Susan London

TOPLINE:

Middle-aged adults who consume more ultra-processed foods have an elevated risk for rheumatoid arthritis (RA) that is mediated in part through circulating biomarkers.

METHODOLOGY: 

• Investigators conducted a retrospective cohort study of 207,012 middle-aged adults without RA from the UK Biobank who completed 24-hour dietary recalls.
• Foods and beverages were classified as (1) unprocessed or minimally processed foods, (2) processed culinary ingredients, (3) processed foods, or (4) ultra-processed foods (eg, soft drinks, sweet or savory packaged snacks, reconstituted meat products, pre-prepared frozen dishes).
• The main outcome was the incident RA based on hospital diagnoses.

TAKEAWAY:

• Overall, 0.9% of participants received an RA diagnosis during a median follow-up of about 12 years.
• Relative to peers in the lowest quintile of ultra-processed food consumption, participants in the highest quintile had a 17% greater adjusted risk for RA.
• The risk rose across quintile (P < .05) and increased by 6% with each standard deviation increase in ultra-processed food intake.
• Mediation analyses suggested that inflammatory, lipid, and liver enzyme biomarkers explained 3.1%-14.8% of the association between ultra-processed food intake and RA risk.
• Findings were similar regardless of participants’ age, sex, body mass index, smoking status, household income, and healthy diet score.

IN PRACTICE: 

“Lower [ultra-processed food] consumption is recommended to reduce RA incidence,” the authors wrote, noting that up to half of the food consumed in the United Kingdom now falls into the ultra-processed category. “Dietary guidelines should prominently feature the detrimental effects of [ultra-processed foods], and recommendations to curtail their consumption should be integrated into public health initiatives, to mitigate the risk of RA,” they added.

SOURCE:

The study was led by Haodong Zhao, Soochow University, Suzhou, China, and was published online in The American Journal of Clinical Nutrition. 

LIMITATIONS:

Limitations included possible recall and social desirability biases, potential residual confounding, and uncertain causality of the observed associations.

DISCLOSURES:

The study was funded by grants from the National Natural Science Foundation of China and other institutions. The authors reported no conflicts of interest.

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

TOPLINE:

Middle-aged adults who consume more ultra-processed foods have an elevated risk for rheumatoid arthritis (RA) that is mediated in part through circulating biomarkers.

METHODOLOGY: 

• Investigators conducted a retrospective cohort study of 207,012 middle-aged adults without RA from the UK Biobank who completed 24-hour dietary recalls.
• Foods and beverages were classified as (1) unprocessed or minimally processed foods, (2) processed culinary ingredients, (3) processed foods, or (4) ultra-processed foods (eg, soft drinks, sweet or savory packaged snacks, reconstituted meat products, pre-prepared frozen dishes).
• The main outcome was the incident RA based on hospital diagnoses.

TAKEAWAY:

• Overall, 0.9% of participants received an RA diagnosis during a median follow-up of about 12 years.
• Relative to peers in the lowest quintile of ultra-processed food consumption, participants in the highest quintile had a 17% greater adjusted risk for RA.
• The risk rose across quintile (P < .05) and increased by 6% with each standard deviation increase in ultra-processed food intake.
• Mediation analyses suggested that inflammatory, lipid, and liver enzyme biomarkers explained 3.1%-14.8% of the association between ultra-processed food intake and RA risk.
• Findings were similar regardless of participants’ age, sex, body mass index, smoking status, household income, and healthy diet score.

IN PRACTICE: 

“Lower [ultra-processed food] consumption is recommended to reduce RA incidence,” the authors wrote, noting that up to half of the food consumed in the United Kingdom now falls into the ultra-processed category. “Dietary guidelines should prominently feature the detrimental effects of [ultra-processed foods], and recommendations to curtail their consumption should be integrated into public health initiatives, to mitigate the risk of RA,” they added.

SOURCE:

The study was led by Haodong Zhao, Soochow University, Suzhou, China, and was published online in The American Journal of Clinical Nutrition. 

LIMITATIONS:

Limitations included possible recall and social desirability biases, potential residual confounding, and uncertain causality of the observed associations.

DISCLOSURES:

The study was funded by grants from the National Natural Science Foundation of China and other institutions. The authors reported no conflicts of interest.

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

TOPLINE:

Middle-aged adults who consume more ultra-processed foods have an elevated risk for rheumatoid arthritis (RA) that is mediated in part through circulating biomarkers.

METHODOLOGY: 

• Investigators conducted a retrospective cohort study of 207,012 middle-aged adults without RA from the UK Biobank who completed 24-hour dietary recalls.
• Foods and beverages were classified as (1) unprocessed or minimally processed foods, (2) processed culinary ingredients, (3) processed foods, or (4) ultra-processed foods (eg, soft drinks, sweet or savory packaged snacks, reconstituted meat products, pre-prepared frozen dishes).
• The main outcome was the incident RA based on hospital diagnoses.

TAKEAWAY:

• Overall, 0.9% of participants received an RA diagnosis during a median follow-up of about 12 years.
• Relative to peers in the lowest quintile of ultra-processed food consumption, participants in the highest quintile had a 17% greater adjusted risk for RA.
• The risk rose across quintile (P < .05) and increased by 6% with each standard deviation increase in ultra-processed food intake.
• Mediation analyses suggested that inflammatory, lipid, and liver enzyme biomarkers explained 3.1%-14.8% of the association between ultra-processed food intake and RA risk.
• Findings were similar regardless of participants’ age, sex, body mass index, smoking status, household income, and healthy diet score.

IN PRACTICE: 

“Lower [ultra-processed food] consumption is recommended to reduce RA incidence,” the authors wrote, noting that up to half of the food consumed in the United Kingdom now falls into the ultra-processed category. “Dietary guidelines should prominently feature the detrimental effects of [ultra-processed foods], and recommendations to curtail their consumption should be integrated into public health initiatives, to mitigate the risk of RA,” they added.

SOURCE:

The study was led by Haodong Zhao, Soochow University, Suzhou, China, and was published online in The American Journal of Clinical Nutrition. 

LIMITATIONS:

Limitations included possible recall and social desirability biases, potential residual confounding, and uncertain causality of the observed associations.

DISCLOSURES:

The study was funded by grants from the National Natural Science Foundation of China and other institutions. The authors reported no conflicts of interest.

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

TOPLINE:

The antimetabolite and immunosuppressant methotrexate, taken orally and in addition to usual analgesia, alleviates pain in patients with knee osteoarthritis.

METHODOLOGY:

• Investigators conducted a phase 3 randomized controlled trial among 155 patients in the United Kingdom with painful radiographic knee osteoarthritis and an inadequate response to their current medication (PROMOTE trial).
• Patients were assigned to oral methotrexate once weekly (6-week escalation from 10 to 25 mg) or placebo for 12 months, added to usual analgesia.
• The main outcome was average knee pain at 6 months on a numerical rating scale from 0 to 10.

TAKEAWAY:

• At 6 months, mean scores for knee pain had decreased by 1.3 points in the methotrexate group and 0.6 points in the placebo group (difference by intention to treat, 0.79 points; P = .030).
• The former also saw greater benefit in terms of Western Ontario and McMaster Universities Osteoarthritis Index scores for stiffness (difference, 0.60 points; P = .045) and physical function (difference, 5.01 points; P = .008).
• Differences between groups were no longer significant at 12 months.
• Benefit of methotrexate appeared to be dose related.
• The groups were similar with respect to nausea and diarrhea; four serious adverse events (two per group) were deemed unrelated to study treatment.

IN PRACTICE:

“Further work is required to understand adequate methotrexate dosing, whether benefits are greater in those with elevated systemic inflammation levels, and to consider cost-effectiveness before introducing this therapy for a potentially large population,” the authors wrote.

SOURCE:

The study was led by Sarah R. Kingsbury, PhD, University of Leeds and National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds, England, and was published online in Annals of Internal Medicine.

LIMITATIONS:

Limitations included a decrease in methotrexate dose between 6 and 12 months, nonallowance of switching to subcutaneous drug for intolerance, and a lack of assessment of the effectiveness of blinding.

DISCLOSURES:

The study was funded by Versus Arthritis, a charity that supports people with arthritis. Some authors reported affiliations with Versus Arthritis and/or companies that develop drugs for arthritis.

A version of this article appeared on Medscape.com.

TOPLINE:

The antimetabolite and immunosuppressant methotrexate, taken orally and in addition to usual analgesia, alleviates pain in patients with knee osteoarthritis.

METHODOLOGY:

• Investigators conducted a phase 3 randomized controlled trial among 155 patients in the United Kingdom with painful radiographic knee osteoarthritis and an inadequate response to their current medication (PROMOTE trial).
• Patients were assigned to oral methotrexate once weekly (6-week escalation from 10 to 25 mg) or placebo for 12 months, added to usual analgesia.
• The main outcome was average knee pain at 6 months on a numerical rating scale from 0 to 10.

TAKEAWAY:

• At 6 months, mean scores for knee pain had decreased by 1.3 points in the methotrexate group and 0.6 points in the placebo group (difference by intention to treat, 0.79 points; P = .030).
• The former also saw greater benefit in terms of Western Ontario and McMaster Universities Osteoarthritis Index scores for stiffness (difference, 0.60 points; P = .045) and physical function (difference, 5.01 points; P = .008).
• Differences between groups were no longer significant at 12 months.
• Benefit of methotrexate appeared to be dose related.
• The groups were similar with respect to nausea and diarrhea; four serious adverse events (two per group) were deemed unrelated to study treatment.

IN PRACTICE:

“Further work is required to understand adequate methotrexate dosing, whether benefits are greater in those with elevated systemic inflammation levels, and to consider cost-effectiveness before introducing this therapy for a potentially large population,” the authors wrote.

SOURCE:

The study was led by Sarah R. Kingsbury, PhD, University of Leeds and National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds, England, and was published online in Annals of Internal Medicine.

LIMITATIONS:

Limitations included a decrease in methotrexate dose between 6 and 12 months, nonallowance of switching to subcutaneous drug for intolerance, and a lack of assessment of the effectiveness of blinding.

DISCLOSURES:

The study was funded by Versus Arthritis, a charity that supports people with arthritis. Some authors reported affiliations with Versus Arthritis and/or companies that develop drugs for arthritis.

A version of this article appeared on Medscape.com.

TOPLINE:

The antimetabolite and immunosuppressant methotrexate, taken orally and in addition to usual analgesia, alleviates pain in patients with knee osteoarthritis.

METHODOLOGY:

• Investigators conducted a phase 3 randomized controlled trial among 155 patients in the United Kingdom with painful radiographic knee osteoarthritis and an inadequate response to their current medication (PROMOTE trial).
• Patients were assigned to oral methotrexate once weekly (6-week escalation from 10 to 25 mg) or placebo for 12 months, added to usual analgesia.
• The main outcome was average knee pain at 6 months on a numerical rating scale from 0 to 10.

TAKEAWAY:

• At 6 months, mean scores for knee pain had decreased by 1.3 points in the methotrexate group and 0.6 points in the placebo group (difference by intention to treat, 0.79 points; P = .030).
• The former also saw greater benefit in terms of Western Ontario and McMaster Universities Osteoarthritis Index scores for stiffness (difference, 0.60 points; P = .045) and physical function (difference, 5.01 points; P = .008).
• Differences between groups were no longer significant at 12 months.
• Benefit of methotrexate appeared to be dose related.
• The groups were similar with respect to nausea and diarrhea; four serious adverse events (two per group) were deemed unrelated to study treatment.

IN PRACTICE:

“Further work is required to understand adequate methotrexate dosing, whether benefits are greater in those with elevated systemic inflammation levels, and to consider cost-effectiveness before introducing this therapy for a potentially large population,” the authors wrote.

SOURCE:

The study was led by Sarah R. Kingsbury, PhD, University of Leeds and National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds, England, and was published online in Annals of Internal Medicine.

LIMITATIONS:

Limitations included a decrease in methotrexate dose between 6 and 12 months, nonallowance of switching to subcutaneous drug for intolerance, and a lack of assessment of the effectiveness of blinding.

DISCLOSURES:

The study was funded by Versus Arthritis, a charity that supports people with arthritis. Some authors reported affiliations with Versus Arthritis and/or companies that develop drugs for arthritis.

A version of this article appeared on Medscape.com.

TOPLINE:

Anti-osteoporosis medications reduce fracture risk similarly, regardless of whether patients are younger or older than 70 years.

METHODOLOGY:

• Investigators conducted the study as part of a  to assess bone mineral density as a surrogate marker for fracture risk.
• Analyses used individual patient data from 23 randomized placebo-controlled trials of anti-osteoporosis medications (11 of bisphosphonates, four of selective estrogen receptor modulators, three of anabolic medications, two of hormone replacement therapy, and one each of odanacatib, denosumab, and romosozumab).
• Overall, 43% of the included 123,164 patients were aged 70 years or older.
• The main outcomes were fractures and bone mineral density.

TAKEAWAY:

• There was a similar benefit regardless of age when it came to the reduction in risks for hip fracture (odds ratio, 0.65 vs 0.72; P for interaction = .50) and any fracture (odds ratio, 0.72 vs 0.70; P for interaction = .20).
• Findings were comparable in analyses restricted to bisphosphonate trials, except that the reduction in hip fracture risk was greater among the younger group (hazard ratio, 0.44 vs 0.79; P for interaction = .02).
• The benefit of anti-osteoporosis medication in increasing hip and spine bone mineral density at 24 months was significantly greater among the older patients.

IN PRACTICE:

Taken together, the study results “strongly support treatment in those over age 70,” the authors wrote. “These are important findings with potential impact in patient treatment since it goes against a common misconception that medications are less effective in older people,” they added.

SOURCE:

The study was led by Marian Schini, MD, PhD, FHEA, University of Sheffield, England, and was published online in the Journal of Bone and Mineral Research.

LIMITATIONS:

Limitations included a preponderance of female patients (99%), possible residual confounding, a lack of analysis of adverse effects, and potentially different findings using alternate age cutoffs.

DISCLOSURES:

The study was funded by the American Society for Bone Mineral Research. Some authors disclosed affiliations with companies that manufacture anti-osteoporosis drugs.

A version of this article appeared on Medscape.com.

TOPLINE:

Anti-osteoporosis medications reduce fracture risk similarly, regardless of whether patients are younger or older than 70 years.

METHODOLOGY:

• Investigators conducted the study as part of a  to assess bone mineral density as a surrogate marker for fracture risk.
• Analyses used individual patient data from 23 randomized placebo-controlled trials of anti-osteoporosis medications (11 of bisphosphonates, four of selective estrogen receptor modulators, three of anabolic medications, two of hormone replacement therapy, and one each of odanacatib, denosumab, and romosozumab).
• Overall, 43% of the included 123,164 patients were aged 70 years or older.
• The main outcomes were fractures and bone mineral density.

TAKEAWAY:

• There was a similar benefit regardless of age when it came to the reduction in risks for hip fracture (odds ratio, 0.65 vs 0.72; P for interaction = .50) and any fracture (odds ratio, 0.72 vs 0.70; P for interaction = .20).
• Findings were comparable in analyses restricted to bisphosphonate trials, except that the reduction in hip fracture risk was greater among the younger group (hazard ratio, 0.44 vs 0.79; P for interaction = .02).
• The benefit of anti-osteoporosis medication in increasing hip and spine bone mineral density at 24 months was significantly greater among the older patients.

IN PRACTICE:

Taken together, the study results “strongly support treatment in those over age 70,” the authors wrote. “These are important findings with potential impact in patient treatment since it goes against a common misconception that medications are less effective in older people,” they added.

SOURCE:

The study was led by Marian Schini, MD, PhD, FHEA, University of Sheffield, England, and was published online in the Journal of Bone and Mineral Research.

LIMITATIONS:

Limitations included a preponderance of female patients (99%), possible residual confounding, a lack of analysis of adverse effects, and potentially different findings using alternate age cutoffs.

DISCLOSURES:

The study was funded by the American Society for Bone Mineral Research. Some authors disclosed affiliations with companies that manufacture anti-osteoporosis drugs.

A version of this article appeared on Medscape.com.

TOPLINE:

Anti-osteoporosis medications reduce fracture risk similarly, regardless of whether patients are younger or older than 70 years.

METHODOLOGY:

• Investigators conducted the study as part of a  to assess bone mineral density as a surrogate marker for fracture risk.
• Analyses used individual patient data from 23 randomized placebo-controlled trials of anti-osteoporosis medications (11 of bisphosphonates, four of selective estrogen receptor modulators, three of anabolic medications, two of hormone replacement therapy, and one each of odanacatib, denosumab, and romosozumab).
• Overall, 43% of the included 123,164 patients were aged 70 years or older.
• The main outcomes were fractures and bone mineral density.

TAKEAWAY:

• There was a similar benefit regardless of age when it came to the reduction in risks for hip fracture (odds ratio, 0.65 vs 0.72; P for interaction = .50) and any fracture (odds ratio, 0.72 vs 0.70; P for interaction = .20).
• Findings were comparable in analyses restricted to bisphosphonate trials, except that the reduction in hip fracture risk was greater among the younger group (hazard ratio, 0.44 vs 0.79; P for interaction = .02).
• The benefit of anti-osteoporosis medication in increasing hip and spine bone mineral density at 24 months was significantly greater among the older patients.

IN PRACTICE:

Taken together, the study results “strongly support treatment in those over age 70,” the authors wrote. “These are important findings with potential impact in patient treatment since it goes against a common misconception that medications are less effective in older people,” they added.

SOURCE:

The study was led by Marian Schini, MD, PhD, FHEA, University of Sheffield, England, and was published online in the Journal of Bone and Mineral Research.

LIMITATIONS:

Limitations included a preponderance of female patients (99%), possible residual confounding, a lack of analysis of adverse effects, and potentially different findings using alternate age cutoffs.

DISCLOSURES:

The study was funded by the American Society for Bone Mineral Research. Some authors disclosed affiliations with companies that manufacture anti-osteoporosis drugs.

A version of this article appeared on Medscape.com.

The antibody-drug conjugate enfortumab vedotin is superior to chemotherapy in patients with previously treated advanced urothelial carcinoma, primary results of the EV-301 trial show.

Findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 393).

“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, and therapeutic options are also limited,” noted first author Thomas Powles, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre, Queen Mary University of London. “Chemotherapy is being used as the global standard of care, but randomized trials supporting these treatment choices are actually lacking. In this setting, new therapeutic agents supported by randomized trials are needed.”

Patients enrolled in EV-301 (NCT03474107), an international open-label, phase 3 trial, had locally advanced or metastatic urothelial carcinoma, had received platinum-based chemotherapy, and had experienced progression during or after immune checkpoint inhibitor therapy (anti–PD1/PD-L1 therapy).

The trial met its primary endpoint, showing that, relative to chemotherapy, enfortumab vedotin reduced the risk of death by 30%, giving patients nearly 4 additional months of life. The toxicity profile was similar to that seen in earlier trials and was manageable.

“Enfortumab vedotin is the first drug, beyond chemotherapy and immunotherapy, to show a significant survival advantage in previously treated urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited,” Dr. Powles maintained.

The drug is also showing promising activity when used in the immunotherapy-treated but cisplatin-ineligible patients in the second cohort of the predecessor EV-201 trial, reported at the symposium as well (Abstract 394), he noted. “I hope that, as we move it earlier, we will show better efficacy.”

The Food and Drug Administration granted enfortumab vedotin accelerated approval as third-line therapy in 2019 on the basis of data from the EV-201 trial’s first cohort. With these new data from both trials, the manufacturers have submitted applications to convert the accelerated approval to regular approval, and to expand the current label to include cisplatin-ineligible patients.
 

Trial details

In EV-301, a total of 608 patients were randomized evenly to enfortumab vedotin (an antibody-drug conjugate that targets nectin-4, a cell-adhesion molecule highly expressed in urothelial carcinoma) or the physician’s choice among three standard chemotherapy options having similar efficacy (docetaxel, paclitaxel, or vinflunine).

“None of these chemotherapy drugs have spectacular response rates, and the overall survival is best described as modest,” Dr. Powles said.

He reported results of the trial’s planned interim analysis, which became the primary analysis because the primary endpoint was positive. Specifically, median overall survival was 12.9 months with enfortumab vedotin and 9.0 months with chemotherapy (hazard ratio, 0.70; P = .00142). Benefit was similar across most patient subgroups.

The enfortumab vedotin group also had a better median progression-free survival (5.6 vs. 3.7 months; HR, 0.62; P < .00001) and investigator-assessed overall response rate (40.6% vs. 17.9%; P < .001).

The rate of grade 3 or worse treatment-related adverse events was 51% with enfortumab vedotin and 50% with chemotherapy. The former was associated with a higher rate of grade 3 or worse maculopapular rash (7% vs. 0%), whereas the latter was associated with higher rates of grade 3 or worse decreased neutrophil count (13% vs. 6%), decreased white blood cell count (7% vs. 1%), and febrile neutropenia (6% vs. 1%).

Regarding events of special interest, enfortumab vedotin led to more grade 3 or worse skin reactions of any type (15% vs. 1%), peripheral neuropathy (5% vs. 2%), and hyperglycemia (4% vs. 0%). However, the majority of all treatment-related adverse events of special interest were mild to moderate in severity and consistent with those previously reported.

“There is a skill associated with the management of toxicity, and there is going to be a learning curve for people who haven’t used the drug before,” Dr. Powles acknowledged. “But my experience is, it’s a manageable drug, and delays and dose interruptions actually make it a relatively straightforward drug to give in the context of the profile that we’ve seen today.”
 

Level 1 evidence

“We now know that enfortumab vedotin is here to stay in the armamentarium for the treatment of urothelial cancer, adding its name to the ranks of others which have shown level 1 evidence, proof of a survival benefit in metastatic urothelial carcinoma,” commented invited discussant Arlene O. Siefker-Radtke, MD, a professor in the department of genitourinary medical oncology, University of Texas MD Anderson Cancer Center, Houston.

“I’ve been impressed not only by the activity of enfortumab vedotin in visceral and liver metastases, but also by the impact in patients with bone metastases as this appears very helpful in controlling bone pain in many patients,” she noted.

Preventing and managing toxicity requires appropriate patient selection, careful monitoring, and dose modifications, with knowledge of the agent’s adverse event profile and of factors conferring elevated risk for events, Dr. Siefker-Radtke said.

“The early evidence for enfortumab vedotin in the postimmunotherapy, platinum-ineligible group suggests that this can help treat patients with an unmet need due to their inability to receive platinum-based therapy,” she concluded. “And while it’s currently approved in the third-line setting, we are all eagerly awaiting the outcomes of the frontline studies of enfortumab vedotin combined with pembrolizumab, which showed such a promising objective response rate, as has been presented at earlier meetings.”

The trial was sponsored by Astellas Pharma and Seagen. Dr. Powles disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and numerous other pharmaceutical and biotechnology companies. Dr. Siefker-Radtke disclosed relationships with AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, and a variety of other pharmaceutical and biotechnology companies, as well as patents, royalties, and/or other intellectual property pertaining to methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.

The antibody-drug conjugate enfortumab vedotin is superior to chemotherapy in patients with previously treated advanced urothelial carcinoma, primary results of the EV-301 trial show.

Findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 393).

“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, and therapeutic options are also limited,” noted first author Thomas Powles, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre, Queen Mary University of London. “Chemotherapy is being used as the global standard of care, but randomized trials supporting these treatment choices are actually lacking. In this setting, new therapeutic agents supported by randomized trials are needed.”

Patients enrolled in EV-301 (NCT03474107), an international open-label, phase 3 trial, had locally advanced or metastatic urothelial carcinoma, had received platinum-based chemotherapy, and had experienced progression during or after immune checkpoint inhibitor therapy (anti–PD1/PD-L1 therapy).

The trial met its primary endpoint, showing that, relative to chemotherapy, enfortumab vedotin reduced the risk of death by 30%, giving patients nearly 4 additional months of life. The toxicity profile was similar to that seen in earlier trials and was manageable.

“Enfortumab vedotin is the first drug, beyond chemotherapy and immunotherapy, to show a significant survival advantage in previously treated urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited,” Dr. Powles maintained.

The drug is also showing promising activity when used in the immunotherapy-treated but cisplatin-ineligible patients in the second cohort of the predecessor EV-201 trial, reported at the symposium as well (Abstract 394), he noted. “I hope that, as we move it earlier, we will show better efficacy.”

The Food and Drug Administration granted enfortumab vedotin accelerated approval as third-line therapy in 2019 on the basis of data from the EV-201 trial’s first cohort. With these new data from both trials, the manufacturers have submitted applications to convert the accelerated approval to regular approval, and to expand the current label to include cisplatin-ineligible patients.
 

Trial details

In EV-301, a total of 608 patients were randomized evenly to enfortumab vedotin (an antibody-drug conjugate that targets nectin-4, a cell-adhesion molecule highly expressed in urothelial carcinoma) or the physician’s choice among three standard chemotherapy options having similar efficacy (docetaxel, paclitaxel, or vinflunine).

“None of these chemotherapy drugs have spectacular response rates, and the overall survival is best described as modest,” Dr. Powles said.

He reported results of the trial’s planned interim analysis, which became the primary analysis because the primary endpoint was positive. Specifically, median overall survival was 12.9 months with enfortumab vedotin and 9.0 months with chemotherapy (hazard ratio, 0.70; P = .00142). Benefit was similar across most patient subgroups.

The enfortumab vedotin group also had a better median progression-free survival (5.6 vs. 3.7 months; HR, 0.62; P < .00001) and investigator-assessed overall response rate (40.6% vs. 17.9%; P < .001).

The rate of grade 3 or worse treatment-related adverse events was 51% with enfortumab vedotin and 50% with chemotherapy. The former was associated with a higher rate of grade 3 or worse maculopapular rash (7% vs. 0%), whereas the latter was associated with higher rates of grade 3 or worse decreased neutrophil count (13% vs. 6%), decreased white blood cell count (7% vs. 1%), and febrile neutropenia (6% vs. 1%).

Regarding events of special interest, enfortumab vedotin led to more grade 3 or worse skin reactions of any type (15% vs. 1%), peripheral neuropathy (5% vs. 2%), and hyperglycemia (4% vs. 0%). However, the majority of all treatment-related adverse events of special interest were mild to moderate in severity and consistent with those previously reported.

“There is a skill associated with the management of toxicity, and there is going to be a learning curve for people who haven’t used the drug before,” Dr. Powles acknowledged. “But my experience is, it’s a manageable drug, and delays and dose interruptions actually make it a relatively straightforward drug to give in the context of the profile that we’ve seen today.”
 

Level 1 evidence

“We now know that enfortumab vedotin is here to stay in the armamentarium for the treatment of urothelial cancer, adding its name to the ranks of others which have shown level 1 evidence, proof of a survival benefit in metastatic urothelial carcinoma,” commented invited discussant Arlene O. Siefker-Radtke, MD, a professor in the department of genitourinary medical oncology, University of Texas MD Anderson Cancer Center, Houston.

“I’ve been impressed not only by the activity of enfortumab vedotin in visceral and liver metastases, but also by the impact in patients with bone metastases as this appears very helpful in controlling bone pain in many patients,” she noted.

Preventing and managing toxicity requires appropriate patient selection, careful monitoring, and dose modifications, with knowledge of the agent’s adverse event profile and of factors conferring elevated risk for events, Dr. Siefker-Radtke said.

“The early evidence for enfortumab vedotin in the postimmunotherapy, platinum-ineligible group suggests that this can help treat patients with an unmet need due to their inability to receive platinum-based therapy,” she concluded. “And while it’s currently approved in the third-line setting, we are all eagerly awaiting the outcomes of the frontline studies of enfortumab vedotin combined with pembrolizumab, which showed such a promising objective response rate, as has been presented at earlier meetings.”

The trial was sponsored by Astellas Pharma and Seagen. Dr. Powles disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and numerous other pharmaceutical and biotechnology companies. Dr. Siefker-Radtke disclosed relationships with AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, and a variety of other pharmaceutical and biotechnology companies, as well as patents, royalties, and/or other intellectual property pertaining to methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.

The antibody-drug conjugate enfortumab vedotin is superior to chemotherapy in patients with previously treated advanced urothelial carcinoma, primary results of the EV-301 trial show.

Findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 393).

“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, and therapeutic options are also limited,” noted first author Thomas Powles, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre, Queen Mary University of London. “Chemotherapy is being used as the global standard of care, but randomized trials supporting these treatment choices are actually lacking. In this setting, new therapeutic agents supported by randomized trials are needed.”

Patients enrolled in EV-301 (NCT03474107), an international open-label, phase 3 trial, had locally advanced or metastatic urothelial carcinoma, had received platinum-based chemotherapy, and had experienced progression during or after immune checkpoint inhibitor therapy (anti–PD1/PD-L1 therapy).

The trial met its primary endpoint, showing that, relative to chemotherapy, enfortumab vedotin reduced the risk of death by 30%, giving patients nearly 4 additional months of life. The toxicity profile was similar to that seen in earlier trials and was manageable.

“Enfortumab vedotin is the first drug, beyond chemotherapy and immunotherapy, to show a significant survival advantage in previously treated urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited,” Dr. Powles maintained.

The drug is also showing promising activity when used in the immunotherapy-treated but cisplatin-ineligible patients in the second cohort of the predecessor EV-201 trial, reported at the symposium as well (Abstract 394), he noted. “I hope that, as we move it earlier, we will show better efficacy.”

The Food and Drug Administration granted enfortumab vedotin accelerated approval as third-line therapy in 2019 on the basis of data from the EV-201 trial’s first cohort. With these new data from both trials, the manufacturers have submitted applications to convert the accelerated approval to regular approval, and to expand the current label to include cisplatin-ineligible patients.
 

Trial details

In EV-301, a total of 608 patients were randomized evenly to enfortumab vedotin (an antibody-drug conjugate that targets nectin-4, a cell-adhesion molecule highly expressed in urothelial carcinoma) or the physician’s choice among three standard chemotherapy options having similar efficacy (docetaxel, paclitaxel, or vinflunine).

“None of these chemotherapy drugs have spectacular response rates, and the overall survival is best described as modest,” Dr. Powles said.

He reported results of the trial’s planned interim analysis, which became the primary analysis because the primary endpoint was positive. Specifically, median overall survival was 12.9 months with enfortumab vedotin and 9.0 months with chemotherapy (hazard ratio, 0.70; P = .00142). Benefit was similar across most patient subgroups.

The enfortumab vedotin group also had a better median progression-free survival (5.6 vs. 3.7 months; HR, 0.62; P < .00001) and investigator-assessed overall response rate (40.6% vs. 17.9%; P < .001).

The rate of grade 3 or worse treatment-related adverse events was 51% with enfortumab vedotin and 50% with chemotherapy. The former was associated with a higher rate of grade 3 or worse maculopapular rash (7% vs. 0%), whereas the latter was associated with higher rates of grade 3 or worse decreased neutrophil count (13% vs. 6%), decreased white blood cell count (7% vs. 1%), and febrile neutropenia (6% vs. 1%).

Regarding events of special interest, enfortumab vedotin led to more grade 3 or worse skin reactions of any type (15% vs. 1%), peripheral neuropathy (5% vs. 2%), and hyperglycemia (4% vs. 0%). However, the majority of all treatment-related adverse events of special interest were mild to moderate in severity and consistent with those previously reported.

“There is a skill associated with the management of toxicity, and there is going to be a learning curve for people who haven’t used the drug before,” Dr. Powles acknowledged. “But my experience is, it’s a manageable drug, and delays and dose interruptions actually make it a relatively straightforward drug to give in the context of the profile that we’ve seen today.”
 

Level 1 evidence

“We now know that enfortumab vedotin is here to stay in the armamentarium for the treatment of urothelial cancer, adding its name to the ranks of others which have shown level 1 evidence, proof of a survival benefit in metastatic urothelial carcinoma,” commented invited discussant Arlene O. Siefker-Radtke, MD, a professor in the department of genitourinary medical oncology, University of Texas MD Anderson Cancer Center, Houston.

“I’ve been impressed not only by the activity of enfortumab vedotin in visceral and liver metastases, but also by the impact in patients with bone metastases as this appears very helpful in controlling bone pain in many patients,” she noted.

Preventing and managing toxicity requires appropriate patient selection, careful monitoring, and dose modifications, with knowledge of the agent’s adverse event profile and of factors conferring elevated risk for events, Dr. Siefker-Radtke said.

“The early evidence for enfortumab vedotin in the postimmunotherapy, platinum-ineligible group suggests that this can help treat patients with an unmet need due to their inability to receive platinum-based therapy,” she concluded. “And while it’s currently approved in the third-line setting, we are all eagerly awaiting the outcomes of the frontline studies of enfortumab vedotin combined with pembrolizumab, which showed such a promising objective response rate, as has been presented at earlier meetings.”

The trial was sponsored by Astellas Pharma and Seagen. Dr. Powles disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and numerous other pharmaceutical and biotechnology companies. Dr. Siefker-Radtke disclosed relationships with AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, and a variety of other pharmaceutical and biotechnology companies, as well as patents, royalties, and/or other intellectual property pertaining to methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

An androgen annihilation strategy using apalutamide significantly slows progression in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), according to final results from the phase 3 ACIS trial.

Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.

Courtesy of Memorial Sloan Kettering Cancer Center

“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.

Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.

With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.

Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.

Study outcomes

The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).

Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.

For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.

The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).

Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.

Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.

“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.

“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
 

Practice changing?

To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.

However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.

Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.

“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”

The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.

An androgen annihilation strategy using apalutamide significantly slows progression in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), according to final results from the phase 3 ACIS trial.

Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.

Courtesy of Memorial Sloan Kettering Cancer Center

“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.

Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.

With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.

Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.

Study outcomes

The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).

Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.

For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.

The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).

Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.

Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.

“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.

“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
 

Practice changing?

To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.

However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.

Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.

“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”

The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.

An androgen annihilation strategy using apalutamide significantly slows progression in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), according to final results from the phase 3 ACIS trial.

Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.

Courtesy of Memorial Sloan Kettering Cancer Center

“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.

Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.

With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.

Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.

Study outcomes

The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).

Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.

For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.

The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).

Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.

Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.

“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.

“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
 

Practice changing?

To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.

However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.

Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.

“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”

The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.

Machine learning models that use routine data present in the electronic health record have identified new risk factors for early-onset colorectal cancer (CRC), according to a new study.

Copyright University of Florida

The models found that hypertension, cough, and asthma, among other factors, were important in explaining the risk of early-onset CRC. For some factors, associations emerged up to 5 years before diagnosis.

These findings were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract PR-10).

“The incidence of early-onset CRC has been rising 2% annually since 1994,” noted Michael B. Quillen, one of the study authors and a medical student at the University of Florida, Gainesville.

Inherited genetic syndromes and predisposing conditions such as inflammatory bowel disease account for about half of cases in this age group, but factors explaining the other half remain a mystery.

To shed light in this area, the investigators undertook a study of patients aged 50 years or younger from the OneFlorida Clinical Research Consortium who had at least 2 years of EHR data. This included 783 cases with CRC and 8,981 incidence density-matched controls, with both groups having a mean age of 36 years.

The patients were split into colon cancer and rectal cancer cohorts, and then further divided into four prediction windows, Mr. Quillen explained. Each prediction window started with the patient’s first recorded encounter date in the EHR and ended at 0, 1, 3, or 5 years before the date of diagnosis.

The investigators used machine-learning models to determine what features (e.g., diagnoses, procedures, demographics) were important in determining risk.

Results were expressed in charts that ranked the features by their SHAP (Shapley Additive Explanations) values, which reflect the average impact of a feature on the magnitude of model output.
 

Results: Top models and features

The top-performing models had areas under the curve of 0.61-0.75 for colon cancer risk, and 0.62-0.73 for rectal cancer risk, reported T. Maxwell Parker, another study author and medical student at the University of Florida, Gainesville.

Copyright University of Florida

For colon cancer, the top features for the 0-year cohort included some highly specific symptoms that would be expected in patients close to the diagnostic date: abdominal pain, anemia, blood in the stool, and various procedures such as CT scans. “These do not need a machine learning algorithm to identify,” Mr. Parker acknowledged.

However, there were also two noteworthy features present – cough and primary hypertension – that became the top features in the 1-year and 3-year cohorts, then dropped out in the 5-year cohort.

Other features that became important moving farther out from the diagnostic date of colon cancer, across the windows studied, were chronic sinusitis, atopic dermatitis, asthma, and upper-respiratory infection.

For rectal cancer, some previously identified factors – immune conditions related to infectious disease (HIV and anogenital warts associated with human papillomavirus) as well as amoxicillin therapy – were prominent in the 0-year cohort and became increasingly important going farther out from the diagnostic date.

Obesity was the top feature in the 3-year cohort, and asthma became important in that cohort as well.

None of the rectal cancer models tested performed well at identifying important features in the 5-year cohort.

The investigators are exploring hypotheses to explain how the identified features, especially the new ones such as hypertension and cough, might contribute to CRC carcinogenesis in young adults, according to Mr. Parker. As inclusion of older patients could confound associations, research restricted to those aged 50 years and younger may be necessary.

“We would like to validate these model findings in a second independent data set, and if they are validated, we would consider a prospective cohort study with those features,” Mr. Parker said. The team also plans to refine the models with the aim of improving their areas under the curve.

Thereafter, the team hopes to explore ways for implementing the findings clinically to support screening, which will require consideration of the context, Mr. Parker concluded. “Should we use high-sensitivity or low-specificity models for screening, or do we use the balance of both? Also, different models may be suitable for different situations,” he said.

Mr. Parker and Mr. Quillen disclosed no conflicts of interest. The study did not receive specific funding.

Machine learning models that use routine data present in the electronic health record have identified new risk factors for early-onset colorectal cancer (CRC), according to a new study.

Copyright University of Florida

The models found that hypertension, cough, and asthma, among other factors, were important in explaining the risk of early-onset CRC. For some factors, associations emerged up to 5 years before diagnosis.

These findings were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract PR-10).

“The incidence of early-onset CRC has been rising 2% annually since 1994,” noted Michael B. Quillen, one of the study authors and a medical student at the University of Florida, Gainesville.

Inherited genetic syndromes and predisposing conditions such as inflammatory bowel disease account for about half of cases in this age group, but factors explaining the other half remain a mystery.

To shed light in this area, the investigators undertook a study of patients aged 50 years or younger from the OneFlorida Clinical Research Consortium who had at least 2 years of EHR data. This included 783 cases with CRC and 8,981 incidence density-matched controls, with both groups having a mean age of 36 years.

The patients were split into colon cancer and rectal cancer cohorts, and then further divided into four prediction windows, Mr. Quillen explained. Each prediction window started with the patient’s first recorded encounter date in the EHR and ended at 0, 1, 3, or 5 years before the date of diagnosis.

The investigators used machine-learning models to determine what features (e.g., diagnoses, procedures, demographics) were important in determining risk.

Results were expressed in charts that ranked the features by their SHAP (Shapley Additive Explanations) values, which reflect the average impact of a feature on the magnitude of model output.
 

Results: Top models and features

The top-performing models had areas under the curve of 0.61-0.75 for colon cancer risk, and 0.62-0.73 for rectal cancer risk, reported T. Maxwell Parker, another study author and medical student at the University of Florida, Gainesville.

Copyright University of Florida

For colon cancer, the top features for the 0-year cohort included some highly specific symptoms that would be expected in patients close to the diagnostic date: abdominal pain, anemia, blood in the stool, and various procedures such as CT scans. “These do not need a machine learning algorithm to identify,” Mr. Parker acknowledged.

However, there were also two noteworthy features present – cough and primary hypertension – that became the top features in the 1-year and 3-year cohorts, then dropped out in the 5-year cohort.

Other features that became important moving farther out from the diagnostic date of colon cancer, across the windows studied, were chronic sinusitis, atopic dermatitis, asthma, and upper-respiratory infection.

For rectal cancer, some previously identified factors – immune conditions related to infectious disease (HIV and anogenital warts associated with human papillomavirus) as well as amoxicillin therapy – were prominent in the 0-year cohort and became increasingly important going farther out from the diagnostic date.

Obesity was the top feature in the 3-year cohort, and asthma became important in that cohort as well.

None of the rectal cancer models tested performed well at identifying important features in the 5-year cohort.

The investigators are exploring hypotheses to explain how the identified features, especially the new ones such as hypertension and cough, might contribute to CRC carcinogenesis in young adults, according to Mr. Parker. As inclusion of older patients could confound associations, research restricted to those aged 50 years and younger may be necessary.

“We would like to validate these model findings in a second independent data set, and if they are validated, we would consider a prospective cohort study with those features,” Mr. Parker said. The team also plans to refine the models with the aim of improving their areas under the curve.

Thereafter, the team hopes to explore ways for implementing the findings clinically to support screening, which will require consideration of the context, Mr. Parker concluded. “Should we use high-sensitivity or low-specificity models for screening, or do we use the balance of both? Also, different models may be suitable for different situations,” he said.

Mr. Parker and Mr. Quillen disclosed no conflicts of interest. The study did not receive specific funding.

Machine learning models that use routine data present in the electronic health record have identified new risk factors for early-onset colorectal cancer (CRC), according to a new study.

Copyright University of Florida

The models found that hypertension, cough, and asthma, among other factors, were important in explaining the risk of early-onset CRC. For some factors, associations emerged up to 5 years before diagnosis.

These findings were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract PR-10).

“The incidence of early-onset CRC has been rising 2% annually since 1994,” noted Michael B. Quillen, one of the study authors and a medical student at the University of Florida, Gainesville.

Inherited genetic syndromes and predisposing conditions such as inflammatory bowel disease account for about half of cases in this age group, but factors explaining the other half remain a mystery.

To shed light in this area, the investigators undertook a study of patients aged 50 years or younger from the OneFlorida Clinical Research Consortium who had at least 2 years of EHR data. This included 783 cases with CRC and 8,981 incidence density-matched controls, with both groups having a mean age of 36 years.

The patients were split into colon cancer and rectal cancer cohorts, and then further divided into four prediction windows, Mr. Quillen explained. Each prediction window started with the patient’s first recorded encounter date in the EHR and ended at 0, 1, 3, or 5 years before the date of diagnosis.

The investigators used machine-learning models to determine what features (e.g., diagnoses, procedures, demographics) were important in determining risk.

Results were expressed in charts that ranked the features by their SHAP (Shapley Additive Explanations) values, which reflect the average impact of a feature on the magnitude of model output.
 

Results: Top models and features

The top-performing models had areas under the curve of 0.61-0.75 for colon cancer risk, and 0.62-0.73 for rectal cancer risk, reported T. Maxwell Parker, another study author and medical student at the University of Florida, Gainesville.

Copyright University of Florida

For colon cancer, the top features for the 0-year cohort included some highly specific symptoms that would be expected in patients close to the diagnostic date: abdominal pain, anemia, blood in the stool, and various procedures such as CT scans. “These do not need a machine learning algorithm to identify,” Mr. Parker acknowledged.

However, there were also two noteworthy features present – cough and primary hypertension – that became the top features in the 1-year and 3-year cohorts, then dropped out in the 5-year cohort.

Other features that became important moving farther out from the diagnostic date of colon cancer, across the windows studied, were chronic sinusitis, atopic dermatitis, asthma, and upper-respiratory infection.

For rectal cancer, some previously identified factors – immune conditions related to infectious disease (HIV and anogenital warts associated with human papillomavirus) as well as amoxicillin therapy – were prominent in the 0-year cohort and became increasingly important going farther out from the diagnostic date.

Obesity was the top feature in the 3-year cohort, and asthma became important in that cohort as well.

None of the rectal cancer models tested performed well at identifying important features in the 5-year cohort.

The investigators are exploring hypotheses to explain how the identified features, especially the new ones such as hypertension and cough, might contribute to CRC carcinogenesis in young adults, according to Mr. Parker. As inclusion of older patients could confound associations, research restricted to those aged 50 years and younger may be necessary.

“We would like to validate these model findings in a second independent data set, and if they are validated, we would consider a prospective cohort study with those features,” Mr. Parker said. The team also plans to refine the models with the aim of improving their areas under the curve.

Thereafter, the team hopes to explore ways for implementing the findings clinically to support screening, which will require consideration of the context, Mr. Parker concluded. “Should we use high-sensitivity or low-specificity models for screening, or do we use the balance of both? Also, different models may be suitable for different situations,” he said.

Mr. Parker and Mr. Quillen disclosed no conflicts of interest. The study did not receive specific funding.