Author: Melina Rodriguez, CST/CMA/CCA

The accelerated approval program is one of the FDA’s most powerful tools for getting effective drugs to patients with serious diseases faster. But it comes with a condition: the drug is approved based on a surrogate endpoint (typically tumor response rate, a measure of whether the tumor shrinks) that is reasonably likely to predict clinical benefit, and continued approval depends on completing a confirmatory trial that demonstrates the actual clinical benefit, whether patients live longer, function better, or have improved quality of life.

When a drug converts from accelerated to traditional approval, it means the confirmatory standard has been met. The FDA has reviewed the totality of evidence and concluded that the benefit originally inferred from surrogate response data is, in fact, real and established. The drug’s position in therapy is strengthened. The post-marketing obligation to verify is fulfilled. The label revision reflects a regulatory maturation, not a discovery.

For Retevmo (selpercatinib, Eli Lilly), this conversion arrived on July 14, 2026, for its tissue-agnostic indication covering RET fusion-positive solid tumors other than the NSCLC and thyroid cancer indications that already held full traditional approval. The drug had been treating patients under accelerated approval in this broader solid tumor population since September 2022. The 47% response rate and 24.5-month median duration of response in the LIBRETTO-001 non-NSCLC/non-thyroid cohort, combined with accumulated clinical experience and responses observed in pediatric patients across rare histologies in LIBRETTO-121, provided the confirmatory evidence base the FDA required.

This post covers what RET gene fusions are and why they matter across cancer types, how selpercatinib works as a selective RET inhibitor, what the complete Retevmo approval history looks like, what the LIBRETTO-001 and LIBRETTO-121 data show, what the regulatory distinction between accelerated and traditional approval means in practice, and what the conversion means for the clinicians and patients who have been using this drug.

What RET Is and Why a Gene Fusion Changes Everything

RET (Rearranged during Transfection) is a proto-oncogene encoding a receptor tyrosine kinase expressed in cells derived from the neural crest, including thyroid parafollicular cells (C cells), renal collecting duct cells, and neurons of the enteric nervous system. In normal cells, the RET kinase requires its ligand (glial cell line-derived neurotrophic factor, GDNF, and related proteins) to activate. Ligand binding triggers receptor dimerization and autophosphorylation, initiating downstream signaling through RAS/MAPK, PI3K/AKT/mTOR, and JAK/STAT pathways that regulate cell growth and survival.

Two types of oncogenic RET alterations drive human cancers: activating point mutations, which constitutively activate RET without requiring ligand binding, and gene fusions, in which chromosomal rearrangements fuse the RET kinase domain to the promoter and partial coding sequence of a partner gene.

RET gene fusions create chimeric proteins in which the kinase domain of RET is constitutively active, continuously signaling for cell proliferation and survival regardless of ligand availability. The fusion partner determines the specific structural features of the chimeric protein (including its dimerization properties and intracellular localization), but in all cases the downstream consequence is uncontrolled kinase activity driving tumor growth.

RET fusions are found across multiple tumor types:

• Non-small cell lung cancer (approximately 1 to 2% of NSCLC): the most common solid tumor context; typically KIF5B-RET or CCDC6-RET fusions
• Thyroid cancer: highly prevalent in papillary thyroid cancer (approximately 10 to 20% of cases) and relevant in other thyroid malignancies
• Pancreatic cancer, colorectal cancer, salivary gland tumors, ovarian cancer, breast cancer, and multiple other histologies: lower individual prevalence but collectively encompassing thousands of patients annually

The tissue-agnostic indication covers this last category: any advanced solid tumor with a confirmed RET gene fusion, regardless of the cancer type in which it occurs, provided the patient has received prior systemic therapy or has no satisfactory alternative treatment options.

The tissue-agnostic regulatory framework reflects a broader shift in oncology toward molecular characterization of cancer over purely anatomic characterization. A RET fusion-positive pancreatic cancer and a RET fusion-positive NSCLC are different diseases in terms of their tissue of origin, their natural history, and their treatment history, but they share the molecular driver that makes them susceptible to RET inhibition. The shared molecular vulnerability justifies a shared approval across tumor types.

How Selpercatinib Works: Selective RET Inhibition

Selpercatinib is an oral, highly selective RET kinase inhibitor designed to potently inhibit both wild-type RET and the common oncogenic RET alterations (fusions and point mutations including RET M918T, the most common mutation in medullary thyroid cancer) while minimizing activity against off-target kinases.

The selectivity design philosophy distinguishes selpercatinib from earlier multi-kinase inhibitors (such as cabozantinib and vandetanib) that had incidental RET activity alongside activity against VEGFR, MET, and other kinases. Those earlier agents’ off-target activity contributed to high rates of adverse events, particularly cardiovascular and dermatological toxicities, and limited the depth and duration of RET-specific therapeutic benefit achievable in clinical practice.

Selpercatinib occupies the ATP-binding pocket of the RET kinase domain in a way that locks the enzyme in an inactive conformation. The drug is also designed to address known resistance mutations: at concentrations achievable in the clinic, it maintains activity against several RET mutations that confer resistance to earlier-generation RET inhibitors, including V804M and V804L (the “gatekeeper” mutations).

The high selectivity translates into an adverse event profile that differs from multi-kinase inhibitors. The most common adverse reactions in LIBRETTO-001 (occurring in 25% or more of the full safety population, n=796) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. These are largely manageable with dose modification and supportive care, and the rates of severe (grade 3 or 4) events are substantially lower than with the older multi-kinase inhibitors used in RET-altered thyroid cancer.

Retevmo’s Full Approval History: A Cumulative Story

Understanding the July 2026 traditional approval requires context for Retevmo’s complete regulatory trajectory. The drug now holds multiple distinct approved indications accumulated over six years.

The July 2026 action completes the regulatory maturation of the tissue-agnostic indication and extends full traditional approval to the pediatric population (ages 2 and older) that had previously held only accelerated approval.

The Evidence Base: LIBRETTO-001 and LIBRETTO-121

LIBRETTO-001: The backbone of the tissue-agnostic indication

LIBRETTO-001 (NCT03157128) is an international, non-randomized, open-label, multi-cohort Phase 1/2 basket trial evaluating selpercatinib across all RET-altered solid tumors. The trial enrolled both RET fusion-positive and RET-mutant cancers across multiple tumor types and is the primary evidence source for most of Retevmo’s approved indications.

The efficacy analysis supporting the traditional approval conversion for the tissue-agnostic indication focused on 75 patients with RET fusion-positive solid tumors excluding NSCLC and thyroid cancer (the tumor types with separate, fully established approval pathways). This population included cancers of the pancreas, colon, rectum, salivary gland, ovary, breast, and other sites, all unified by the presence of a confirmed RET gene fusion.

Source: LIBRETTO-001. NCT03157128. FDA traditional approval summary July 14, 2026.

A 47% ORR and 24.5-month median DOR in a pan-tumor, pretreated population with diverse histologies is a clinically meaningful and durable response. The median DOR of nearly 2 years means that among the patients who responded, approximately half maintained that response beyond 24 months. In the context of heavily pretreated advanced solid tumors, which typically show short-duration responses to available cytotoxic chemotherapy, this durability distinguishes the targeted RET inhibitor approach from standard cytotoxic alternatives.

The supporting efficacy evidence from the NSCLC and thyroid cancer cohorts in LIBRETTO-001, both of which carry traditional approval, provides additional confirmation that selpercatinib’s anti-tumor activity is a real, consistent pharmacological phenomenon rather than a statistical artifact of small-cohort data.

LIBRETTO-121: The pediatric evidence base

LIBRETTO-121 (NCT03899792) is a multicenter, open-label, multi-cohort trial evaluating selpercatinib specifically in pediatric and young adult patients with RET-altered cancers. The trial evaluated patients with locally advanced refractory RET fusion-positive solid tumors who were unresponsive to available therapies or had no standard systemic curative therapy.

The evidence from LIBRETTO-121 supporting the July 2026 traditional approval included:

• One patient with congenital infantile fibrosarcoma: response observed
• One patient with spindle cell sarcoma: response observed
• Patients with RET fusion-positive thyroid cancer: responses observed

Congenital infantile fibrosarcoma and spindle cell sarcoma are rare pediatric tumors that carry ETV6-NTRK3 or other fusions in many cases, but the subset with RET fusions represents an ultra-rare population with very limited treatment options. A documented response in even a single patient with a rare pediatric sarcoma histology is clinically meaningful in a disease where treatment options are severely constrained.

The pediatric dosing framework for selpercatinib in LIBRETTO-121 includes weight-based dosing for children under 50 kg and adult dosing (160 mg twice daily) for patients at or above 50 kg or aged 12 and older meeting weight criteria. The prescribing information specifies dosing tables by weight for the pediatric population.

The Accelerated to Traditional Approval Conversion: What It Means and Why It Matters

Accelerated approval is a regulatory pathway created to make drugs available earlier for serious conditions with unmet medical need, based on surrogate endpoints that are “reasonably likely to predict” clinical benefit. Response rate is the most commonly used surrogate: if a tumor shrinks, the inference is that the patient will likely benefit clinically, even if survival data are not yet mature.

The limitation of accelerated approval is exactly that: it is based on an inference. A tumor can shrink and still not provide meaningful clinical benefit if the response is short, if the toxicity is prohibitive, or if the shrinkage does not translate into longer survival or better function. These are the cases where confirmatory trials sometimes reveal that the surrogate did not predict the expected clinical benefit, and the drug’s accelerated approval is subsequently withdrawn.

The conversion to traditional approval is the opposite event: it means the FDA has reviewed additional evidence demonstrating that the drug delivers genuine clinical benefit. For selpercatinib, the combination of the extended response durations observed in LIBRETTO-001 (median DOR of 24.5 months across the diverse non-NSCLC/non-thyroid cohort), the fully established traditional approval in NSCLC and thyroid cancer, and the pediatric response data in LIBRETTO-121 together provided the evidentiary confirmation required.

The practical implications of the conversion for patients and prescribers:

The indication does not change. The patient population, dosing, and required testing are identical before and after the conversion.

The regulatory confidence in the drug’s benefit is strengthened. Traditional approval removes the qualifier from the label indicating that continued approval may depend on a confirmatory trial. The clinical benefit is established.

The post-marketing verification requirement is fulfilled. Under accelerated approval, sponsors are legally required to conduct and submit confirmatory trial data. That obligation is discharged when traditional approval is granted.

Payer coverage is sometimes affected. Some commercial payers treat accelerated-approval drugs with greater scrutiny in prior authorization decisions, viewing them as having a higher evidentiary uncertainty. Traditional approval can support broader formulary access and simpler authorization pathways in some systems.

RET Testing: A Required Prerequisite

The tissue-agnostic indication for Retevmo requires RET gene fusion detection using an FDA-approved test. This testing requirement is embedded in the indication language: “locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test.”

For oncologists managing patients with advanced solid tumors: comprehensive genomic profiling (CGP) panels, which assess for RET fusions alongside hundreds of other clinically relevant alterations in a single assay, are the most efficient approach to RET testing in practice. Major approved CGP tests include Foundation Medicine’s FoundationOne CDx and Liquid CDx platforms, MSKCC’s MSK-IMPACT, and others. RNA-based sequencing is particularly important for RET fusion detection because DNA-based sequencing may miss some intronic fusion breakpoints; laboratories offering solid tumor profiling should ideally include RNA-based detection for fusion genes.

Patients whose tumors have not previously undergone molecular profiling and who are progressing on first-line therapy should be considered for testing at the earliest opportunity, because tissue requirements for a repeat biopsy may limit testing access later in the disease course. Cell-free DNA (liquid biopsy) is also available and can detect RET fusions from a blood draw, though with lower sensitivity than tissue testing for some rare fusion partners.

Safety: What the Prescribing Information Covers

The safety profile of selpercatinib from LIBRETTO-001 is well-characterized across the approximately 796-patient full safety population with advanced solid tumors. The July 14, 2026 conversion does not change the safety profile or the warnings; it confirms the established benefit-risk assessment.

Most common adverse reactions (25% or more in the full safety population): edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

Most common grade 3 or 4 laboratory abnormalities (5% or more): decreased lymphocytes, increased ALT, increased AST, decreased sodium, and decreased calcium.

Key warnings and precautions:

The pediatric-specific warning for slipped capital femoral epiphysis (SCFE), a disruption of the growth plate at the femoral head, was added to the prescribing information with the 2024 pediatric expansion and remains in place with the 2026 traditional approval. Pediatric patients receiving selpercatinib should be monitored for hip or knee pain, and any such complaint should prompt orthopedic evaluation.

Retevmo’s Current Complete Indication Coverage

After July 14, 2026, Retevmo (selpercatinib) holds the following approved indications:

All indications now hold traditional approval. Retevmo has no remaining accelerated approval indications. The regulatory maturation of the drug is complete across its full clinical scope.

What This Means for Oncologists and Patients

For oncologists managing patients with advanced solid tumors

The practical implication for clinical practice is modest because the indication, the patient population, and the drug are unchanged. What the traditional approval provides is regulatory confirmation of clinical benefit, which strengthens the position of selpercatinib in treatment guidelines and may support broader formulary access in payer systems that treat accelerated-approval drugs differently.

For patients currently receiving selpercatinib under the prior accelerated approval: nothing changes about their treatment. The drug they are taking is the same; the benefit they are receiving is now confirmed rather than inferred.

For oncologists identifying new patients with RET fusion-positive solid tumors (outside of NSCLC and thyroid cancer): the traditional approval removes any label-language qualifier about provisional status. The evidence base is established. The indication is full.

The response rate of 47% and median DOR of 24.5 months represent the expected clinical outcomes in a heavily pretreated pan-tumor population. Individual patient outcomes will vary based on tumor histology, prior treatment burden, performance status, and specific RET fusion partner, but these numbers provide a reasonable framework for pre-treatment counseling.

For patients with rare RET fusion-positive cancers

The tissue-agnostic nature of this indication remains one of its most important features for patients. A patient with RET fusion-positive pancreatic cancer or colon cancer does not have a separate lung cancer drug or a thyroid cancer drug being offered off-label. They have a drug approved specifically for their cancer type, based on the molecular driver their tumor carries, regardless of where in the body the tumor originated. That clarity matters for insurance coverage, for informed consent, and for the patient’s understanding of why this specific drug was recommended.

The full traditional approval now reinforces that position. For patients who were told in 2022 or 2023 that they were receiving a drug under accelerated approval pending confirmatory data, the July 2026 update means that confirmatory standard has been met. The benefit is established.

For related HED coverage on precision oncology and targeted kinase inhibitor approvals, see our post on Revtorpyk (gedatolisib) becoming the first approved targeted therapy for PIK3CA wild-type HR+/HER2- breast cancer and our post on daraxonrasib (RMC-6236) generating a standing ovation at ASCO 2026 for its Phase 3 results in KRAS-driven pancreatic cancer.

Sources

FDA traditional approval announcement: FDA grants traditional approval to selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. FDA.gov. July 14, 2026. Full announcement at FDA.gov. Eli Lilly and Company

CancerNetwork coverage (trial support overview): FDA Traditionally Approves Selpercatinib in RET+ Solid Tumors. cancernetwork.com. July 2026.

OncLive (ORR 47% and DOR 24.5 months data): FDA Awards Traditional Approval to Selpercatinib for RET+ Advanced Solid Tumors. onclive.com. July 2026.

Healio (n=75 population, LIBRETTO-001 cohort detail): FDA grants traditional approval to Retevmo for RET fusion-positive solid tumors. healio.com. July 2026.

CURE (patient-focused conversion explanation, LIBRETTO-121 histologies): FDA Grants Traditional Approval to Retevmo for RET Fusion-Positive Solid Tumors. curetoday.com. July 2026.

ASCO Post (complete indication language, LIBRETTO-121 context): FDA Grants Traditional Approval to Selpercatinib for Locally Advanced or Metastatic RET Fusion-Positive Solid Tumors. ascopost.com. July 2026.

Oncology Nursing News (regulatory conversion context): FDA Grants Traditional Approval to Selpercatinib for RET-Fusion Solid Tumors. oncnursingnews.com. July 2026.

Lilly accelerated approval press release (September 2022): FDA Approves Lilly’s Retevmo (selpercatinib), the First and Only RET Inhibitor for Adults with Advanced or Metastatic Solid Tumors with a RET Gene Fusion. Eli Lilly. September 21, 2022.

LIBRETTO-001 FDA review article (PMC): FDA accelerated approval summary for selpercatinib RET fusion-positive solid tumors (2022). PMC10524590.

LIBRETTO-001 trial registration: NCT03157128. ClinicalTrials.gov.

LIBRETTO-121 trial registration: NCT03899792. ClinicalTrials.gov.

Drugs.com approval news: FDA Grants Traditional Approval to Retevmo (selpercatinib) for Locally Advanced or Metastatic RET Fusion-Positive Solid Tumors. drugs.com. July 14, 2026.

Retevmo prescribing information: RETEVMO (selpercatinib) Prescribing Information. Eli Lilly and Company. 2026.

Retevmo approval history: Retevmo FDA Approval History. drugs.com.

Patient resources: LUNGevity Foundation: RET+ resources | Thyroid Cancer Alliance | RET Research Foundation | ClinicalTrials.gov: search selpercatinib | Lilly Cares patient support for Retevmo

Bladder cancer is the fourth most common cancer in men in the United States and is diagnosed in approximately 84,000 Americans per year. The majority of bladder cancers are non-muscle-invasive at diagnosis and are managed with local resection and intravesical therapy. But when cancer invades the muscular wall of the bladder, the clinical calculus changes fundamentally. Muscle-invasive bladder cancer (MIBC) carries a 5-year overall survival rate of approximately 50 to 60% with optimal treatment, meaning that even with the best available care, roughly half of patients will die of the disease within five years.

For nearly 25 years, the best available care in the neoadjuvant setting meant one thing: cisplatin-based chemotherapy before surgery. The combination of gemcitabine plus cisplatin administered before radical cystectomy produces pathologic complete response (pCR, meaning no residual tumor at surgery) in approximately 30 to 40% of patients and improves survival compared to surgery alone. That survival benefit, established in meta-analyses and multiple randomized trials, made neoadjuvant cisplatin the standard of care and kept it there for more than two decades.

The problem: approximately half of patients with MIBC cannot receive cisplatin. Kidney function decline, hearing loss, neuropathy, and performance status limitations all contribute to cisplatin ineligibility in a patient population that skews older and commonly has significant comorbidities. For these patients, surgery alone had been the standard, with all the survival disadvantage that comes from not having neoadjuvant systemic therapy.

Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) has now closed both gaps. The November 2025 approval for cisplatin-ineligible patients, based on KEYNOTE-905/EV-303, gave that neglected population their first perioperative systemic therapy option. The July 10, 2026 approval, based on KEYNOTE-B15/EV-304, extends the same regimen to cisplatin-eligible patients, where it did not just match cisplatin but surpassed it: median EFS not reached with EV plus pembrolizumab versus 48.5 months with gemcitabine plus cisplatin, pCR rate 55.8% versus 32.5%, and an overall survival advantage. All three primary and key secondary endpoints met in a 808-patient randomized Phase 3 trial.

As Dr. Matthew Galsky of the Icahn School of Medicine at Mount Sinai, who presented the KEYNOTE-B15 data at ASCO GU 2026, put it: this is a pivotal moment. For the first time since cisplatin-based neoadjuvant therapy was shown to improve outcomes in patients with MIBC almost 25 years ago, a non-platinum-based regimen has surpassed it.

What Muscle-Invasive Bladder Cancer Is and Why Surgery Alone Is Not Enough

Bladder cancer originates in the urothelium, the transitional epithelial lining of the urinary tract. Non-muscle-invasive bladder cancer (stages Ta, T1, and carcinoma in situ) involves only the superficial layers and can be managed with transurethral resection and intravesical agents. Muscle-invasive disease (stage T2 or higher) has penetrated the detrusor muscle of the bladder wall, dramatically increasing metastatic risk and fundamentally changing treatment strategy.

MIBC is staged using the TNM system. Stage T2 invades the inner half of the muscle; T3 extends through the muscle into perivesical fat; T4 invades adjacent structures including the prostate, uterus, or pelvic wall. Lymph node status (N0/N1) is assessed at surgery. All patients with resectable MIBC without distant metastasis are candidates for radical cystectomy with pelvic lymph node dissection as the definitive surgical approach.

Radical cystectomy is curative in approximately 60 to 70% of patients with organ-confined (T2) disease but in only about 25 to 35% of patients with T3 to T4 or node-positive disease. The primary driver of recurrence and death is occult micrometastatic disease that is present but not detectable at the time of surgery. Systemic therapy before surgery (neoadjuvant) attacks this micrometastatic burden while the tumor is still accessible and the patient has not yet undergone the physiological stress of a major operation.

The concept of pathologic complete response is important in MIBC: patients who have no residual tumor at the time of cystectomy (pCR, or ypT0N0) after neoadjuvant therapy have substantially better long-term outcomes than those with residual disease. A pCR rate of 55.8% in KEYNOTE-B15 means that more than half of cisplatin-eligible MIBC patients treated with perioperative EV plus pembrolizumab had no viable tumor left at surgery, compared with approximately 1 in 3 patients on standard cisplatin-based chemotherapy.

What Enfortumab Vedotin Is: The Nectin-4 ADC Mechanism

Enfortumab vedotin-ejfv (Padcev) is an antibody-drug conjugate (ADC) that targets Nectin-4, a cell adhesion molecule that is highly expressed in urothelial carcinoma and in a variety of other cancer types, while having more limited expression in normal adult tissues. This differential expression creates a therapeutic window for tumor-directed drug delivery.

The three components of enfortumab vedotin:

The antibody: anti-Nectin-4. A fully human monoclonal antibody that binds with high affinity to Nectin-4 on the surface of urothelial cancer cells and is internalized through receptor-mediated endocytosis.

The linker: protease-cleavable. A maleimide-based linker that is cleaved by cathepsins in the acidic lysosomal environment of the internalized cell, releasing the cytotoxic payload selectively inside the tumor cell. The linker also allows a bystander killing effect: free payload diffuses from the targeted cell to adjacent cancer cells, even those with lower Nectin-4 expression.

The payload: MMAE (monomethyl auristatin E). A potent microtubule-disrupting agent that binds to tubulin and prevents polymerization, triggering G2/M cell cycle arrest and apoptosis. MMAE is approximately 100 to 1,000 times more potent than conventional chemotherapy on a per-molecule basis, which is why the ADC delivery format can produce activity at relatively low doses compared to systemic MMAE administration.

Nectin-4 is expressed in more than 97% of urothelial carcinomas at moderate to high levels, making it one of the most broadly applicable ADC targets in any solid tumor type. This near-universal expression means that patient selection by Nectin-4 testing is not currently required: essentially all urothelial cancer patients are likely to have Nectin-4-expressing tumors.

The Two-Trial Evidence Base: KEYNOTE-905 and KEYNOTE-B15

The July 10, 2026 approval covers all MIBC patients regardless of cisplatin eligibility, resting on two separate Phase 3 trials that together cover the complete MIBC population.

KEYNOTE-905/EV-303: The cisplatin-ineligible population (November 2025 approval)

KEYNOTE-905/EV-303 (NCT03924895) enrolled 344 patients with MIBC who were ineligible for or declined cisplatin-based chemotherapy, randomized 1:1 to neoadjuvant EV plus pembrolizumab followed by cystectomy followed by adjuvant EV plus pembrolizumab, or immediate cystectomy alone.

Source: KEYNOTE-905/EV-303. NCT03924895.

The 57.1% pCR rate in a cisplatin-ineligible population that had no approved perioperative systemic therapy option before this trial was the most striking finding from KEYNOTE-905. The November 2025 FDA approval made EV plus pembrolizumab the first perioperative regimen available to this half of the MIBC population.

KEYNOTE-B15/EV-304: The cisplatin-eligible population (July 2026 approval)

KEYNOTE-B15/EV-304 (NCT04700124) enrolled 808 patients with previously untreated MIBC who were eligible for cisplatin-based therapy and candidates for radical cystectomy with pelvic lymph node dissection. Patients required central pathology and imaging confirmation of clinical stage cT2 to T4aN0M0 or T1 to T4aN1M0 disease. They were randomized 1:1 to:

EV plus pembrolizumab arm (n=405): 4 cycles of neoadjuvant EV 1.25 mg/kg on days 1 and 8 plus pembrolizumab 200 mg on day 1, every 3 weeks, followed by radical cystectomy plus PLND, then 5 additional cycles of adjuvant EV plus 13 additional cycles of adjuvant pembrolizumab (or pembrolizumab dosed 400 mg every 6 weeks for 7 cycles).

Gemcitabine plus cisplatin arm (n=403): 4 cycles of neoadjuvant gemcitabine 1,000 mg/m2 on days 1 and 8 plus cisplatin 70 mg/m2 on day 1, every 3 weeks, followed by radical cystectomy plus PLND, then observation.

The primary endpoint was EFS by blinded independent central review. Key secondary endpoints included pCR by central pathologist review and OS. The data were presented at the 2026 ASCO GU Symposium in San Francisco and published in the Journal of Clinical Oncology.

Source: Galsky MD et al. KEYNOTE-B15/EV-304, JCO ASCO 2026 LBA630. doi:10.1200/JCO.2026.44.7_suppl.LBA630. NCT04700124.

The primary endpoint finding of a 47% reduction in EFS risk, with median EFS not yet reached in the EV plus pembrolizumab arm versus 48.5 months in the cisplatin-based chemotherapy arm, is one of the most compelling perioperative oncology datasets in bladder cancer history. The EFS result was statistically significant and clinically substantial, meeting the primary endpoint convincingly.

The pCR data further anchors the magnitude of the benefit: 55.8% of cisplatin-eligible patients treated with EV plus pembrolizumab had no residual viable tumor at cystectomy, compared with 32.5% on standard gemcitabine plus cisplatin. A 23-percentage-point improvement in pCR is a large absolute difference in a surgically curable disease where pCR is strongly associated with long-term disease-free survival.

The OS benefit (HR 0.65, p=0.0029) is particularly significant. Overall survival advantages in the neoadjuvant setting in bladder cancer have historically required large meta-analyses to establish with the available single-trial data. Demonstrating a statistically significant OS advantage in a single 808-patient trial reflects the genuine magnitude of the EV plus pembrolizumab benefit over cisplatin-based standard of care.

The Complete Treatment Sequence: What Perioperative Means in Practice

The approved regimen covers three sequential phases for patients eligible for cystectomy, and understanding the full treatment timeline is essential for patient counseling and multidisciplinary care coordination.

Phase 1 — Neoadjuvant (before surgery), 4 cycles (12 weeks):

• Enfortumab vedotin 1.25 mg/kg (maximum 125 mg for patients at or above 100 kg) IV on days 1 and 8 of each 21-day cycle
• Pembrolizumab 200 mg IV on day 1 every 3 weeks, or 400 mg IV every 6 weeks; or Keytruda Qlex subcutaneous on corresponding schedule
• 4 total neoadjuvant cycles

Surgery: Radical cystectomy with pelvic lymph node dissection, performed after completing the 4 neoadjuvant cycles.

Phase 2 — Adjuvant (after surgery), continuation:

• Enfortumab vedotin continues for 5 additional cycles (same dosing as neoadjuvant)
• Pembrolizumab continues: 200 mg IV every 3 weeks for 13 total adjuvant cycles (approximately 39 weeks), or 400 mg every 6 weeks for 7 adjuvant cycles; or Keytruda Qlex equivalents

The total treatment duration is approximately 12 weeks neoadjuvant plus the adjuvant phase, which extends approximately a year post-surgery for the full pembrolizumab course. This is a longer treatment commitment than neoadjuvant chemotherapy alone (which has no adjuvant component beyond surveillance), and the logistics of 18 months of combined therapy require careful coordination between the medical oncologist, urologic oncologist, and the patient’s support systems.

A notable feature of the EV-304 trial is that 262 of 405 EV-plus-pembrolizumab patients started the adjuvant phase and 208 completed it, reflecting real-world dropout rates from the surgical pathway and treatment tolerance over a prolonged regimen. Understanding that not all patients who start neoadjuvant treatment will complete the full intended adjuvant course is important for setting expectations in clinical practice.

The Cisplatin-Ineligibility Problem This Approval Resolves

Understanding why “regardless of cisplatin eligibility” matters requires understanding why approximately half of MIBC patients cannot receive cisplatin to begin with.

Cisplatin nephrotoxicity is the primary limiting factor. Standard cisplatin eligibility criteria require GFR at or above 50 to 60 mL/min/1.73m2 depending on the institutional protocol. Bladder cancer skews toward older adults and is associated with smoking-related comorbidities including cardiovascular and renal disease; many patients have renal function below this threshold at diagnosis. Other cisplatin eligibility barriers include hearing loss (cisplatin is ototoxic), peripheral neuropathy, Eastern Cooperative Oncology Group performance status of 2 or higher, and New York Heart Association class 3 or 4 heart failure.

Before KEYNOTE-905, cisplatin-ineligible patients with MIBC had no approved perioperative systemic therapy option at all. They went directly to surgery without neoadjuvant treatment, accepting the survival disadvantage that came from operating on disease that neoadjuvant therapy might have downstaged or eliminated. KEYNOTE-905 gave this population their first approved option. KEYNOTE-B15 then went further, demonstrating that even patients who are eligible for cisplatin are better served by the ADC plus checkpoint inhibitor combination.

The combined impact of both trials and both approvals means that MIBC patients in 2026 have a single effective perioperative regimen that is appropriate regardless of their renal function, hearing status, or other cisplatin eligibility criteria. The treatment algorithm has simplified: if a patient is a candidate for cystectomy, EV plus pembrolizumab is an appropriate perioperative treatment. The question of whether they can tolerate cisplatin is no longer the gating question for neoadjuvant therapy access.

Safety: What the KEYNOTE-B15 Profile Shows

The safety profile of EV plus pembrolizumab in KEYNOTE-B15 was consistent with the established safety experience from prior trials, with no new safety signals identified. The grade 3 or higher adverse event rate was 75.7% in the EV plus pembrolizumab arm versus 67.2% in the gemcitabine plus cisplatin arm, a numerically higher rate that requires clinical context.

Enfortumab vedotin’s adverse event profile reflects both the MMAE payload and on-target skin effects from Nectin-4 expression in the epidermis:

Boxed warnings for Padcev (enfortumab vedotin-ejfv):

Skin reactions: Severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported, some with fatal outcomes. Skin reactions are one of the most clinically significant toxicities unique to enfortumab vedotin. Patients should be monitored for new or worsening skin reactions. Grade 3 skin reactions require treatment interruption; Stevens-Johnson syndrome or TEN require permanent discontinuation.

Hyperglycemia: Clinically significant hyperglycemia, including new-onset diabetes and diabetic ketoacidosis, has occurred. Monitor blood glucose before each infusion. Withhold for glucose greater than 250 mg/dL.

Additional warnings and precautions:

The safety profile across the neoadjuvant and adjuvant EV plus pembrolizumab combination represents the superimposition of the two drugs’ individual toxicity profiles. Oncology teams experienced in managing ADC skin and neuropathy toxicities, and in managing checkpoint inhibitor immune-mediated adverse events, will find the combination manageable with established protocols. Teams less experienced with either drug class may benefit from multidisciplinary support, particularly for severe skin reactions and immune-mediated toxicities.

Padcev’s Complete Indication Picture After July 2026

What This Means for Patients and Multidisciplinary Bladder Cancer Teams

For patients with newly diagnosed MIBC who are candidates for cystectomy

This approval means that for the first time, a single perioperative treatment regimen is appropriate and approved for all MIBC patients regardless of cisplatin eligibility. Patients who were previously told they could not receive chemotherapy before surgery because of kidney function, hearing, or other cisplatin barriers now have an effective neoadjuvant option.

For patients who are cisplatin-eligible, the KEYNOTE-B15 data make a compelling case that EV plus pembrolizumab should be considered as the preferred perioperative approach over gemcitabine plus cisplatin, based on superior EFS, pCR, and OS. Clinical practice changes of this magnitude take time to be incorporated into guidelines and routine care, and the conversation with patients should honestly present the KEYNOTE-B15 data alongside the established cisplatin-based evidence. The higher grade 3 or higher AE rate with EV plus pembrolizumab (75.7% versus 67.2%) and the specific skin and neuropathy toxicity profile are relevant factors for shared decision-making.

For patients whose surgeons and medical oncologists are now coordinating a perioperative regimen: the critical addition to the care pathway is pre-surgical integration of the neoadjuvant cycles, which now include 12 weeks of combination therapy before cystectomy, followed by surgical planning, and then the adjuvant phase. Patients should understand the full duration of treatment commitment before beginning.

For urologic oncologists and medical oncologists

KEYNOTE-B15 establishes EV plus pembrolizumab as a perioperative option that is superior to the standard gemcitabine plus cisplatin regimen in cisplatin-eligible MIBC on all three key endpoints: EFS, pCR, and OS. Dr. Christopher Hoimes of Duke Cancer Institute, a principal investigator for EV-304, described the data as supporting EV plus pembrolizumab as a novel treatment option and potential standard of care for MIBC patients regardless of cisplatin eligibility.

Incorporating this into multidisciplinary tumor board discussions and treatment protocols requires coordination between urology, medical oncology, and supportive care teams, particularly given the skin reaction boxed warning and the monitoring requirements for neuropathy, hyperglycemia, and immune-mediated adverse events. Subspecialty dermatology access and ophthalmology evaluation pathways should be integrated into the perioperative care plan for patients starting EV.

For related HED coverage on bladder cancer and checkpoint inhibitor combination approvals, see our post on Keytruda Qlex receiving its new first-line TNBC indication alongside Trodelvy and our post on Revtorpyk (gedatolisib) becoming the first targeted therapy for PIK3CA wild-type HR+/HER2- breast cancer.

For patients and families navigating a muscle-invasive bladder cancer diagnosis, the Bladder Cancer Advocacy Network (bcan.org; 1-888-901-BCAN) and the American Cancer Society’s Bladder Cancer resource page maintain current treatment information and patient support resources.

Sources

FDA approval announcement: FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA.gov. July 10, 2026.

Pfizer/Astellas press release: U.S. FDA Approves PADCEV plus Keytruda as Neoadjuvant and Adjuvant Treatment for Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility. Pfizer Inc. July 10, 2026.

Astellas press release: U.S. FDA Approves PADCEV plus Keytruda as Neoadjuvant and Adjuvant Treatment for Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility. newsroom.astellas.com. July 10, 2026.

Drugs.com approval news: U.S. FDA Approves Padcev plus Keytruda or Keytruda Qlex as Neoadjuvant and Adjuvant Treatment for Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility. drugs.com. July 10, 2026.

KEYNOTE-B15/EV-304 JCO ASCO 2026 primary abstract: Galsky MD et al. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with MIBC who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. JCO ASCO 2026 LBA630. doi:10.1200/JCO.2026.44.7_suppl.LBA630.

KEYNOTE-B15 trial registration: NCT04700124. ClinicalTrials.gov.

OncLive (EFS primary endpoint data, all three endpoints met): Perioperative Enfortumab Vedotin/Pembrolizumab Meets EFS, OS, pCR End Points in Cisplatin-Eligible MIBC. onclive.com. July 2026.

Targeted Oncology (median EFS not reached versus 48.5 months): Enfortumab Vedotin/Pembrolizumab Redefines Neoadjuvant Therapy for MIBC. targetedonc.com. June 2026.

GU Oncology Now (HR 0.53 EFS, Dr. Galsky quote): EV/Pembro Improved EFS, OS in Cisplatin-Eligible MIBC. guoncologynow.com. March 2026.

Cancer Therapy Advisor (pCR 55.8% vs 32.5%, OS HR 0.65 exact data): ASCO GU 2026: Are Combinatorial Therapies the Future Standard of Care in RCC and MIBC? cancertherapyadvisor.com. February 2026.

Urology Times (full trial design detail, Dr. Galsky presentation context): KEYNOTE-B15: EV/pembro sets new benchmark before cystectomy in MIBC. urologytimes.com. 2026.

Pharmacy Times (cisplatin ineligibility context, global MIBC epidemiology): Phase 3 Data Back a New Perioperative Standard for Cisplatin-Eligible Muscle-Invasive Bladder Cancer. pharmacytimes.com. June 2026.

UroToday (Dr. Hoimes investigator quote, Pfizer/Astellas/Merck collaboration context): U.S. FDA Approves PADCEV plus Keytruda as Neoadjuvant and Adjuvant Treatment for MIBC Regardless of Cisplatin Eligibility. urotoday.com. July 2026.

KEYNOTE-905/EV-303 prior approval (November 2025): FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer (cisplatin-ineligible). FDA.gov. November 21, 2025.

KEYNOTE-905 trial registration: NCT03924895. ClinicalTrials.gov.

Bladder cancer overview: Bladder Cancer. StatPearls. NCBI.

Padcev prescribing information: PADCEV (enfortumab vedotin-ejfv) Prescribing Information. Astellas Pharma US, Inc. 2026.

Padcev approval history: Padcev FDA Approval History. drugs.com.

Patient resources: Bladder Cancer Advocacy Network: 1-888-901-BCAN | American Cancer Society Bladder Cancer resources | Pfizer Padcev patient support | ClinicalTrials.gov: search bladder cancer enfortumab