Renal Cell Carcinoma

The biggest cancer research meeting of the year has been canceled as a reaction to the novel coronavirus (COVID-19) outbreak, which has also led to many other medical conferences being canceled or postponed.

The annual meeting of the American Association for Cancer Research (AACR) was due to take place April 24-29 in San Diego, California. More than 24,000 delegates from 80 countries and more than 500 exhibitors were expected to attend.

There are plans to reschedule it for later this year.

This has been a “difficult decision,” said the AACR board of directors, but “we believe that the decision to postpone the meeting is absolutely the correct one to safeguard our meeting participants from further potential exposure to the coronavirus.”

The board goes on to explain that “this evidence-based decision was made after a thorough review and discussion of all factors impacting the annual meeting, including the US government’s enforcement of restrictions on international travelers to enter the US; the imposition of travel restrictions issued by US government agencies, cancer centers, academic institutions, and pharmaceutical and biotech companies; and the counsel of infectious disease experts. It is clear that all of these elements significantly affect the ability of delegates, speakers, presenters of proffered papers, and exhibitors to participate fully in the annual meeting.”

Other cancer conferences that were planned for March and that have been canceled include the following:

• European Breast Cancer Conference (EBCC), Barcelona, Spain, which was to have taken place March 18-20. This conference has been postponed and will now take place September 30 to October 2 at the same venue. Abstracts that have been accepted for the initial conference will remain in the program, and organizers will reopen abstract submissions in May.
• National Comprehensive Cancer Network (NCCN), Orlando, Florida, was scheduled for March 19-22. This conference has been postponed. No new dates have been provided, but the society notes that “NCCN staff is working as quickly as possible to notify all conference registrants about the postponement and further information regarding the refund process.”
• European Association of Urology (EAU), Amsterdam, the Netherlands, at which there is always new research presented on prostate, kidney, and bladder cancer, was due to take place March 20-24. This conference has been postponed to July 2020.
• Society of Gynecologic Oncology (SGO), in Toronto, Canada, which was scheduled for March 28-31. SGO is “exploring alternatives for delivering the science and education.”

Overall, the move to cancel medical conferences over the next few months is a good idea, commented F. Perry Wilson, MD, MSCE, associate professor of medicine and director of Yale’s Program of Applied Translational Research, in a Medscape Medical News commentary.

“There’s a pretty straightforward case here,” he argued. “Medical professionals are at higher risk for exposure to coronavirus because we come into contact with lots and lots of patients. Gathering a large group of medical professionals in a single place increases the risk for exposure further. Factor in airplane flights to and from the conferences, and the chance that infection is spread is significant.”

This article first appeared on Medscape.com.

The biggest cancer research meeting of the year has been canceled as a reaction to the novel coronavirus (COVID-19) outbreak, which has also led to many other medical conferences being canceled or postponed.

The annual meeting of the American Association for Cancer Research (AACR) was due to take place April 24-29 in San Diego, California. More than 24,000 delegates from 80 countries and more than 500 exhibitors were expected to attend.

There are plans to reschedule it for later this year.

This has been a “difficult decision,” said the AACR board of directors, but “we believe that the decision to postpone the meeting is absolutely the correct one to safeguard our meeting participants from further potential exposure to the coronavirus.”

The board goes on to explain that “this evidence-based decision was made after a thorough review and discussion of all factors impacting the annual meeting, including the US government’s enforcement of restrictions on international travelers to enter the US; the imposition of travel restrictions issued by US government agencies, cancer centers, academic institutions, and pharmaceutical and biotech companies; and the counsel of infectious disease experts. It is clear that all of these elements significantly affect the ability of delegates, speakers, presenters of proffered papers, and exhibitors to participate fully in the annual meeting.”

Other cancer conferences that were planned for March and that have been canceled include the following:

• European Breast Cancer Conference (EBCC), Barcelona, Spain, which was to have taken place March 18-20. This conference has been postponed and will now take place September 30 to October 2 at the same venue. Abstracts that have been accepted for the initial conference will remain in the program, and organizers will reopen abstract submissions in May.
• National Comprehensive Cancer Network (NCCN), Orlando, Florida, was scheduled for March 19-22. This conference has been postponed. No new dates have been provided, but the society notes that “NCCN staff is working as quickly as possible to notify all conference registrants about the postponement and further information regarding the refund process.”
• European Association of Urology (EAU), Amsterdam, the Netherlands, at which there is always new research presented on prostate, kidney, and bladder cancer, was due to take place March 20-24. This conference has been postponed to July 2020.
• Society of Gynecologic Oncology (SGO), in Toronto, Canada, which was scheduled for March 28-31. SGO is “exploring alternatives for delivering the science and education.”

Overall, the move to cancel medical conferences over the next few months is a good idea, commented F. Perry Wilson, MD, MSCE, associate professor of medicine and director of Yale’s Program of Applied Translational Research, in a Medscape Medical News commentary.

“There’s a pretty straightforward case here,” he argued. “Medical professionals are at higher risk for exposure to coronavirus because we come into contact with lots and lots of patients. Gathering a large group of medical professionals in a single place increases the risk for exposure further. Factor in airplane flights to and from the conferences, and the chance that infection is spread is significant.”

This article first appeared on Medscape.com.

The biggest cancer research meeting of the year has been canceled as a reaction to the novel coronavirus (COVID-19) outbreak, which has also led to many other medical conferences being canceled or postponed.

The annual meeting of the American Association for Cancer Research (AACR) was due to take place April 24-29 in San Diego, California. More than 24,000 delegates from 80 countries and more than 500 exhibitors were expected to attend.

There are plans to reschedule it for later this year.

This has been a “difficult decision,” said the AACR board of directors, but “we believe that the decision to postpone the meeting is absolutely the correct one to safeguard our meeting participants from further potential exposure to the coronavirus.”

The board goes on to explain that “this evidence-based decision was made after a thorough review and discussion of all factors impacting the annual meeting, including the US government’s enforcement of restrictions on international travelers to enter the US; the imposition of travel restrictions issued by US government agencies, cancer centers, academic institutions, and pharmaceutical and biotech companies; and the counsel of infectious disease experts. It is clear that all of these elements significantly affect the ability of delegates, speakers, presenters of proffered papers, and exhibitors to participate fully in the annual meeting.”

Other cancer conferences that were planned for March and that have been canceled include the following:

• European Breast Cancer Conference (EBCC), Barcelona, Spain, which was to have taken place March 18-20. This conference has been postponed and will now take place September 30 to October 2 at the same venue. Abstracts that have been accepted for the initial conference will remain in the program, and organizers will reopen abstract submissions in May.
• National Comprehensive Cancer Network (NCCN), Orlando, Florida, was scheduled for March 19-22. This conference has been postponed. No new dates have been provided, but the society notes that “NCCN staff is working as quickly as possible to notify all conference registrants about the postponement and further information regarding the refund process.”
• European Association of Urology (EAU), Amsterdam, the Netherlands, at which there is always new research presented on prostate, kidney, and bladder cancer, was due to take place March 20-24. This conference has been postponed to July 2020.
• Society of Gynecologic Oncology (SGO), in Toronto, Canada, which was scheduled for March 28-31. SGO is “exploring alternatives for delivering the science and education.”

Overall, the move to cancel medical conferences over the next few months is a good idea, commented F. Perry Wilson, MD, MSCE, associate professor of medicine and director of Yale’s Program of Applied Translational Research, in a Medscape Medical News commentary.

“There’s a pretty straightforward case here,” he argued. “Medical professionals are at higher risk for exposure to coronavirus because we come into contact with lots and lots of patients. Gathering a large group of medical professionals in a single place increases the risk for exposure further. Factor in airplane flights to and from the conferences, and the chance that infection is spread is significant.”

This article first appeared on Medscape.com.

The combination of bevacizumab and pembrolizumab demonstrated acceptable safety and activity in patients with metastatic renal cell carcinoma (mRCC) in a phase 1b/2 study, according to researchers.

Grade 3-4 adverse events were seen in 45% of patients, which “compares favorably” with other combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors, according to study author Arkadiusz Z. Dudek, MD, PhD, of HealthPartners Regions Cancer Care Center in St. Paul, Minn. and colleagues. Their report was published in the Journal of Clinical Oncology.

Phase 1b

The phase 1b portion of the study included 13 patients with clear cell mRCC that relapsed after or was refractory to multiple prior lines of therapy. The patients’ median age was 55 years (range, 33-68 years), and most were men (84.6%).

The patients received infusions of pembrolizumab at 200 mg plus bevacizumab at 10 mg/kg or 15 mg/kg every 3 weeks. The primary objective of the phase 1b component was to determine safety and identify the maximum tolerated dose of the combination.

The overall response rate was 41.7%. Five patients had partial responses, six had stable disease, one had progressive disease, and one was not evaluable.

The median progression-free survival was 9.9 months, and the median overall survival was 17.9 months. No dose-limiting toxicities were observed.
 

Phase 2

The phase 2 component included 48 patients with clear cell mRCC, all of whom were treatment naive. Their median age was 61 years (range, 42-84 years), and most were men (68.8%).

Based on the phase 1b data, the phase 2 dose of bevacizumab was 15 mg/kg every 3 weeks.

After a median time on treatment of 298 days, the overall response rate was 60.9%. One patient achieved a complete response, and two patients had complete responses in target lesions. Of the remaining patients, 25 achieved partial responses, 18 had stable disease, and 2 were unevaluable.

The median progression-free survival was 20.7 months, and the median overall survival was not reached at 28.3 months.
 

Safety

In the combined safety analysis, the most frequent treatment-related grade 3 adverse events were hypertension (25%), proteinuria (10%), adrenal insufficiency (6.7%), and pain/headaches (5.0%).

The most common grade 3 immune-related adverse events were adrenal insufficiency (6.7%), pneumonitis (3.3%), hepatitis (1.7%), skin rash (1.7%), gastritis (1.7%), hypothyroidism (1.7%), and oral mucositis (1.7%).

Two grade 4 adverse events (hyponatremia and duodenal ulcer) were reported. There were no treatment-related grade 5 events.

“The combination of 200 mg of pembrolizumab and a 15-mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC,” the authors wrote. “[The combination] could be further tested in patient populations where TKIs [tyrosine kinase inhibitors] are not well tolerated and can cause early treatment discontinuation.”

This study was funded by Merck. The authors disclosed financial affiliations with Merck and other companies.

SOURCE: Dudek AZ et al. J Clin Oncol. 2020 Feb 25. doi: 10.1200/JCO.19.02394.

The combination of bevacizumab and pembrolizumab demonstrated acceptable safety and activity in patients with metastatic renal cell carcinoma (mRCC) in a phase 1b/2 study, according to researchers.

Grade 3-4 adverse events were seen in 45% of patients, which “compares favorably” with other combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors, according to study author Arkadiusz Z. Dudek, MD, PhD, of HealthPartners Regions Cancer Care Center in St. Paul, Minn. and colleagues. Their report was published in the Journal of Clinical Oncology.

Phase 1b

The phase 1b portion of the study included 13 patients with clear cell mRCC that relapsed after or was refractory to multiple prior lines of therapy. The patients’ median age was 55 years (range, 33-68 years), and most were men (84.6%).

The patients received infusions of pembrolizumab at 200 mg plus bevacizumab at 10 mg/kg or 15 mg/kg every 3 weeks. The primary objective of the phase 1b component was to determine safety and identify the maximum tolerated dose of the combination.

The overall response rate was 41.7%. Five patients had partial responses, six had stable disease, one had progressive disease, and one was not evaluable.

The median progression-free survival was 9.9 months, and the median overall survival was 17.9 months. No dose-limiting toxicities were observed.
 

Phase 2

The phase 2 component included 48 patients with clear cell mRCC, all of whom were treatment naive. Their median age was 61 years (range, 42-84 years), and most were men (68.8%).

Based on the phase 1b data, the phase 2 dose of bevacizumab was 15 mg/kg every 3 weeks.

After a median time on treatment of 298 days, the overall response rate was 60.9%. One patient achieved a complete response, and two patients had complete responses in target lesions. Of the remaining patients, 25 achieved partial responses, 18 had stable disease, and 2 were unevaluable.

The median progression-free survival was 20.7 months, and the median overall survival was not reached at 28.3 months.
 

Safety

In the combined safety analysis, the most frequent treatment-related grade 3 adverse events were hypertension (25%), proteinuria (10%), adrenal insufficiency (6.7%), and pain/headaches (5.0%).

The most common grade 3 immune-related adverse events were adrenal insufficiency (6.7%), pneumonitis (3.3%), hepatitis (1.7%), skin rash (1.7%), gastritis (1.7%), hypothyroidism (1.7%), and oral mucositis (1.7%).

Two grade 4 adverse events (hyponatremia and duodenal ulcer) were reported. There were no treatment-related grade 5 events.

“The combination of 200 mg of pembrolizumab and a 15-mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC,” the authors wrote. “[The combination] could be further tested in patient populations where TKIs [tyrosine kinase inhibitors] are not well tolerated and can cause early treatment discontinuation.”

This study was funded by Merck. The authors disclosed financial affiliations with Merck and other companies.

SOURCE: Dudek AZ et al. J Clin Oncol. 2020 Feb 25. doi: 10.1200/JCO.19.02394.

The combination of bevacizumab and pembrolizumab demonstrated acceptable safety and activity in patients with metastatic renal cell carcinoma (mRCC) in a phase 1b/2 study, according to researchers.

Grade 3-4 adverse events were seen in 45% of patients, which “compares favorably” with other combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors, according to study author Arkadiusz Z. Dudek, MD, PhD, of HealthPartners Regions Cancer Care Center in St. Paul, Minn. and colleagues. Their report was published in the Journal of Clinical Oncology.

Phase 1b

The phase 1b portion of the study included 13 patients with clear cell mRCC that relapsed after or was refractory to multiple prior lines of therapy. The patients’ median age was 55 years (range, 33-68 years), and most were men (84.6%).

The patients received infusions of pembrolizumab at 200 mg plus bevacizumab at 10 mg/kg or 15 mg/kg every 3 weeks. The primary objective of the phase 1b component was to determine safety and identify the maximum tolerated dose of the combination.

The overall response rate was 41.7%. Five patients had partial responses, six had stable disease, one had progressive disease, and one was not evaluable.

The median progression-free survival was 9.9 months, and the median overall survival was 17.9 months. No dose-limiting toxicities were observed.
 

Phase 2

The phase 2 component included 48 patients with clear cell mRCC, all of whom were treatment naive. Their median age was 61 years (range, 42-84 years), and most were men (68.8%).

Based on the phase 1b data, the phase 2 dose of bevacizumab was 15 mg/kg every 3 weeks.

After a median time on treatment of 298 days, the overall response rate was 60.9%. One patient achieved a complete response, and two patients had complete responses in target lesions. Of the remaining patients, 25 achieved partial responses, 18 had stable disease, and 2 were unevaluable.

The median progression-free survival was 20.7 months, and the median overall survival was not reached at 28.3 months.
 

Safety

In the combined safety analysis, the most frequent treatment-related grade 3 adverse events were hypertension (25%), proteinuria (10%), adrenal insufficiency (6.7%), and pain/headaches (5.0%).

The most common grade 3 immune-related adverse events were adrenal insufficiency (6.7%), pneumonitis (3.3%), hepatitis (1.7%), skin rash (1.7%), gastritis (1.7%), hypothyroidism (1.7%), and oral mucositis (1.7%).

Two grade 4 adverse events (hyponatremia and duodenal ulcer) were reported. There were no treatment-related grade 5 events.

“The combination of 200 mg of pembrolizumab and a 15-mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC,” the authors wrote. “[The combination] could be further tested in patient populations where TKIs [tyrosine kinase inhibitors] are not well tolerated and can cause early treatment discontinuation.”

This study was funded by Merck. The authors disclosed financial affiliations with Merck and other companies.

SOURCE: Dudek AZ et al. J Clin Oncol. 2020 Feb 25. doi: 10.1200/JCO.19.02394.

A new tumor neoantigenicity metric may improve prediction of response to immunotherapy in patients with melanoma, lung cancer, and kidney cancer, a retrospective analysis suggests.

The new metric, known as the Cauchy-Schwarz index of neoantigens (CSiN) score, incorporates both immunogenicity and clonality, according to lead study author Tianshi Lu, a PhD candidate at the University of Texas Southwestern Medical Center in Dallas, and colleagues.

“The major biological insight from this study is that the neoantigen clonal structure in each tumor specimen and the immunogenicity of the neoantigens (represented by the MHC-binding strength in our study) are predictive of response to checkpoint inhibitors and prognosis,” the investigators wrote in Science Immunology.

The study involved 2,479 patients with various cancers, including immunogenic types such as renal cell carcinoma (RCC), and nonimmunogenic types, such as pediatric acute lymphocytic leukemia.

The investigators first evaluated CSiN in relation to clinical outcome among patients with immunogenic cancers who received immunotherapy. Drawing data from multiple cohorts, the investigators found that patients who had better responses to therapy were significantly more likely to have above average CSiN scores than those who had worse responses.

In one cohort of patients with melanoma who received anti–CTLA-4 therapy, those with better responses were more likely to have high CSiN scores (P = .009). In another cohort of melanoma patients who received anti–CTLA-4 therapy, those with higher CSiN scores were more likely to achieve durable clinical benefit (response or stable disease for more than 6 months), compared with patients who had lower CSiN scores (P = .033).

Among patients with clear cell RCC treated with anti-PD-1/PD-L1 therapy, there was a significant positive association between higher CSiN scores and better response (P = .036). Among T effector-high patients with metastatic clear cell RCC, there was a significant association between higher CSiN scores and better response to atezolizumab (P = .028) but not sunitinib (P = .890).

SOURCE: Lu et al. Sci Immunol. 2020 Feb 21. doi: 10.1126/sciimmunol.aaz3199.

A new tumor neoantigenicity metric may improve prediction of response to immunotherapy in patients with melanoma, lung cancer, and kidney cancer, a retrospective analysis suggests.

The new metric, known as the Cauchy-Schwarz index of neoantigens (CSiN) score, incorporates both immunogenicity and clonality, according to lead study author Tianshi Lu, a PhD candidate at the University of Texas Southwestern Medical Center in Dallas, and colleagues.

“The major biological insight from this study is that the neoantigen clonal structure in each tumor specimen and the immunogenicity of the neoantigens (represented by the MHC-binding strength in our study) are predictive of response to checkpoint inhibitors and prognosis,” the investigators wrote in Science Immunology.

The study involved 2,479 patients with various cancers, including immunogenic types such as renal cell carcinoma (RCC), and nonimmunogenic types, such as pediatric acute lymphocytic leukemia.

The investigators first evaluated CSiN in relation to clinical outcome among patients with immunogenic cancers who received immunotherapy. Drawing data from multiple cohorts, the investigators found that patients who had better responses to therapy were significantly more likely to have above average CSiN scores than those who had worse responses.

In one cohort of patients with melanoma who received anti–CTLA-4 therapy, those with better responses were more likely to have high CSiN scores (P = .009). In another cohort of melanoma patients who received anti–CTLA-4 therapy, those with higher CSiN scores were more likely to achieve durable clinical benefit (response or stable disease for more than 6 months), compared with patients who had lower CSiN scores (P = .033).

Among patients with clear cell RCC treated with anti-PD-1/PD-L1 therapy, there was a significant positive association between higher CSiN scores and better response (P = .036). Among T effector-high patients with metastatic clear cell RCC, there was a significant association between higher CSiN scores and better response to atezolizumab (P = .028) but not sunitinib (P = .890).

SOURCE: Lu et al. Sci Immunol. 2020 Feb 21. doi: 10.1126/sciimmunol.aaz3199.

A new tumor neoantigenicity metric may improve prediction of response to immunotherapy in patients with melanoma, lung cancer, and kidney cancer, a retrospective analysis suggests.

The new metric, known as the Cauchy-Schwarz index of neoantigens (CSiN) score, incorporates both immunogenicity and clonality, according to lead study author Tianshi Lu, a PhD candidate at the University of Texas Southwestern Medical Center in Dallas, and colleagues.

“The major biological insight from this study is that the neoantigen clonal structure in each tumor specimen and the immunogenicity of the neoantigens (represented by the MHC-binding strength in our study) are predictive of response to checkpoint inhibitors and prognosis,” the investigators wrote in Science Immunology.

The study involved 2,479 patients with various cancers, including immunogenic types such as renal cell carcinoma (RCC), and nonimmunogenic types, such as pediatric acute lymphocytic leukemia.

The investigators first evaluated CSiN in relation to clinical outcome among patients with immunogenic cancers who received immunotherapy. Drawing data from multiple cohorts, the investigators found that patients who had better responses to therapy were significantly more likely to have above average CSiN scores than those who had worse responses.

In one cohort of patients with melanoma who received anti–CTLA-4 therapy, those with better responses were more likely to have high CSiN scores (P = .009). In another cohort of melanoma patients who received anti–CTLA-4 therapy, those with higher CSiN scores were more likely to achieve durable clinical benefit (response or stable disease for more than 6 months), compared with patients who had lower CSiN scores (P = .033).

Among patients with clear cell RCC treated with anti-PD-1/PD-L1 therapy, there was a significant positive association between higher CSiN scores and better response (P = .036). Among T effector-high patients with metastatic clear cell RCC, there was a significant association between higher CSiN scores and better response to atezolizumab (P = .028) but not sunitinib (P = .890).

SOURCE: Lu et al. Sci Immunol. 2020 Feb 21. doi: 10.1126/sciimmunol.aaz3199.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

SAN FRANCISCO – Using stereotactic body radiation therapy (SBRT) to stimulate the immune response may boost the efficacy of immunotherapy in metastatic renal cell carcinoma (RCC), results of the RADVAX RCC trial suggest.

Susan London/MDedge News

More than half of patients (56%) who received SBRT plus nivolumab and ipilimumab achieved a response in nonirradiated lesions, but the prespecified threshold for efficacy was not met (70%). Still, the combination was active and well tolerated, and it warrants further investigation, according to Hans J. Hammers, MD, PhD, of the University of Texas, Dallas.

Dr. Hammers presented results from the RADVAX RCC trial at the 2020 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Study details

The phase 2 trial enrolled 25 patients with metastatic clear-cell RCC. They had at least two metastatic sites, one of which was measurable for response. Forty percent had received at least one prior line of systemic therapy, and 30% had tumors positive for programmed death–ligand 1 expression. Almost a third had not undergone nephrectomy and therefore still had their primary tumor.

Patients received SBRT (50 Gy in five fractions) at one or two sites while also receiving nivolumab and ipilimumab. SBRT was given right after the first of four nivolumab-ipilimumab treatments and was delivered to lesions in the lung (56% of patients), lymph nodes (20%), bone or soft tissue (12%), and kidney (12%). Patients went on to receive maintenance nivolumab monotherapy.

At a median follow-up of 24 months, 56% of patients achieved a response in nonirradiated lesions. All were partial responses.

The 56% response rate fell short of the trial’s predefined efficacy endpoint of 70%. However, “we felt that an increase to around 60% [with the addition of SBRT] would probably be a reasonable signal for this small signal-finding study,” Dr. Hammers said, noting that this would be in line with the increase seen with intratumoral injections of immune stimulators.

“I would say we are not that far off if the numbers are real,” he added. “That certainly needs to be confirmed and expanded. And I’m sure we can make it more intelligent by choosing which tumors we go after because, right now, we are doing it completely blindly.”

The lack of any complete responses is likely explained, in part, by the large share of patients still having their primary tumor, Dr. Hammers said.

The median duration of response was not reached. The median progression-free survival was 8.21 months, and the median overall survival was not reached.

Thirty-six percent of patients experienced grade 3-4 adverse events, all gastrointestinal. Of the two patients (8%) experiencing grade 2 radiation pneumonitis, one was a case of radiation recall. Some patients needed high-dose corticosteroids (40%) and additional immune suppression (28%) for side effect management.

Should SBRT move forward in RCC?

“We feel that the combination of SBRT with dual immune checkpoint inhibition is feasible and associated with an acceptable safety profile,” Dr. Hammers said. “We do see an encouraging antitumor activity that we believe warrants further investigation.”

A proposed RADVAX II trial would assess programmed death–ligand 1 expression across tumor sites using PET. “We would then direct the radiation to the cold [noninflamed] tumors to derive potentially the maximum benefit in the sense of in situ vaccination,” Dr. Hammers explained.

Susan London/MDedge News

Invited discussant Thomas Powles, MD, PhD, of the Barts Cancer Institute in London, questioned whether SBRT plus immunotherapy should move forward in RCC patients. He noted that the abscopal effect was first described in the 1950s, but evidence of its clinical efficacy remains limited and inconsistent.

“We are in an era where we are keen to believe that this [phenomenon] exists,” Dr. Powles said. “But just because we can do SBRT in our hospitals doesn’t mean we should be doing it without robust data. The robustness of this data in renal cancer is not there at the moment.”

The 56% response rate seen in the RADVAX RCC trial was somewhat better than the 42% response rate seen in the CheckMate 214 trial with nivolumab and ipilimumab alone among patients with metastatic RCC treated in the first-line setting (Lancet Oncol. 2019;20:1370-85), Dr. Powles noted, while acknowledging the limitations of a cross-trial comparison.

“[However,] there were no complete responses, and this is therefore not a home run, in my opinion,” he said. “Progression-free survival was modest. Clearly, tolerability was okay.”

“In this work, the null hypothesis has not been rejected,” he added. “That’s an English way of saying it didn’t work very well. The question I put to you is, if [SBRT and immunotherapy] were a drug combination, would we be taking it further in randomized trials? And I suspect the answer to that is probably no.”

This trial was funded by KidneyCAN. Dr. Hammers and Dr. Powles disclosed relationships with Bristol-Myers Squibb, which markets nivolumab and ipilimumab, as well as other companies.

SOURCE: Hammers HJ et al. GUCS 2020, Abstract 614.

SAN FRANCISCO – Using stereotactic body radiation therapy (SBRT) to stimulate the immune response may boost the efficacy of immunotherapy in metastatic renal cell carcinoma (RCC), results of the RADVAX RCC trial suggest.

Susan London/MDedge News

More than half of patients (56%) who received SBRT plus nivolumab and ipilimumab achieved a response in nonirradiated lesions, but the prespecified threshold for efficacy was not met (70%). Still, the combination was active and well tolerated, and it warrants further investigation, according to Hans J. Hammers, MD, PhD, of the University of Texas, Dallas.

Dr. Hammers presented results from the RADVAX RCC trial at the 2020 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Study details

The phase 2 trial enrolled 25 patients with metastatic clear-cell RCC. They had at least two metastatic sites, one of which was measurable for response. Forty percent had received at least one prior line of systemic therapy, and 30% had tumors positive for programmed death–ligand 1 expression. Almost a third had not undergone nephrectomy and therefore still had their primary tumor.

Patients received SBRT (50 Gy in five fractions) at one or two sites while also receiving nivolumab and ipilimumab. SBRT was given right after the first of four nivolumab-ipilimumab treatments and was delivered to lesions in the lung (56% of patients), lymph nodes (20%), bone or soft tissue (12%), and kidney (12%). Patients went on to receive maintenance nivolumab monotherapy.

At a median follow-up of 24 months, 56% of patients achieved a response in nonirradiated lesions. All were partial responses.

The 56% response rate fell short of the trial’s predefined efficacy endpoint of 70%. However, “we felt that an increase to around 60% [with the addition of SBRT] would probably be a reasonable signal for this small signal-finding study,” Dr. Hammers said, noting that this would be in line with the increase seen with intratumoral injections of immune stimulators.

“I would say we are not that far off if the numbers are real,” he added. “That certainly needs to be confirmed and expanded. And I’m sure we can make it more intelligent by choosing which tumors we go after because, right now, we are doing it completely blindly.”

The lack of any complete responses is likely explained, in part, by the large share of patients still having their primary tumor, Dr. Hammers said.

The median duration of response was not reached. The median progression-free survival was 8.21 months, and the median overall survival was not reached.

Thirty-six percent of patients experienced grade 3-4 adverse events, all gastrointestinal. Of the two patients (8%) experiencing grade 2 radiation pneumonitis, one was a case of radiation recall. Some patients needed high-dose corticosteroids (40%) and additional immune suppression (28%) for side effect management.

Should SBRT move forward in RCC?

“We feel that the combination of SBRT with dual immune checkpoint inhibition is feasible and associated with an acceptable safety profile,” Dr. Hammers said. “We do see an encouraging antitumor activity that we believe warrants further investigation.”

A proposed RADVAX II trial would assess programmed death–ligand 1 expression across tumor sites using PET. “We would then direct the radiation to the cold [noninflamed] tumors to derive potentially the maximum benefit in the sense of in situ vaccination,” Dr. Hammers explained.

Susan London/MDedge News

Invited discussant Thomas Powles, MD, PhD, of the Barts Cancer Institute in London, questioned whether SBRT plus immunotherapy should move forward in RCC patients. He noted that the abscopal effect was first described in the 1950s, but evidence of its clinical efficacy remains limited and inconsistent.

“We are in an era where we are keen to believe that this [phenomenon] exists,” Dr. Powles said. “But just because we can do SBRT in our hospitals doesn’t mean we should be doing it without robust data. The robustness of this data in renal cancer is not there at the moment.”

The 56% response rate seen in the RADVAX RCC trial was somewhat better than the 42% response rate seen in the CheckMate 214 trial with nivolumab and ipilimumab alone among patients with metastatic RCC treated in the first-line setting (Lancet Oncol. 2019;20:1370-85), Dr. Powles noted, while acknowledging the limitations of a cross-trial comparison.

“[However,] there were no complete responses, and this is therefore not a home run, in my opinion,” he said. “Progression-free survival was modest. Clearly, tolerability was okay.”

“In this work, the null hypothesis has not been rejected,” he added. “That’s an English way of saying it didn’t work very well. The question I put to you is, if [SBRT and immunotherapy] were a drug combination, would we be taking it further in randomized trials? And I suspect the answer to that is probably no.”

This trial was funded by KidneyCAN. Dr. Hammers and Dr. Powles disclosed relationships with Bristol-Myers Squibb, which markets nivolumab and ipilimumab, as well as other companies.

SOURCE: Hammers HJ et al. GUCS 2020, Abstract 614.

SAN FRANCISCO – Using stereotactic body radiation therapy (SBRT) to stimulate the immune response may boost the efficacy of immunotherapy in metastatic renal cell carcinoma (RCC), results of the RADVAX RCC trial suggest.

Susan London/MDedge News

More than half of patients (56%) who received SBRT plus nivolumab and ipilimumab achieved a response in nonirradiated lesions, but the prespecified threshold for efficacy was not met (70%). Still, the combination was active and well tolerated, and it warrants further investigation, according to Hans J. Hammers, MD, PhD, of the University of Texas, Dallas.

Dr. Hammers presented results from the RADVAX RCC trial at the 2020 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Study details

The phase 2 trial enrolled 25 patients with metastatic clear-cell RCC. They had at least two metastatic sites, one of which was measurable for response. Forty percent had received at least one prior line of systemic therapy, and 30% had tumors positive for programmed death–ligand 1 expression. Almost a third had not undergone nephrectomy and therefore still had their primary tumor.

Patients received SBRT (50 Gy in five fractions) at one or two sites while also receiving nivolumab and ipilimumab. SBRT was given right after the first of four nivolumab-ipilimumab treatments and was delivered to lesions in the lung (56% of patients), lymph nodes (20%), bone or soft tissue (12%), and kidney (12%). Patients went on to receive maintenance nivolumab monotherapy.

At a median follow-up of 24 months, 56% of patients achieved a response in nonirradiated lesions. All were partial responses.

The 56% response rate fell short of the trial’s predefined efficacy endpoint of 70%. However, “we felt that an increase to around 60% [with the addition of SBRT] would probably be a reasonable signal for this small signal-finding study,” Dr. Hammers said, noting that this would be in line with the increase seen with intratumoral injections of immune stimulators.

“I would say we are not that far off if the numbers are real,” he added. “That certainly needs to be confirmed and expanded. And I’m sure we can make it more intelligent by choosing which tumors we go after because, right now, we are doing it completely blindly.”

The lack of any complete responses is likely explained, in part, by the large share of patients still having their primary tumor, Dr. Hammers said.

The median duration of response was not reached. The median progression-free survival was 8.21 months, and the median overall survival was not reached.

Thirty-six percent of patients experienced grade 3-4 adverse events, all gastrointestinal. Of the two patients (8%) experiencing grade 2 radiation pneumonitis, one was a case of radiation recall. Some patients needed high-dose corticosteroids (40%) and additional immune suppression (28%) for side effect management.

Should SBRT move forward in RCC?

“We feel that the combination of SBRT with dual immune checkpoint inhibition is feasible and associated with an acceptable safety profile,” Dr. Hammers said. “We do see an encouraging antitumor activity that we believe warrants further investigation.”

A proposed RADVAX II trial would assess programmed death–ligand 1 expression across tumor sites using PET. “We would then direct the radiation to the cold [noninflamed] tumors to derive potentially the maximum benefit in the sense of in situ vaccination,” Dr. Hammers explained.

Susan London/MDedge News

Invited discussant Thomas Powles, MD, PhD, of the Barts Cancer Institute in London, questioned whether SBRT plus immunotherapy should move forward in RCC patients. He noted that the abscopal effect was first described in the 1950s, but evidence of its clinical efficacy remains limited and inconsistent.

“We are in an era where we are keen to believe that this [phenomenon] exists,” Dr. Powles said. “But just because we can do SBRT in our hospitals doesn’t mean we should be doing it without robust data. The robustness of this data in renal cancer is not there at the moment.”

The 56% response rate seen in the RADVAX RCC trial was somewhat better than the 42% response rate seen in the CheckMate 214 trial with nivolumab and ipilimumab alone among patients with metastatic RCC treated in the first-line setting (Lancet Oncol. 2019;20:1370-85), Dr. Powles noted, while acknowledging the limitations of a cross-trial comparison.

“[However,] there were no complete responses, and this is therefore not a home run, in my opinion,” he said. “Progression-free survival was modest. Clearly, tolerability was okay.”

“In this work, the null hypothesis has not been rejected,” he added. “That’s an English way of saying it didn’t work very well. The question I put to you is, if [SBRT and immunotherapy] were a drug combination, would we be taking it further in randomized trials? And I suspect the answer to that is probably no.”

This trial was funded by KidneyCAN. Dr. Hammers and Dr. Powles disclosed relationships with Bristol-Myers Squibb, which markets nivolumab and ipilimumab, as well as other companies.

SOURCE: Hammers HJ et al. GUCS 2020, Abstract 614.

Shorter time to metastatic development was associated with shorter time to treatment failure and shorter overall survival in an international review of over 7,000 renal cell carcinoma (RCC) patients treated with first-line tyrosine kinase inhibitors.

“Patients with synchronous disease, compared with patients with metachronous disease, have more adverse prognostic features, significantly shorter TTF [time to treatment failure], and poorer survival. This may help in patient counseling and may be taken into consideration in clinical trial designs in the future, in order to avoid an imbalance between treatment arms,” wrote investigators led by Frede Donskov, MD, a clinical professor at Aarhus (Denmark) University Hospital, in European Urology Oncology.

In the largest study to date to address the impact of timing of metastases on outcomes from tyrosine kinase inhibitor (TKI) treatment, something that’s been unclear until now, Dr. Donskov and associates turned to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare outcomes of 3,906 patients with synchronous metastases, meaning metastases within 3 months of initial RCC diagnosis, with 3,480 with metachronous disease, meaning metastases after that point.

They found that more patients with synchronous versus metachronous disease had higher T stage (T1-2, 19% vs. 34%), N1 disease (21% vs. 6%), presence of sarcomatoid differentiation (15.8% vs. 7.9%), Karnofsky performance status less than 80 (25.9% vs. 15.1%), anemia (62.5% vs. 42.3%), elevated neutrophils (18.9% vs. 10.9%), elevated platelets (21.6% vs. 11.4%), bone metastases (40.4% vs. 29.8%); and IMDC poor risk (40.6% vs.11.3%).

Synchronous versus metachronous disease by intervals of more than 3-12 months, more than 1-2 years, more than 2-7 years, and more than 7 years correlated with poor TTF (5.6 months vs. 7.3, 8.0, 10.8, and 13.3 months; P less than .0001) and poor overall survival (median, 16.7 months vs. 23.8, 30.2, 34.8, and 41.7 months; P less than .0001).

On multivariable regressions adjusting for baseline variables, metachronous disease was protective versus synchronous RCC on overall survival and TTF, with a greater protective effect the longer it took for the disease to metastasize.

“Synchronous disease may represent a distinct pathologic and molecular phenotype ... a high proportion of patients with synchronous disease have tumors with punctuated evolution, harboring aggressive disease features, consolidating in worse risk factors, requiring systemic therapy earlier, and having almost half the expected survival after the initiation of targeted therapy, compared with the latest metastatic timing, as shown in our study,” the investigators wrote.

The findings “reflect the underlying aggressive tumor biology. Whether [time to metastasis] impacts outcome to checkpoint immunotherapy is yet to be elucidated,” they added.

Patients were a median of 59 years at diagnosis, and 72.9% were men. None of the synchronous patients had a surgical nephrectomy, compared with 95.4% of metachronous patients; 67.2% of patients in both groups were treated with the TKI sunitinib (Sutent).

The work was funded by the IMDC. The lead investigator reported institutional grants from Ipsen and Pfizer, maker of sunitinib.
 

[email protected]

SOURCE: Donskov F et al. Eur Urol Oncol. 2020 Feb 6. doi: 10.1016/j.euo.2020.01.001.

Shorter time to metastatic development was associated with shorter time to treatment failure and shorter overall survival in an international review of over 7,000 renal cell carcinoma (RCC) patients treated with first-line tyrosine kinase inhibitors.

“Patients with synchronous disease, compared with patients with metachronous disease, have more adverse prognostic features, significantly shorter TTF [time to treatment failure], and poorer survival. This may help in patient counseling and may be taken into consideration in clinical trial designs in the future, in order to avoid an imbalance between treatment arms,” wrote investigators led by Frede Donskov, MD, a clinical professor at Aarhus (Denmark) University Hospital, in European Urology Oncology.

In the largest study to date to address the impact of timing of metastases on outcomes from tyrosine kinase inhibitor (TKI) treatment, something that’s been unclear until now, Dr. Donskov and associates turned to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare outcomes of 3,906 patients with synchronous metastases, meaning metastases within 3 months of initial RCC diagnosis, with 3,480 with metachronous disease, meaning metastases after that point.

They found that more patients with synchronous versus metachronous disease had higher T stage (T1-2, 19% vs. 34%), N1 disease (21% vs. 6%), presence of sarcomatoid differentiation (15.8% vs. 7.9%), Karnofsky performance status less than 80 (25.9% vs. 15.1%), anemia (62.5% vs. 42.3%), elevated neutrophils (18.9% vs. 10.9%), elevated platelets (21.6% vs. 11.4%), bone metastases (40.4% vs. 29.8%); and IMDC poor risk (40.6% vs.11.3%).

Synchronous versus metachronous disease by intervals of more than 3-12 months, more than 1-2 years, more than 2-7 years, and more than 7 years correlated with poor TTF (5.6 months vs. 7.3, 8.0, 10.8, and 13.3 months; P less than .0001) and poor overall survival (median, 16.7 months vs. 23.8, 30.2, 34.8, and 41.7 months; P less than .0001).

On multivariable regressions adjusting for baseline variables, metachronous disease was protective versus synchronous RCC on overall survival and TTF, with a greater protective effect the longer it took for the disease to metastasize.

“Synchronous disease may represent a distinct pathologic and molecular phenotype ... a high proportion of patients with synchronous disease have tumors with punctuated evolution, harboring aggressive disease features, consolidating in worse risk factors, requiring systemic therapy earlier, and having almost half the expected survival after the initiation of targeted therapy, compared with the latest metastatic timing, as shown in our study,” the investigators wrote.

The findings “reflect the underlying aggressive tumor biology. Whether [time to metastasis] impacts outcome to checkpoint immunotherapy is yet to be elucidated,” they added.

Patients were a median of 59 years at diagnosis, and 72.9% were men. None of the synchronous patients had a surgical nephrectomy, compared with 95.4% of metachronous patients; 67.2% of patients in both groups were treated with the TKI sunitinib (Sutent).

The work was funded by the IMDC. The lead investigator reported institutional grants from Ipsen and Pfizer, maker of sunitinib.
 

[email protected]

SOURCE: Donskov F et al. Eur Urol Oncol. 2020 Feb 6. doi: 10.1016/j.euo.2020.01.001.

Shorter time to metastatic development was associated with shorter time to treatment failure and shorter overall survival in an international review of over 7,000 renal cell carcinoma (RCC) patients treated with first-line tyrosine kinase inhibitors.

“Patients with synchronous disease, compared with patients with metachronous disease, have more adverse prognostic features, significantly shorter TTF [time to treatment failure], and poorer survival. This may help in patient counseling and may be taken into consideration in clinical trial designs in the future, in order to avoid an imbalance between treatment arms,” wrote investigators led by Frede Donskov, MD, a clinical professor at Aarhus (Denmark) University Hospital, in European Urology Oncology.

In the largest study to date to address the impact of timing of metastases on outcomes from tyrosine kinase inhibitor (TKI) treatment, something that’s been unclear until now, Dr. Donskov and associates turned to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare outcomes of 3,906 patients with synchronous metastases, meaning metastases within 3 months of initial RCC diagnosis, with 3,480 with metachronous disease, meaning metastases after that point.

They found that more patients with synchronous versus metachronous disease had higher T stage (T1-2, 19% vs. 34%), N1 disease (21% vs. 6%), presence of sarcomatoid differentiation (15.8% vs. 7.9%), Karnofsky performance status less than 80 (25.9% vs. 15.1%), anemia (62.5% vs. 42.3%), elevated neutrophils (18.9% vs. 10.9%), elevated platelets (21.6% vs. 11.4%), bone metastases (40.4% vs. 29.8%); and IMDC poor risk (40.6% vs.11.3%).

Synchronous versus metachronous disease by intervals of more than 3-12 months, more than 1-2 years, more than 2-7 years, and more than 7 years correlated with poor TTF (5.6 months vs. 7.3, 8.0, 10.8, and 13.3 months; P less than .0001) and poor overall survival (median, 16.7 months vs. 23.8, 30.2, 34.8, and 41.7 months; P less than .0001).

On multivariable regressions adjusting for baseline variables, metachronous disease was protective versus synchronous RCC on overall survival and TTF, with a greater protective effect the longer it took for the disease to metastasize.

“Synchronous disease may represent a distinct pathologic and molecular phenotype ... a high proportion of patients with synchronous disease have tumors with punctuated evolution, harboring aggressive disease features, consolidating in worse risk factors, requiring systemic therapy earlier, and having almost half the expected survival after the initiation of targeted therapy, compared with the latest metastatic timing, as shown in our study,” the investigators wrote.

The findings “reflect the underlying aggressive tumor biology. Whether [time to metastasis] impacts outcome to checkpoint immunotherapy is yet to be elucidated,” they added.

Patients were a median of 59 years at diagnosis, and 72.9% were men. None of the synchronous patients had a surgical nephrectomy, compared with 95.4% of metachronous patients; 67.2% of patients in both groups were treated with the TKI sunitinib (Sutent).

The work was funded by the IMDC. The lead investigator reported institutional grants from Ipsen and Pfizer, maker of sunitinib.
 

[email protected]

SOURCE: Donskov F et al. Eur Urol Oncol. 2020 Feb 6. doi: 10.1016/j.euo.2020.01.001.

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

ORLANDO – Combining intratumoral injections of ilixadencel, an off-the-shelf dendritic cell–based primer, with sunitinib improved responses in patients with newly diagnosed synchronous metastatic renal cell carcinoma in the phase 2 MERECA trial.

Sharon Worcester/MDEdge News

The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.

The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.

The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.

There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.

“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.

The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.

MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.

Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.

Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.

There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.

“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.

He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.

This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.

[email protected]

SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.

ORLANDO – Combining intratumoral injections of ilixadencel, an off-the-shelf dendritic cell–based primer, with sunitinib improved responses in patients with newly diagnosed synchronous metastatic renal cell carcinoma in the phase 2 MERECA trial.

Sharon Worcester/MDEdge News

The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.

The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.

The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.

There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.

“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.

The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.

MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.

Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.

Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.

There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.

“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.

He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.

This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.

[email protected]

SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.

ORLANDO – Combining intratumoral injections of ilixadencel, an off-the-shelf dendritic cell–based primer, with sunitinib improved responses in patients with newly diagnosed synchronous metastatic renal cell carcinoma in the phase 2 MERECA trial.

Sharon Worcester/MDEdge News

The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.

The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.

The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.

There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.

“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.

The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.

MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.

Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.

Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.

There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.

“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.

He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.

This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.

[email protected]

SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.