Moshe Ornstein, MD, MA

In this closing segment on advanced renal cell carcinoma, Dr. Ornstein synthesizes key themes from the case discussion, emphasizing how disease biology and clinical presentation guide second-line treatment decisions. He highlights that patients with early progression after frontline therapy represent a higher-risk group that often requires a more aggressive treatment approach.

In this case-based segment on advanced renal cell carcinoma, Dr. Ornstein introduces a patient with high disease burden who progresses within 8 months of frontline immunotherapy plus VEGF receptor targeted therapy, highlighting a more aggressive disease course. He emphasizes that early progression and limited depth of response raise concern for more refractory disease biology.

In this forward-looking segment on advanced renal cell carcinoma, Dr. Ornstein asks the panel to consider how treatment decisions may evolve if newer combination therapies become available in the second-line setting. He introduces the potential role of lenvatinib combined with belzutifan and asks how this regimen might fit into clinical practice.

In this segment on advanced renal cell carcinoma, Dr. Ornstein asks how clinicians differentiate among VEGF receptor targeted therapies when selecting treatment for patients with slower disease progression after prior immunotherapy. He highlights the perception that different TKIs may vary in both efficacy and toxicity.

In this case-based segment on advanced renal cell carcinoma, Dr. Ornstein presents a patient with intermediate-risk disease who experienced progression after 14 months of frontline dual immune checkpoint inhibitor therapy. He highlights the importance of interpreting prior treatment response and clinical status when selecting second-line therapy.

In this case-based segment on advanced renal cell carcinoma, Dr. Ornstein presents a patient who progresses after frontline immunotherapy plus VEGF receptor targeted therapy, with prior tolerability challenges including hand-foot syndrome and diarrhea. He highlights the expanding range of second-line options, including HIF-2α inhibitors.

In this case-based segment on advanced renal cell carcinoma, Dr. Ornstein presents a clinical scenario of a patient with disease progression after frontline dual immune checkpoint inhibitor therapy, emphasizing the need to individualize second-line treatment decisions in the absence of certain emerging approvals.

In this segment on advanced renal cell carcinoma, Dr. Ornstein explores real-world transition rates from first-line to subsequent lines of therapy, asking how often patients reach second- and third-line treatment in clinical practice.

In this segment on advanced renal cell carcinoma, Dr. Ornstein transitions the discussion to the second-line setting, noting that most patients will eventually experience disease progression and require additional therapy. He highlights that treatment goals evolve in the refractory setting, where achieving disease control becomes the primary objective rather than long-term durable remission.

In this segment on advanced renal cell carcinoma, Dr. Ornstein emphasizes that treatment is only effective if patients are able to remain on therapy, framing dose management as a critical component of clinical care. He asks how clinicians approach dosing and tolerability, particularly with VEGF receptor targeted therapy–based combinations.

In this segment on advanced renal cell carcinoma, Dr. Ornstein raises the important issue of real-world treatment attrition, noting that not all patients are able to receive subsequent lines of therapy after disease progression. He frames this as a key consideration when selecting first-line treatment.

In this segment on advanced renal cell carcinoma, Dr. Ornstein shifts the discussion to the role of treatment sequencing when selecting first-line therapy. He raises the question of how anticipated second-line options may influence initial treatment decisions in the context of multiple effective frontline regimens.

In this segment on advanced renal cell carcinoma, Dr. Ornstein guides the discussion toward differentiating available frontline treatment options, focusing on the choice between dual immune checkpoint inhibitor therapy and combinations of immunotherapy with VEGF receptor targeted therapies.

In this opening segment on advanced renal cell carcinoma, Ornstein introduces the evolving frontline treatment landscape, highlighting the expanded role of immune checkpoint inhibitor–based combinations and VEGF receptor–targeted therapies.

Panelists discuss how pembrolizumab plus lenvatinib has established a new benchmark and become the preferred first-line treatment option for more than 95% of patients with non–clear cell renal cell carcinoma (RCC), according to national guidelines, demonstrating activity across all major histological subtypes despite the heterogeneous nature of these diseases, while acknowledging that specific rare histologies may still require tailored approaches.

Panelists discuss how managing the safety profile of pembrolizumab plus lenvatinib requires proactive patient education and early toxicity identification, with approximately 25% of patients discontinuing therapy due to adverse events in both clinical trials and real-world practice, emphasizing the importance of distinguishing between tyrosine kinase inhibitor (TKI) and immunotherapy-related adverse events for appropriate management.

Panelists discuss how the KEYNOTE-B61 study demonstrated impressive survival outcomes with a median progression-free survival (PFS) of 17.9 months and median overall survival (OS) of 41.5 months, effectively doubling the historical tyrosine kinase inhibitor (TKI) monotherapy benchmarks of 8 to 9 months PFS and 21 months OS in patients with non–clear cell renal cell carcinoma (RCC).

Panelists discuss the ongoing challenges and progress in treating non–clear cell renal cell carcinoma (nccRCC), emphasizing the need for subtype-specific trials, mechanistically driven therapy, and international collaboration to move beyond data extrapolation from clear cell RCC (ccRCC) and toward truly evidence-based, personalized care.

Panelists discuss the future of clear cell renal cell carcinoma (ccRCC) treatment, focusing on optimizing sequencing and combinations of existing therapies, integrating novel agents like belzutifan and cellular therapies, and advancing research through clinical trials and investigator-led studies to drive more personalized and effective care.

Panelists discuss how the durability of response data was particularly compelling, with a median duration of response of approximately 2 years and 35% of patients maintaining responses at 3 years, especially noting the surprising 31% response rate in chromophobe renal cell carcinoma (RCC) despite this histology's historically poor responsiveness to immunotherapy due to low tumor mutational burden.

Panelists discuss how the KEYNOTE-B61 study demonstrated remarkable efficacy with a 50.6% objective response rate and 82% disease control rate across all non–clear cell renal cell carcinoma (RCC) histologies, representing a significant improvement over historical tyrosine kinase inhibitor (TKI) data that showed response rates below 30% and setting a new treatment benchmark for this patient population.

Panelists discuss the ongoing challenge of lacking reliable biomarkers in renal cell carcinoma (RCC), emphasizing promising advances in RNA expression signatures and emerging tools like protein biomarkers and circulating tumor DNA (ctDNA) to personalize treatment and improve real-time therapy decisions despite current limitations.

Panelists discuss the nuanced approach to adverse effect management in non–clear cell renal cell carcinoma (nccRCC), highlighting a shift from aggressive toxicity management in the first-line setting aimed at prolonging survival to a patient-centered focus on quality of life and tolerability in later lines, emphasizing open communication and long-term treatment endurance.

Panelists discuss how the KEYNOTE-B61 study population truly represents real-world clinical practice, with papillary renal cell carcinoma (RCC) being the most common subtype followed by chromophobe, unclassified, and translocation RCC as the top 4 subtypes typically encountered in clinic, while rarer variants comprise only 2% to 3% of non–clear cell cases.

Panelists discuss the complex management of papillary renal cell carcinoma (RCC) after first-line progression, focusing on balancing effective second-line therapies like lenvatinib plus pembrolizumab with quality of life, the role of multidisciplinary care and surgery, the importance of close monitoring, and the critical need for clinical trial enrollment and genomic profiling to guide personalized treatment.

Panelists discuss how the KEYNOTE-B61 phase 2 single-arm study represents the largest prospective trial evaluating pembrolizumab plus lenvatinib as first-line treatment for advanced non–clear cell renal cell carcinoma (RCC), enrolling 158 patients across all major histological subtypes with an impressive median follow-up of 41.6 months and updated 3-year survival data.

Panelists discuss how non–clear cell renal cell carcinoma (RCC) represents a challenging, heterogeneous collection of rare tumors comprising 25% to 30% of all RCC cases, requiring careful histological review and individualized risk stratification based on tumor biology, disease tempo, and burden rather than traditional treatment algorithms used for clear cell RCC.

Panelists discuss how they will review the KEYNOTE-B61 phase 2 study examining pembrolizumab plus lenvatinib for previously untreated advanced non–clear cell renal cell carcinoma (RCC), including an overview of non–clear cell RCC and integration of the 3-year follow-up data into clinical practice.

Panelists discuss the challenges of treating non–clear cell renal cell carcinoma (nccRCC) after first-line progression, emphasizing the limited second-line options, the emerging use of immunotherapy (IO) and combination regimens, the need for subtype-specific strategies, and the critical role of clinical trial enrollment to advance care in this heterogeneous disease.

Panelists discuss recent advances in non–clear cell renal cell carcinoma (nccRCC) treatment, highlighting the emerging role of immunotherapy plus tyrosine kinase inhibitor (TKI) combinations—particularly lenvatinib and pembrolizumab—in improving response rates, progression-free survival, and overall survival across diverse subtypes, while emphasizing individualized care and proactive management.