A Q&A with David Aggen, MD, PhD, MSK Genitourinary Medical Oncologist and Cellular Therapist
A new era in the treatment of muscle-invasive bladder cancer (MIBC) is on the horizon, with the combination of enfortumab vedotin plus pembrolizumab poised to become the new standard of care in the perioperative treatment of cisplatin-ineligible or cisplatin-refusing patients. As questions remain about whether the combination is necessary for all of these patients, physicians and scientists at MSK are already looking ahead, testing a variety of new treatment approaches.
We spoke with Dr. Aggen to discuss the evidence supporting this potential new standard-of-care and the groundbreaking news from the IMVigor011 study, the first prospective circulating tumor DNA (ctDNA) trial in MIBC announced at ESMO Congress 2025.
Additionally, Dr. Aggen provided highlights of five clinical trials that are currently open or will soon be open to patients with MIBC and metastatic urothelial cancer (UC). The trials include investigations of ctDNA-based stratification to adjuvant therapy or serial surveillance, two antibody-drug conjugates, a bispecific antibody, a T cell engager therapy, and testing enfortumab vedotin in the neoadjuvant setting.
For the third year in a row, U.S News and World Report ranked MSK as the number one hospital nationally for urology care in it’s annual Best Hospitals listing published in July 2025. The MSK urology service team is comprised of world-class specialists in surgery, medical oncology, chemotherapy, radiation oncology, radiology, pathology, and nursing, who collaborate to deliver the best treatment for each patient.
If perioperative (neoadjuvant/adjuvant) enfortumab vedotin plus pembrolizumab is approved later this year and becomes a new standard of care for patients with MIBC, that will be exciting news. Did MSK play a role in the development of this approach?
Jonathan Rosenberg, MD, Chief of the MSK Genitourinary Oncology Service, has led multiple trials testing the antibody-drug conjugate enfortumab vedotin, either alone or in combination with other drugs, for bladder cancer. As an invited discussant for a Presidential Symposium at ESMO Congress 2025, he provided his perspectives on the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895) of enfortumab vedotin plus pembrolizumab versus pembrolizumab or cystectomy alone for patients with MIBC in the adjuvant setting. MSK did not participate in the study.
KEYNOTE-905/EV-303 found that event-free and overall survival were dramatically improved for the combination versus pembrolizumab monotherapy, with hazard ratios of 0.4 and 0.5, respectively. This was big news given that about 50% of patients with MIBC are ineligible to receive cisplatin-based chemotherapy due to comorbidities such as poor performance status, impaired renal function, hearing loss, neuropathy, and heart failure.
Toxicity was higher with the combination, but the impressive survival outcomes suggested that the benefits outweighed the toxicity for many patients. What remains unanswered, though, is whether all of these patients required adjuvant therapy. Undertreatment and overtreatment are both problematic.
Results from the IMVigor011 trial recently made headlines at ESMO Congress 2025. Why were the results so groundbreaking?
IMVigor011 (NCT04660344) was an international, phase 3 trial sponsored by Genentech that evaluated the efficacy and safety of adjuvant atezolizumab versus placebo in patients with high-risk MIBC who have undergone cystectomy.
Notably, IMVigor011 was the first prospective trial to stratify ctDNA-positive patients to adjuvant therapy and ctDNA-negative patients to serial surveillance, up to seven times in the first year post-cystectomy. CtDNA status was determined using the Signatera molecular residual disease test (Natera, Inc.), which is customized to detect each patient’s ctDNA.
The results presented at ESMO Congress 2025 were exceptional. CtDNA-positive patients treated with atezolizumab had a two-fold increase in median disease-free survival (DFS) compared to placebo (9.9 months versus 4.8 months, respectively). The treatment group also had a statistically significant and clinically meaningfully improvement in overall survival (OS) compared to the placebo arm (32.8 months versus 21.1 months, respectively, a 41% improvement).
CtDNA-negative patients experienced excellent outcomes without adjuvant immunotherapy. Those who remained persistently negative during surveillance had a very low recurrence risk, with a DFS of 95.4% at one year and 88.4% at two years. OS results were also very strong.
This study was the first to demonstrate that ctDNA results can extend the adjuvant treatment decision window to one-year after cystectomy without jeopardizing oncologic outcomes, sparing patients who are persistently ctDNA negative from unnecessary treatment and potential toxicity.
MSK chose not to participate in the IMVigor011 trial. However, we have been using the Signatera test as our standard of care to inform adjuvant therapy decisions for patients with MIBC for more than two years. We are also watching closely several other molecular residual disease (MRD) tests in development for this indication, such as the Haystack MRD test (Quest Diagnostics).
Is MSK conducting any ctDNA-based clinical trials for patients with MIBC?
MSK is participating in the phase 2/3 MODERN trial, sponsored by the Alliance for Clinical Trials in Oncology (NCT05987241). MODERN is evaluating ctDNA-based optimization of adjuvant nivolumab or nivolumab plus relatlimab in patients with urothelial cancer of the bladder, kidney, ureter, or urethra.
At MSK, we are recruiting patients with bladder cancer who have undergone radical cystectomy. CtDNA-positive patients receive adjuvant therapy, and those who are ctDNA-negative are randomized to adjuvant therapy or serial surveillance. Patients in the surveillance group who become ctDNA positive are converted to treatment as required.
The primary objectives of the trial include determining whether ctDNA can better identify patients who require additional treatment, if treatment prolongs DFS and OS, as well as comparing ctDNA clearance at 12 weeks for ctDNA-positive patients in the treatment arms, and assessing quality-of-life measures. Learn more about the MODERN trial at MSK.
Are there any antibody-drug conjugate trials at MSK currently recruiting patients with bladder cancer?
We are conducting several clinical trials of antibody-drug conjugates for patients with advanced bladder cancer who have previously received enfortumab vedotin plus pembrolizumab.
First, MSK is participating in the international phase 2 TROPION-PanTumor03 study of datopotamab deruxtecan (Dato-DXd) as monotherapy and in combination with other drugs in patients with various advanced solid tumor types, including patients with advanced or metastatic urothelial cancer. The study is sponsored by AstraZeneca (NCT05489211).
Dato-DXd is a Trop-2-directed antibody and topoisomerase inhibitor. The antibody targets the Trop-2 surface antigen found on cancer cells, and the topoisomerase inhibitor blocks enzymes that are crucial for cell division. Dato-DXd is already approved for unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer and locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC). Learn more about the TROPION-PanTumor 03 Trial of Dato-DXd at MSK.
The second study is the international phase 1 EXCEED trial of LY4101174, a next-generation antibody-drug conjugate targeting nectin-4 in patients with recurrent, advanced, or metastatic solid tumors (NCT06238479). LY4101174 contains a humanized IgG1 Fc-silent monoclonal antibody linked to exatecan, a topoisomerase 1 inhibitor. LY4101174 demonstrated robust efficacy in preclinical in vivo research.
The trial, sponsored by Eli Lilly, aims to enroll a total of 490 patients across the eligible indications. Dr. Rosenberg is the principal investigator at MSK, where we are recruiting patients with advanced bladder and prostate cancers. The EXCEED trial may identify a new antibody-drug conjugate treatment option beyond enfortumab vedotin, which is associated with clinically significant toxicities, such as skin rash, peripheral neuropathy, and hyperglycemia. Learn more about the LY4101174 trial at MSK.
MSK is participating in the global, first-in-human study of DS-2243a, a T cell-engaging bispecific antibody for treating advanced solid tumors. How does the new drug work, and when will recruiting open for patients with bladder cancer?
DS-2243a binds to NY-ESO-1, a tumor-associated antigen complexed with human leukocyte antigen HLA-A*02 and an antigen found on cytotoxic T cells. Designed by Daiichi Sankyo, the drug is given by subcutaneous injection.
MSK is participating in the global, first-in-human phase 1 trial of DS-2243a as a treatment for unresectable locally advanced or metastatic synovial sarcoma, myxoid/round cell liposarcoma, NSCLC, and urothelial cancer in patients who are HLA-A*02 and/or NY-ESO positive (NCT06644755).
The dose escalation part of the study is underway in participants with sarcoma, led by the principal investigator MSK sarcoma medical oncologist and cellular therapist Sandra D’Angelo, MD. The sponsor invited me to be a co-investigator, given my experience with translational research into T cell engagers. I look forward to opening recruiting for patients with urothelial cancer starting in the spring of 2026. Learn more about the DS-2243a trial at MSK.
Are there any neoadjuvant therapies under investigation at MSK for patients with MIBC?
The investigator-initiated phase 2 EV-ECLIPSE trial, available exclusively at MSK, has completed accrual for patients newly diagnosed patients with locally advanced MIBC that has spread to lymph nodes and who will be undergoing radical cystectomy (NCT05239624).
Patients are treated with neoadjuvant enfortumab vedotin plus pembrolizumab to see if the combination can shrink MIBC before surgery and eliminate cancer within the lymph nodes.
As the principal investigator for EV-ECLIPSE, I am hopeful that this treatment approach will improve pathological complete response and event-free survival at two years for patients with locally advanced disease, who historically may have not been candidates for curative intent surgery. Learn more about the EV-ECLIPSE trial at MSK.
In summary, have we entered a new era of clinical research for patients with MIBC and advanced bladder cancer?
Definitely. It’s a very exciting time for bladder cancer research across the spectrum of disease from MIBC to metastatic UC, with several clinical trials testing different therapeutic approaches. The approval of enfortumab vedotin will be a welcome addition to our armamentarium and guiding adjuvant therapy decisions using ctDNA will be practice-changing. At the same time, we are already evaluating next-generation targeted therapies in clinical trials, continuing the quest to improve outcomes for patients with MIBC.