ONCAlert | Upfront Therapy for mRCC

mRCC: Impact of CABOSUN and CheckMate-214

Martin H. Voss, MD
Published Online:12:21 PM, Fri July 27, 2018

Martin H. Voss, MD: We have 2 recent trials that have changed the treatment paradigm in the first-line setting, which is a big change for the field. Both of these studies have successfully challenged sunitinib (Sutent) as the standard of care in the treatment of metastatic kidney cancer. And Sutent has been one of the gold standards over 10 years now since its original approval back in 2006. Now, we’re going to be discussing both of these studies today. First, a TKI study, CABOSUN, which is a randomized phase II study that tested a novel tyrosine kinase inhibitor, cabozantinib, in comparison with sunitinib. And second, an immunotherapy/TKI comparison in the phase III CheckMate-214 study that led to the approval of ipilimumab plus nivolumab in this disease.

With cabozantinib, it’s important to know it had previously been FDA approved in TKI-pretreated patients, which predates the analysis of this study. This trial, the CABOSUN trial, is a smaller randomized phase II study that was conducted in the Cooperative Group mechanism. It was an Alliance study that was published by Toni Choueiri, et al, in the Journal of Clinical Oncology last year. And this study was a randomized phase II trial that enrolled about 150 patients and randomized them 1:1 to receive either sunitinib or cabozantinib for the treatment of metastatic disease. This trial limited enrollment to patients with IMDC-intermediate or poor-risk disease. It was unique in that way, and it pursued a primary endpoint of progression-free survival.

So, it was a positive study that demonstrated superior PFS in patients treated with a novel tyrosine kinase inhibitor, cabozantinib, which is distinctly different from sunitinib in that it not only blocks VEGF receptor signaling but also AXL and MET, both of which are thought to mediate angiogenesis alternative to VEGF-mediated neovasculature. Both AXL and MET signaling have been shown to be upregulated in patient samples treated with sunitinib with acquired resistance to that drug. So, in this trial, it was now shown that, indeed, cabozantinib was superior. The FDA approved the drug for the first-line indication regardless of IMDC risk status. Although in the trial, it’s important to know it was conducted exclusively in patients with intermediate- or poor-risk IMDC status.

The second study we’re going to be discussing is the CheckMate-214 study that led to the FDA approval of ipilimumab/nivolumab combination in treatment-naïve patients with intermediate- or poor-risk disease. This was a very large phase III global trial that randomized patients 1:1 to receive either standard sunitinib or the combination of ipilimumab/nivolumab for the treatment of metastatic disease. This brought on about 1100 patients, and patients were stratified by IMDC risk and by geographic region.

This was an interesting trial in its statistical design. It had 3 coprimary endpoints and it was powered to demonstrate a difference in all 3, the first being overall survival, the second being objective response rate, and the third being progression-free survival. And in order to accommodate all 3, the alpha was split between the 3. So, there was a higher threshold or rather a lower P value necessary than what we’re used to seeing in order to demonstrate significance for each of these 3. Patients were treated on a standard sunitinib schedule with 4-week, 2-week, 50 mg daily. And ipilimumab/nivolumab treatment schedule, it’s important to note it’s actually different from what is approved for melanoma and that’s based on the phase I work that had been done in kidney cancer specifically.

This study was successful in demonstrating superiority in 2 of the 3 primary endpoints. So, overall survival was superior for the immunotherapy combination with a hazard ratio of 0.63. And landmark analyses had also suggested that more patients were alive at 12 and 18 months in the immunotherapy arm than the TKI arm. There were also superior objective responses for the immunotherapy combination. That, importantly, included a 9% complete remission rate in patients with intermediate- or poor-risk disease. It’s important to note that these primary analyses were conducted in the intermediate- and poor-risk population only. So, while the trial brought on patients with favorable intermediate- and poor-risk disease, the primary endpoint analyses were conceptualized so they were limited to patients with intermediate- and poor-risk disease. And that was done based on a prior experience with a combination that suggested higher efficacy in this population. The third primary endpoint, progression-free survival, was numerically in favor of the immunotherapy combination but did not meet the prespecified threshold for significance.

Transcript edited for clarity.

Martin H. Voss, MD: We have 2 recent trials that have changed the treatment paradigm in the first-line setting, which is a big change for the field. Both of these studies have successfully challenged sunitinib (Sutent) as the standard of care in the treatment of metastatic kidney cancer. And Sutent has been one of the gold standards over 10 years now since its original approval back in 2006. Now, we’re going to be discussing both of these studies today. First, a TKI study, CABOSUN, which is a randomized phase II study that tested a novel tyrosine kinase inhibitor, cabozantinib, in comparison with sunitinib. And second, an immunotherapy/TKI comparison in the phase III CheckMate-214 study that led to the approval of ipilimumab plus nivolumab in this disease.

With cabozantinib, it’s important to know it had previously been FDA approved in TKI-pretreated patients, which predates the analysis of this study. This trial, the CABOSUN trial, is a smaller randomized phase II study that was conducted in the Cooperative Group mechanism. It was an Alliance study that was published by Toni Choueiri, et al, in the Journal of Clinical Oncology last year. And this study was a randomized phase II trial that enrolled about 150 patients and randomized them 1:1 to receive either sunitinib or cabozantinib for the treatment of metastatic disease. This trial limited enrollment to patients with IMDC-intermediate or poor-risk disease. It was unique in that way, and it pursued a primary endpoint of progression-free survival.

So, it was a positive study that demonstrated superior PFS in patients treated with a novel tyrosine kinase inhibitor, cabozantinib, which is distinctly different from sunitinib in that it not only blocks VEGF receptor signaling but also AXL and MET, both of which are thought to mediate angiogenesis alternative to VEGF-mediated neovasculature. Both AXL and MET signaling have been shown to be upregulated in patient samples treated with sunitinib with acquired resistance to that drug. So, in this trial, it was now shown that, indeed, cabozantinib was superior. The FDA approved the drug for the first-line indication regardless of IMDC risk status. Although in the trial, it’s important to know it was conducted exclusively in patients with intermediate- or poor-risk IMDC status.

The second study we’re going to be discussing is the CheckMate-214 study that led to the FDA approval of ipilimumab/nivolumab combination in treatment-naïve patients with intermediate- or poor-risk disease. This was a very large phase III global trial that randomized patients 1:1 to receive either standard sunitinib or the combination of ipilimumab/nivolumab for the treatment of metastatic disease. This brought on about 1100 patients, and patients were stratified by IMDC risk and by geographic region.

This was an interesting trial in its statistical design. It had 3 coprimary endpoints and it was powered to demonstrate a difference in all 3, the first being overall survival, the second being objective response rate, and the third being progression-free survival. And in order to accommodate all 3, the alpha was split between the 3. So, there was a higher threshold or rather a lower P value necessary than what we’re used to seeing in order to demonstrate significance for each of these 3. Patients were treated on a standard sunitinib schedule with 4-week, 2-week, 50 mg daily. And ipilimumab/nivolumab treatment schedule, it’s important to note it’s actually different from what is approved for melanoma and that’s based on the phase I work that had been done in kidney cancer specifically.

This study was successful in demonstrating superiority in 2 of the 3 primary endpoints. So, overall survival was superior for the immunotherapy combination with a hazard ratio of 0.63. And landmark analyses had also suggested that more patients were alive at 12 and 18 months in the immunotherapy arm than the TKI arm. There were also superior objective responses for the immunotherapy combination. That, importantly, included a 9% complete remission rate in patients with intermediate- or poor-risk disease. It’s important to note that these primary analyses were conducted in the intermediate- and poor-risk population only. So, while the trial brought on patients with favorable intermediate- and poor-risk disease, the primary endpoint analyses were conceptualized so they were limited to patients with intermediate- and poor-risk disease. And that was done based on a prior experience with a combination that suggested higher efficacy in this population. The third primary endpoint, progression-free survival, was numerically in favor of the immunotherapy combination but did not meet the prespecified threshold for significance.

Transcript edited for clarity.
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