Is There Still a Role for Cytoreductive Nephrectomy? Analysis from the CARMENA Trial, Journal Club - Christopher Wallis & Zachary Klaassen
August 30, 2022
Christopher Wallis and Zachary Klaassen discuss an update on the CARMENA trial. CARMENA was a phase III trial in 450 patients with metastatic renal cell carcinoma (mRCC) enrolled from 2009 to 2017. The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront cytoreductive nephrectomy.
Biographies:
Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Biographies:
Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Read the Full Video Transcript
Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club. Today we are discussing the recent publication from the CARMENA trial entitled, Sunitinib Alone or After Nephrectomy for Patients with Metastatic Renal Cell Carcinoma: Is There Still a Role for Cytoreductive Nephrectomy?
I'm Chris Wallis, an Assistant Professor in the Division of Urology at The University of Toronto, and with me today is Zach Klaassen, an Assistant Professor in the Division of Urology at The Medical College of Georgia. This is the citation for this recent publication found in European Urology. It follows the initial publication of CARMENA.
So, the real defining role of cytoreductive nephrectomy came in the early 2000s. We had both the SWOG and EORTC trials, which examined the combination of cytoreductive nephrectomy with cytokine therapy or cytokine therapy alone. While you see on the left side in this Kaplan–Meier plot that survival outcomes were not that good in either group, there was a significant benefit for the combination of cytoreduction with cytokine therapy, and this here is the pooled analyses of these two trials demonstrating approximately a 30% reduction.
We then move on with the progress in the systemic therapy for renal cell carcinoma, and moving from the cytokine therapy era, to the targeted therapy era was the next predominant treatment approach, which lasted for approximately 15 years. And sunitinib came to be the standard of care and most widely used approach during this time.
So the question then is, does cytoreductive nephrectomy retain the same benefit for patients who are receiving systemic targeted therapies as compared to those who received cytokine-based approaches? And so these are three observational studies, each of which suggested there is a survival benefit for the use of cytoreduction, although we know observational data of these sorts are affected by selection bias and confounding by indication.
So we then moved to randomized data, and this is the original report of the CARMENA trial. And just to highlight the methodology here, this enrolled patients with metastatic clear cell renal cell carcinoma who were treatment-naive and had intermediate or poor-risk disease according to the Motzer criteria. Patients were then randomized in a one-to-one fashion to receive either sunitinib alone or cytoreductive nephrectomy followed by sunitinib.
As you can see here on the lower left, there was no significant difference in overall survival between the two arms at the time of the primary report. However, there are a few limitations when we apply these data. First, outcomes are somewhat worse in both arms than might be expected from the contemporary use of sunitinib, and this implies that the population may be enriched with patients with more aggressive disease.
Additionally, subgroup analyses suggested there may be a heterogeneity effect with a potential benefit of cytoreductive nephrectomy in a subset of patients with lower volumes of disease. So to that end, the present work seeks to provide an updated analysis of the CARMENA trial and to assess whether some subgroups of patients may benefit from cytoreduction.
Again, to highlight, this as a prospective, multi-center, open-label, randomized phase III trial. Patients are included if they had metastatic clear cell renal cell carcinoma, had not received prior therapy, and had intermediate or poor-risk disease according to the Motzer criteria. This was a non-inferiority design with non-inferiority defined as a hazard ratio for overall survival of less than 1.2.
So this updated analysis relies on a data cutoff of October 2018, at which time there were 358 overall survival events. And it does warrant mention that this is revised from the initial plan of analysis at the time of 476 events as a result of overall poor accrual to the trial and early termination due to sampling size concerns.
Additionally, in this analysis, they reclassified patients using the IMDC criteria rather than Motzer criteria, given the emerging evidence that IMDC performs better. And so, in keeping with IMDC risk criteria, intermediate-risk was defined as one or two risk factors and poor-risk as three to six.
The authors performed a number of analyses, including assessing overall survival in the whole study cohort as well as subgroups defined based on IMDC risk, number of tumor sites, and the presence of delayed cytoreduction. They also assessed four different populations, including the intention to treat population, and per-protocol one, two, and three. And so you can see the definitions here, where they include slightly different subgroups of patients on the basis of the rigidity to which per-protocol analyses were stuck.
The authors used the Kaplan-Meier method to estimate overall survival rates and confidence intervals. And again, as we highlighted before, sunitinib alone was considered non-inferior to sunitinib with cytoreduction if the upper limit of the 95% confidence interval of the hazard ratio for overall survival was less than 1.20.
At this point in time, I'm now going to hand it over to Zach to walk us through the results of this updated analysis from the CARMENA trial.
Zachary Klaassen: Thanks, Chris. This is the updated randomization, treatment, and follow-up figure. And so, as we know, there were 450 patients that were enrolled and randomized in the intention to treat population, 226 to receive cytoreductive nephrectomy followed by sunitinib, and then 224 that were assigned to receive sunitinib alone. And you can see that, ultimately, on the right side 40 patients underwent subsequent nephrectomy, and on the left side 16 patients did not undergo surgery, and over the course of the updated follow-up, 179 patients in each arm have died.
These are the patient demographics and disease characteristics in the intention to treat population. Arm A is nephrectomy plus sunitinib, and Arm B is sunitinib alone. These were well balanced in terms of age at 63 years of age for Arm A and 62 in Arm B. the majority of patients were male at three-quarters of the patients.
The MSKCC score was predominantly intermediate at 56% in Arm A and 59% in Arm B, which also correlates quite well with the IMDC score, intermediate-risk 56% in Arm A, and 62% in Arm B.
In terms of ECOG Performance Status, just over half of patients were ECOG 0 at 58% in Arm A and 55% in Arm B.
This is the updated overall survival Kaplan-Meier curve in the intention to treat population. You can see Arm A, nephrectomy plus sunitinib, in blue, Arm B, sunitinib alone, in red, and with the updated analysis, sunitinib alone remained non-inferior to nephrectomy plus sunitinib with a hazard ratio of 0.97 and a 95% confidence interval of 0.79 to 1.19.
This table looks at the overall survival in patients with intermediate-risk disease stratified by one versus two risk factors. Overall, you can see that the median overall survival in Arm A was 19 and in Arm B was 27.9 with a hazard ratio of 0.94 and a 95% confidence interval of 0.70 to 1.24.
In patients with one IMDC risk factor, the median overall survival in Arm A was 31.4 months compared to 25.2 months in Arm B with a hazard ratio of 1.30 and a 95% confidence interval of 0.85 to 1.98.
Interestingly, if you look down halfway through the table, at two IMDC risk factors, the median overall survival in Arm A was only 17.6 months, whereas with Arm B was 31.2 months with a hazard ratio favoring sunitinib alone of 0.65 and a 95% confidence interval of 0.44 to 0.97.
If your flavor is more of the Kaplan-Meier curve approach, this is similar data looking at these comparisons in the intermediate IMDC risk group. I've highlighted on the right the summary of this Kaplan-Meier curve. So, in patients with one IMDC risk factor, looking at cytoreductive nephrectomy versus sunitinib alone, the hazard ratio of 1.30, and a 95% confidence interval of 0.85 to 1.98. In the greater than or equal to two IMDC risk factors, sunitinib versus cytoreductive nephrectomy, the hazard ratio of 0.65 and a 95% confidence interval of 0.44 to 0.97. And then if we stratify in the sunitinib alone group, greater than two versus one IMDC risk factor, a hazard ratio of 0.88, with a 95% confidence interval of 0.59 to 1.30. And if we look at the greater than two versus one IMDC risk factor, cytoreductive nephrectomy versus sunitinib had a hazard ratio of 1.69 and a 95% confidence interval of 1.11 to 2.57.
This table looks at the overall survival with one metastatic site versus two or more metastatic sites, a similar table to the previous one. Looking at one metastatic site, Arm A with a median overall survival of 23.2 months, and a similar overall survival in Arm B of 22.7 months with a hazard ratio of 1.09 and a 95% confidence interval of 0.75 to 1.59. Looking at two or more sites, Arm A, median overall survival of 14.4 months, and in Arm B, 16.7 months with a hazard ratio of 0.87 and a 95% confidence interval of 0.68 to 1.12.
A similar figure to the previous one, this is for stratification by one metastatic site versus two. When looking at one metastatic site specifically, cytoreductive nephrectomy versus sunitinib had a hazard ratio of 1.09 and a 95% confidence interval of 0.75 to 1.59. Looking at greater than or equal to two metastatic sites, sunitinib versus cytoreductive nephrectomy, a hazard ratio of 0.87 and a 95% confidence interval of 0.68 to 1.12.
Among patients that had cytoreductive nephrectomy plus sunitinib, stratified by greater than or equal to two metastatic sites versus one, the hazard ratio of 1.42 and a 95% confidence interval statistically significant at 1.03 to 1.96. And finally, in the patients that received sunitinib alone, greater than or equal to two versus one metastatic site, a hazard ratio of 1.19, with a 95% confidence interval of 0.86 to 1.64.
This Kaplan-Meier curve looks at the overall survival in patients with secondary nephrectomy in Arm B. These are the patients that were stratified to just sunitinib alone. And there have been several studies since the publication of CARMENA discussing delayed cytoreductive nephrectomy. And you can see here that delayed nephrectomy is in blue and no surgery is in red. And we see that the secondary cytoreductive nephrectomy versus no nephrectomy was significant with a hazard ratio of 0.34 and a 95% confidence interval of 0.22 to 0.54.
So, several discussion points from this updated analysis from CARMENA. We see that with longer follow-up, treatment with sunitinib alone was not inferior to cytoreductive nephrectomy followed by sunitinib treatment with regards to overall survival in patients with metastatic renal cell carcinoma. We also saw that a similar trend was observed in several per-protocol analyses, although non-inferiority was not met in these subgroups.
Reclassification of patients initially stratified by MSKCC risk, which was the original trial design, into IMDC risk groups showed consistent overall survival findings.
So, overall, IMDC intermediate-risk patients demonstrated a higher overall survival with sunitinib alone compared with cytoreductive nephrectomy followed by sunitinib. However, as we saw on the previous slides, in patients with only one risk factor, longer overall survival in the cytoreductive nephrectomy plus sunitinib group compared with sunitinib alone was shown, although this was not statistically significant.
And finally, patients that underwent delayed cytoreductive nephrectomy showed a longer overall survival compared to patients that received sunitinib alone. And this is supported by data from the SURTIME trial that looked at sunitinib followed by cytoreductive nephrectomy versus immediate cytoreductive nephrectomy with a statistically significant hazard ratio of 0.57 and a 95% confidence interval of 0.34 to 0.95.
In conclusion, these further analyses from the CARMENA trial confirm that cytoreductive nephrectomy should not be considered as the standard of care in patients with synchronous metastatic renal cell carcinoma who require systemic treatment. These findings will help to guide treatment decisions for certain subgroups, particularly those with only one IMDC risk factor who may still benefit from upfront cytoreductive nephrectomy.
Thank you very much, and we hope you enjoyed this UroToday Journal Club discussing the updated CARMENA trial analyses.
Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club. Today we are discussing the recent publication from the CARMENA trial entitled, Sunitinib Alone or After Nephrectomy for Patients with Metastatic Renal Cell Carcinoma: Is There Still a Role for Cytoreductive Nephrectomy?
I'm Chris Wallis, an Assistant Professor in the Division of Urology at The University of Toronto, and with me today is Zach Klaassen, an Assistant Professor in the Division of Urology at The Medical College of Georgia. This is the citation for this recent publication found in European Urology. It follows the initial publication of CARMENA.
So, the real defining role of cytoreductive nephrectomy came in the early 2000s. We had both the SWOG and EORTC trials, which examined the combination of cytoreductive nephrectomy with cytokine therapy or cytokine therapy alone. While you see on the left side in this Kaplan–Meier plot that survival outcomes were not that good in either group, there was a significant benefit for the combination of cytoreduction with cytokine therapy, and this here is the pooled analyses of these two trials demonstrating approximately a 30% reduction.
We then move on with the progress in the systemic therapy for renal cell carcinoma, and moving from the cytokine therapy era, to the targeted therapy era was the next predominant treatment approach, which lasted for approximately 15 years. And sunitinib came to be the standard of care and most widely used approach during this time.
So the question then is, does cytoreductive nephrectomy retain the same benefit for patients who are receiving systemic targeted therapies as compared to those who received cytokine-based approaches? And so these are three observational studies, each of which suggested there is a survival benefit for the use of cytoreduction, although we know observational data of these sorts are affected by selection bias and confounding by indication.
So we then moved to randomized data, and this is the original report of the CARMENA trial. And just to highlight the methodology here, this enrolled patients with metastatic clear cell renal cell carcinoma who were treatment-naive and had intermediate or poor-risk disease according to the Motzer criteria. Patients were then randomized in a one-to-one fashion to receive either sunitinib alone or cytoreductive nephrectomy followed by sunitinib.
As you can see here on the lower left, there was no significant difference in overall survival between the two arms at the time of the primary report. However, there are a few limitations when we apply these data. First, outcomes are somewhat worse in both arms than might be expected from the contemporary use of sunitinib, and this implies that the population may be enriched with patients with more aggressive disease.
Additionally, subgroup analyses suggested there may be a heterogeneity effect with a potential benefit of cytoreductive nephrectomy in a subset of patients with lower volumes of disease. So to that end, the present work seeks to provide an updated analysis of the CARMENA trial and to assess whether some subgroups of patients may benefit from cytoreduction.
Again, to highlight, this as a prospective, multi-center, open-label, randomized phase III trial. Patients are included if they had metastatic clear cell renal cell carcinoma, had not received prior therapy, and had intermediate or poor-risk disease according to the Motzer criteria. This was a non-inferiority design with non-inferiority defined as a hazard ratio for overall survival of less than 1.2.
So this updated analysis relies on a data cutoff of October 2018, at which time there were 358 overall survival events. And it does warrant mention that this is revised from the initial plan of analysis at the time of 476 events as a result of overall poor accrual to the trial and early termination due to sampling size concerns.
Additionally, in this analysis, they reclassified patients using the IMDC criteria rather than Motzer criteria, given the emerging evidence that IMDC performs better. And so, in keeping with IMDC risk criteria, intermediate-risk was defined as one or two risk factors and poor-risk as three to six.
The authors performed a number of analyses, including assessing overall survival in the whole study cohort as well as subgroups defined based on IMDC risk, number of tumor sites, and the presence of delayed cytoreduction. They also assessed four different populations, including the intention to treat population, and per-protocol one, two, and three. And so you can see the definitions here, where they include slightly different subgroups of patients on the basis of the rigidity to which per-protocol analyses were stuck.
The authors used the Kaplan-Meier method to estimate overall survival rates and confidence intervals. And again, as we highlighted before, sunitinib alone was considered non-inferior to sunitinib with cytoreduction if the upper limit of the 95% confidence interval of the hazard ratio for overall survival was less than 1.20.
At this point in time, I'm now going to hand it over to Zach to walk us through the results of this updated analysis from the CARMENA trial.
Zachary Klaassen: Thanks, Chris. This is the updated randomization, treatment, and follow-up figure. And so, as we know, there were 450 patients that were enrolled and randomized in the intention to treat population, 226 to receive cytoreductive nephrectomy followed by sunitinib, and then 224 that were assigned to receive sunitinib alone. And you can see that, ultimately, on the right side 40 patients underwent subsequent nephrectomy, and on the left side 16 patients did not undergo surgery, and over the course of the updated follow-up, 179 patients in each arm have died.
These are the patient demographics and disease characteristics in the intention to treat population. Arm A is nephrectomy plus sunitinib, and Arm B is sunitinib alone. These were well balanced in terms of age at 63 years of age for Arm A and 62 in Arm B. the majority of patients were male at three-quarters of the patients.
The MSKCC score was predominantly intermediate at 56% in Arm A and 59% in Arm B, which also correlates quite well with the IMDC score, intermediate-risk 56% in Arm A, and 62% in Arm B.
In terms of ECOG Performance Status, just over half of patients were ECOG 0 at 58% in Arm A and 55% in Arm B.
This is the updated overall survival Kaplan-Meier curve in the intention to treat population. You can see Arm A, nephrectomy plus sunitinib, in blue, Arm B, sunitinib alone, in red, and with the updated analysis, sunitinib alone remained non-inferior to nephrectomy plus sunitinib with a hazard ratio of 0.97 and a 95% confidence interval of 0.79 to 1.19.
This table looks at the overall survival in patients with intermediate-risk disease stratified by one versus two risk factors. Overall, you can see that the median overall survival in Arm A was 19 and in Arm B was 27.9 with a hazard ratio of 0.94 and a 95% confidence interval of 0.70 to 1.24.
In patients with one IMDC risk factor, the median overall survival in Arm A was 31.4 months compared to 25.2 months in Arm B with a hazard ratio of 1.30 and a 95% confidence interval of 0.85 to 1.98.
Interestingly, if you look down halfway through the table, at two IMDC risk factors, the median overall survival in Arm A was only 17.6 months, whereas with Arm B was 31.2 months with a hazard ratio favoring sunitinib alone of 0.65 and a 95% confidence interval of 0.44 to 0.97.
If your flavor is more of the Kaplan-Meier curve approach, this is similar data looking at these comparisons in the intermediate IMDC risk group. I've highlighted on the right the summary of this Kaplan-Meier curve. So, in patients with one IMDC risk factor, looking at cytoreductive nephrectomy versus sunitinib alone, the hazard ratio of 1.30, and a 95% confidence interval of 0.85 to 1.98. In the greater than or equal to two IMDC risk factors, sunitinib versus cytoreductive nephrectomy, the hazard ratio of 0.65 and a 95% confidence interval of 0.44 to 0.97. And then if we stratify in the sunitinib alone group, greater than two versus one IMDC risk factor, a hazard ratio of 0.88, with a 95% confidence interval of 0.59 to 1.30. And if we look at the greater than two versus one IMDC risk factor, cytoreductive nephrectomy versus sunitinib had a hazard ratio of 1.69 and a 95% confidence interval of 1.11 to 2.57.
This table looks at the overall survival with one metastatic site versus two or more metastatic sites, a similar table to the previous one. Looking at one metastatic site, Arm A with a median overall survival of 23.2 months, and a similar overall survival in Arm B of 22.7 months with a hazard ratio of 1.09 and a 95% confidence interval of 0.75 to 1.59. Looking at two or more sites, Arm A, median overall survival of 14.4 months, and in Arm B, 16.7 months with a hazard ratio of 0.87 and a 95% confidence interval of 0.68 to 1.12.
A similar figure to the previous one, this is for stratification by one metastatic site versus two. When looking at one metastatic site specifically, cytoreductive nephrectomy versus sunitinib had a hazard ratio of 1.09 and a 95% confidence interval of 0.75 to 1.59. Looking at greater than or equal to two metastatic sites, sunitinib versus cytoreductive nephrectomy, a hazard ratio of 0.87 and a 95% confidence interval of 0.68 to 1.12.
Among patients that had cytoreductive nephrectomy plus sunitinib, stratified by greater than or equal to two metastatic sites versus one, the hazard ratio of 1.42 and a 95% confidence interval statistically significant at 1.03 to 1.96. And finally, in the patients that received sunitinib alone, greater than or equal to two versus one metastatic site, a hazard ratio of 1.19, with a 95% confidence interval of 0.86 to 1.64.
This Kaplan-Meier curve looks at the overall survival in patients with secondary nephrectomy in Arm B. These are the patients that were stratified to just sunitinib alone. And there have been several studies since the publication of CARMENA discussing delayed cytoreductive nephrectomy. And you can see here that delayed nephrectomy is in blue and no surgery is in red. And we see that the secondary cytoreductive nephrectomy versus no nephrectomy was significant with a hazard ratio of 0.34 and a 95% confidence interval of 0.22 to 0.54.
So, several discussion points from this updated analysis from CARMENA. We see that with longer follow-up, treatment with sunitinib alone was not inferior to cytoreductive nephrectomy followed by sunitinib treatment with regards to overall survival in patients with metastatic renal cell carcinoma. We also saw that a similar trend was observed in several per-protocol analyses, although non-inferiority was not met in these subgroups.
Reclassification of patients initially stratified by MSKCC risk, which was the original trial design, into IMDC risk groups showed consistent overall survival findings.
So, overall, IMDC intermediate-risk patients demonstrated a higher overall survival with sunitinib alone compared with cytoreductive nephrectomy followed by sunitinib. However, as we saw on the previous slides, in patients with only one risk factor, longer overall survival in the cytoreductive nephrectomy plus sunitinib group compared with sunitinib alone was shown, although this was not statistically significant.
And finally, patients that underwent delayed cytoreductive nephrectomy showed a longer overall survival compared to patients that received sunitinib alone. And this is supported by data from the SURTIME trial that looked at sunitinib followed by cytoreductive nephrectomy versus immediate cytoreductive nephrectomy with a statistically significant hazard ratio of 0.57 and a 95% confidence interval of 0.34 to 0.95.
In conclusion, these further analyses from the CARMENA trial confirm that cytoreductive nephrectomy should not be considered as the standard of care in patients with synchronous metastatic renal cell carcinoma who require systemic treatment. These findings will help to guide treatment decisions for certain subgroups, particularly those with only one IMDC risk factor who may still benefit from upfront cytoreductive nephrectomy.
Thank you very much, and we hope you enjoyed this UroToday Journal Club discussing the updated CARMENA trial analyses.