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Deconstructing IO Therapy: Three Combinations, 
Three Viewpoints from Key Opinion Leaders ﷯ Rana Mckay, MD Moores Cancer Center, 
University of California, San Diego 
San Diego, California ﷯ Matthew Milowsky, MD 1 UNC Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina ﷯ Thomas Powles, FRCP Barts Cancer Institute London, England In this wide-ranging discussion, three opinion leaders address essential issues related to the use of immunotherapy combinations in the frontline space for RCC. As they compare the rationale for the use of these respective combinations, each participant offers a unique perspective, including key messages from the pivotal trials supporting IO treatment. The particpants include Rana Mckay MD, Matthew Milowsky, MD, and Thomas Powles, FRCP. The discussion is chaired by Robert Figlin, MD, Editor-in-Chief of Kidney Cancer Journal. n Combining Ipilimumab and Nivolumab Dr Figlin: In the ever changing landscape for the management of RCCa, please summarize the key takeaways from the recent data on ipi/nivo in the frontline setting? Dr Mckay: Data regarding nivo and ipi in patients with metastatic RCC have dramatically changed the way we approach newly diagnosed patients. For the first time, we are challenging the treatment paradigm of frontline TKI alone. The combination of nivo/ipi in a large randomized phase 3 trial, CheckMate-214 was actually shown to be superior to sunitinib and is one of the first studies to demonstrate superiority of non-VEGF agents in the frontline space. The big takeaway from this study—the primary endpoint of the study was actually to look at objective response, PFS, and overall survival in patients with intermediate and poor-risk disease. The study included about 51% of patients with intermediate risk disease and 17% of patients with poor-risk disease. When we look at the breakdown of patients with intermediate and poor-risk disease we see a statistically significant improvement in objective response rate with the combination of nivo/ipi. What’s striking is that the complete response rate was 9% in this patient population. Additionally, there was an improvement in PFS and an updated efficacy analysis showing it was statistically significant. Overall survival was also superior to sunitinib with a HR of 0.66 in the updated analysis which was statistically significant and practice changing. While the primary endpoint of the study did not evaluate favorable risk disease, it’s important to look at the favorable risk patients and try to understand what does the combination of nivo/ipi do with this patient population. While the objective response rate was higher with sunitinib compared to nivo/ipi, when we look at that complete response rate, we see that it is actually higher in the nivo/ipi patients. The CR rate in favorable risk patients in CheckMate-214 was around 6% in sunitinib-treated patients but 11% in the nivo/ipi patients, suggesting that there probably is a subset of patients with favorable risk disease who may derive benefit from the combination of nivo/ipi. Additionally, when looking at the intent to treat population, nivo/ipi showed improved ORR, PFS, and OS compared to sunitinib. The other thing to point out is when we look at the favorable risk patients who were enrolled in the CheckMate-214 we see an overperformance of the controlled arm. The PFS of sunitinib-treated patients approaches 25.1 months, higher than frontline trials that used sunitinib as a comparator arm. Nivo/ipi has certainly changed the frontline space. It clearly has demonstrated improved responses and survival for patients with advanced diseease, and for the first time we see patients entering durable remissions with IO combination therapy. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Mckay: At the present time, most of our biomarkers to guide clinical decision marking are based on clinical parameters. We have clinical risk stratification systems that help inform prognosis and they have been utilized in guiding treatment decisions, however these are not predictive. Unfortunately, we do not have any soluble, blood-based biomarkers that have proven to be validated across mRCC. The combination nivo/ipi has demonstrated efficacy for those with intermediate and poor risk disease and those who are able to receive IO therapy and do not have significant autoimmune disease that would preclude therapy. While overall, patients with favorable risk disease did better with sunitinib in this study, the CR rate was higher with nivo/ipi frontline. I’m not automatically saying no to ipi/nivo in patients with favorable risk disease. I’m looking at their presentation, at co-morbidities, performance status. The number of patients in the current era who would receive a single agent TKI in the frontline space is limited. There is cabozantinib as an option in this regard for those with bone metastases based on the CABOSUN trial. But we need to question the use of VEGF TKIs in the frontline space. The current data support IO-IO combinations or IO-VEGF TKI in the frontline. Dr Figlin: Do you use existing risk stratification systems (ie, IMDC, MSKCC) in making this assessment? Dr Mckay: The MSKCC risk factors were validated in the cytokine era. Now the IMDC system has been validated in the TKI era. While it has not yet been validated with use of IO therapy, it is nonetheless a critical risk stratification to think about when you see a patient with metastatic disease. Where I see the risk stratification system coming in very handy is in thinking about the role of cytoreductive nephrectomy in the context of patients with metastatic disease. We’re being a bit more prudent in deciding which patients derive benefit from upfront CN as opposed to delayed CN. IMDC risk parameters really come into play when thinking about starting a patient on systemic therapy first or CN and system therapy later. Overall, risk stratification systems are really helpful when thinking about the integration of surgery with systemic therapy for patients with advanced disease. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Mckay: When reviewing the IO-IO and VEGF-IO trials, each of these studies used a totally different assay to determine PD-L1 expression status. The percentages of PD-L1 expression based on the assays that were used varied across the studies. For example, in CheckMate-214, PD-L1 expression was seen in 24% of the total population and in KEYNOTE-426 and JAVELIN 101 there were different assays used, and the number was around 60% and 53%. We have a lot more to learn about the utility of PD-L1. And the other thing to consider is that the bulk of these tests were done on archival nephrectomy specimens as opposed to fresh biopsies at baseline. We know that PD-L1 status is very dynamic and there are temporal and spatial changes in this biomarker. PD-L1 is certainly prognostic in RCC. Those who have PD-L1 expression do worse than those without. However its role as a predictive biomarker in RCC is still evolving. Dr Figlin: Are there specific sites of metastasis (ie, brain, bone, other) that would make you less likely to use this regimen? Dr Mckay: We know that patients with bone metastases have historically done worse than those without bone metastases. We have great data from the CABOSUN study demonstrating efficacy of cabozantinib over sunitinib in the frontline phase. And while that’s a phase 2 study, I think there is rationale for using cabozantinib in the frontline for those who have bone metastases that may negatively impact their quality of life. Additional studies are investigating IO combinations with cabozantinib in the frontline. These studies will further inform management of advanced RCC. Also, one more thing about patients with brain metastases: we can learn from the melanoma literature about the safety of IO therapies in patients who have brain metastases. Dr Figlin: Are there specific co-morbidities that would make you less likely to use this regimen? Dr Mckay: Patients who have underlying or concurrent autoimmune disease—that would be a red flag. Currently, a study is being conducted by the NCI looking at immunotherapy in patients who have autoimmune disease. We recently conducted a retrospective analysis of patients with RCC who have autoimmune disease who received IO therapy and we are reporting on their outcomes. Management needs to be coordinated with rheumatologists and other consultants to make sure the risk/benefit ratio is sound. n Combining Avelumab and Axitinib Dr Figlin: In the ever changing landscape for the management of advanced RCCa, please summarize the key takeaways from the recent data on avelumab/axitinib in the frontline setting? Dr Milowsky: In terms of the landscape in the frontline setting for metastatic RCC, the benefit for avelumab/axitinib was established in the JAVELIN Renal 101 Study. 886 patients were randomized to avelumab, a PD-L1 inhibitor plus axitinib, a VEGF receptor TKI compared to sunitinib, another VEGF receptor TKI. For the primary endpoint of the study, there was a significant improvement in progression free survival (PFS) in the PD-L1-selected (defined as greater than or equal to 1% of the immune cells staining positive) individuals. The PFS was 14 months for the combination vs 7 months for sunitinib with an HR of 0.61 for progression or death. The benefit was also seen in the overall population for ave- lumab/axitinib over sunitinib. At this first pre-planned interim analysis with a median followup of 11.6 months, there was not a significant improvement in overall survival for the combination with an HR of 0.788 (P=0.14). Also important in this study is the response rate which was substantially higher for patients who were treated with the combination in both the PD-L1 selected and overall population (55% in the PD-L1 selected avelumab/axitinib group vs 25% for sunitinib). The tolerability was similar to sunitinib including grade 3 adverse events. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Milowsky: These are first-line patients, so they are previously untreated and have advanced RCC. The data from this study showed that over 80% did have a prior nephrectomy. We do not know how that ultimately plays into things. In terms of the population, if you look at the the combination, the benefit was seen in all subgroups. The majority of subjects, over 60%, were intermediate risk. If you have patients who need a robust and relatively rapid response—the median time to response was 2.5 months—it represents a great option. With the Checkmate 214 data for ipi/nivo (ipilimumab/nivolumab) demonstrating a benefit in intermediate and poor risk patients, our standard for favorable risk patients remained sunitinib. Now, with the combination data for avelumab/axitinib we have benefit in favorable risk patients as well. This approach now represents a standard of care in the IMDC favorable risk group as well as in patients with intermediate and poor risk disease. Dr Figlin: Do you use existing risk stratification systems (ie: IMDC, MSKCC), others) in making this assessment? Dr Milowsky: We use the IMDC groups in the clinic for prognostication. With newer therapies, this is likely to change with the potential for additional variables to include within these models. In the context of IO therapies, the future is likely to include new predictive and prognostic models. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Milowsky: Initially the JAVELIN study was designed differently based on a phase 1b study that showed there was a higher percentage of patients with high PD-L1 expression benefiting from avelumab and axitinib. The primary endpoint of the JAVELIN Renal 101 Study was subsequently changed to look specifically in patients with high PD-L1 status. There was a benefit in the high PD-L1 group but there was also a benefit in the overall population. Based on JAVELIN 101, PD-L1 status should not be used to guide treatment decisions unless we see additional information such as more mature survival data that could change this interpretation. Dr. Choueiri et al presented an important biomarker analysis from JAVELIN 101 at the ASCO Annual Meeting 2019 looking at PD-L1 expression, tumor mutational burden, T-cell subsets, and immune gene expression signatures. This type of work will help guide us in the future. Dr Figlin: Are there specific sites of metastasis (ie, brain, bone, other) that would make you less likely to use this regimen? Dr Milowsky: Within the context of this study, there was no clear information to suggest that site of disease should guide therapy with the combination. Over 50% of patients had at least two sites of disease. The study excluded patients with active CNS metastases. We would use the combination in patients with treated CNS metastases. The study excluded active autoimmune disease and we need to be cautious in patients with autoimmune disease. The study does not speak to a particular patient population that should or shouldn’t be treated. The real question is: are there patients that benefit more from IO-IO therapy vs IO-TKI? Dr Figlin: Are there specific co-morbidities that would make you less likely to use this regimen? Dr Milowsky: In general, it is a regimen that is very usable. The study, however, excluded active autoimmune disease and again we need to be cautious about the use of IO in patients with active autoimmune disease or in the case of VEGFR TKI therapy, in patients with difficult to control hypertension as one example. Overall, the toxicity is manageable. n Combining Pembrolizumab 
and Axitinib Dr Figlin: In the ever changing landscape for the management of advanced RCCA, please summarize the key takeaways from the recent Keynote-426 data on pem- bro/axitinib in the front line setting? Dr Powles: The key messages are that this randomized, frontline, phase 3 trial, which enrolled all comers, was the first trial to show a response rate of progression-free survival and overall survival advantage. And it was associated with a 47% reduction in the risk of death and a PFS of just over 15 months. Putting that together is an exceptionally good result. The drugs seem to work in good, intermediate and poor-risk patients, in all risk groups. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Powles: The regimen is suited for all risk groups or PD-L1 status. It is an all comers-type approach. Dr Figlin: Do you use existing risk stratification systems (ie: IMDC, MSKCC, others) in making this assessment? Dr Powles: We do not need to do that. It’s useful from a patient perspective to know which group they are in. Essentially, what we see from this trial is that the drugs (pembrolizumab and axitinib) seem to work whether across the board and seem to work particularly well in poor-risk patients. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Powles: No, not really. In the competitive arm it suggests that ipi/nivo is more suited to the intermediate and poor-risk patients and as a biomarker it may be important. Dr Figlin: Are there specific sites of metastasis (ie: brain, bone, other) that would make you less likely to use this regimen? Dr Powles: There do not appear to be subgroups in which it is ineffective. Dr Figlin: Are there specific co morbidities that would make you less likely to use this regimen? Dr Powles: I think we have to look into questions with underlying immune diseases. Those patients were excluded from the trial. Overall, patients on immune suppressive drugs or patients with active infections—those patients were excluded from the trial. But the majority of patients appeared to have a relatively good rating. Dr Figlin: Has the Keynote-426 trial changed your paradigm or approach? Dr Powles: We’ve seen a change in European guidelines, the European Association of Urology guidelines, and the NCCN (National Comprehensive Cancer Network) American guidelines. But that changed very rapidly off the back of this trial. This is the best survival signal we’ve ever seen in a randomized perspective. And it’s the first time we’ve seen a survival signal for a VEGF-targeted therapy combined with an immune therapy. So there are many firsts with this trial, which is why it is so important. Axitinib and pembrolizumab should be considered as a standard of care for unselected patients and it appears to maximize survival outcomes, which is really exciting. KCJ

 

Copyright © 2019

 

The Official Journal of the Kidney Cancer Association

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Deconstructing IO Therapy: Three Combinations, 
Three Viewpoints from Key Opinion Leaders ﷯ Rana Mckay, MD Moores Cancer Center, 
University of California, San Diego 
San Diego, California ﷯ Matthew Milowsky, MD 1 UNC Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina ﷯ Thomas Powles, FRCP Barts Cancer Institute London, England In this wide-ranging discussion, three opinion leaders address essential issues related to the use of immunotherapy combinations in the frontline space for RCC. As they compare the rationale for the use of these respective combinations, each participant offers a unique perspective, including key messages from the pivotal trials supporting IO treatment. The particpants include Rana Mckay MD, Matthew Milowsky, MD, and Thomas Powles, FRCP. The discussion is chaired by Robert Figlin, MD, Editor-in-Chief of Kidney Cancer Journal. n Combining Ipilimumab and Nivolumab Dr Figlin: In the ever changing landscape for the management of RCCa, please summarize the key takeaways from the recent data on ipi/nivo in the frontline setting? Dr Mckay: Data regarding nivo and ipi in patients with metastatic RCC have dramatically changed the way we approach newly diagnosed patients. For the first time, we are challenging the treatment paradigm of frontline TKI alone. The combination of nivo/ipi in a large randomized phase 3 trial, CheckMate-214 was actually shown to be superior to sunitinib and is one of the first studies to demonstrate superiority of non-VEGF agents in the frontline space. The big takeaway from this study—the primary endpoint of the study was actually to look at objective response, PFS, and overall survival in patients with intermediate and poor-risk disease. The study included about 51% of patients with intermediate risk disease and 17% of patients with poor-risk disease. When we look at the breakdown of patients with intermediate and poor-risk disease we see a statistically significant improvement in objective response rate with the combination of nivo/ipi. What’s striking is that the complete response rate was 9% in this patient population. Additionally, there was an improvement in PFS and an updated efficacy analysis showing it was statistically significant. Overall survival was also superior to sunitinib with a HR of 0.66 in the updated analysis which was statistically significant and practice changing. While the primary endpoint of the study did not evaluate favorable risk disease, it’s important to look at the favorable risk patients and try to understand what does the combination of nivo/ipi do with this patient population. While the objective response rate was higher with sunitinib compared to nivo/ipi, when we look at that complete response rate, we see that it is actually higher in the nivo/ipi patients. The CR rate in favorable risk patients in CheckMate-214 was around 6% in sunitinib-treated patients but 11% in the nivo/ipi patients, suggesting that there probably is a subset of patients with favorable risk disease who may derive benefit from the combination of nivo/ipi. Additionally, when looking at the intent to treat population, nivo/ipi showed improved ORR, PFS, and OS compared to sunitinib. The other thing to point out is when we look at the favorable risk patients who were enrolled in the CheckMate-214 we see an overperformance of the controlled arm. The PFS of sunitinib-treated patients approaches 25.1 months, higher than frontline trials that used sunitinib as a comparator arm. Nivo/ipi has certainly changed the frontline space. It clearly has demonstrated improved responses and survival for patients with advanced diseease, and for the first time we see patients entering durable remissions with IO combination therapy. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Mckay: At the present time, most of our biomarkers to guide clinical decision marking are based on clinical parameters. We have clinical risk stratification systems that help inform prognosis and they have been utilized in guiding treatment decisions, however these are not predictive. Unfortunately, we do not have any soluble, blood-based biomarkers that have proven to be validated across mRCC. The combination nivo/ipi has demonstrated efficacy for those with intermediate and poor risk disease and those who are able to receive IO therapy and do not have significant autoimmune disease that would preclude therapy. While overall, patients with favorable risk disease did better with sunitinib in this study, the CR rate was higher with nivo/ipi frontline. I’m not automatically saying no to ipi/nivo in patients with favorable risk disease. I’m looking at their presentation, at co-morbidities, performance status. The number of patients in the current era who would receive a single agent TKI in the frontline space is limited. There is cabozantinib as an option in this regard for those with bone metastases based on the CABOSUN trial. But we need to question the use of VEGF TKIs in the frontline space. The current data support IO-IO combinations or IO-VEGF TKI in the frontline. Dr Figlin: Do you use existing risk stratification systems (ie, IMDC, MSKCC) in making this assessment? Dr Mckay: The MSKCC risk factors were validated in the cytokine era. Now the IMDC system has been validated in the TKI era. While it has not yet been validated with use of IO therapy, it is nonetheless a critical risk stratification to think about when you see a patient with metastatic disease. Where I see the risk stratification system coming in very handy is in thinking about the role of cytoreductive nephrectomy in the context of patients with metastatic disease. We’re being a bit more prudent in deciding which patients derive benefit from upfront CN as opposed to delayed CN. IMDC risk parameters really come into play when thinking about starting a patient on systemic therapy first or CN and system therapy later. Overall, risk stratification systems are really helpful when thinking about the integration of surgery with systemic therapy for patients with advanced disease. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Mckay: When reviewing the IO-IO and VEGF-IO trials, each of these studies used a totally different assay to determine PD-L1 expression status. The percentages of PD-L1 expression based on the assays that were used varied across the studies. For example, in CheckMate-214, PD-L1 expression was seen in 24% of the total population and in KEYNOTE-426 and JAVELIN 101 there were different assays used, and the number was around 60% and 53%. We have a lot more to learn about the utility of PD-L1. And the other thing to consider is that the bulk of these tests were done on archival nephrectomy specimens as opposed to fresh biopsies at baseline. We know that PD-L1 status is very dynamic and there are temporal and spatial changes in this biomarker. PD-L1 is certainly prognostic in RCC. Those who have PD-L1 expression do worse than those without. However its role as a predictive biomarker in RCC is still evolving. Dr Figlin: Are there specific sites of metastasis (ie, brain, bone, other) that would make you less likely to use this regimen? Dr Mckay: We know that patients with bone metastases have historically done worse than those without bone metastases. We have great data from the CABOSUN study demonstrating efficacy of cabozantinib over sunitinib in the frontline phase. And while that’s a phase 2 study, I think there is rationale for using cabozantinib in the frontline for those who have bone metastases that may negatively impact their quality of life. Additional studies are investigating IO combinations with cabozantinib in the frontline. These studies will further inform management of advanced RCC. Also, one more thing about patients with brain metastases: we can learn from the melanoma literature about the safety of IO therapies in patients who have brain metastases. Dr Figlin: Are there specific co-morbidities that would make you less likely to use this regimen? Dr Mckay: Patients who have underlying or concurrent autoimmune disease—that would be a red flag. Currently, a study is being conducted by the NCI looking at immunotherapy in patients who have autoimmune disease. We recently conducted a retrospective analysis of patients with RCC who have autoimmune disease who received IO therapy and we are reporting on their outcomes. Management needs to be coordinated with rheumatologists and other consultants to make sure the risk/benefit ratio is sound. n Combining Avelumab and Axitinib Dr Figlin: In the ever changing landscape for the management of advanced RCCa, please summarize the key takeaways from the recent data on avelumab/axitinib in the frontline setting? Dr Milowsky: In terms of the landscape in the frontline setting for metastatic RCC, the benefit for avelumab/axitinib was established in the JAVELIN Renal 101 Study. 886 patients were randomized to avelumab, a PD-L1 inhibitor plus axitinib, a VEGF receptor TKI compared to sunitinib, another VEGF receptor TKI. For the primary endpoint of the study, there was a significant improvement in progression free survival (PFS) in the PD-L1-selected (defined as greater than or equal to 1% of the immune cells staining positive) individuals. The PFS was 14 months for the combination vs 7 months for sunitinib with an HR of 0.61 for progression or death. The benefit was also seen in the overall population for ave- lumab/axitinib over sunitinib. At this first pre-planned interim analysis with a median followup of 11.6 months, there was not a significant improvement in overall survival for the combination with an HR of 0.788 (P=0.14). Also important in this study is the response rate which was substantially higher for patients who were treated with the combination in both the PD-L1 selected and overall population (55% in the PD-L1 selected avelumab/axitinib group vs 25% for sunitinib). The tolerability was similar to sunitinib including grade 3 adverse events. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Milowsky: These are first-line patients, so they are previously untreated and have advanced RCC. The data from this study showed that over 80% did have a prior nephrectomy. We do not know how that ultimately plays into things. In terms of the population, if you look at the the combination, the benefit was seen in all subgroups. The majority of subjects, over 60%, were intermediate risk. If you have patients who need a robust and relatively rapid response—the median time to response was 2.5 months—it represents a great option. With the Checkmate 214 data for ipi/nivo (ipilimumab/nivolumab) demonstrating a benefit in intermediate and poor risk patients, our standard for favorable risk patients remained sunitinib. Now, with the combination data for avelumab/axitinib we have benefit in favorable risk patients as well. This approach now represents a standard of care in the IMDC favorable risk group as well as in patients with intermediate and poor risk disease. Dr Figlin: Do you use existing risk stratification systems (ie: IMDC, MSKCC), others) in making this assessment? Dr Milowsky: We use the IMDC groups in the clinic for prognostication. With newer therapies, this is likely to change with the potential for additional variables to include within these models. In the context of IO therapies, the future is likely to include new predictive and prognostic models. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Milowsky: Initially the JAVELIN study was designed differently based on a phase 1b study that showed there was a higher percentage of patients with high PD-L1 expression benefiting from avelumab and axitinib. The primary endpoint of the JAVELIN Renal 101 Study was subsequently changed to look specifically in patients with high PD-L1 status. There was a benefit in the high PD-L1 group but there was also a benefit in the overall population. Based on JAVELIN 101, PD-L1 status should not be used to guide treatment decisions unless we see additional information such as more mature survival data that could change this interpretation. Dr. Choueiri et al presented an important biomarker analysis from JAVELIN 101 at the ASCO Annual Meeting 2019 looking at PD-L1 expression, tumor mutational burden, T-cell subsets, and immune gene expression signatures. This type of work will help guide us in the future. Dr Figlin: Are there specific sites of metastasis (ie, brain, bone, other) that would make you less likely to use this regimen? Dr Milowsky: Within the context of this study, there was no clear information to suggest that site of disease should guide therapy with the combination. Over 50% of patients had at least two sites of disease. The study excluded patients with active CNS metastases. We would use the combination in patients with treated CNS metastases. The study excluded active autoimmune disease and we need to be cautious in patients with autoimmune disease. The study does not speak to a particular patient population that should or shouldn’t be treated. The real question is: are there patients that benefit more from IO-IO therapy vs IO-TKI? Dr Figlin: Are there specific co-morbidities that would make you less likely to use this regimen? Dr Milowsky: In general, it is a regimen that is very usable. The study, however, excluded active autoimmune disease and again we need to be cautious about the use of IO in patients with active autoimmune disease or in the case of VEGFR TKI therapy, in patients with difficult to control hypertension as one example. Overall, the toxicity is manageable. n Combining Pembrolizumab 
and Axitinib Dr Figlin: In the ever changing landscape for the management of advanced RCCA, please summarize the key takeaways from the recent Keynote-426 data on pem- bro/axitinib in the front line setting? Dr Powles: The key messages are that this randomized, frontline, phase 3 trial, which enrolled all comers, was the first trial to show a response rate of progression-free survival and overall survival advantage. And it was associated with a 47% reduction in the risk of death and a PFS of just over 15 months. Putting that together is an exceptionally good result. The drugs seem to work in good, intermediate and poor-risk patients, in all risk groups. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Powles: The regimen is suited for all risk groups or PD-L1 status. It is an all comers-type approach. Dr Figlin: Do you use existing risk stratification systems (ie: IMDC, MSKCC, others) in making this assessment? Dr Powles: We do not need to do that. It’s useful from a patient perspective to know which group they are in. Essentially, what we see from this trial is that the drugs (pembrolizumab and axitinib) seem to work whether across the board and seem to work particularly well in poor-risk patients. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Powles: No, not really. In the competitive arm it suggests that ipi/nivo is more suited to the intermediate and poor-risk patients and as a biomarker it may be important. Dr Figlin: Are there specific sites of metastasis (ie: brain, bone, other) that would make you less likely to use this regimen? Dr Powles: There do not appear to be subgroups in which it is ineffective. Dr Figlin: Are there specific co morbidities that would make you less likely to use this regimen? Dr Powles: I think we have to look into questions with underlying immune diseases. Those patients were excluded from the trial. Overall, patients on immune suppressive drugs or patients with active infections—those patients were excluded from the trial. But the majority of patients appeared to have a relatively good rating. Dr Figlin: Has the Keynote-426 trial changed your paradigm or approach? Dr Powles: We’ve seen a change in European guidelines, the European Association of Urology guidelines, and the NCCN (National Comprehensive Cancer Network) American guidelines. But that changed very rapidly off the back of this trial. This is the best survival signal we’ve ever seen in a randomized perspective. And it’s the first time we’ve seen a survival signal for a VEGF-targeted therapy combined with an immune therapy. So there are many firsts with this trial, which is why it is so important. Axitinib and pembrolizumab should be considered as a standard of care for unselected patients and it appears to maximize survival outcomes, which is really exciting. KCJ
Deconstructing IO Therapy: Three Combinations, 
Three Viewpoints from Key Opinion Leaders ﷯ Rana Mckay, MD Moores Cancer Center, 
University of California, San Diego 
San Diego, California ﷯ Matthew Milowsky, MD 1 UNC Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina ﷯ Thomas Powles, FRCP Barts Cancer Institute London, England In this wide-ranging discussion, three opinion leaders address essential issues related to the use of immunotherapy combinations in the frontline space for RCC. As they compare the rationale for the use of these respective combinations, each participant offers a unique perspective, including key messages from the pivotal trials supporting IO treatment. The particpants include Rana Mckay MD, Matthew Milowsky, MD, and Thomas Powles, FRCP. The discussion is chaired by Robert Figlin, MD, Editor-in-Chief of Kidney Cancer Journal. n Combining Ipilimumab and Nivolumab Dr Figlin: In the ever changing landscape for the management of RCCa, please summarize the key takeaways from the recent data on ipi/nivo in the frontline setting? Dr Mckay: Data regarding nivo and ipi in patients with metastatic RCC have dramatically changed the way we approach newly diagnosed patients. For the first time, we are challenging the treatment paradigm of frontline TKI alone. The combination of nivo/ipi in a large randomized phase 3 trial, CheckMate-214 was actually shown to be superior to sunitinib and is one of the first studies to demonstrate superiority of non-VEGF agents in the frontline space. The big takeaway from this study—the primary endpoint of the study was actually to look at objective response, PFS, and overall survival in patients with intermediate and poor-risk disease. The study included about 51% of patients with intermediate risk disease and 17% of patients with poor-risk disease. When we look at the breakdown of patients with intermediate and poor-risk disease we see a statistically significant improvement in objective response rate with the combination of nivo/ipi. What’s striking is that the complete response rate was 9% in this patient population. Additionally, there was an improvement in PFS and an updated efficacy analysis showing it was statistically significant. Overall survival was also superior to sunitinib with a HR of 0.66 in the updated analysis which was statistically significant and practice changing. While the primary endpoint of the study did not evaluate favorable risk disease, it’s important to look at the favorable risk patients and try to understand what does the combination of nivo/ipi do with this patient population. While the objective response rate was higher with sunitinib compared to nivo/ipi, when we look at that complete response rate, we see that it is actually higher in the nivo/ipi patients. The CR rate in favorable risk patients in CheckMate-214 was around 6% in sunitinib-treated patients but 11% in the nivo/ipi patients, suggesting that there probably is a subset of patients with favorable risk disease who may derive benefit from the combination of nivo/ipi. Additionally, when looking at the intent to treat population, nivo/ipi showed improved ORR, PFS, and OS compared to sunitinib. The other thing to point out is when we look at the favorable risk patients who were enrolled in the CheckMate-214 we see an overperformance of the controlled arm. The PFS of sunitinib-treated patients approaches 25.1 months, higher than frontline trials that used sunitinib as a comparator arm. Nivo/ipi has certainly changed the frontline space. It clearly has demonstrated improved responses and survival for patients with advanced diseease, and for the first time we see patients entering durable remissions with IO combination therapy. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Mckay: At the present time, most of our biomarkers to guide clinical decision marking are based on clinical parameters. We have clinical risk stratification systems that help inform prognosis and they have been utilized in guiding treatment decisions, however these are not predictive. Unfortunately, we do not have any soluble, blood-based biomarkers that have proven to be validated across mRCC. The combination nivo/ipi has demonstrated efficacy for those with intermediate and poor risk disease and those who are able to receive IO therapy and do not have significant autoimmune disease that would preclude therapy. While overall, patients with favorable risk disease did better with sunitinib in this study, the CR rate was higher with nivo/ipi frontline. I’m not automatically saying no to ipi/nivo in patients with favorable risk disease. I’m looking at their presentation, at co-morbidities, performance status. The number of patients in the current era who would receive a single agent TKI in the frontline space is limited. There is cabozantinib as an option in this regard for those with bone metastases based on the CABOSUN trial. But we need to question the use of VEGF TKIs in the frontline space. The current data support IO-IO combinations or IO-VEGF TKI in the frontline. Dr Figlin: Do you use existing risk stratification systems (ie, IMDC, MSKCC) in making this assessment? Dr Mckay: The MSKCC risk factors were validated in the cytokine era. Now the IMDC system has been validated in the TKI era. While it has not yet been validated with use of IO therapy, it is nonetheless a critical risk stratification to think about when you see a patient with metastatic disease. Where I see the risk stratification system coming in very handy is in thinking about the role of cytoreductive nephrectomy in the context of patients with metastatic disease. We’re being a bit more prudent in deciding which patients derive benefit from upfront CN as opposed to delayed CN. IMDC risk parameters really come into play when thinking about starting a patient on systemic therapy first or CN and system therapy later. Overall, risk stratification systems are really helpful when thinking about the integration of surgery with systemic therapy for patients with advanced disease. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Mckay: When reviewing the IO-IO and VEGF-IO trials, each of these studies used a totally different assay to determine PD-L1 expression status. The percentages of PD-L1 expression based on the assays that were used varied across the studies. For example, in CheckMate-214, PD-L1 expression was seen in 24% of the total population and in KEYNOTE-426 and JAVELIN 101 there were different assays used, and the number was around 60% and 53%. We have a lot more to learn about the utility of PD-L1. And the other thing to consider is that the bulk of these tests were done on archival nephrectomy specimens as opposed to fresh biopsies at baseline. We know that PD-L1 status is very dynamic and there are temporal and spatial changes in this biomarker. PD-L1 is certainly prognostic in RCC. Those who have PD-L1 expression do worse than those without. However its role as a predictive biomarker in RCC is still evolving. Dr Figlin: Are there specific sites of metastasis (ie, brain, bone, other) that would make you less likely to use this regimen? Dr Mckay: We know that patients with bone metastases have historically done worse than those without bone metastases. We have great data from the CABOSUN study demonstrating efficacy of cabozantinib over sunitinib in the frontline phase. And while that’s a phase 2 study, I think there is rationale for using cabozantinib in the frontline for those who have bone metastases that may negatively impact their quality of life. Additional studies are investigating IO combinations with cabozantinib in the frontline. These studies will further inform management of advanced RCC. Also, one more thing about patients with brain metastases: we can learn from the melanoma literature about the safety of IO therapies in patients who have brain metastases. Dr Figlin: Are there specific co-morbidities that would make you less likely to use this regimen? Dr Mckay: Patients who have underlying or concurrent autoimmune disease—that would be a red flag. Currently, a study is being conducted by the NCI looking at immunotherapy in patients who have autoimmune disease. We recently conducted a retrospective analysis of patients with RCC who have autoimmune disease who received IO therapy and we are reporting on their outcomes. Management needs to be coordinated with rheumatologists and other consultants to make sure the risk/benefit ratio is sound. n Combining Avelumab and Axitinib Dr Figlin: In the ever changing landscape for the management of advanced RCCa, please summarize the key takeaways from the recent data on avelumab/axitinib in the frontline setting? Dr Milowsky: In terms of the landscape in the frontline setting for metastatic RCC, the benefit for avelumab/axitinib was established in the JAVELIN Renal 101 Study. 886 patients were randomized to avelumab, a PD-L1 inhibitor plus axitinib, a VEGF receptor TKI compared to sunitinib, another VEGF receptor TKI. For the primary endpoint of the study, there was a significant improvement in progression free survival (PFS) in the PD-L1-selected (defined as greater than or equal to 1% of the immune cells staining positive) individuals. The PFS was 14 months for the combination vs 7 months for sunitinib with an HR of 0.61 for progression or death. The benefit was also seen in the overall population for ave- lumab/axitinib over sunitinib. At this first pre-planned interim analysis with a median followup of 11.6 months, there was not a significant improvement in overall survival for the combination with an HR of 0.788 (P=0.14). Also important in this study is the response rate which was substantially higher for patients who were treated with the combination in both the PD-L1 selected and overall population (55% in the PD-L1 selected avelumab/axitinib group vs 25% for sunitinib). The tolerability was similar to sunitinib including grade 3 adverse events. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Milowsky: These are first-line patients, so they are previously untreated and have advanced RCC. The data from this study showed that over 80% did have a prior nephrectomy. We do not know how that ultimately plays into things. In terms of the population, if you look at the the combination, the benefit was seen in all subgroups. The majority of subjects, over 60%, were intermediate risk. If you have patients who need a robust and relatively rapid response—the median time to response was 2.5 months—it represents a great option. With the Checkmate 214 data for ipi/nivo (ipilimumab/nivolumab) demonstrating a benefit in intermediate and poor risk patients, our standard for favorable risk patients remained sunitinib. Now, with the combination data for avelumab/axitinib we have benefit in favorable risk patients as well. This approach now represents a standard of care in the IMDC favorable risk group as well as in patients with intermediate and poor risk disease. Dr Figlin: Do you use existing risk stratification systems (ie: IMDC, MSKCC), others) in making this assessment? Dr Milowsky: We use the IMDC groups in the clinic for prognostication. With newer therapies, this is likely to change with the potential for additional variables to include within these models. In the context of IO therapies, the future is likely to include new predictive and prognostic models. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Milowsky: Initially the JAVELIN study was designed differently based on a phase 1b study that showed there was a higher percentage of patients with high PD-L1 expression benefiting from avelumab and axitinib. The primary endpoint of the JAVELIN Renal 101 Study was subsequently changed to look specifically in patients with high PD-L1 status. There was a benefit in the high PD-L1 group but there was also a benefit in the overall population. Based on JAVELIN 101, PD-L1 status should not be used to guide treatment decisions unless we see additional information such as more mature survival data that could change this interpretation. Dr. Choueiri et al presented an important biomarker analysis from JAVELIN 101 at the ASCO Annual Meeting 2019 looking at PD-L1 expression, tumor mutational burden, T-cell subsets, and immune gene expression signatures. This type of work will help guide us in the future. Dr Figlin: Are there specific sites of metastasis (ie, brain, bone, other) that would make you less likely to use this regimen? Dr Milowsky: Within the context of this study, there was no clear information to suggest that site of disease should guide therapy with the combination. Over 50% of patients had at least two sites of disease. The study excluded patients with active CNS metastases. We would use the combination in patients with treated CNS metastases. The study excluded active autoimmune disease and we need to be cautious in patients with autoimmune disease. The study does not speak to a particular patient population that should or shouldn’t be treated. The real question is: are there patients that benefit more from IO-IO therapy vs IO-TKI? Dr Figlin: Are there specific co-morbidities that would make you less likely to use this regimen? Dr Milowsky: In general, it is a regimen that is very usable. The study, however, excluded active autoimmune disease and again we need to be cautious about the use of IO in patients with active autoimmune disease or in the case of VEGFR TKI therapy, in patients with difficult to control hypertension as one example. Overall, the toxicity is manageable. n Combining Pembrolizumab 
and Axitinib Dr Figlin: In the ever changing landscape for the management of advanced RCCA, please summarize the key takeaways from the recent Keynote-426 data on pem- bro/axitinib in the front line setting? Dr Powles: The key messages are that this randomized, frontline, phase 3 trial, which enrolled all comers, was the first trial to show a response rate of progression-free survival and overall survival advantage. And it was associated with a 47% reduction in the risk of death and a PFS of just over 15 months. Putting that together is an exceptionally good result. The drugs seem to work in good, intermediate and poor-risk patients, in all risk groups. Dr Figlin: What populations of patients are best suited for this approach in your practice? Dr Powles: The regimen is suited for all risk groups or PD-L1 status. It is an all comers-type approach. Dr Figlin: Do you use existing risk stratification systems (ie: IMDC, MSKCC, others) in making this assessment? Dr Powles: We do not need to do that. It’s useful from a patient perspective to know which group they are in. Essentially, what we see from this trial is that the drugs (pembrolizumab and axitinib) seem to work whether across the board and seem to work particularly well in poor-risk patients. Dr Figlin: Is PD-L1 scoring useful in deciding how best to use this regimen? Dr Powles: No, not really. In the competitive arm it suggests that ipi/nivo is more suited to the intermediate and poor-risk patients and as a biomarker it may be important. Dr Figlin: Are there specific sites of metastasis (ie: brain, bone, other) that would make you less likely to use this regimen? Dr Powles: There do not appear to be subgroups in which it is ineffective. Dr Figlin: Are there specific co morbidities that would make you less likely to use this regimen? Dr Powles: I think we have to look into questions with underlying immune diseases. Those patients were excluded from the trial. Overall, patients on immune suppressive drugs or patients with active infections—those patients were excluded from the trial. But the majority of patients appeared to have a relatively good rating. Dr Figlin: Has the Keynote-426 trial changed your paradigm or approach? Dr Powles: We’ve seen a change in European guidelines, the European Association of Urology guidelines, and the NCCN (National Comprehensive Cancer Network) American guidelines. But that changed very rapidly off the back of this trial. This is the best survival signal we’ve ever seen in a randomized perspective. And it’s the first time we’ve seen a survival signal for a VEGF-targeted therapy combined with an immune therapy. So there are many firsts with this trial, which is why it is so important. Axitinib and pembrolizumab should be considered as a standard of care for unselected patients and it appears to maximize survival outcomes, which is really exciting. KCJ