First-Line Immunotherapy, Targeted Therapy, and Combination Therapy Associated with Improved OS for Metastatic Clear Cell Renal Cell Carcinoma, Journal Club - Christopher Wallis & Zachary Klaass
September 7, 2021
In this UroToday Journal Club, Christopher Wallis and Zachary Klaassen discuss a publication entitled Real-World Survival Outcomes Associated With First-Line Immunotherapy, Targeted Therapy, and Combination Therapy for Metastatic Clear Cell Renal Cell Carcinoma. The discussion begins with a history of the targeted therapy era, progressing into the introduction of combination approaches, beginning first with nivolumab and ipilimumab, which have reshaped the treatment approaches for metastatic renal cell carcinoma (RCC) and have formed the basis for the new NCCN guidelines. This analysis of a nationally representative real-world cohort demonstrated that both immunotherapy and combination targeted therapy and immunotherapy were associated with improved overall survival for patients with metastatic clear cell RCC compared to targeted therapy alone.
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 a recent publication entitled, Real-World Survival Outcomes Associated With First-Line Immunotherapy, Targeted Therapy, and Combination Therapy for Metastatic Clear Cell Renal Cell Carcinoma. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, 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 work published in JAMA Network Open and led by the group from Moffitt.
By way of background, we can see here the evolving treatment landscape for metastatic renal cell carcinoma. While the targeted therapy era lasted for nearly 15 years, since 2018, we have now seen the introduction of combination approaches, beginning first with nivolumab and ipilimumab, and subsequently a variety of combinations of pembrolizumab and axitinib, avelumab and axitinib, cabozantinib and nivolumab, lenvatinib and pembrolizumab. And so these approaches have really reshaped our treatment approaches for metastatic renal cell carcinoma and have formed the basis for the new NCCN guidelines.
As you can see here, in both favorable and poor, and intermediate-risk diseases, these new treatment approaches have become the preferred treatment regime for patients treated with metastatic kidney cancer. However, while efficacy has been proven based on these randomized control trials, population-level effectiveness, as well as population-level safety have not been proven, and so the authors sought to assess this in the present manuscript.
These authors set about doing just that, and to do so they used the National Cancer Database and identified patients with clear cell renal cell carcinoma who were diagnosed between January 1st, 2015 and December 31st, 2017, who had de novo metastatic disease stage 4 at diagnosis and were age 18 to 100 years. They further had to have complete staging and demographic data and have undergone treatment with either immunotherapy, targeted therapy, or the combination thereof. These were defined according to the standard treatment fields within the NCDB.
Their primary outcome was overall survival defined based on the time from the initial diagnosis to the date of death or censoring at last follow-up. First-line treatments were used to define treatment groups regardless of subsequent therapy. The author used a 1:1:1 nearest neighbor propensity score matching to account for baseline demographic differences, including age, sex, race and ethnicity, comorbidity, facility type, insurance, year of diagnosis, clinical T stage, clinical N stage, and the cytoreductive nephrectomy status. They then used Cox proportional hazards models to perform pairwise comparisons and corrected their alpha based on a Bonferroni correction for multiple comparisons.
At this point in time, I am now going to hand it over to Zach to walk us through the results of this study.
Zachary Klaassen: Thanks, Chris. This is the flow diagram detailing the selection of the study population. In the top left, you can see that there were 569,685 patients with kidney cancer in the NCDB from 2004 to 2017. Ultimately, the authors selected 5,872 patients that were included in the final study population, including 4,755 that underwent targeted therapy, 638 that underwent immunotherapy, and 479 patients that underwent a combination of these two treatments.
This is table one pre matching patient tumor characteristics. Looking at this by therapy type, you can see that in the three groups, the patients undergoing targeted therapy were slightly older, at 64 years, compared to 61 in the immunotherapy and 62 in the combination therapy. We can see that there were more male patients in the immunotherapy group, at 74%, compared to 70% in the targeted therapy and 67% in the combination therapy groups. In terms of race and ethnicity, these were well balanced. In terms of Charleson's comorbidity score, these were slightly healthier patients undergoing treatment for immunotherapy at 75%, Charleson morbidity score of 0, 74% in the combination group, and only 69% in the targeted therapy group.
Looking at the facility type, we can see that patients that are undergoing immunotherapy, 49%, were more likely to undergo immunotherapy at an academic center compared to 41% for targeted therapy and 45% for combination therapy. In terms of insurance, the majority of patients had either Medicare or private insurance that you can see listed here. In terms of year of diagnosis, more patients diagnosed later underwent immunotherapy, as well as combination therapy, compared to the earlier years of targeted therapy. In terms of the clinical T stage, most commonly was pretty actually, well-delineated across T1, T2 and T3, and most patients, upwards of two-thirds, had clinical N0 disease. Finally, looking at the bottom, cytoreductive nephrectomy, 53% for immunotherapy, 42% for the combination therapy, and 38% for targeted therapy.
This is a graphic looking at the incidence of first-line treatment regimens over time, stratified by the treatment types. Certainly, targeted therapy has been the most common during these 3 years, but as we move through from 2015 to 2017, we see an uptick in the amount of immunotherapy and combination therapy being used.
This is a table just showing the post-matching of the patient demographics and characteristics, and as you can see here on the right, the p-values are all non-significant, so these patients after matching were well-matched on these characteristics.
In terms of the outcomes, looking at the univariable Cox proportional hazard regression model for overall survival in the matched cohort, we can see on the left here, the targeted therapy group was the reference group, and when compared to immunotherapy, immunotherapy had improved overall survival, with a hazard ratio of 0.60 and a 95% confidence interval of 0.48 to 0.75. This is also seen with the combination therapy group, with a hazard ratio of 0.74 and a 95% confidence interval of 0.60 to 0.91. Finally, when immunotherapy was compared to combination therapy, there was no difference in survival.
This Kaplan-Meier curve looks at the overall survival stratified by treatment group. You can see here, the blue line is combination therapy, the orange line is immunotherapy, and the dark gray line is targeted therapy. Comparing these three groups together, the log-rank p-value is significant, at 0.02, and looking at it closer, the 12-month overall survival rate was highest for the immunotherapy group, at 73%, followed by 68% for the combination therapy group, and 59% for the targeted therapy group.
We think there are several important discussion points from this study, and notably that this study provides external validation for the overall survival benefit of immunotherapy and combination therapy compared to targeted therapy alone for first-line metastatic RCC treatment. The comparison between immunotherapy and targeted therapy in this study, which resulted in the hazard ratio of 0.60 and a 95% confidence interval of 0.48 to 0.75, confirms the findings seen in CheckMate 214, which looked at nivolumab plus ipilimumab compared to sunitinib, and that hazard ratio of 0.63 and a 95% confidence interval of 0.44 to 0.89. Additionally, the comparison between combination therapy and targeted therapy in this study, which had a hazard ratio of 0.74 and a 95% confidence interval of 0.60 to 0.91, confirmed the findings of the KEYNOTE-426 study, which looked at axi plus pembro compared to sunitinib, and that hazard ratio of 0.53 and 95% confidence interval of 0.38 to 0.74.
In conclusion, this analysis of a nationally representative real-world cohort demonstrated that both immunotherapy and combination targeted therapy and immunotherapy were associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma compared to targeted therapy alone. Ultimately, these findings imply the broader generalizability of previously reported clinical trial outcomes.
Thank you very much and we hope you enjoyed this UroToday Journal Club.
Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing a recent publication entitled, Real-World Survival Outcomes Associated With First-Line Immunotherapy, Targeted Therapy, and Combination Therapy for Metastatic Clear Cell Renal Cell Carcinoma. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, 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 work published in JAMA Network Open and led by the group from Moffitt.
By way of background, we can see here the evolving treatment landscape for metastatic renal cell carcinoma. While the targeted therapy era lasted for nearly 15 years, since 2018, we have now seen the introduction of combination approaches, beginning first with nivolumab and ipilimumab, and subsequently a variety of combinations of pembrolizumab and axitinib, avelumab and axitinib, cabozantinib and nivolumab, lenvatinib and pembrolizumab. And so these approaches have really reshaped our treatment approaches for metastatic renal cell carcinoma and have formed the basis for the new NCCN guidelines.
As you can see here, in both favorable and poor, and intermediate-risk diseases, these new treatment approaches have become the preferred treatment regime for patients treated with metastatic kidney cancer. However, while efficacy has been proven based on these randomized control trials, population-level effectiveness, as well as population-level safety have not been proven, and so the authors sought to assess this in the present manuscript.
These authors set about doing just that, and to do so they used the National Cancer Database and identified patients with clear cell renal cell carcinoma who were diagnosed between January 1st, 2015 and December 31st, 2017, who had de novo metastatic disease stage 4 at diagnosis and were age 18 to 100 years. They further had to have complete staging and demographic data and have undergone treatment with either immunotherapy, targeted therapy, or the combination thereof. These were defined according to the standard treatment fields within the NCDB.
Their primary outcome was overall survival defined based on the time from the initial diagnosis to the date of death or censoring at last follow-up. First-line treatments were used to define treatment groups regardless of subsequent therapy. The author used a 1:1:1 nearest neighbor propensity score matching to account for baseline demographic differences, including age, sex, race and ethnicity, comorbidity, facility type, insurance, year of diagnosis, clinical T stage, clinical N stage, and the cytoreductive nephrectomy status. They then used Cox proportional hazards models to perform pairwise comparisons and corrected their alpha based on a Bonferroni correction for multiple comparisons.
At this point in time, I am now going to hand it over to Zach to walk us through the results of this study.
Zachary Klaassen: Thanks, Chris. This is the flow diagram detailing the selection of the study population. In the top left, you can see that there were 569,685 patients with kidney cancer in the NCDB from 2004 to 2017. Ultimately, the authors selected 5,872 patients that were included in the final study population, including 4,755 that underwent targeted therapy, 638 that underwent immunotherapy, and 479 patients that underwent a combination of these two treatments.
This is table one pre matching patient tumor characteristics. Looking at this by therapy type, you can see that in the three groups, the patients undergoing targeted therapy were slightly older, at 64 years, compared to 61 in the immunotherapy and 62 in the combination therapy. We can see that there were more male patients in the immunotherapy group, at 74%, compared to 70% in the targeted therapy and 67% in the combination therapy groups. In terms of race and ethnicity, these were well balanced. In terms of Charleson's comorbidity score, these were slightly healthier patients undergoing treatment for immunotherapy at 75%, Charleson morbidity score of 0, 74% in the combination group, and only 69% in the targeted therapy group.
Looking at the facility type, we can see that patients that are undergoing immunotherapy, 49%, were more likely to undergo immunotherapy at an academic center compared to 41% for targeted therapy and 45% for combination therapy. In terms of insurance, the majority of patients had either Medicare or private insurance that you can see listed here. In terms of year of diagnosis, more patients diagnosed later underwent immunotherapy, as well as combination therapy, compared to the earlier years of targeted therapy. In terms of the clinical T stage, most commonly was pretty actually, well-delineated across T1, T2 and T3, and most patients, upwards of two-thirds, had clinical N0 disease. Finally, looking at the bottom, cytoreductive nephrectomy, 53% for immunotherapy, 42% for the combination therapy, and 38% for targeted therapy.
This is a graphic looking at the incidence of first-line treatment regimens over time, stratified by the treatment types. Certainly, targeted therapy has been the most common during these 3 years, but as we move through from 2015 to 2017, we see an uptick in the amount of immunotherapy and combination therapy being used.
This is a table just showing the post-matching of the patient demographics and characteristics, and as you can see here on the right, the p-values are all non-significant, so these patients after matching were well-matched on these characteristics.
In terms of the outcomes, looking at the univariable Cox proportional hazard regression model for overall survival in the matched cohort, we can see on the left here, the targeted therapy group was the reference group, and when compared to immunotherapy, immunotherapy had improved overall survival, with a hazard ratio of 0.60 and a 95% confidence interval of 0.48 to 0.75. This is also seen with the combination therapy group, with a hazard ratio of 0.74 and a 95% confidence interval of 0.60 to 0.91. Finally, when immunotherapy was compared to combination therapy, there was no difference in survival.
This Kaplan-Meier curve looks at the overall survival stratified by treatment group. You can see here, the blue line is combination therapy, the orange line is immunotherapy, and the dark gray line is targeted therapy. Comparing these three groups together, the log-rank p-value is significant, at 0.02, and looking at it closer, the 12-month overall survival rate was highest for the immunotherapy group, at 73%, followed by 68% for the combination therapy group, and 59% for the targeted therapy group.
We think there are several important discussion points from this study, and notably that this study provides external validation for the overall survival benefit of immunotherapy and combination therapy compared to targeted therapy alone for first-line metastatic RCC treatment. The comparison between immunotherapy and targeted therapy in this study, which resulted in the hazard ratio of 0.60 and a 95% confidence interval of 0.48 to 0.75, confirms the findings seen in CheckMate 214, which looked at nivolumab plus ipilimumab compared to sunitinib, and that hazard ratio of 0.63 and a 95% confidence interval of 0.44 to 0.89. Additionally, the comparison between combination therapy and targeted therapy in this study, which had a hazard ratio of 0.74 and a 95% confidence interval of 0.60 to 0.91, confirmed the findings of the KEYNOTE-426 study, which looked at axi plus pembro compared to sunitinib, and that hazard ratio of 0.53 and 95% confidence interval of 0.38 to 0.74.
In conclusion, this analysis of a nationally representative real-world cohort demonstrated that both immunotherapy and combination targeted therapy and immunotherapy were associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma compared to targeted therapy alone. Ultimately, these findings imply the broader generalizability of previously reported clinical trial outcomes.
Thank you very much and we hope you enjoyed this UroToday Journal Club.