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Clinical

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Clinical Focus

Howard I. Scher, MD; Scott T. Tagawa, MD, MS, FACP; Mary-Ellen Taplin, MD

Medical Crossfire®: How Does Recent Evidence on PARP Inhibitors and Combinations Inform Treatment Planning for Prostate Cancer Now and In the Future?

Overall, 76% of patients with a CD70 TPS of at least 50% achieved a reduction in tumor burden. 

ALLO-316 shows encouraging CAR activity in advanced ccRCC

“Based on these data, casdatifan has the potential to be a future treatment option for kidney cancer," says Toni K. Choueiri, MD.

Casdatifan demonstrates encouraging clinical activity in renal cell carcinoma

The RMAT designation is supported by interim data from the ongoing phase 1 TRAVERSE trial.

FDA grants Regenerative Medicine Advanced Therapy designation to ALLO-316 for RCC

"The encouraging results suggest that alternating pazopanib with bevacizumab is a promising treatment regimen for renal cell carcinoma patients in the favorable risk group," says Saby George, MD, FACP. 

Pazopanib plus bevacizumab shows promising phase 2 efficacy in ccRCC

According to the authors, "These results support the use of Benmelstobart plus anlotinib as a new first-line treatment for advanced RCC.”

Benmelstobart plus anlotinib improves PFS, ORR vs sunitinib in aRCC

Tang discusses the limitations in available data, but nonetheless high potential, of SBRT in kidney cancer.

Chad Tang, MD: Considerations for SBRT in metastatic RCC

American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting

 in Washington DC, this month, Chad Tang, MD, of the department of GU Radiation Oncology at the MD Anderson Cancer Center, discussed the utility of stereotactic body radiation therapy (SBRT) in the treatment of patients with metastatic 

As Tang noted in his ASTRO 2024 presentation topic, SBRT has been linked to significantly high rates of patients achieving progression-free survival, even without systemic therapy, for kidney cancer over about the span of a year now—though more research needs to inform the promising early evidence.

“There’s no high-level data, there’s no phase 3 randomized trials comparing these different strategies for both oligometastatic and oligo-progressive (RCC),” Tang said. “Another area I would want to highlight is that there’s a big gap in treating the primary in patients with metastatic disease.”

Regardless, SBRT’s position as an option to spare use of systemic therapy or possibly even change patients’ natural history is not being undone by any more recent study findings.

“And as we all know, (RCC) can be quite indolent sometimes,” Tang said. “We know it can be quite heterogeneous sometimes in terms of its genetic makeup, and sometimes one site just has a different evolution and it progresses while on IO/IO and IO/TKIO, and we can control that.”

Regarding the clinician-patient discussion around SBRT to treat metastatic RCC, Tang recommended his colleagues practice frankness around the level of available data supporting the treatment strategy—especially based on the patient’s age.

“In my experience, a lot of younger patients want the kitchen sink thrown at them for any possible benefit,” Tang said. “You have to be frank about, 'We can do this, but the level of evidence is thus, and not robust usually.' But usually, we also say that a lot of these techniques that we've done, the side effect profile is relatively modest.”

Videos

Stereotactic body radiation therapy (SBRT) is emerging as a promising treatment for metastatic renal cell carcinoma (RCC), potentially offering progression-free survival without systemic therapy. Despite the lack of high-level data or phase 3 trials, SBRT remains a viable option, especially for oligometastatic and oligo-progressive RCC. The treatment's efficacy may vary due to RCC's genetic heterogeneity. Clinicians are advised to discuss the limited evidence supporting SBRT with patients, particularly younger ones, while noting its relatively modest side effect profile.

News

Zaorsky discusses the patient safety misconceptions around radiotherapy for RCC, and considering patient-reported outcomes in future randomized controlled trials.

Considering patient-reported outcomes in kidney cancer care, with Nicholas Zaorsky, MD, PhD

 in Washington, DC, showed stereotactic body radiotherapy (SBRT), along with partial nephrectomies and ablative therapies, are less likely to impact longterm kidney function versus radical nephrectomy in patients with localized 

The findings, presented by study author Nicholas Zaorsky, MD, MS, of the University Hospitals Case Medical Center, may shine a light on a prevalent misconception regarding the risks of stereotactic radiation for clinicians outside of radiation oncology.

In the second segment of an interview with 

 Zaorsky discussed the greater takeaways of his team’s research—namely the observed low toxicity rate associated with radiation therapy for RCC. The findings buck against major trends of care for kidney cancer.

“Our research specifically looked at the trying to quantify renal function, and trying to quantify how much are the kidneys impacted by this treatment, and how do we best go forward in looking at minimizing the impact on the kidneys while hopefully still maintaining patient quality of life,” Zaorsky said. “If you look at the National Cancer database, which is the US database that looks at the treatments that are used for cancer, about 90% of patients currently receive some form of surgery for their kidney cancer.“

Zaorsky additionally discussed the prospect of advancing the findings of these analyses toward a randomized controlled trial that specifically considered patient-reported quality of life outcomes associated with different RCC treatment modalities—outcomes generally not considered in the initiation and follow-through of kidney cancer therapy.

“If we want to increase the use of something like radiation therapy, or build a randomized controlled trial that compares the treatments—or even get the patients an opinion about radiation therapy—I think that it's critical for the patients to be discussed at multidisciplinary tumor boards and to have that patient see multiple physicians,” Zaorsky said. “It's also important to note that radiation therapy is already listed in the NCCN guidelines as a category 1 recommendation for many patients, and so I think it's very reasonable for surgeons and for oncologists to have to basically automatically refer patients once they're diagnosed to have them meet with a radiation oncologist.”

Rajoulh C, Ali M, Wang M, Siva S et al. Renal Function after Definitive Local Therapy for Primary Renal Cell Carcinoma: A Meta-Analysis. Poster presented at: American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting. Washington, DC. September 29 – October 2, 2024.

Kunzmann K. Nicholas Zaorsky, MD, MS: Protecting kidney function after local renal cell carcinoma therapy. 

. Published October 1, 2024. https://www.urologytimes.com/view/nicholas-zaorsky-md-ms-protecting-kidney-function-after-local-renal-cell-carcinoma-therapy

Zaorsky discusses his team's ASTRO 2024 abstract showing clear benefit of radiotherapy and ablation in reduced kidney effects in patients with RCC.

 Nicholas Zaorsky, MD, MS: Protecting kidney function after local renal cell carcinoma therapy

Stereotactic body radiotherapy (SBRT), partial nephrectomy (PN), and ablative therapies are linked to less harmful effects on kidney function among the options for localized 

 in Washington, DC, this week showed SBRT, PN and ablation were linked to lesser declines in estimated glomerular filtration rate (eGFR) versus radical nephrectomy (RN) among patients treated for RCC. Investigators additionally observed the fewest rates of grade ≥3 toxicities with SABR treatment compared to the other local therapy options.

Presented by investigator Nicholas Zaorsky, MD, MS, of the University Hospitals Case Medical Center, investigators believe the findings could help inform patient-tailored care conversations around long-term RCC management. The systematic review and meta-analysis may also help inform future clinical trials assessing disparities in local RCC therapy options.

 during ASTRO 2024, Zaorsky discussed the significance of his team’s findings—particularly at a time when kidney cancer diagnoses have increased dramatically due to innovation in cross-section imaging. With this rise of new cases, there have been more datapoints to observe the effect of the 3 pathways of treatment: nephrectomies, ablations, and radiation.

“We know that there are no randomized studies out there that compare them head-to-head—there's no prospective trial that has compared treatment 1 versus 2, etc.," Zaorsky said. "And we know at the same time that each of these treatments can affect kidney function.”

Their meta-analysis findings confirmed that radiation therapy, specifically SBRT, may provide the best combination of preserved renal function and significantly lowered toxicity rates among all the observed treatment arms.

“This, in combination with the results of trials that have been presented and published within the past few years from the IROC consortium—where we see that the cancer control rate is above 95% or close to 100%—we think that radiation therapy is one of the best treatment options available for kidney cancer,” Zaorsky said. “And so, we hope that this study can help guide discussions among physicians and patients, in terms of selecting the best treatment option, and it can also help to guide a randomized, controlled trial—and powering the trial appropriately, so that we can get some prospective data to compare the different treatments.”

Toni K. Choueiri, MD, shares the background and key findings from the study, “Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): Results of the phase III TiNivo-2 study,”

Toni K. Choueiri, MD, on key takeaways from TiNivo-2 trial 

, shares the background and key findings from the study, “Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): Results of the phase III TiNivo-2 study,” which was presented at the 2024 

European Society for Medical Oncology Annual Congress

 in Barcelona, Spain. Choueiri is the director of the Lack Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

The TiNivo-2 trial was a phase 3 study that asked the question of immune checkpoint blockers, PD-1, PD-L1 inhibitor, rechallenge in metastatic renal cell cancer. The design included a TKI, tivozanib, in both arms and then adding nivolumab, a PD-1 inhibitor. Again, patients should have had experienced disease progression on prior PD-1 inhibitor. This is a soaring question in the field of kidney cancer and in solid tumors in general. I don't think this was asked. We had a study last year that showed adding atezolizumab as a rechallenge to a TKI does not at all improve clinical outcomes. But here the difference [is] that we have a PD-1 inhibitor, and the last therapy was not always an immune checkpoint inhibitor. 

So, the study was dead negative. PFS, OS, [and] response rate were similar in both arms. Though I would say also that the dose in the combination arm of tivozanib was lower because of earlier studies showing increased risk of grade 3/4 hypertension. Again, this is the second study of ICI, immune checkpoint inhibitor, rechallenge, both published in The Lancet 1 year apart. [They] showed that re-challenging, at least, I would say in metastatic RCC with an immune checkpoint inhibitor, should be discouraged outside some specific situations, such as a long duration from prior immune checkpoint inhibitor–the patients that were not included in TiNivo-2.

This transcription has been edited for clarity. 

The TiNivo-2 trial demonstrated that rechallenging ICI therapy does not improve outcomes in patients with renal cell carcinoma.

Dr. Toni Choueiri on key takeaways from TiNivo-2 trial 

Eric Jonasch, MD, discusses next steps and potential implications of findings from an ongoing phase 1/2 study of the investigational oral HIF-2α inhibitor NKT2152

ESMO 2024: Dr. Jonasch on implications of positive HIF-2α inhibitor data in ccRCC

, discusses next steps and potential implications of findings from an ongoing phase 1/2 study (NCT05119335) of the investigational oral HIF-2α inhibitor NKT2152, which were presented at the 2024 European Society for Medical Oncology Annual Congress in Barcelona, Spain. Overall, 

 that NKT2152 demonstrated strong anti-tumor activity in patients with heavily pretreated advanced clear cell renal cell carcinoma.

Jonasch is a professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

What are the next steps for this agent based on these findings?

It's clear this agent is active. The question now really would be, what would be an appropriate registrational strategy to move this agent forward as a potential treatment for patients with renal cell carcinoma? That's a matter of discussion at this point in time by the company, and they're going to be deciding on how to move forward.

What are the potential clinical implications of this research?

It clearly shows that blocking HIF-2α is a meaningful way of interacting with disease biology in clear cell renal cell carcinoma. It may be good to have more than 1 agent of the same class. We clearly need to learn much more though about which patients are most likely to respond, why does resistance occur, and what would be the best partners in terms of combination strategies for this agent.

This transcription has been edited for clarity.

"It clearly shows that blocking HIF-2α is a meaningful way of interacting with disease biology in clear cell renal cell carcinoma," says Eric Jonasch, MD.  

Dr. Fallah on “Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a U.S. FDA pooled analysis.”

Expert discusses pooled analysis of cytoreductive nephrectomy

 paper, “Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a U.S. FDA pooled analysis.” Fallah is a medical oncologist with the FDA.

How do the treatments in the study compare to patients with metastatic kidney cancer today?

As I mentioned earlier, we did not include the trial of ipilimumab and nivolumab in this analysis, and the combination of atezolizumab and bevacizumab that we included in the pool has not been approved for treatment of RCC. However, the other 4 trials that were included in this pooled analysis led to FDA approval of the investigative combinations of immune checkpoint inhibitor and VEGF TKI.

Within the confines of the limitations, are there certain patients for whom the study suggests would benefit most from CN over others?

We may be tempted to conclude a causal relationship based on the results of this analysis; however, we should avoid making statements implying a causal relationship. For example, we cannot say that cytoreductive nephrectomy improves patient outcomes, and we cannot conclude it provides any benefit in this setting. Our analysis only demonstrated an association, which may be due to the effects of nephrectomy or confounding factors associated with patient selection for nephrectomy, or both. And to answer this question, we need a randomized trial.

This transcription was edited for clarity.

“We may be tempted to conclude a causal relationship based on the results of this analysis; however, we should avoid making statements implying a causal relationship,” says Jaleh Fallah, MD.

Dr. Fallah on “Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a U.S. FDA pooled analysis.” 

Dr. Fallah on limitations of pooled analysis of cytoreductive nephrectomy

What are the major limitations of the pooled analysis?

Our pooled analysis had a couple of limitations. It was a retrospective analysis, and there were variations across trials in terms of previously collected information. For example, the studies did not indicate if nephrectomy was conducted with curative or cytoreductive intent. And the date of nephrectomy was not available in many of the cases. So, we only included patients who had metastatic disease at diagnosis in whom the indication for nephrectomy would be cytoreduction. This did not allow us to include studies that did not provide this information, such as Checkmate 214, which evaluated ipilimumab [Yervoy] and nivolumab [Opdivo] vs sunitinib [Sutent], and this issue limited the number of patients in our pooled analysis. Another important limitation of this analysis is the lack of randomization. We tried to account for the impact of potential imbalances in baseline characteristics by adjusting for factors that are commonly thought to be involved in patient selection for nephrectomy, such as patient's age and performance status. However, there are likely other factors that were not adequately captured in these trials and could not be fully controlled for, and in the absence of a pre-specified randomization, the results of any analysis on the effect of cytoreductive nephrectomy on outcomes should only be considered exploratory and hypothesis generating. This means that our results only found an association between prior cytoreductive nephrectomy and better outcomes. However, outside a randomized trial, we cannot make any conclusion about the causal relationship between conducting cytoreductive nephrectomy and improved outcomes.

"Outside a randomized trial, we cannot make any conclusion about the causal relationship between conducting cytoreductive nephrectomy and improved outcomes," says Jaleh Fallah, MD.

Paper aims to explore questions surrounding cytoreductive nephrectomy

Why did the FDA decide this project was worth conducting?

The Oncology Center of Excellence or OCE supports FDA oncology staff who participate in regulatory science research, including internal research projects and collaborations with external experts. Scientific research that can inform our regulatory work is part of our mission. Despite the results of SURTIME and CARMENA, among others, we continue to hear discussions about the role of cytoreductive nephrectomy in conferences and literature, suggesting that this remains a question that has not been fully addressed, particularly given the changes in the therapeutic landscape since those trials were conducted, and we didn't have access to the data needed to explore the study question.

"Despite the results of SURTIME and CARMENA, among others, we continue to hear discussions about the role of cytoreductive nephrectomy in conferences and literature, suggesting that this remains a question that has not been fully addressed," says Jaleh Fallah, MD.

Dr. Fallah discusses recent research on cytoreductive nephrectomy

There have been a number of studies on the topic of cytoreductive nephrectomy; what is new about this one?

Most of the studies, including SURTIME and CARMENA, were conducted prior to the era of immune checkpoint inhibitors when VEGF TKI was the standard of care for frontline treatment of metastatic RCC. Our study looked at data from 5 trials of the combination therapy with an immune checkpoint inhibitor and the VEGF TKI evaluating if there's still any potential role for cytoreductive nephrectomy that is worth being investigated in prospective studies. In addition, from a regulatory perspective, the observed association between cytoreductive nephrectomy and better outcomes indicate that stratification of randomized trials by cytoreductive nephrectomy can potentially provide a better balance of baseline characteristics across study arms, and helps evaluating the treatment effect of investigational intervention more accurately in patients with and without cytoreductive nephrectomy.

"Our study looked at data from 5 trials of the combination therapy with an immune checkpoint inhibitor and the VEGF TKI evaluating if there's still any potential role for cytoreductive nephrectomy that is worth being investigated in prospective studies," says Jaleh Fallah, MD.

Dr. Bukavina on "Association Between GLP1R Agonists and Prostate, Kidney, and Bladder Cancers.”

Potential Impact of PET/CT Imaging on Improving Patient Care

UroView

Urologists review clinical trials investigating new imaging options in kidney cancer, including the ZIRCON study looking at girentuximab.

Overview of Clinical Trials for New Imaging Options for Kidney Cancer

Kidney cancer specialists discuss recent advances in imaging for diagnosis and disease management, highlighting sestamibi and zirconium scans.

Advances in Imaging for Kidney Cancer Diagnosis and Management

Brian Shuch, MD, and Neal Shore, MD, FACS, discuss the staging and treatment of kidney cancer, including when to biopsy and how often to do follow-up imaging.

Staging and Treatment Decisions for Kidney Cancer

Limitations of Conventional Imaging for Assessing Renal Masses

Experts on kidney cancer review challenges associated with limitations of conventional imaging for assessing renal masses and how to potentially improve sensitivity and specificity.

Video Series

Diagnostic Tests for Kidney Cancer

Urologists provide an overview of diagnostic tests for patients with kidney cancer, highlighting lab tests, imaging, and considerations for biopsy. 

Diagnostic Tests for Kidney Cancer 

A Growing Incidence of Renal Masses

Neal Shore, MD, FACS, and Brian M. Shuch, MD, introduce themselves and discuss the growing incidence of kidney cancer, the general prognosis, and early signs and symptoms. 

Kidney Cancer

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