Renal Cell Carcinoma

It’s a “champagne problem” many of us have encountered over the past few years in the clinic.

A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.

In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.

Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.

The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.

Though we don’t want to overtreat our patients, the question remains: Will patients do just as well off treatment, with the potential to resume as needed?

One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.

This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.

Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.

We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.

In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.

Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.

Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.

How should we interpret these data for the patient who is in the exam room with us?

The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.

I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.

We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.

Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?

These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.

In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?

Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.

A version of this article first appeared on Medscape.com.

It’s a “champagne problem” many of us have encountered over the past few years in the clinic.

A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.

In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.

Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.

The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.

Though we don’t want to overtreat our patients, the question remains: Will patients do just as well off treatment, with the potential to resume as needed?

One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.

This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.

Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.

We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.

In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.

Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.

Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.

How should we interpret these data for the patient who is in the exam room with us?

The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.

I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.

We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.

Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?

These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.

In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?

Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.

A version of this article first appeared on Medscape.com.

It’s a “champagne problem” many of us have encountered over the past few years in the clinic.

A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.

In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.

Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.

The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.

Though we don’t want to overtreat our patients, the question remains: Will patients do just as well off treatment, with the potential to resume as needed?

One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.

This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.

Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.

We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.

In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.

Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.

Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.

How should we interpret these data for the patient who is in the exam room with us?

The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.

I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.

We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.

Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?

These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.

In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?

Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.

A version of this article first appeared on Medscape.com.

A systematic review of immune checkpoint inhibitor (ICI) combinations for advanced renal cancer finds that treatment with ICIs has a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib. The combination treatment should be made readily available worldwide to patients with advanced renal cell carcinoma (RCC), the authors said.

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials have examined ICIs in combination with VEGF-directed therapies.

In a review published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and 1 each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared to sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate poor-risk patients compared to sunitinib, but the combination led to more frequent discontinuation due to toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation due to toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation due to toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggest that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual ICI combination therapy were similar to those seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors noted that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, International Metastatic RCC Database Consortium (IMDC) risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

A systematic review of immune checkpoint inhibitor (ICI) combinations for advanced renal cancer finds that treatment with ICIs has a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib. The combination treatment should be made readily available worldwide to patients with advanced renal cell carcinoma (RCC), the authors said.

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials have examined ICIs in combination with VEGF-directed therapies.

In a review published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and 1 each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared to sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate poor-risk patients compared to sunitinib, but the combination led to more frequent discontinuation due to toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation due to toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation due to toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggest that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual ICI combination therapy were similar to those seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors noted that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, International Metastatic RCC Database Consortium (IMDC) risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

A systematic review of immune checkpoint inhibitor (ICI) combinations for advanced renal cancer finds that treatment with ICIs has a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib. The combination treatment should be made readily available worldwide to patients with advanced renal cell carcinoma (RCC), the authors said.

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials have examined ICIs in combination with VEGF-directed therapies.

In a review published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and 1 each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared to sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate poor-risk patients compared to sunitinib, but the combination led to more frequent discontinuation due to toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation due to toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation due to toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggest that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual ICI combination therapy were similar to those seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors noted that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, International Metastatic RCC Database Consortium (IMDC) risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

Adjuvant immunotherapy with atezolizumab for patients with renal cell carcinoma who have had a nephrectomy with or without a metastasectomy, failed to improve clinical outcomes in a group of patients who are at high risk of recurrence, finds a new international study conducted across 28 countries.

The study, called IMmotion010 and published in The Lancet, was a randomized, double-blind, multicenter, phase 3 trial of 778 adult patients with renal cell carcinoma (RCC) with a clear cell or sarcomatoid component. The study failed to meet its primary endpoint which was defined as a statistically significant improvement in disease-free survival as compared with placebo.

“Our results add to an emerging body of literature around the role of adjuvant immunotherapy for renal cell carcinoma. With the longest duration of follow-up to date to our knowledge. We observed no evidence of clinical benefit in disease-free survival or overall survival with adjuvant atezolizumab in patients with high-risk localized or fully resected renal cell carcinoma,” wrote the authors who were led by Sumanta Kumar Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif. “Given a growing list of trials that have not shown benefit with adjuvant immunotherapy, the results call for greater attention to patient selection with this approach.”

Dr. Pal and associates conducted the study to gain more insight into the potential role of adjuvant immunotherapy in patients with renal cell carcinoma who have undergone the standard treatment of nephrectomy with or without metastasectomy. Previous studies of anti-VEGF treatments have produced mixed results, including the large phase 3 ASSURE trial, the authors wrote. “Given these mixed results, use of adjuvant targeted therapy in renal cell carcinoma remains infrequent,” Dr. Pal and associates wrote.

However, pembrolizumab (Keytruda, Merck) a programmed death receptor-1–blocking antibody, is an immunotherapy which, in combination with axitinib, is approved as a first-line treatment for patients with advanced RCC.

Atezolizumab (Tecentriq, Genentech) is approved for treatment in urothelial carcinoma, non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), and melanoma. There are currently a number of ongoing studies that are exploring the use of atezolizumab as a treatment for renal cell carcinoma.

The study details

This new study was conducted between 2017 and 2019. It included 778 patients from 215 clinics in 28 countries who were assigned to the treatment arm (1,200 mg of IV atezolizumab (n = 390, 50%) once every 3 weeks for 16 cycles or 1 year, which ever came first – or, they were assigned to the placebo group (n = 388, 50%). The two groups were similar: average age 60-61, 72%-74% male, 78%-83% white, and 36%-37% based in North America. Most patients, (92%-93%) had clear cell cancer, and 64%-65% were at pathological disease stage T2 or T3a.

The 3-year disease-free survival rate at 36 months was 65.0% (95% confidence interval, 59.9-70.2) in the treatment group and 62.7% (95% CI, 57.5-67.9) in the placebo group. At follow-up at 44.7 months, there was no statistically significant difference in median disease-free survival between atezolizumab (57.2 months; 95% CI, 44.6 to not evaluable) and placebo (49.5 months; 95% CI, 47.4 to not evaluable).

While there were no deaths attributable to treatment, 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo experienced a serious adverse event.

“The results of IMmotion010 do not support the use of adjuvant atezolizumab for fully resected renal cell carcinoma. Future work will include exploration of clinical-based or biomarker-based subsets that might derive benefit from this approach,” the authors wrote.

The researchers acknowledge their findings contrast with those of the KEYNOTE-564 trial of adjuvant immunotherapy with pembrolizumab after nephrectomy in renal cell carcinoma. KEYNOTE-564 reported a disease-free survival benefit of over 24 months and in an analysis done at 30 months. But in KEYNOTE-564, the study comprised only 6% of patients with M1 no evidence of disease. And, it included only patients with synchronous metastases or metastases resected within 1 year of nephrectomy. In the new study, 14% of patients had M1 no evidence of disease, and it included both synchronous and metachronous disease with recurrence within 1year of surgery.

Adjuvant immunotherapy with pembrolizumab is considered optional for patients with intermediate-risk or high-risk operable clear cell renal cell carcinoma per European Society for Medical Oncology and European Association of Urology guidelines because of the lack of confirmed overall survival benefit and toxicity-related considerations associated with immunotherapy.

“These factors must be considered in the adjuvant setting as, following nephrectomy, patients are cancer free and might be cured by surgery alone. As such, additional trials are needed to clarify the role of adjuvant immunotherapy in this disease space,” the authors wrote.

What’s next? “Biomarker work is underway to determine whether tumor genomic characteristics or circulating biomarkers can identify patient populations who derive benefit from adjuvant atezolizumab,” Dr. Pal and associates wrote. “There is precedent for tissue-based adjuvant therapy selection in other diseases, such as HER2-based and endocrine receptor–based approaches in breast cancer and EGFR mutation–directed therapy in lung cancer.”

The study was funded by F Hoffmann-La Roche and Genentech. The academic authors of the study collaborated with F Hoffmann-La Roche and Genentech on all facets of the trial.

Adjuvant immunotherapy with atezolizumab for patients with renal cell carcinoma who have had a nephrectomy with or without a metastasectomy, failed to improve clinical outcomes in a group of patients who are at high risk of recurrence, finds a new international study conducted across 28 countries.

The study, called IMmotion010 and published in The Lancet, was a randomized, double-blind, multicenter, phase 3 trial of 778 adult patients with renal cell carcinoma (RCC) with a clear cell or sarcomatoid component. The study failed to meet its primary endpoint which was defined as a statistically significant improvement in disease-free survival as compared with placebo.

“Our results add to an emerging body of literature around the role of adjuvant immunotherapy for renal cell carcinoma. With the longest duration of follow-up to date to our knowledge. We observed no evidence of clinical benefit in disease-free survival or overall survival with adjuvant atezolizumab in patients with high-risk localized or fully resected renal cell carcinoma,” wrote the authors who were led by Sumanta Kumar Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif. “Given a growing list of trials that have not shown benefit with adjuvant immunotherapy, the results call for greater attention to patient selection with this approach.”

Dr. Pal and associates conducted the study to gain more insight into the potential role of adjuvant immunotherapy in patients with renal cell carcinoma who have undergone the standard treatment of nephrectomy with or without metastasectomy. Previous studies of anti-VEGF treatments have produced mixed results, including the large phase 3 ASSURE trial, the authors wrote. “Given these mixed results, use of adjuvant targeted therapy in renal cell carcinoma remains infrequent,” Dr. Pal and associates wrote.

However, pembrolizumab (Keytruda, Merck) a programmed death receptor-1–blocking antibody, is an immunotherapy which, in combination with axitinib, is approved as a first-line treatment for patients with advanced RCC.

Atezolizumab (Tecentriq, Genentech) is approved for treatment in urothelial carcinoma, non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), and melanoma. There are currently a number of ongoing studies that are exploring the use of atezolizumab as a treatment for renal cell carcinoma.

The study details

This new study was conducted between 2017 and 2019. It included 778 patients from 215 clinics in 28 countries who were assigned to the treatment arm (1,200 mg of IV atezolizumab (n = 390, 50%) once every 3 weeks for 16 cycles or 1 year, which ever came first – or, they were assigned to the placebo group (n = 388, 50%). The two groups were similar: average age 60-61, 72%-74% male, 78%-83% white, and 36%-37% based in North America. Most patients, (92%-93%) had clear cell cancer, and 64%-65% were at pathological disease stage T2 or T3a.

The 3-year disease-free survival rate at 36 months was 65.0% (95% confidence interval, 59.9-70.2) in the treatment group and 62.7% (95% CI, 57.5-67.9) in the placebo group. At follow-up at 44.7 months, there was no statistically significant difference in median disease-free survival between atezolizumab (57.2 months; 95% CI, 44.6 to not evaluable) and placebo (49.5 months; 95% CI, 47.4 to not evaluable).

While there were no deaths attributable to treatment, 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo experienced a serious adverse event.

“The results of IMmotion010 do not support the use of adjuvant atezolizumab for fully resected renal cell carcinoma. Future work will include exploration of clinical-based or biomarker-based subsets that might derive benefit from this approach,” the authors wrote.

The researchers acknowledge their findings contrast with those of the KEYNOTE-564 trial of adjuvant immunotherapy with pembrolizumab after nephrectomy in renal cell carcinoma. KEYNOTE-564 reported a disease-free survival benefit of over 24 months and in an analysis done at 30 months. But in KEYNOTE-564, the study comprised only 6% of patients with M1 no evidence of disease. And, it included only patients with synchronous metastases or metastases resected within 1 year of nephrectomy. In the new study, 14% of patients had M1 no evidence of disease, and it included both synchronous and metachronous disease with recurrence within 1year of surgery.

Adjuvant immunotherapy with pembrolizumab is considered optional for patients with intermediate-risk or high-risk operable clear cell renal cell carcinoma per European Society for Medical Oncology and European Association of Urology guidelines because of the lack of confirmed overall survival benefit and toxicity-related considerations associated with immunotherapy.

“These factors must be considered in the adjuvant setting as, following nephrectomy, patients are cancer free and might be cured by surgery alone. As such, additional trials are needed to clarify the role of adjuvant immunotherapy in this disease space,” the authors wrote.

What’s next? “Biomarker work is underway to determine whether tumor genomic characteristics or circulating biomarkers can identify patient populations who derive benefit from adjuvant atezolizumab,” Dr. Pal and associates wrote. “There is precedent for tissue-based adjuvant therapy selection in other diseases, such as HER2-based and endocrine receptor–based approaches in breast cancer and EGFR mutation–directed therapy in lung cancer.”

The study was funded by F Hoffmann-La Roche and Genentech. The academic authors of the study collaborated with F Hoffmann-La Roche and Genentech on all facets of the trial.

Adjuvant immunotherapy with atezolizumab for patients with renal cell carcinoma who have had a nephrectomy with or without a metastasectomy, failed to improve clinical outcomes in a group of patients who are at high risk of recurrence, finds a new international study conducted across 28 countries.

The study, called IMmotion010 and published in The Lancet, was a randomized, double-blind, multicenter, phase 3 trial of 778 adult patients with renal cell carcinoma (RCC) with a clear cell or sarcomatoid component. The study failed to meet its primary endpoint which was defined as a statistically significant improvement in disease-free survival as compared with placebo.

“Our results add to an emerging body of literature around the role of adjuvant immunotherapy for renal cell carcinoma. With the longest duration of follow-up to date to our knowledge. We observed no evidence of clinical benefit in disease-free survival or overall survival with adjuvant atezolizumab in patients with high-risk localized or fully resected renal cell carcinoma,” wrote the authors who were led by Sumanta Kumar Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif. “Given a growing list of trials that have not shown benefit with adjuvant immunotherapy, the results call for greater attention to patient selection with this approach.”

Dr. Pal and associates conducted the study to gain more insight into the potential role of adjuvant immunotherapy in patients with renal cell carcinoma who have undergone the standard treatment of nephrectomy with or without metastasectomy. Previous studies of anti-VEGF treatments have produced mixed results, including the large phase 3 ASSURE trial, the authors wrote. “Given these mixed results, use of adjuvant targeted therapy in renal cell carcinoma remains infrequent,” Dr. Pal and associates wrote.

However, pembrolizumab (Keytruda, Merck) a programmed death receptor-1–blocking antibody, is an immunotherapy which, in combination with axitinib, is approved as a first-line treatment for patients with advanced RCC.

Atezolizumab (Tecentriq, Genentech) is approved for treatment in urothelial carcinoma, non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), and melanoma. There are currently a number of ongoing studies that are exploring the use of atezolizumab as a treatment for renal cell carcinoma.

The study details

This new study was conducted between 2017 and 2019. It included 778 patients from 215 clinics in 28 countries who were assigned to the treatment arm (1,200 mg of IV atezolizumab (n = 390, 50%) once every 3 weeks for 16 cycles or 1 year, which ever came first – or, they were assigned to the placebo group (n = 388, 50%). The two groups were similar: average age 60-61, 72%-74% male, 78%-83% white, and 36%-37% based in North America. Most patients, (92%-93%) had clear cell cancer, and 64%-65% were at pathological disease stage T2 or T3a.

The 3-year disease-free survival rate at 36 months was 65.0% (95% confidence interval, 59.9-70.2) in the treatment group and 62.7% (95% CI, 57.5-67.9) in the placebo group. At follow-up at 44.7 months, there was no statistically significant difference in median disease-free survival between atezolizumab (57.2 months; 95% CI, 44.6 to not evaluable) and placebo (49.5 months; 95% CI, 47.4 to not evaluable).

While there were no deaths attributable to treatment, 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo experienced a serious adverse event.

“The results of IMmotion010 do not support the use of adjuvant atezolizumab for fully resected renal cell carcinoma. Future work will include exploration of clinical-based or biomarker-based subsets that might derive benefit from this approach,” the authors wrote.

The researchers acknowledge their findings contrast with those of the KEYNOTE-564 trial of adjuvant immunotherapy with pembrolizumab after nephrectomy in renal cell carcinoma. KEYNOTE-564 reported a disease-free survival benefit of over 24 months and in an analysis done at 30 months. But in KEYNOTE-564, the study comprised only 6% of patients with M1 no evidence of disease. And, it included only patients with synchronous metastases or metastases resected within 1 year of nephrectomy. In the new study, 14% of patients had M1 no evidence of disease, and it included both synchronous and metachronous disease with recurrence within 1year of surgery.

Adjuvant immunotherapy with pembrolizumab is considered optional for patients with intermediate-risk or high-risk operable clear cell renal cell carcinoma per European Society for Medical Oncology and European Association of Urology guidelines because of the lack of confirmed overall survival benefit and toxicity-related considerations associated with immunotherapy.

“These factors must be considered in the adjuvant setting as, following nephrectomy, patients are cancer free and might be cured by surgery alone. As such, additional trials are needed to clarify the role of adjuvant immunotherapy in this disease space,” the authors wrote.

What’s next? “Biomarker work is underway to determine whether tumor genomic characteristics or circulating biomarkers can identify patient populations who derive benefit from adjuvant atezolizumab,” Dr. Pal and associates wrote. “There is precedent for tissue-based adjuvant therapy selection in other diseases, such as HER2-based and endocrine receptor–based approaches in breast cancer and EGFR mutation–directed therapy in lung cancer.”

The study was funded by F Hoffmann-La Roche and Genentech. The academic authors of the study collaborated with F Hoffmann-La Roche and Genentech on all facets of the trial.

Early-onset cancer – often defined as cancers diagnosed in adults younger than age 50 years – is an emerging global epidemic, according to a recent review.

While the rising incidence of early-onset colorectal cancer (CRC) is a well-documented problem, the trend appears to extend far beyond CRC. The authors traced patterns of early-onset cancer diagnoses across 14 different cancer types, including breast, prostate, and thyroid, over the past 3 decades and found increases in many countries.

Among the 14 cancers explored, eight relate to the digestive system, which highlights the potential role diet and the oral and gut microbiome may play in cancer risk, the authors noted.

And many of the factors that appear to influence cancer risk – such as diet, exercise, sleep, and vaccination against HPV and other cancer-causing microorganisms – are modifiable.

“[Our] immediate goals should be to raise awareness of the early-onset cancer epidemic and reduce exposure to [these] risk factors,” authors Tomotaka Ugai, MD, PhD, and Shuji Ogino, MD, PhD, with Harvard School of Public Health, Boston, noted in a joint email.

The paper was published in Nature Reviews Clinical Oncology.

While the rise in cancer screenings has contributed to earlier detection of cancers, a genuine increase in the incidence of some early-onset cancers also appears to be happening.

In the current review, Dr. Ugai, Dr. Ogino, and colleagues reviewed the literature and mapped trends in the incidence of 14 cancer types among 20- to 49-year-old adults in 44 countries between 2002 and 2012.

The authors found that, since the 1990s, the incidence of early-onset cancers in the breast, colorectum, endometrium, esophagus, extrahepatic bile duct, gallbladder, head/neck, kidney, liver, bone marrow, pancreas, prostate, stomach, and thyroid, has increased around the world. Looking at the United States, for instance, the average annual percent changes for kidney cancer was 3.6% in women and 4.1% in men and for multiple myeloma was 2% in women and 3% in men for 2002 to 2012.

This overall trend could reflect increased exposures to risk factors in early life and young adulthood, although “specific effects of individual exposures remain largely unknown,” the authors acknowledged.

Since the mid-20th century, substantial changes have occurred in diet, sleep, smoking, obesity, type 2 diabetes, and environmental exposures – all of which may influence the gut microbiome or interact with our genes to increase the incidence of early-onset cancers, the authors explained. For instance, obesity, smoking, and alcohol are all established risk factors for pancreatic cancer and have been linked with early-onset disease risk as well.

“Cancer is a multifactorial disease, and we are aware of the importance of genetics as a risk factor and screening for early detection, but this paper importantly brings to light the importance of correctable lifestyle habits that may slow the rise of early onset cancers,” oncologist Marleen Meyers, MD, director of the survivorship program at NYU Langone Perlmutter Cancer Center, who wasn’t involved in the review, said in an interview.

Although modifiable factors such as diet and exercise may ease the burden of these cancers, such changes are often difficult to implement, Dr. Meyers added. In addition, understanding the impact that certain factors, such as alcohol, obesity, physical activity, and delayed reproduction play in cancer risk requires more research to tease out, but “there is enough reason at this point to address these risk factors for both personal and public health benefits,” Dr. Meyers said.

Support for this research was provided in part by the U.S. National Institutes of Health, Cancer Research UK, Prevent Cancer Foundation, Japan Society for the Promotion of Science, and the Mishima Kaiun Memorial Foundation. Dr. Ugai, Dr. Ogino, and Dr. Meyers have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Early-onset cancer – often defined as cancers diagnosed in adults younger than age 50 years – is an emerging global epidemic, according to a recent review.

While the rising incidence of early-onset colorectal cancer (CRC) is a well-documented problem, the trend appears to extend far beyond CRC. The authors traced patterns of early-onset cancer diagnoses across 14 different cancer types, including breast, prostate, and thyroid, over the past 3 decades and found increases in many countries.

Among the 14 cancers explored, eight relate to the digestive system, which highlights the potential role diet and the oral and gut microbiome may play in cancer risk, the authors noted.

And many of the factors that appear to influence cancer risk – such as diet, exercise, sleep, and vaccination against HPV and other cancer-causing microorganisms – are modifiable.

“[Our] immediate goals should be to raise awareness of the early-onset cancer epidemic and reduce exposure to [these] risk factors,” authors Tomotaka Ugai, MD, PhD, and Shuji Ogino, MD, PhD, with Harvard School of Public Health, Boston, noted in a joint email.

The paper was published in Nature Reviews Clinical Oncology.

While the rise in cancer screenings has contributed to earlier detection of cancers, a genuine increase in the incidence of some early-onset cancers also appears to be happening.

In the current review, Dr. Ugai, Dr. Ogino, and colleagues reviewed the literature and mapped trends in the incidence of 14 cancer types among 20- to 49-year-old adults in 44 countries between 2002 and 2012.

The authors found that, since the 1990s, the incidence of early-onset cancers in the breast, colorectum, endometrium, esophagus, extrahepatic bile duct, gallbladder, head/neck, kidney, liver, bone marrow, pancreas, prostate, stomach, and thyroid, has increased around the world. Looking at the United States, for instance, the average annual percent changes for kidney cancer was 3.6% in women and 4.1% in men and for multiple myeloma was 2% in women and 3% in men for 2002 to 2012.

This overall trend could reflect increased exposures to risk factors in early life and young adulthood, although “specific effects of individual exposures remain largely unknown,” the authors acknowledged.

Since the mid-20th century, substantial changes have occurred in diet, sleep, smoking, obesity, type 2 diabetes, and environmental exposures – all of which may influence the gut microbiome or interact with our genes to increase the incidence of early-onset cancers, the authors explained. For instance, obesity, smoking, and alcohol are all established risk factors for pancreatic cancer and have been linked with early-onset disease risk as well.

“Cancer is a multifactorial disease, and we are aware of the importance of genetics as a risk factor and screening for early detection, but this paper importantly brings to light the importance of correctable lifestyle habits that may slow the rise of early onset cancers,” oncologist Marleen Meyers, MD, director of the survivorship program at NYU Langone Perlmutter Cancer Center, who wasn’t involved in the review, said in an interview.

Although modifiable factors such as diet and exercise may ease the burden of these cancers, such changes are often difficult to implement, Dr. Meyers added. In addition, understanding the impact that certain factors, such as alcohol, obesity, physical activity, and delayed reproduction play in cancer risk requires more research to tease out, but “there is enough reason at this point to address these risk factors for both personal and public health benefits,” Dr. Meyers said.

Support for this research was provided in part by the U.S. National Institutes of Health, Cancer Research UK, Prevent Cancer Foundation, Japan Society for the Promotion of Science, and the Mishima Kaiun Memorial Foundation. Dr. Ugai, Dr. Ogino, and Dr. Meyers have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Early-onset cancer – often defined as cancers diagnosed in adults younger than age 50 years – is an emerging global epidemic, according to a recent review.

While the rising incidence of early-onset colorectal cancer (CRC) is a well-documented problem, the trend appears to extend far beyond CRC. The authors traced patterns of early-onset cancer diagnoses across 14 different cancer types, including breast, prostate, and thyroid, over the past 3 decades and found increases in many countries.

Among the 14 cancers explored, eight relate to the digestive system, which highlights the potential role diet and the oral and gut microbiome may play in cancer risk, the authors noted.

And many of the factors that appear to influence cancer risk – such as diet, exercise, sleep, and vaccination against HPV and other cancer-causing microorganisms – are modifiable.

“[Our] immediate goals should be to raise awareness of the early-onset cancer epidemic and reduce exposure to [these] risk factors,” authors Tomotaka Ugai, MD, PhD, and Shuji Ogino, MD, PhD, with Harvard School of Public Health, Boston, noted in a joint email.

The paper was published in Nature Reviews Clinical Oncology.

While the rise in cancer screenings has contributed to earlier detection of cancers, a genuine increase in the incidence of some early-onset cancers also appears to be happening.

In the current review, Dr. Ugai, Dr. Ogino, and colleagues reviewed the literature and mapped trends in the incidence of 14 cancer types among 20- to 49-year-old adults in 44 countries between 2002 and 2012.

The authors found that, since the 1990s, the incidence of early-onset cancers in the breast, colorectum, endometrium, esophagus, extrahepatic bile duct, gallbladder, head/neck, kidney, liver, bone marrow, pancreas, prostate, stomach, and thyroid, has increased around the world. Looking at the United States, for instance, the average annual percent changes for kidney cancer was 3.6% in women and 4.1% in men and for multiple myeloma was 2% in women and 3% in men for 2002 to 2012.

This overall trend could reflect increased exposures to risk factors in early life and young adulthood, although “specific effects of individual exposures remain largely unknown,” the authors acknowledged.

Since the mid-20th century, substantial changes have occurred in diet, sleep, smoking, obesity, type 2 diabetes, and environmental exposures – all of which may influence the gut microbiome or interact with our genes to increase the incidence of early-onset cancers, the authors explained. For instance, obesity, smoking, and alcohol are all established risk factors for pancreatic cancer and have been linked with early-onset disease risk as well.

“Cancer is a multifactorial disease, and we are aware of the importance of genetics as a risk factor and screening for early detection, but this paper importantly brings to light the importance of correctable lifestyle habits that may slow the rise of early onset cancers,” oncologist Marleen Meyers, MD, director of the survivorship program at NYU Langone Perlmutter Cancer Center, who wasn’t involved in the review, said in an interview.

Although modifiable factors such as diet and exercise may ease the burden of these cancers, such changes are often difficult to implement, Dr. Meyers added. In addition, understanding the impact that certain factors, such as alcohol, obesity, physical activity, and delayed reproduction play in cancer risk requires more research to tease out, but “there is enough reason at this point to address these risk factors for both personal and public health benefits,” Dr. Meyers said.

Support for this research was provided in part by the U.S. National Institutes of Health, Cancer Research UK, Prevent Cancer Foundation, Japan Society for the Promotion of Science, and the Mishima Kaiun Memorial Foundation. Dr. Ugai, Dr. Ogino, and Dr. Meyers have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

A version of this article first appeared on Medscape.com.

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

A version of this article first appeared on Medscape.com.

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

A version of this article first appeared on Medscape.com.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.