumab plus lenvatinib and quavonlimab/pembrolizumab plus pembrolizumab are being evaluated in the phase 3 LITESPARK-012 study (NCT047367706).

DISCLOSURES: Suarez Rodriguez noted research funding and medical writing support from Merck Sharp & Dohme (MSD) LLC; research funding from Bristol Myers Squibb, Ipsen, Pfizer, and Roche; advisory board membership with Astellas, AstraZeneca, Bristol Myers Squibb, and MSD; travel accommodations from Bayer, speakers’ bureau membership with AstraZeneca, Astellas, Bristol Myers Squibb, Ipsen, and MSD; an invited speaker for Bristol Myers Squibb and MSD; and expert testimony for Bristol Myers Squibb and MSD.

Reference

1. Suarez Rodriguez C, Rojas CI, Shin SJ, et al. First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA96. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA96.html.pdf

The combination of lenvatinib (Lenvima) and everolimus (Afinitor) reduced the risk of progression or death by 49% compared with cabozantinib (Cabometyx) for patients with metastatic clear cell renal cell carcinoma (ccRCC) following progression on a PD-1 inhibitor, according to findings from a phase 2 study presented at the European Society for Medical Oncology Congress 2025 and simultaneously published in the Annals of Oncology.^1,2

In the multicenter phase 2 study, the median progression-free survival (PFS), which was the primary end point of the study, was 15.7 months with the combination of lenvatinib plus everolimus compared with 10.2 months with cabozantinib (HR, 0.51; 95% CI, 0.29-0.89; P = .02). There were more adverse events (AEs) observed with the combination, but these differences were not deemed statistically significant. Grade 3/4 AEs were experienced by 67.5% of those treated with lenvatinib plus everolimus compared with 50% of those receiving cabozantinib (odds ratio [OR], 2.08; 95% CI, 0.86-5.02).

“Lenvatinib plus everolimus significantly prolonged progression-free survival over cabozantinib,” Andrew W. Hahn, MD, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said during a presentation of the results. “As the first head-to-head randomized comparison of contemporary second-line or later treatments after immune checkpoint inhibition, these results are relevant to treatment sequencing and inform oncology practice.”

The study enrolled 86 patients, with 40 receiving the combination and 46 receiving cabozantinib. For the combination arm, lenvatinib was administered at 18 mg per day and everolimus was given at 5 mg per day. Cabozantinib was administered at 60 mg per day. The most common prior treatment was the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), which was received by 70.9% of patients enrolled in the study. This was followed by the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) for 16.3%, adjuvant pembrolizumab for 4.7%, and any other checkpoint inhibitor for 8.1%.

Baseline characteristics were well balanced between the groups with most patients (69.8%) in each group having received 1 prior line of therapy and 30.2% having received 2 prior lines of therapy. Nearly half of patients had received prior VEGF-targeted therapy (45% for the combination arm and 41.3% for the single agent group). The IMDC risk was primarily intermediate in both groups (80% for combination and 73.9% for single agent). The IMDC risk was poor for 7.5% of those in the combination arm and for 8.7% of those in the control arm.

The objective response rate was 52.6% with lenvatinib plus everolimus compared with 38.6% with cabozantinib. Although numerically higher, this rate did not pass the bar for statistical significance (OR, 1.87; 95% CI, 0.75-4.6; P = .17). In addition to responses, stable disease was observed in 39.5% of those receiving the combination and for 54.5% of those in the single-agent arm.

The study was not designed to assess differences in overall survival (OS) and findings for this end point were still immature, Hahn noted. After a median of 20 months of follow-up, there had been 11 events in the combination arm and 13 in the control group. The 1-year OS probability was 87.0% with lenvatinib plus everolimus compared with 84.6% with cabozantinib (HR, 1.05; 95% CI, 0.47-2.38; P = .86).

Serious AEs were experienced by 27.5% of those treated with lenvatinib plus everolimus compared with 19.6% of those in the cabozantinib arm (OR, 1.56; 95% CI, 0.57-4.24). Dose interruptions were necessary for 70% of those in the combination arm compared with 78.3% of those in the cabozantinib group (OR, 0.65; 0.24-1.73). Dose reductions were necessary for 57% and 60.9% of those in the combination and control arm, respectively (OR, 0.80; 95% CI, 0.33-1.93). Treatment discontinuation was more common in the combination group at 20% compared with the single agent at 10.9% (OR, 2.05; 95% CI, 0.61-6.91).

“Of the 8 patients who discontinued treatment with lenvatinib plus everolimus, 5 of those were due to proteinuria,” said Hahn.

The most commonly observed AEs in the study aligned with those historically associated with each agent, Hahn noted. For the combination and single agent arms, respectively, the most common all-grade AEs were diarrhea (70% vs 73.9%), fatigue (72.5% vs 60.9%), proteinuria (65% vs 37%), hypertension (57.5% vs 39.1%), nausea (40% vs 39.1%), palmar-plantar erythrodysesthesia (20% vs 52.2%), vomiting (32.5% vs 34.8%), and oral mucositis (15% vs 43.5%).

“This is a positive phase 2 trial and demonstrates improved PFS and response compared with cabozantinib, but with higher toxicity,” said invited discussant Lisa M. Pickering, consultant medical oncologist at The Royal Marsden, MD, PhD, FRCP. “So, is it positive enough? I think that depends on you and your patient, but I would say that we can and should consider using lenvatinib/everolimus, particularly in patients for whom the priority is response and to who the toxicity rate is acceptable.”

The combination of lenvatinib and everolimus was approved by the FDA in 2016 for the treatment of patients with advanced RCC after a prior anti-angiogenic agent.³ The phase 2 study was completed to assess the combination in a more contemporary treatment setting, Hahn noted.

References

1. Hahn AW, Chahoud J, Skelton W, et al. LenCabo: A randomized phase II multicenter trial of lenvatinib plus everolimus (len/eve) versus (vs) cabozantinib (cabo) in patients (pts) with metastatic clear cell RCC (ccRCC) that progressed on PD-1 immune checkpoint inhibition (ICI). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA94.
2. Hahn AW, Chahoud J, Skelton WP, et al. A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear cell RCC that progressed on PD-1 immune checkpoint inhibition (LenCabo). Ann Oncol. 2025. Doi:10.1016/j.annonc.2025.10.009.
3. Lenvatinib in combination with Everolimus. FDA. May 16, 2016. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/lenvatinib-combination-everolimus