2025 Review and Renew Sedona: Updates from ASCO GU with Dr Sonpavde
Presenter:
Guru Sonpavde, MD
Conference:
2025 Review and Renew Sedona
Part 1: Updates in Metastatic Urothelial Carcinoma (mUC) and Muscle-Invasive Bladder Cancer (MIBC)
Therapeutic Landscape in mUC: Evolving First-Line Paradigms
Dr Sonpavde emphasized the rapidly evolving treatment landscape for metastatic urothelial carcinoma (mUC), noting that enfortumab vedotin plus pembrolizumab (EV+P) has become the new preferred standard of care in the frontline setting for both cisplatin-eligible and ineligible patients. This shift is driven by updated results from the EV-302 trial, which Dr Sonpavde described as “a landmark trial” that “further established the strong role for EV pembrolizumab as the first-line therapy in most patients with advanced urothelial carcinoma.” The updated data presented at ASCO GU 2025 show that progression-free survival (PFS) doubled from 6.3 months with chemotherapy to 12.5 months with EV+P, and overall survival (OS) improved dramatically from 15.9 to 33.8 months (HR 0.51). Importantly, this benefit was consistent regardless of cisplatin eligibility, with benefit seen in cisplatin-eligible patients (36.7 months vs. 18.7 months) and cisplatin-ineligible patients (25.6 months vs. 12.7 months).
Dr Sonpavde also noted key findings of duration of response (DoR) and complete response (CR), with a median DoR with EV+P of 23.3 months versus 7.0 months with chemotherapy, and a CR rate of ~30% with EV+P. Dr Sonpavde also emphasized that 74.3% of patients who achieved a CR on EV+P remained in CR at two years, as compared with only 43.2% in the chemotherapy arm. “The median [duration of complete response] has not been reached… around 75 percent are still in CR at two years,” Dr Sonpavde noted, adding that “these data establish further the strong role for EV-pembrolizumab.”
A New Adjuvant Strategy: The NIAGARA Trial
The NIAGARA trial, presented by Dr. Matthew D. Galsky at GU ASCO 2025, was called out by Dr Sonpavde as another practice-changing study. It evaluated the use of perioperative durvalumab in combination with gemcitabine and cisplatin (GC) for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). In this trial, durvalumab was administered both neoadjuvantly and adjuvantly. Results from the trial showed that event-free survival was improved, with a hazard ratio [HR] of 0.68, OS was improved, with a HR of 0.75, and pathologic complete response rate (pCR) increased from 27.5% to 37.3% (+10%), with no compromise in surgical feasibility or unexpected immune-related adverse events. Dr Sonpavde noted that the US Food and Drug Administration (FDA) approval for this regimen on March 28, 2025 formalizes it as a new standard for cisplatin-eligible MIBC patients. “Whether or not the patient achieved a pCR, there was a benefit for perioperative durvalumab,” Dr Sonpavde emphasized, underscoring the robustness of the survival impact.
CheckMate 274: Extended Follow-Up
Dr Sonpavde also reviewed updated data from CheckMate 274, supporting the adjuvant use of nivolumab in high-risk MIBC. The trial demonstrated continued benefit in disease-free survival (DFS) with extended follow-up, especially in patients with a programmed death ligand expression (PD-L1) of ≥1%. For these patients, the median DFS was 52.6 vs. 8.4 months (HR 0.52), while the median DFS for all-comers in the trials was 25.6 vs. 8.5 months (HR 0.63) and a benefit was seen regardless of use of prior neoadjuvant chemotherapy. “With extended follow-up, adjuvant nivolumab continues to show DFS benefit… and a strong trend for OS improvement,” he remarked, noting the additional convenience of subcutaneous nivolumab now available.
Challenges Ahead: Post-IO Treatment Sequencing
One critical issue flagged by Dr Sonpavde was that the impact of prior perioperative PD-1/L1 inhibition on treatment efficacy in the mUC setting remains unclear. As more patients receive durvalumab or nivolumab pre-/post-operatively, the treatment landscape for frontline mUC landscape may require reconsideration. “We need to understand whether the reinstitution of checkpoint inhibition is a valid approach… This is a question we need to study more,” he warned, advocating for future trials in this space.
Biomarker-Driven Approaches and Emerging Therapies
While discussing available treatments in the salvage setting and targeted agents, Dr Sonpavde noted ongoing efforts involving the use of erdafitinib in patients with FGFR3-mutant tumors, the use of antibody drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) in patients with HER2-positive (IHC 3+) tumors, and the use of other emergent ADCs like BL-B01D1 (targeting EGFR/HER3) and datopotamab deruxtecan (targeting Trop2). He also highlighted some notable advances in intravesical delivery systems, such as TAR-200 (gemcitabine) and TAR-210 (sustained-release erdafitinib), for non–muscle-invasive bladder cancer. Lastly, he emphasized the growing role of tumor-informed circulating tumor DNA (ctDNA) to detect minimal residual disease (MRD), encouraging clinical trial enrollment to accelerate development.
Updates in mUC and MIBC from ASCO GU 2025 – Clinical Insights from Dr Sonpavde
“EV pembrolizumab remains the preferred standard in most [mUC] patients… regardless of cisplatin eligibility.”
“The NIAGARA trial is practice-changing [in MIBC]. There is a benefit whether patients achieved pCR or not.”
“Adjuvant nivolumab continues to demonstrate benefit across subgroups [in MIBC] … even with longer follow-up.”
“We need to study the impact of prior perioperative checkpoint inhibition on mUC treatment algorithms.”
Part 2: Updates in Renal Cell Carcinoma (RCC)
Shifts in the First-Line RCC Landscape
Dr Sonpavde began the RCC updates portion of his presentation by emphasizing that, while no data from ASCO GU 2025 were immediately practice-changing, recent trial updates continue to strengthen the evidence base for existing regimens. The frontline therapeutic backbone in clear cell RCC (ccRCC), for example, remains immune checkpoint inhibitors (IOs) in combination with VEGF-targeted therapies, or in select cases, dual IO therapy (ipilimumab/nivolumab). “The treatment of RCC remains what it has been, but we’re seeing exciting long-term updates and new targets like HIF2α and MRD biomarkers gaining traction,” he noted. The CheckMate 9ER trial, Dr Sonpavde noted, provided the most compelling long-term data. This study compared cabozantinib plus nivolumab (Cabo/Nivo) to sunitinib in the frontline setting; with over 5 years of follow-up, the Cabo/Nivo combination showed a median PFS of 16.4 months versus 8.3 months with sunitinib, with a durable benefit observed. Additional results show a median OS of 46.5 versus 35.5 months, an overall response rate (ORR) of ~56%, and a median DoR of 22.1 months (vs. 15.2 for sunitinib). He further noted that the observed benefits were consistent across IMDC risk groups and metastatic sites—including lung, liver, and notably bone, where the hazard ratio for PFS appeared more favorable. “The Cabo/Nivo regimen continues to show long-term efficacy, particularly in patients with bone metastases—a group historically harder to treat…”
CheckMate 214: Revisiting Ipi/Nivo in Favorable Risk
Dr Sonpavde noted that, although CheckMate 214 initially excluded most favorable-risk patients from its IO/IO combination of nivolumab and ipilimumab, extended follow-up data now demonstrate a separation in survival curves, even in this population. “The survival curve is now separating in favor of Ipi/Nivo, even in favorable risk [patients], though this remains a category 2 recommendation,” he added, reinforcing that while compelling, the data still lack the statistical power to be practice-changing in this group.
Emerging Therapies and Novel Targets
Dr Sonpavde also highlighted some promising experimental combinations involving HIF2α inhibition, particularly with belzutifan. He noted results from the Keymaker-U03 platform trial, which evaluated post-IO therapy combinations, with the lenvatinib plus belzutifan combination showing the most promising signal (ORR, 46.9%; Median DoR, 22.1 months; Median PFS, 12.5 months). He noted this combination outperformed pembrolizumab + belzutifan and lenvatinib + pembrolizumab in the post-IO setting, suggesting synergistic activity between VEGFR and HIF2α blockade. “This is a glimpse of where RCC drug development is going—VEGF plus HIF2α targeting appears highly promising,” he commented. An ongoing Phase III trial, LITESPARK-011, will also evaluate lenvatinib + belzutifan versus cabozantinib in the post–PD-1 therapy setting, and Dr Sonpavde highlighted this as a potentially pivotal study to confirm these early efficacy signals.
Biomarkers: KIM-1 as a Prognostic and Predictive Tool
One of the most forward-looking updates in RCC which Dr Sonpavde highlighted addressed the use of KIM-1 (Kidney Injury Molecule-1) as an emerging biomarker for minimal residual disease (MRD) in RCC. Using a blood-based proteomics approach, KIM-1 was analyzed in the CheckMate 214 trial to assess its correlation with treatment outcomes. Some of the key findings in this trial demonstrated that high baseline KIM-1 was associated with worse OS and PFS, regardless of treatment. In addition, early decreases in KIM-1 at Week 3 after initiating therapy correlated with better outcomes in the Nivo/Ipi arm, but not in the sunitinib arm. “Dynamic changes in KIM-1, particularly in the immune checkpoint setting, appear prognostic... But these findings need validation,” Dr Sonpavde stated, pointing to the need for standardized cutoff values and prospective trials.
Remaining Gaps and the Role of Biomarker-Guided Therapy
Despite these advancements, however, Dr Sonpavde stressed that validated molecular signatures for selecting first-line therapy in clear cell RCC remain elusive. While signatures such as Teff or angiogenesis-related expression have been retrospectively associated with response to IO or VEGF based regimens, they have not influenced trial design or clinical decision-making thus far. He also highlighted the unmet need for patients progressing after adjuvant pembrolizumab, as there is currently no standard frontline therapy in this setting. “The next generation of first-line advances is still on the horizon—until then, we rely on clinical factors like IMDC risk and histology…” he concluded.
Updates in RCC from ASCO GU 2025 – Clinical Insights from Dr Sonpavde
“Cabo/Nivo continues to show benefit even at five years—especially in bone metastases.”
“The combination of lenvatinib and belzutifan looks quite impressive post–PD-1.”
“KIM-1 dynamic changes seem to matter—but we need more data before using this in clinic.”
“We’re still in need of validated molecular markers to select therapy in RCC.”
Speaker Disclosure Information: Dr Sonpavde reported the following disclosures for this presentation: Speakers Bureau: Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Pfizer, Merck, Aveo, Astrazeneca; Advisory Boards: EMD Serono, BMS, Merck, Seattle Genetics, Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly, Loxo Oncology, Vial, Aktis, Daiichi-Sankyo; Consulting Fee: Syapse, Merck, Servier, Syncorp, Ellipses; Contracted Research: EMD Serono, Jazz Therapeutics, Bayer, Sumitomo Pharma, Blue Earth Diagnostics; Promotional Services Provided: None; Ownership Interest: None; Other: Family employment- Myriad Genetics, Exact Sciences; Travel cost- BMS, Astellas.