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Healthy lifestyle may offset genetic risk in prostate cancer
In men at the highest risk of dying from prostate cancer, having the highest healthy lifestyle scores cut the risk of fatal disease in half, said study author Anna Plym, PhD, of Brigham and Women’s Hospital and Harvard School of Public Health, both in Boston. She presented these findings at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 822).
Dr. Plym noted that about 58% of the variability in prostate cancer risk is accounted for by genetic factors, with common single-nucleotide polymorphisms (SNPs) accounting for a substantial proportion of prostate cancer susceptibility.
A recent study showed that a polygenic risk score (PRS) derived by combining information from 269 SNPs was “highly predictive” of prostate cancer, Dr. Plym said. There was a 10-fold gradient in disease risk between the lowest and highest genetic risk deciles, and the pattern was consistent across ethnic groups.
In addition, Dr. Plym noted, previous studies have suggested that a healthy lifestyle reduces lethal prostate cancer risk.
What has remained unclear is whether the risk for both developing prostate cancer and experiencing progression to lethal disease can be offset by adherence to a healthy lifestyle.
To investigate, Dr. Plym and colleagues used the 269-SNP PRS to quantify the genetic risk of prostate cancer in 10,443 men enrolled in the Health Professionals Follow-up Study. The men were divided into quartiles according to genetic risk.
The investigators also classified the men using a validated lifestyle score. For this score, one point was given for each of the following: not currently smoking or having quit 10 or more years ago, body mass index under 30 kg/m2, high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Patients with 1-2 points were considered the least healthy, those with 3 points were moderately healthy, and those with 4-6 points were the most healthy.
The outcomes assessed were overall prostate cancer and lethal prostate cancer (i.e., metastatic disease or prostate cancer–specific death).
No overall benefit of healthy lifestyle
At a median follow-up of 18 years, 2,111 cases of prostate cancer were observed. And at a median follow-up of 22 years, 238 lethal prostate cancer events occurred.
Men in the highest genetic risk quartile were five times more likely to develop prostate cancer (hazard ratio, 5.39; 95% confidence interval, 4.59-6.34) and three times more likely to develop lethal prostate cancer (HR, 3.43; 95% CI, 2.29-5.14), when compared with men in the lowest genetic risk quartile.
Adherence to a healthy lifestyle did not decrease the risk of prostate cancer overall (HR, 1.01; 95% CI, 0.84-1.22), nor did it affect men in the lower genetic risk quartiles.
However, healthy lifestyle did appear to affect men in the highest genetic risk quartile. Men with the highest healthy lifestyle scores had roughly half the risk of lethal prostate cancer, compared to men with the lowest lifestyle scores (3% vs. 6%).
A counterbalance to genetic risk
Dr. Plym observed that the rate of lethal disease in men with the best lifestyle scores matched the rate for the study population as a whole (3%), suggesting that healthy lifestyle may counterbalance high genetic risk.
She added that previous research has confirmed physical activity as a protective factor, but more study is needed to shed light on the relative benefit of the healthy lifestyle components.
In addition, further research is necessary to explain why the benefit was limited to lethal prostate cancer risk in men with the highest genetic risk.
Dr. Plym speculated that the genetic variants contributing to a high PRS may also be the variants that have the strongest interaction with lifestyle factors. For men with a genetic predisposition to prostate cancer, she added, these findings underscore the potential value of surveillance.
“Our findings add to current evidence suggesting that men with a high genetic risk may benefit from a targeted prostate cancer screening program, aiming at detecting a potentially lethal prostate cancer while it is still curable,” she said.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, raised the possibility that competing risk issues could be at play.
If a healthy lifestyle leads to longer life, he asked, does that make it more likely that patients will live long enough to die from their prostate cancer because they are not dying from cardiovascular disease, complications of diabetes, etc.? In that case, is the healthy lifestyle really affecting prostate cancer at all?
Dr. Plym responded that, among those in the highest genetic risk group with an unhealthy lifestyle, the increased risk for prostate cancer exceeded the risk for other illnesses.
This study was funded by the DiNovi Family Foundation, the National Cancer Institute, the William Casey Foundation, the Swedish Society for Medical Research, and the Prostate Cancer Foundation. Dr. Plym declared no conflicts of interest. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
In men at the highest risk of dying from prostate cancer, having the highest healthy lifestyle scores cut the risk of fatal disease in half, said study author Anna Plym, PhD, of Brigham and Women’s Hospital and Harvard School of Public Health, both in Boston. She presented these findings at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 822).
Dr. Plym noted that about 58% of the variability in prostate cancer risk is accounted for by genetic factors, with common single-nucleotide polymorphisms (SNPs) accounting for a substantial proportion of prostate cancer susceptibility.
A recent study showed that a polygenic risk score (PRS) derived by combining information from 269 SNPs was “highly predictive” of prostate cancer, Dr. Plym said. There was a 10-fold gradient in disease risk between the lowest and highest genetic risk deciles, and the pattern was consistent across ethnic groups.
In addition, Dr. Plym noted, previous studies have suggested that a healthy lifestyle reduces lethal prostate cancer risk.
What has remained unclear is whether the risk for both developing prostate cancer and experiencing progression to lethal disease can be offset by adherence to a healthy lifestyle.
To investigate, Dr. Plym and colleagues used the 269-SNP PRS to quantify the genetic risk of prostate cancer in 10,443 men enrolled in the Health Professionals Follow-up Study. The men were divided into quartiles according to genetic risk.
The investigators also classified the men using a validated lifestyle score. For this score, one point was given for each of the following: not currently smoking or having quit 10 or more years ago, body mass index under 30 kg/m2, high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Patients with 1-2 points were considered the least healthy, those with 3 points were moderately healthy, and those with 4-6 points were the most healthy.
The outcomes assessed were overall prostate cancer and lethal prostate cancer (i.e., metastatic disease or prostate cancer–specific death).
No overall benefit of healthy lifestyle
At a median follow-up of 18 years, 2,111 cases of prostate cancer were observed. And at a median follow-up of 22 years, 238 lethal prostate cancer events occurred.
Men in the highest genetic risk quartile were five times more likely to develop prostate cancer (hazard ratio, 5.39; 95% confidence interval, 4.59-6.34) and three times more likely to develop lethal prostate cancer (HR, 3.43; 95% CI, 2.29-5.14), when compared with men in the lowest genetic risk quartile.
Adherence to a healthy lifestyle did not decrease the risk of prostate cancer overall (HR, 1.01; 95% CI, 0.84-1.22), nor did it affect men in the lower genetic risk quartiles.
However, healthy lifestyle did appear to affect men in the highest genetic risk quartile. Men with the highest healthy lifestyle scores had roughly half the risk of lethal prostate cancer, compared to men with the lowest lifestyle scores (3% vs. 6%).
A counterbalance to genetic risk
Dr. Plym observed that the rate of lethal disease in men with the best lifestyle scores matched the rate for the study population as a whole (3%), suggesting that healthy lifestyle may counterbalance high genetic risk.
She added that previous research has confirmed physical activity as a protective factor, but more study is needed to shed light on the relative benefit of the healthy lifestyle components.
In addition, further research is necessary to explain why the benefit was limited to lethal prostate cancer risk in men with the highest genetic risk.
Dr. Plym speculated that the genetic variants contributing to a high PRS may also be the variants that have the strongest interaction with lifestyle factors. For men with a genetic predisposition to prostate cancer, she added, these findings underscore the potential value of surveillance.
“Our findings add to current evidence suggesting that men with a high genetic risk may benefit from a targeted prostate cancer screening program, aiming at detecting a potentially lethal prostate cancer while it is still curable,” she said.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, raised the possibility that competing risk issues could be at play.
If a healthy lifestyle leads to longer life, he asked, does that make it more likely that patients will live long enough to die from their prostate cancer because they are not dying from cardiovascular disease, complications of diabetes, etc.? In that case, is the healthy lifestyle really affecting prostate cancer at all?
Dr. Plym responded that, among those in the highest genetic risk group with an unhealthy lifestyle, the increased risk for prostate cancer exceeded the risk for other illnesses.
This study was funded by the DiNovi Family Foundation, the National Cancer Institute, the William Casey Foundation, the Swedish Society for Medical Research, and the Prostate Cancer Foundation. Dr. Plym declared no conflicts of interest. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
In men at the highest risk of dying from prostate cancer, having the highest healthy lifestyle scores cut the risk of fatal disease in half, said study author Anna Plym, PhD, of Brigham and Women’s Hospital and Harvard School of Public Health, both in Boston. She presented these findings at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 822).
Dr. Plym noted that about 58% of the variability in prostate cancer risk is accounted for by genetic factors, with common single-nucleotide polymorphisms (SNPs) accounting for a substantial proportion of prostate cancer susceptibility.
A recent study showed that a polygenic risk score (PRS) derived by combining information from 269 SNPs was “highly predictive” of prostate cancer, Dr. Plym said. There was a 10-fold gradient in disease risk between the lowest and highest genetic risk deciles, and the pattern was consistent across ethnic groups.
In addition, Dr. Plym noted, previous studies have suggested that a healthy lifestyle reduces lethal prostate cancer risk.
What has remained unclear is whether the risk for both developing prostate cancer and experiencing progression to lethal disease can be offset by adherence to a healthy lifestyle.
To investigate, Dr. Plym and colleagues used the 269-SNP PRS to quantify the genetic risk of prostate cancer in 10,443 men enrolled in the Health Professionals Follow-up Study. The men were divided into quartiles according to genetic risk.
The investigators also classified the men using a validated lifestyle score. For this score, one point was given for each of the following: not currently smoking or having quit 10 or more years ago, body mass index under 30 kg/m2, high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Patients with 1-2 points were considered the least healthy, those with 3 points were moderately healthy, and those with 4-6 points were the most healthy.
The outcomes assessed were overall prostate cancer and lethal prostate cancer (i.e., metastatic disease or prostate cancer–specific death).
No overall benefit of healthy lifestyle
At a median follow-up of 18 years, 2,111 cases of prostate cancer were observed. And at a median follow-up of 22 years, 238 lethal prostate cancer events occurred.
Men in the highest genetic risk quartile were five times more likely to develop prostate cancer (hazard ratio, 5.39; 95% confidence interval, 4.59-6.34) and three times more likely to develop lethal prostate cancer (HR, 3.43; 95% CI, 2.29-5.14), when compared with men in the lowest genetic risk quartile.
Adherence to a healthy lifestyle did not decrease the risk of prostate cancer overall (HR, 1.01; 95% CI, 0.84-1.22), nor did it affect men in the lower genetic risk quartiles.
However, healthy lifestyle did appear to affect men in the highest genetic risk quartile. Men with the highest healthy lifestyle scores had roughly half the risk of lethal prostate cancer, compared to men with the lowest lifestyle scores (3% vs. 6%).
A counterbalance to genetic risk
Dr. Plym observed that the rate of lethal disease in men with the best lifestyle scores matched the rate for the study population as a whole (3%), suggesting that healthy lifestyle may counterbalance high genetic risk.
She added that previous research has confirmed physical activity as a protective factor, but more study is needed to shed light on the relative benefit of the healthy lifestyle components.
In addition, further research is necessary to explain why the benefit was limited to lethal prostate cancer risk in men with the highest genetic risk.
Dr. Plym speculated that the genetic variants contributing to a high PRS may also be the variants that have the strongest interaction with lifestyle factors. For men with a genetic predisposition to prostate cancer, she added, these findings underscore the potential value of surveillance.
“Our findings add to current evidence suggesting that men with a high genetic risk may benefit from a targeted prostate cancer screening program, aiming at detecting a potentially lethal prostate cancer while it is still curable,” she said.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, raised the possibility that competing risk issues could be at play.
If a healthy lifestyle leads to longer life, he asked, does that make it more likely that patients will live long enough to die from their prostate cancer because they are not dying from cardiovascular disease, complications of diabetes, etc.? In that case, is the healthy lifestyle really affecting prostate cancer at all?
Dr. Plym responded that, among those in the highest genetic risk group with an unhealthy lifestyle, the increased risk for prostate cancer exceeded the risk for other illnesses.
This study was funded by the DiNovi Family Foundation, the National Cancer Institute, the William Casey Foundation, the Swedish Society for Medical Research, and the Prostate Cancer Foundation. Dr. Plym declared no conflicts of interest. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
FROM AACR 2021
Deadly brain tumor: Survival extended by oncolytic virus product
This is a rapidly fatal form of brain cancer. Among historical control patients, the median overall survival was only 5.3 months.
The new results show a median overall survival of 12.2 months.
They come from a phase 1 trial conducted in 12 patients aged 7-18 years who had high-grade gliomas. All of the patients received the experimental therapy, dubbed G207, which was infused directly into the brain tumors.
“In our secondary objectives, we saw promising overall survival data ... [and] we saw that G207 turned immunologically ‘cold’ tumors to ‘hot,’ ” said lead investigator Gregory K. Friedman, MD, from the University of Alabama at Birmingham.
Dr. Friedman presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT018). The study was also published simultaneously online in the New England Journal of Medicine.
Although the number of patients in the study was small, the data from this early trial look promising, commented Howard Kaufman, MD, director of the Oncolytic Virus Research Laboratory at Massachusetts General Hospital, Boston, who was not involved in the study.
“This is just a horrendous disease that hasn’t really responded to anything, so seeing some signs of benefit as well as a pretty tolerable safety profile is a very important observation that I think merits further investigation,” he said in an interview.
Engineered virus
G207 is an oncolytic form of HSV-1 created through genetic engineering in which a neurovirulence gene was deleted and viral nucleotide reductase was disabled. The engineered mutations prevent HSV-1 from infecting normal cells while allowing the virus to replicate in tumor cells.
The oncolytic virus product can be inoculated directly into tumors to circumvent the blood-brain barrier, and it preferentially infects neural tissue, making it ideal for treating brain tumors, the investigators explain.
One example of this type of product is already on the market. Talimogene laherparepvec is an oncolytic HSV-1 therapy that was approved in 2015 by the Food and Drug Administration for local treatment (i.e., injection directly into the skin lesion) of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.
In their article, Dr. Friedman and colleagues summarized some of the data with G207 that “provided a strong rationale for conducting a trial involving children and adolescents.
“In addition to infecting and lysing tumor cells directly, G207 can reverse tumor immune evasion, increase cross-presentation of tumor antigens, and promote an antitumor immune response even in the absence of virus permissivity,” they wrote. “A single radiation dose enhances G207 efficacy in animal models by increasing viral replication and spread.”
In preclinical studies using tumor xenografts, pediatric brain tumors were 11-fold more sensitive to G207, compared with glioblastomas in adults.
The researchers hypothesized that intratumoral G207 would increase the amount of tumor-infiltrating lymphocytes and thereby convert immunologically “cold” pediatric brain tumors to “hot” and “inflamed” tumors.
Phase 1 trial
The phase 1 trial included four dose cohorts of children and adolescents with a pathologically proven malignant supratentorial brain tumor of at least 1 cm in diameter that had progressed after surgery, radiotherapy, or chemotherapy.
There were three patients in each dose cohort. One cohort received 107 plaque-forming units, the second received 108 PFU, the third received 107 PFU with 5 Gy of radiation, and the fourth received 108 PFU with 5 Gy radiation.
The patients first underwent stereotactic placement of up to four intratumoral catheters. The next day, they underwent infusion of the assigned PFU doses by controlled-rate infusion over 6 hours.
For the patients who received radiation, 5 Gy were administered to the gross tumor volume within 24 hours following G207 administration.
Among the 12 patients, tumors included 10 glioblastomas, one anaplastic astrocytoma, and one high-grade glioma not otherwise specified.
Responses (radiographic, neuropathologic, or clinical) occurred in 11 of the 12 patients.
Four patients were still alive 18 months after treatment, “which exceeds the life expectancy for newly diagnosed patients,” Dr. Friedman noted. Most patients die within 1 year of being diagnosed with pediatric glioma.
The investigators also found evidence to suggest that survival may be improved for patients who experience seroconversion after exposure to HSV-1 in comparison to patients with HSV-1 antibodies from prior HSV-1 infection. The median overall survival was 18.3 months for patients who experienced seroconversion, compared with 5.1 months for three patients who, at baseline, had IgG antibodies to HSV-1.
No dose-limiting toxicities or serious adverse events attributable to G207 occurred. There were 20 grade 1 adverse events that were potentially related to G207.
There was no evidence of peripheral G207 shedding or viremia, the investigators reported.
Radiation effect?
Commenting on the results in an interview, Dr. Kaufman noted that the sample size (12 patients) in this study was too small to determine whether the radiation received by patients in two of the four cohorts had any additive effect.
“Whether to move forward with virus alone or to add the radiation remains an open question that I don’t think was adequately answered,” he said.
Regarding the evidence suggesting that survival was better among patients who did not have antibodies to HSV-1 at baseline, Dr. Kaufman said, “We’ve looked at that in the melanoma population but haven’t seen any correlation there, so that’s interesting.”
The finding could be related to the fact that this was a pediatric population, or it could be related to the location of the tumors in the brain.
“It’s an interesting finding, and it suggests that, in future studies, they might want to select patients who are HSV seronegative up front,” he said.
Dr. Friedman and colleagues are currently planning a phase 2 trial of G207 with 5 Gy of radiation for children and adolescents with recurrent or progressive high-grade gliomas.
The study was supported by grants from the FDA, the National Institutes of Health, Cannonball Kids’ Cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, the Department of Defense, the Andrew McDonough B+ Foundation, and the Kaul Pediatric Research Institute; by NIH/National Cancer Institute Cancer Center support grants to the University of Alabama at Birmingham and to the Memorial Sloan Kettering Cancer Center; and by Kelsie’s Crew, Eli’s Block Party Childhood Cancer Foundation, the Eli Jackson Foundation, Jaxon’s FROG Foundation, Battle for a Cure Foundation, and Sandcastle Kids. Dr. Friedman has received grants/support from the organizations listed above, as well as from Eli Lilly and Pfizer. Dr. Kaufman disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This is a rapidly fatal form of brain cancer. Among historical control patients, the median overall survival was only 5.3 months.
The new results show a median overall survival of 12.2 months.
They come from a phase 1 trial conducted in 12 patients aged 7-18 years who had high-grade gliomas. All of the patients received the experimental therapy, dubbed G207, which was infused directly into the brain tumors.
“In our secondary objectives, we saw promising overall survival data ... [and] we saw that G207 turned immunologically ‘cold’ tumors to ‘hot,’ ” said lead investigator Gregory K. Friedman, MD, from the University of Alabama at Birmingham.
Dr. Friedman presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT018). The study was also published simultaneously online in the New England Journal of Medicine.
Although the number of patients in the study was small, the data from this early trial look promising, commented Howard Kaufman, MD, director of the Oncolytic Virus Research Laboratory at Massachusetts General Hospital, Boston, who was not involved in the study.
“This is just a horrendous disease that hasn’t really responded to anything, so seeing some signs of benefit as well as a pretty tolerable safety profile is a very important observation that I think merits further investigation,” he said in an interview.
Engineered virus
G207 is an oncolytic form of HSV-1 created through genetic engineering in which a neurovirulence gene was deleted and viral nucleotide reductase was disabled. The engineered mutations prevent HSV-1 from infecting normal cells while allowing the virus to replicate in tumor cells.
The oncolytic virus product can be inoculated directly into tumors to circumvent the blood-brain barrier, and it preferentially infects neural tissue, making it ideal for treating brain tumors, the investigators explain.
One example of this type of product is already on the market. Talimogene laherparepvec is an oncolytic HSV-1 therapy that was approved in 2015 by the Food and Drug Administration for local treatment (i.e., injection directly into the skin lesion) of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.
In their article, Dr. Friedman and colleagues summarized some of the data with G207 that “provided a strong rationale for conducting a trial involving children and adolescents.
“In addition to infecting and lysing tumor cells directly, G207 can reverse tumor immune evasion, increase cross-presentation of tumor antigens, and promote an antitumor immune response even in the absence of virus permissivity,” they wrote. “A single radiation dose enhances G207 efficacy in animal models by increasing viral replication and spread.”
In preclinical studies using tumor xenografts, pediatric brain tumors were 11-fold more sensitive to G207, compared with glioblastomas in adults.
The researchers hypothesized that intratumoral G207 would increase the amount of tumor-infiltrating lymphocytes and thereby convert immunologically “cold” pediatric brain tumors to “hot” and “inflamed” tumors.
Phase 1 trial
The phase 1 trial included four dose cohorts of children and adolescents with a pathologically proven malignant supratentorial brain tumor of at least 1 cm in diameter that had progressed after surgery, radiotherapy, or chemotherapy.
There were three patients in each dose cohort. One cohort received 107 plaque-forming units, the second received 108 PFU, the third received 107 PFU with 5 Gy of radiation, and the fourth received 108 PFU with 5 Gy radiation.
The patients first underwent stereotactic placement of up to four intratumoral catheters. The next day, they underwent infusion of the assigned PFU doses by controlled-rate infusion over 6 hours.
For the patients who received radiation, 5 Gy were administered to the gross tumor volume within 24 hours following G207 administration.
Among the 12 patients, tumors included 10 glioblastomas, one anaplastic astrocytoma, and one high-grade glioma not otherwise specified.
Responses (radiographic, neuropathologic, or clinical) occurred in 11 of the 12 patients.
Four patients were still alive 18 months after treatment, “which exceeds the life expectancy for newly diagnosed patients,” Dr. Friedman noted. Most patients die within 1 year of being diagnosed with pediatric glioma.
The investigators also found evidence to suggest that survival may be improved for patients who experience seroconversion after exposure to HSV-1 in comparison to patients with HSV-1 antibodies from prior HSV-1 infection. The median overall survival was 18.3 months for patients who experienced seroconversion, compared with 5.1 months for three patients who, at baseline, had IgG antibodies to HSV-1.
No dose-limiting toxicities or serious adverse events attributable to G207 occurred. There were 20 grade 1 adverse events that were potentially related to G207.
There was no evidence of peripheral G207 shedding or viremia, the investigators reported.
Radiation effect?
Commenting on the results in an interview, Dr. Kaufman noted that the sample size (12 patients) in this study was too small to determine whether the radiation received by patients in two of the four cohorts had any additive effect.
“Whether to move forward with virus alone or to add the radiation remains an open question that I don’t think was adequately answered,” he said.
Regarding the evidence suggesting that survival was better among patients who did not have antibodies to HSV-1 at baseline, Dr. Kaufman said, “We’ve looked at that in the melanoma population but haven’t seen any correlation there, so that’s interesting.”
The finding could be related to the fact that this was a pediatric population, or it could be related to the location of the tumors in the brain.
“It’s an interesting finding, and it suggests that, in future studies, they might want to select patients who are HSV seronegative up front,” he said.
Dr. Friedman and colleagues are currently planning a phase 2 trial of G207 with 5 Gy of radiation for children and adolescents with recurrent or progressive high-grade gliomas.
The study was supported by grants from the FDA, the National Institutes of Health, Cannonball Kids’ Cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, the Department of Defense, the Andrew McDonough B+ Foundation, and the Kaul Pediatric Research Institute; by NIH/National Cancer Institute Cancer Center support grants to the University of Alabama at Birmingham and to the Memorial Sloan Kettering Cancer Center; and by Kelsie’s Crew, Eli’s Block Party Childhood Cancer Foundation, the Eli Jackson Foundation, Jaxon’s FROG Foundation, Battle for a Cure Foundation, and Sandcastle Kids. Dr. Friedman has received grants/support from the organizations listed above, as well as from Eli Lilly and Pfizer. Dr. Kaufman disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This is a rapidly fatal form of brain cancer. Among historical control patients, the median overall survival was only 5.3 months.
The new results show a median overall survival of 12.2 months.
They come from a phase 1 trial conducted in 12 patients aged 7-18 years who had high-grade gliomas. All of the patients received the experimental therapy, dubbed G207, which was infused directly into the brain tumors.
“In our secondary objectives, we saw promising overall survival data ... [and] we saw that G207 turned immunologically ‘cold’ tumors to ‘hot,’ ” said lead investigator Gregory K. Friedman, MD, from the University of Alabama at Birmingham.
Dr. Friedman presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT018). The study was also published simultaneously online in the New England Journal of Medicine.
Although the number of patients in the study was small, the data from this early trial look promising, commented Howard Kaufman, MD, director of the Oncolytic Virus Research Laboratory at Massachusetts General Hospital, Boston, who was not involved in the study.
“This is just a horrendous disease that hasn’t really responded to anything, so seeing some signs of benefit as well as a pretty tolerable safety profile is a very important observation that I think merits further investigation,” he said in an interview.
Engineered virus
G207 is an oncolytic form of HSV-1 created through genetic engineering in which a neurovirulence gene was deleted and viral nucleotide reductase was disabled. The engineered mutations prevent HSV-1 from infecting normal cells while allowing the virus to replicate in tumor cells.
The oncolytic virus product can be inoculated directly into tumors to circumvent the blood-brain barrier, and it preferentially infects neural tissue, making it ideal for treating brain tumors, the investigators explain.
One example of this type of product is already on the market. Talimogene laherparepvec is an oncolytic HSV-1 therapy that was approved in 2015 by the Food and Drug Administration for local treatment (i.e., injection directly into the skin lesion) of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.
In their article, Dr. Friedman and colleagues summarized some of the data with G207 that “provided a strong rationale for conducting a trial involving children and adolescents.
“In addition to infecting and lysing tumor cells directly, G207 can reverse tumor immune evasion, increase cross-presentation of tumor antigens, and promote an antitumor immune response even in the absence of virus permissivity,” they wrote. “A single radiation dose enhances G207 efficacy in animal models by increasing viral replication and spread.”
In preclinical studies using tumor xenografts, pediatric brain tumors were 11-fold more sensitive to G207, compared with glioblastomas in adults.
The researchers hypothesized that intratumoral G207 would increase the amount of tumor-infiltrating lymphocytes and thereby convert immunologically “cold” pediatric brain tumors to “hot” and “inflamed” tumors.
Phase 1 trial
The phase 1 trial included four dose cohorts of children and adolescents with a pathologically proven malignant supratentorial brain tumor of at least 1 cm in diameter that had progressed after surgery, radiotherapy, or chemotherapy.
There were three patients in each dose cohort. One cohort received 107 plaque-forming units, the second received 108 PFU, the third received 107 PFU with 5 Gy of radiation, and the fourth received 108 PFU with 5 Gy radiation.
The patients first underwent stereotactic placement of up to four intratumoral catheters. The next day, they underwent infusion of the assigned PFU doses by controlled-rate infusion over 6 hours.
For the patients who received radiation, 5 Gy were administered to the gross tumor volume within 24 hours following G207 administration.
Among the 12 patients, tumors included 10 glioblastomas, one anaplastic astrocytoma, and one high-grade glioma not otherwise specified.
Responses (radiographic, neuropathologic, or clinical) occurred in 11 of the 12 patients.
Four patients were still alive 18 months after treatment, “which exceeds the life expectancy for newly diagnosed patients,” Dr. Friedman noted. Most patients die within 1 year of being diagnosed with pediatric glioma.
The investigators also found evidence to suggest that survival may be improved for patients who experience seroconversion after exposure to HSV-1 in comparison to patients with HSV-1 antibodies from prior HSV-1 infection. The median overall survival was 18.3 months for patients who experienced seroconversion, compared with 5.1 months for three patients who, at baseline, had IgG antibodies to HSV-1.
No dose-limiting toxicities or serious adverse events attributable to G207 occurred. There were 20 grade 1 adverse events that were potentially related to G207.
There was no evidence of peripheral G207 shedding or viremia, the investigators reported.
Radiation effect?
Commenting on the results in an interview, Dr. Kaufman noted that the sample size (12 patients) in this study was too small to determine whether the radiation received by patients in two of the four cohorts had any additive effect.
“Whether to move forward with virus alone or to add the radiation remains an open question that I don’t think was adequately answered,” he said.
Regarding the evidence suggesting that survival was better among patients who did not have antibodies to HSV-1 at baseline, Dr. Kaufman said, “We’ve looked at that in the melanoma population but haven’t seen any correlation there, so that’s interesting.”
The finding could be related to the fact that this was a pediatric population, or it could be related to the location of the tumors in the brain.
“It’s an interesting finding, and it suggests that, in future studies, they might want to select patients who are HSV seronegative up front,” he said.
Dr. Friedman and colleagues are currently planning a phase 2 trial of G207 with 5 Gy of radiation for children and adolescents with recurrent or progressive high-grade gliomas.
The study was supported by grants from the FDA, the National Institutes of Health, Cannonball Kids’ Cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, the Department of Defense, the Andrew McDonough B+ Foundation, and the Kaul Pediatric Research Institute; by NIH/National Cancer Institute Cancer Center support grants to the University of Alabama at Birmingham and to the Memorial Sloan Kettering Cancer Center; and by Kelsie’s Crew, Eli’s Block Party Childhood Cancer Foundation, the Eli Jackson Foundation, Jaxon’s FROG Foundation, Battle for a Cure Foundation, and Sandcastle Kids. Dr. Friedman has received grants/support from the organizations listed above, as well as from Eli Lilly and Pfizer. Dr. Kaufman disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AACR 2021
Combo provides ‘broad benefit’ across NHL subtypes
The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.
Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
Patient and treatment details
The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).
All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.
The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.
Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
Progression-free survival benefit
At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).
The PFS advantage with copanlisib was seen across subtypes:
- Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
- Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
- Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
- Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)
The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.
He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.
The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
More than double the rate of serious AEs
The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.
There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.
Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.
More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.
Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.
In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.
Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.
The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.
Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
Patient and treatment details
The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).
All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.
The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.
Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
Progression-free survival benefit
At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).
The PFS advantage with copanlisib was seen across subtypes:
- Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
- Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
- Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
- Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)
The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.
He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.
The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
More than double the rate of serious AEs
The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.
There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.
Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.
More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.
Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.
In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.
Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.
The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.
Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
Patient and treatment details
The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).
All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.
The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.
Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
Progression-free survival benefit
At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).
The PFS advantage with copanlisib was seen across subtypes:
- Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
- Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
- Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
- Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)
The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.
He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.
The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
More than double the rate of serious AEs
The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.
There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.
Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.
More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.
Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.
In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.
Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.
The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
FROM AACR 2021
Presurgical nivo/chemo boosts pCR rates in NSCLC
Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.
However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.
Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.
Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.
This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.
This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.
“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.
Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).
The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.
The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
Change in trial design
Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.
However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).
“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.
Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”
She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.
“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
CheckMate 816 particulars
CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.
Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.
Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.
In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.
Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).
In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
Safety similar
“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.
The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.
Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.
Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.
The investigators are continuing to assess event-free survival and overall survival.
CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.
A version of this article first appeared on Medscape.com.
Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.
However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.
Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.
Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.
This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.
This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.
“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.
Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).
The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.
The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
Change in trial design
Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.
However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).
“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.
Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”
She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.
“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
CheckMate 816 particulars
CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.
Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.
Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.
In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.
Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).
In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
Safety similar
“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.
The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.
Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.
Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.
The investigators are continuing to assess event-free survival and overall survival.
CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.
A version of this article first appeared on Medscape.com.
Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.
However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.
Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.
Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.
This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.
This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.
“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.
Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).
The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.
The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
Change in trial design
Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.
However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).
“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.
Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”
She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.
“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
CheckMate 816 particulars
CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.
Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.
Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.
In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.
Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).
In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
Safety similar
“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.
The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.
Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.
Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.
The investigators are continuing to assess event-free survival and overall survival.
CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.
A version of this article first appeared on Medscape.com.
FROM AACR 2021