Dr Gopal on a Case Study of a Patient With Bladder Cancer

Nikhil Gopal, MD, assistant professor, urology, College of Medicine, Memphis Department of Urology, The University of Tennessee Health Science Center, discusses details from a case study of a patient with bladder cancer.

 State of the Science Summit™ on urothelial cancer, Gopal and colleagues discussed a case study of a patient with bladder cancer that evolved over time. This patient presented with recurrent, high-grade, T1 disease with carcinoma in situ (CIS) despite undergoing several prior rounds of intravesical therapy, Gopal says. This was a challenging case to treat because the patient did not respond to therapy, spurring concerns that they had undiagnosed muscle-invasive bladder cancer (MIBC), Gopal notes. Furthermore, T1 disease with CIS has high progression rates, Gopal explains.

Typically, patients with this disease presentation undergo early cystectomy, which may be curative and help them avoid the morbidity of untreated MIBC progression, according to Gopal. However, the bladder cancer treatment paradigm is expanding to include therapeutic alternatives for patients who have progressed on several rounds of intravesical therapy and are not eligible for or refuse cystectomy, Gopal emphasizes. In this case, the patient refused early cystectomy, progressed to MIBC, underwent repeat transurethral resection of their bladder tumor, and was eventually diagnosed with node-positive, locally advanced urothelial cancer, Gopal says.

Regarding the role of adjuvant therapy for patients such as this one, Gopal highlights that the phase 3 CheckMate-274 trial (NCT02632409) demonstrated a disease-free survival (DFS) benefit with nivolumab (Opdivo) vs placebo in patients with MIBC who had unfavorable prognostic features. Conversely, the phase 3 AMBASSADOR trial (NCT03244384) evaluated pembrolizumab (Keytruda) vs observation following surgery in patients with localized MIBC. However, this trial did not complete enrollment because of the successful findings from CheckMate-247. AMBASSADOR showed a DFS benefit with pembrolizumab but failed to demonstrate an overall survival benefit. Given these collective trial findings, Gopal and colleagues determined that the optimal treatment for the patient in this case study was adjuvant nivolumab instead of adjuvant pembrolizumab, Gopal concludes.

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Nikhil Gopal, MD, discusses details from a case discussion of a patient with bladder cancer.

Nikhil A. Gopal, MD, discusses future research directions for the treatment of various renal cell carcinoma histologies.

Dr Gopal on Future Research Directions in Non-ccRCC

Nikhil A. Gopal, MD, assistant professor, urology, assistant professor, College of Medicine - Memphis, Department of Urology, The University of Tennessee Health Science Center, discusses future research directions for immuno-oncology (IO)/TKI combinations across renal cell carcinoma histologies.

In frontline metastatic clear cell renal cell carcinoma (ccRCC), there is currently a robust selection of agents that have significantly improved patient outcomes. Accordingly, this offers oncologists a range of effective treatment options to choose from, Gopal begins. Looking ahead, the focus of research is shifting towards developing novel treatment strategies in non-clear cell RCC, Gopal states. There is particular interest in papillary RCC, which is the second most common subtype of kidney cancer, he adds. Although single-agent therapies such as cabozantinib (Cabometyx) have demonstrated promising results, combination regimens may hold greater potential for optimizing outcomes in this patient population, Gopal explains.

There is currently a lack of data supporting the use of combination therapies in non-ccRCC, Gopal continues. However, ongoing trials are investigating immune checkpoint inhibitor combinations for this population, and are expected to provide valuable insights into the benefit of these regimens, he states. Understanding the efficacy and safety of these combinations is crucial for advancing treatment paradigms beyond ccRCC, Gopal emphasizes.

Notably, patients with sarcomatoid histology have demonstrated favorable responses when treated with immunotherapy, Gopal says, adding that this underscores the importance of exploring novel approaches that encompass variant RCC histologies in clinical trials. In the coming years, Gopal expresses that he hopes to witness a transformation in the focus of RCC research, with a renewed commitment to addressing key questions and refining treatment strategies specifically tailored to non-ccRCC subtypes.

As the field progresses beyond ccRCC, advancements in IO combinations and tailored therapies in non-ccRCC variants hold promise for improving outcomes and expanding treatment options for patients with variant RCC histologies, Gopal concludes.

Nikhil A. Gopal, MD, discusses treatment selection in second-line relapsed/refractory metastatic urothelial cancer.  

Dr Gopal on Treatment Selection in Second-Line R/R mUC

Nikhil A. Gopal, MD, assistant professor, urology, assistant professor, College of Medicine - Memphis, Department of Urology, The University of Tennessee Health Science Center, discusses treatment selection in the second line and beyond for patients with relapsed/refractory metastatic urothelial cancer.

In recent years, the treatment arsenal for relapsed/refractory metastatic urothelial cancer has expanded significantly with the approval of novel agents targeting specific molecular alterations, Gopal begins. Antibody-drug conjugates (ADCs) such as enfortumab-ejfv vedotin (Padcev) and sacituzumab govitecan-hziy (Trodelvy) have demonstrated significant efficacy in the second line, as have targeted therapies such as erdafitinib (Balversa), he states.

Navigating treatment selection for patients with relapsed/refractory disease in the second line and beyond should therefore involve a selective precision medicine strategy, driven by molecular and genetic profiling of the tumor, Gopal states. He explains that this profiling helps guide treatment decisions based on specific mutations and biomarkers present in the tumor.

 mutations in a patient's tumor may make them a candidate for erdafitinib, Gopal says. There is also interest in utilizing anti-HER2 agents such as trastuzumab (Herceptin) for tumors expressing HER2 mutations, he adds. Furthermore, evaluating tumor mutational burden or microsatellite instability (MSI) status can inform the use of immunotherapy regimens, which may be more effective in tumors with high mutational burden or MSI-high status, Gopal explains.

It is also crucial to consider the toxicity profiles of available treatments alongside molecular findings, Gopal continues. Although enfortumab vedotin is a highly effective regimen, a patient with neuropathy may experience more significant adverse effects (AEs). Conversely, erdafitinib is associated with ocular toxicities, making it less appropriate for patients with pre-existing eye disorders, Gopal states.

This underscores the importance of utilizing precision medicine to tailor therapy to each patient's unique tumor characteristics, optimizing treatment efficacy while minimizing the risk of AEs, Gopal emphasizes. Moving forward, the integration of comprehensive molecular profiling into routine clinical practice will continue to guide therapeutic decision-making in this challenging disease setting, he concludes.

Nikhil A. Gopal, MD, discusses treatment selection in second-line relapsed/ refractory metastatic urothelial cancer.
 

Nikhil A. Gopal, MD, discusses the nuances of treatment decision-making in advanced renal cell carcinoma.

Dr Gopal on the Nuances of IO/TKI Selection in Advanced RCC

Nikhil A. Gopal, MD, assistant professor, urology, assistant professor, College of Medicine - Memphis, Department of Urology, The University of Tennessee Health Science Center, discusses the nuances of selecting between the currently available immuno-oncology (IO)/TKI approaches in advanced renal cell carcinoma.

When analyzing current data on ipilimumab (Yervoy) plus nivolumab (Opidvo), it's essential to consider the evolving landscape of treatment options for patients, Gopal begins. Unlike previous years when patients had fewer alternatives upon progression, the availability of various therapies now influences the interpretation of outcomes, he explains.

For example, the phase 3 CheckMate-214 trial (NCT02231749) demonstrated significantly higher overall survival (OS) and objective response rates (ORR) with nivolumab plus ipilimumab compared with sunitinib (Sutent) among intermediate– and poor-risk patients with previously untreated advanced RCC, Gopal expands.These results supported the 

FDA approval of nivolumab plus ipilimumab

 in this patient population on April 16, 2018. However, the trial was conducted at a time when immunotherapy was not as established, potentially impacting the observed reduction in OS benefits compared with more recent studies, Gopal states.

Overall, Gopal goes on to state that it is crucial to always rely on the available data. Ipilimumab with nivolumab demonstrates the longest OS benefit due to its extensive history in clinical use, he says. For patients who prioritize factors like quality of life and are capable of tolerating the increased adverse effects associated with dual immune checkpoint inhibitor therapy, this regimen may be favored over other agents, Gopal asserts. This decision-making process exemplifies the complexities faced by clinicians in selecting the most appropriate treatment strategy amidst a plethora of available options, he adds.

Ultimately, weighing the benefits and risks of each therapeutic approach in the context of individual patient characteristics and preferences is paramount, Gopal emphasizes. Despite the expanding treatment landscape, ensuring that patients receive personalized and optimized care remains a central tenet of oncology practice, he concludes.

Nikhil A. Gopal, MD, discusses the transition of treatment with TKIs to treatment with TKI/IO combinations for those with renal cell carcinoma.

Dr Gopal on the Evolution of TKI/IO Combination Approaches in RCC

Nikhil A. Gopal, MD, assistant professor, urology, assistant professor, College of Medicine - Memphis, Department of Urology, The University of Tennessee Health Science Center, discusses the transition of the use of single-TKIs to TKI/immuno-oncology (IO) combinations in the treatment of patients with renal cell carcinoma (RCC).

In recent years, TKI/IO treatment combinations have become a standard of care in the frontline setting for patients with RCC, with the notable exception being the IO/IO combination of nivolumab (Opdivo) and ipilimumab (Yervoy), Gopal begins. He goes on to emphasize that it is notable how immunotherapy has evolved from being scarcely discussed in 2014 and 2015, to now having 5 agents approved for frontline use. The challenge now lies in determining the most suitable combination for each patient, Gopal adds, saying that in his perspective, the combination of TKIs and IO therapies appears to yield higher objective response rates (ORRs).

For example, the TKI/IO combinations of pembrolizumab (Keytruda) plus axitinib (Inlyta) and lenvatinib (Lenvima) plus pembrolizumab elicited higher ORRs in clinical trials that supported their FDA approvals compared with nivolumab plus ipilimumab, which was approved based on data from the phase 3 CheckMate 214 trial (NCT02231749), he continues. Therefore, for patients with significant disease burden and concerns about disease progression leading to critical complications such as impending cord compression or debilitating bone pains hindering mobility could benefit a TKI/IO combination over nivolumab and ipilimumab, Gopal elucidates.

Although it is challenging to directly compare results across different trials, real-world decision-making often necessitates such comparisons to provide patients with actionable insights, Gopal expands. On the other hand, nivolumab and ipilimumab offer the advantage of the longest follow-up time, with data extending up to 8 years, he says Interestingly, and with this extended follow-up, the overall survival curves continue to demonstrate a benefit compared with sunitinib (Sutent) alone, Gopal concludes.

Dr Gopal on the Evolution of TKI/IO Combination Approaches in RCC 

Dr Gopal on the Significance of the EV-302 and CheckMate 901 Trials in mUC

Nikhil A. Gopal, MD, assistant professor, urology, assistant professor, College of Medicine - Memphis, Department of Urology, The University of Tennessee Health Science Center, discusses how the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) and CheckMate 901 trials (NCT03036098) have shifted the treatment paradigm in metastatic urothelial cancer.

These 2 studies, which were presented at the 

 showed a survival benefit beyond platinum-based chemotherapy alone, further reshaping the treatment paradigm for metastatic urothelial carcinoma, Gopal begins.

The first of these was the CheckMate 901 trial evaluating the triplet regimen of nivolumab (Opdivo) plus gemcitabine and cisplatin in metastatic or unresectable urothelial carcinoma, Gopal states. The triplet showed a survival benefit in the frontline setting for cisplatin-eligible patients, producing a median OS of 21.7 months (95% CI, 18.6-26.4) vs 18.9 months (95% CI, 14.7-22.4) with chemotherapy alone (HR, 0.78; 95% CI, 0.63-0.96; 

 = .0171), he details. Although the trial represents one of the first studies to demonstrate a prolonged survival benefit with cisplatin-based chemotherapy and immunotherapy in the frontline setting, these results were accompanied b by equally impressive findings from the EV-302 study, Gopal notes.

EV-302 investigated enfortumab-ejfv (Padcev) vedotin plus pembrolizumab (Keytruda) vs standard-of-care (SOC) platinum-based chemotherapy therapy in treatment-naive patients with metastatic urothelial cancer. The regimen produced a median OS of 31.5 months (95% CI, 25.4-not reached) vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy at a median follow-up of 17.2 months, Gopal reports.

Consequently, enfortumab vedotin plus pembrolizumab has become the SOC in the frontline setting for metastatic urothelial carcinoma following its 

full FDA approval for patients with locally advanced or metastatic urothelial cancer

 on December 15, 2023, Gopal says. This combination therapy has demonstrated superiority over traditional agents used in this setting, which were primarily platinum-based chemotherapy combinations, Gopal states. Prior to the approval of this regimen, patients had not consistently experienced a sustained overall survival (OS) benefit from standard therapies beyond approximately 18 to 20 months, Gopal explains.

Despite its efficicy, the accessibility and cost of this treatment remain important real-world considerations, especially given its higher cost compared to platinum-based therapy, Gopal notes. Nonetheless, the approval of enfortumab vedotin plus pembrolizumab represents a paradigm shift in the management of metastatic urothelial carcinoma, particularly for cisplatin-ineligible patients who previously lacked effective treatment options, he concludes.

Nikhil A. Gopal, MD, discusses how the phase 3 EV-302 and CheckMate 901 trials have advanced the treatment paradigm in metastatic urothelial cancer.

Dr Gopal on the Advantages and Potential Benefit of Belzutifan in RCC  

Nikhil A. Gopal, MD, assistant professor, urology, assistant professor, College of Medicine - Memphis, Department of Urology, The University of Tennessee Health Science Center, discusses the benefit of belzutifan (Welireg) for patients with renal cell carcinoma (RCC), as well as its potential use in the frontline setting.

The highly selective HIF2α inhibitor belzutifan has demonstrated efficacy in the treatment of patients with clear cell RCC (ccRCC), particularly in those who have progressed on prior therapy, Gopal begins. The phase 3 LITESPARK-005 trial (NCT04195750) demonstrated the superior efficacy of belzutifan over everolimus (Afinitor) and led to improved patient-reported quality of life (QOL) outcomes in this setting, Gopal details. Ongoing phase 2 trials are also investigating the efficacy of belzutifan in combination with cabozantinib (Cabometyx) for treatment-naive patients, he adds.

One notable advantage of belzutifan is its selectivity in targeting the HIF2α pathway, which is upregulated in most ccRCC cases due to loss of the von Hippel-Lindau gene, Gopal details. The resulting upregulation of HIF2α leads to increased transcription of angiogenesis factors such as VEGF, contributing to tumor growth and progression. By specifically targeting HIF2α, belzutifan blocks the angiogenesis pathway without affecting other pathways targeted by agents such as sunitinib (Sutent) or immunotherapy, Gopal explains.

On December 14, 2023, the FDA granted approval to belzutifan

 for the treatment of patients with advanced RCC who have undergone treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI based on data from LITESPARK-005. The safety profile of belzutifan in this trial appears favorable, with the main adverse effect (AE) being anemia, Gopal says. This approval indicates the tolerability of belzutifan even in patients with early-stage disease who are often high functioning, he emphasizes. Notably, most patients on the trial continued on belzutifan therapy for over 2 years with minimal treatment discontinuation, suggesting the agent's tolerability and efficacy. This ability to provide effective therapy with minimal AEs is particularly exciting for patients who can maintain a good QOL during treatment, according to Gopal.

Overall, belzutifan represents a promising treatment option for ccRCC, offering selective targeting of the HIF2α pathway and demonstrating efficacy in both refractory and treatment-naive settings with a favorable safety profile. Further research and clinical trials will continue to explore the potential of belzutifan in improving outcomes for patients with ccRCC.

Nikhil A. Gopal, MD, discusses the benefit of belzutifan for patients with renal cell carcinoma.


Nikhil A. Gopal, MD

Articles

Dr Gopal on a Case Study of a Patient With Bladder Cancer

Dr Gopal on Future Research Directions in Non-ccRCC

Dr Gopal on Treatment Selection in Second-Line R/R mUC

Dr Gopal on the Nuances of IO/TKI Selection in Advanced RCC

Dr Gopal on the Evolution of TKI/IO Combination Approaches in RCC

Dr Gopal on the Significance of the EV-302 and CheckMate 901 Trials in mUC

Dr Gopal on the Advantages and Potential Benefit of Belzutifan in RCC