Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine, professor of internal medicine, University of Michigan, discusses the design of the phase 3 PROBE trial (NCT04510597) in advanced renal cell carcinoma (RCC).

This randomized, open-label trial is evaluating the efficacy of standard-of-care immunotherapy-based combinations with or without nephrectomy in patients with advanced, metastatic RCC. All potential patients are treated with either 240 mg of intravenous (IV) nivolumab (opdivo) every 2 weeks, 480 mg of IV nivolumab every 4 weeks, 200 mg of IV pembrolizumab (Keytruda) every 3 weeks plus 5 mg of oral axitinib (Inlyta) twice per day, or 5 10 mg/kg of IV avelumab (Bavencio) every 2 weeks plus 5 mg of oral axitinib 5 mg oral twice per day. Patients are then randomized to receive nephrectomy or continue on treatment alone. Nephrectomies are conducted 8 weeks after randomization.

The primary endpoint of the trial is overall survival, and patients are stratified by ECOG performance status and risk level prior to randomization, Vaishampayan says. If patients are rapidly progressing while on any of the immunotherapy-based regimens, they are not considered eligible for the study, Vaishampayan explains.

Patients are required to have stable disease to be randomized and considered for nephrectomy. Randomization occurs between weeks 10 and 14 after the start of immunotherapy-based treatment, Vaishampayan concludes.

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Ulka Nitin Vaishampayan, MBBS, discusses the design of the phase 3 PROBE trial in advanced renal cell carcinoma.


Dr. Vaishampayan on the Design of the PROBE Trial in RCC

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine, professor of internal medicine, University of Michigan, discusses the utility of FGFR inhibitors in ​metastatic urothelial cancer.

FGFR inhibitors are a targeted therapy option for patients with metastatic urothelial cancer who harbor 

 fusions, Vaishampayan says. Erdafitinib (Balversa) is an FDA approved FGFR inhibitor that can be administered orally and has demonstrated significant efficacy in this patient population, Vaishampayan explains. 

Overall, it is essential to conduct next-generation sequencing earl​y to determine whether FGFR inhibitors are a therapeutic option for patients with newly diagnosed metastatic urothelial cancer, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses the utility of FGFR inhibitors in ​metastatic urothelial cancer. 


Dr. Vaishampayan on the Utility of FGFR Inhibitors in Urothelial Cancer 

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine,professor of internal medicine, University of Michigan, discusses future directions for second-line treatment in urothelial cancer.

Beyond chemotherapy, several novel treatment options are available for the management of urothelial carcinoma, and it is important to profile tumors to inform available options, Vaishampayan explains. Moreover, as chemotherapy and immunotherapy are moving into earlier-line settings, some of the second-and third-line options will likely be moved earlier in the disease state, including the frontline setting, for patients with metastatic disease, Vaishampayan adds.

Antibody-drug conjugates (ADCs) have demonstrated remarkable efficacy in patients with advanced urothelial cancer, Vaishampayan continues. Currently, 2 ADCs are FDA approved, both utilizing distinct mechanisms of actions and associated with different safety profiles of non-overlapping toxicities, Vaishampayan concludes. 

Ulka Nitin Vaishampayan, MBBS, discusses future directions for second-line treatment in urothelial cancer. 

Dr. Vaishampayan on the Future Directions for Second-Line Treatment in Urothelial Cancer 

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the expanding role of TKI/immunotherapy combinations in metastatic renal cell carcinoma (mRCC). 

Several ​VEGF TKI/immunotherapy combinations have established efficacy in metastatic RCC, says Vaishampayan.

Inlyta) plus pembrolizumab (Keytruda) and axitinib plus avelumab (Bavencio) are approved for the treatment of patients with mRCC, says Vaishampayan. Both regimens have shown significant improvement​s in overall response rate (ORR) and progression-free survival (PFS) compared with sunitinib 

Additionally, findings from the phase 3 KEYNOTE-426 trial demonstrated an overall survival (OS) benefit with the combination of axitinib and pembrolizumab​.

Notably, results from the phase 3 CheckMate​-9ER trial, which were presented during the 

, demonstrated superiority with the combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) ​vs sunitinib in terms of PFS, OS and ORR ​for the first-line treatment of patients with ​advanced RCC. 

In fact, the median PFS was doubled from 8​.3 months with sunitinib to 16.6 months with the combination, Vaishampayan concludes.

Ulka N. Vaishampayan, MBBS, FAB, discusses the expanding role of TKI/immunotherapy combinations in metastatic renal cell carcinoma. 

Dr. Vaishampayan on the Expanding Role of TKI/Immunotherapy Combinations in mRCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the safety profiles of tivozanib (Fotivda) versus sorafenib (Nexavar) in advanced renal cell carcinoma.

In terms of efficacy, tivozanib has shown to be superior in progression-free survival compared with sorafenib, says Vaishampayan. However, a statistically significant benefit in overall survival had not been observed with tivozanib over sorafenib. 

When choosing between the agents, the toxicity profiles of both agents have to be considered, as well as their mechanisms of action. Sorafenib has a RAF kinase inhibitor activity, as well as VEGF TKI activity, whereas tivozanib is a preferential VEGF TKI inhibitor only with selective activity against VEGF.

The toxicity profile of sorafenib seems to reflect a higher risk of hand-foot syndrome and skin rashes as compared with tivozanib. The risk of hypertension and other toxicities that are VEGF-related appear to be comparable between the agents, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the safety of tivozanib versus sorafenib in advanced renal cell carcinoma.

Dr. Vaishampayan on the Safety of Tivozanib Versus Sorafenib in RCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the potential of tivozanib (Fotivda) in advanced renal cell carcinoma (RCC).

At present, tivozanib is not approved for use in the United States for patients with advanced RCC, although it has been approved in Europe; it is used as a single-agent VEGF TKI in this patient population, says Vaishampayan. In the United States, given the results of the phase 3 TIVO-3 trial, tivozanib could be a reasonable third-line option to consider for patients who have already received both VEGF TKI and immune-based regimens, adds Vaishampayan.

Tivozanib appears to prolong progressing-free survival, is relatively well-tolerated, and may provide patients with an additional efficacy benefit in the pretreated setting, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the potential of tivozanib in advanced renal cell carcinoma.

Dr. Vaishampayan on the Potential of Tivozanib in Advanced RCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the need to develop novel therapies for patients with metastatic renal cell carcinoma (mRCC).

About 50% to 60% of patients with mRCC do not derive a response to immunotherapy or are considered refractory to immunotherapy, Vaishampayan says.

Although these patients may be salvaged with VEGF TKIs, the majority of patients are not being cured of their disease, explains Vaishampayan. 

As such, developing novel drugs and targets is critically important to continue moving the field of advanced RCC forward, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the need to develop novel therapies for patients with metastatic renal cell carcinoma.



Dr. Vaishampayan on the Need to Develop Novel Therapies in mRCC 

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the benefit of axitinib (Inlyta) and pembrolizumab (Keytruda) in advanced renal cell carcinoma (RCC).

Updated results from the phase 3 KEYNOTE-426 trial showed that at 24 months of follow-up, patients who were given axitinib/pembrolizumab still experienced an improvement in survival, says Vaishampayan. The 2-year overall survival rate for patients who received sunitinib (Sutent) was 66% versus 74% of those who received the combination. The difference in benefit continues to be statistically significant, and as such, the immunotherapy-based regimen is still considered as the frontline therapy of choice for patients with RCC. adds Vaishampayan.

However, when looking at the International Metastatic RCC Database risk criteria, the favorable-risk subgroup did not show a benefit with axitinib/pembrolizumab; both arms experienced relatively similar outcomes. In the intermediate- and poor-risk subgroup, the difference remained and favored the axitinib/pembrolizumab regimen, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the benefit of axitinib and pembrolizumab in advanced renal cell carcinoma.

Ulka N. Vaishampayan, MBBS, FAB

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