AVAHO

There is an urgent need to raise global awareness about the direct link between alcohol consumption and cancer risk.

That message was delivered by Isabelle Soerjomataram, PhD, with the International Agency for Research on Cancer (IARC), Lyon, France, at a session devoted to alcohol and cancer at the annual meeting of the European Society for Medical Oncology.

“Global awareness about the link between alcohol and cancer continues to be very low,” Dr. Soerjomataram told the audience. “Health professionals – oncologists, nurses, medical doctors, GPs – have an important role in increasing awareness and bringing this knowledge to people, which may lead to reduced consumption.”

Session chair Gilberto Morgan, MD, medical oncologist, Skåne University Hospital, Lund, Sweden, agreed.

Dr. Morgan noted that healthcare professionals tend to downplay their influence over patients’ drinking habits and often don’t address these behaviors.

But that needs to change.

“We have absolutely no problem asking patients if they take supplements or vitamins or if they’re eating [healthy],” Dr. Morgan said. “So, what is the difference? Why not recommend that they cut down their alcohol intake and leave it up to everybody’s personal choice to do it or not?”

In the session, Dr. Soerjomataram highlighted the global statistics on alcohol use. IARC data show, for instance, that nearly half (46%) of the world’s population consumes alcohol, with rates higher in men (54%) than women (38%).

How much are people drinking?

Globally, on average, the amount comes to about six liters of pure ethanol per year per drinker, or about one wine bottle per week. However, consumption patterns vary widely by country. In France, people consume about 12 liters per year or about two wine bottles per week.

Dr. Soerjomataram stressed the link between alcohol consumption and cancer.

According to IARC data, heavy drinking – defined as more than 60 g/day or about six daily drinks – accounts for 47% of the alcohol-attributable cancers. Risky drinking – between 20 and 60 g/day – accounts for 29%, she explained, while moderate drinking – less than 20 g/day or about two daily drinks – accounts for roughly 14% of cases of alcohol-attributable cancers.

Globally, alcohol intake accounted for 4% of all cancers diagnosed in 2020, according to a 2021 analysis by IARC. 

In the United Kingdom alone, “alcohol drinking caused nearly 17,000 cases of cancer in 2020,” Dr. Soerjomataram said, and breast cancer made up almost one in four of those new cases.

In addition to breast cancer, six other cancer types – oral cavity, pharyngeal, laryngeal, esophageal, colorectal, and liver cancer – can be attributed to alcohol consumption, and emerging evidence suggests stomach and pancreatic cancer may be as well.

The good news, said Dr. Soerjomataram, is that long-term trends show declines in alcohol drinking in many countries, including the high wine-producing countries of France and Italy, where large reductions in consumption have been noted since the peak of intake in the 1920s.

“If it’s possible in these countries, I can imagine it’s possible elsewhere,” said Dr. Soerjomataram. 

Dr. Soerjomataram and Dr. Morgan report no relevant financial relationships.

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

There is an urgent need to raise global awareness about the direct link between alcohol consumption and cancer risk.

That message was delivered by Isabelle Soerjomataram, PhD, with the International Agency for Research on Cancer (IARC), Lyon, France, at a session devoted to alcohol and cancer at the annual meeting of the European Society for Medical Oncology.

“Global awareness about the link between alcohol and cancer continues to be very low,” Dr. Soerjomataram told the audience. “Health professionals – oncologists, nurses, medical doctors, GPs – have an important role in increasing awareness and bringing this knowledge to people, which may lead to reduced consumption.”

Session chair Gilberto Morgan, MD, medical oncologist, Skåne University Hospital, Lund, Sweden, agreed.

Dr. Morgan noted that healthcare professionals tend to downplay their influence over patients’ drinking habits and often don’t address these behaviors.

But that needs to change.

“We have absolutely no problem asking patients if they take supplements or vitamins or if they’re eating [healthy],” Dr. Morgan said. “So, what is the difference? Why not recommend that they cut down their alcohol intake and leave it up to everybody’s personal choice to do it or not?”

In the session, Dr. Soerjomataram highlighted the global statistics on alcohol use. IARC data show, for instance, that nearly half (46%) of the world’s population consumes alcohol, with rates higher in men (54%) than women (38%).

How much are people drinking?

Globally, on average, the amount comes to about six liters of pure ethanol per year per drinker, or about one wine bottle per week. However, consumption patterns vary widely by country. In France, people consume about 12 liters per year or about two wine bottles per week.

Dr. Soerjomataram stressed the link between alcohol consumption and cancer.

According to IARC data, heavy drinking – defined as more than 60 g/day or about six daily drinks – accounts for 47% of the alcohol-attributable cancers. Risky drinking – between 20 and 60 g/day – accounts for 29%, she explained, while moderate drinking – less than 20 g/day or about two daily drinks – accounts for roughly 14% of cases of alcohol-attributable cancers.

Globally, alcohol intake accounted for 4% of all cancers diagnosed in 2020, according to a 2021 analysis by IARC. 

In the United Kingdom alone, “alcohol drinking caused nearly 17,000 cases of cancer in 2020,” Dr. Soerjomataram said, and breast cancer made up almost one in four of those new cases.

In addition to breast cancer, six other cancer types – oral cavity, pharyngeal, laryngeal, esophageal, colorectal, and liver cancer – can be attributed to alcohol consumption, and emerging evidence suggests stomach and pancreatic cancer may be as well.

The good news, said Dr. Soerjomataram, is that long-term trends show declines in alcohol drinking in many countries, including the high wine-producing countries of France and Italy, where large reductions in consumption have been noted since the peak of intake in the 1920s.

“If it’s possible in these countries, I can imagine it’s possible elsewhere,” said Dr. Soerjomataram. 

Dr. Soerjomataram and Dr. Morgan report no relevant financial relationships.

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

There is an urgent need to raise global awareness about the direct link between alcohol consumption and cancer risk.

That message was delivered by Isabelle Soerjomataram, PhD, with the International Agency for Research on Cancer (IARC), Lyon, France, at a session devoted to alcohol and cancer at the annual meeting of the European Society for Medical Oncology.

“Global awareness about the link between alcohol and cancer continues to be very low,” Dr. Soerjomataram told the audience. “Health professionals – oncologists, nurses, medical doctors, GPs – have an important role in increasing awareness and bringing this knowledge to people, which may lead to reduced consumption.”

Session chair Gilberto Morgan, MD, medical oncologist, Skåne University Hospital, Lund, Sweden, agreed.

Dr. Morgan noted that healthcare professionals tend to downplay their influence over patients’ drinking habits and often don’t address these behaviors.

But that needs to change.

“We have absolutely no problem asking patients if they take supplements or vitamins or if they’re eating [healthy],” Dr. Morgan said. “So, what is the difference? Why not recommend that they cut down their alcohol intake and leave it up to everybody’s personal choice to do it or not?”

In the session, Dr. Soerjomataram highlighted the global statistics on alcohol use. IARC data show, for instance, that nearly half (46%) of the world’s population consumes alcohol, with rates higher in men (54%) than women (38%).

How much are people drinking?

Globally, on average, the amount comes to about six liters of pure ethanol per year per drinker, or about one wine bottle per week. However, consumption patterns vary widely by country. In France, people consume about 12 liters per year or about two wine bottles per week.

Dr. Soerjomataram stressed the link between alcohol consumption and cancer.

According to IARC data, heavy drinking – defined as more than 60 g/day or about six daily drinks – accounts for 47% of the alcohol-attributable cancers. Risky drinking – between 20 and 60 g/day – accounts for 29%, she explained, while moderate drinking – less than 20 g/day or about two daily drinks – accounts for roughly 14% of cases of alcohol-attributable cancers.

Globally, alcohol intake accounted for 4% of all cancers diagnosed in 2020, according to a 2021 analysis by IARC. 

In the United Kingdom alone, “alcohol drinking caused nearly 17,000 cases of cancer in 2020,” Dr. Soerjomataram said, and breast cancer made up almost one in four of those new cases.

In addition to breast cancer, six other cancer types – oral cavity, pharyngeal, laryngeal, esophageal, colorectal, and liver cancer – can be attributed to alcohol consumption, and emerging evidence suggests stomach and pancreatic cancer may be as well.

The good news, said Dr. Soerjomataram, is that long-term trends show declines in alcohol drinking in many countries, including the high wine-producing countries of France and Italy, where large reductions in consumption have been noted since the peak of intake in the 1920s.

“If it’s possible in these countries, I can imagine it’s possible elsewhere,” said Dr. Soerjomataram. 

Dr. Soerjomataram and Dr. Morgan report no relevant financial relationships.

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

CHICAGO—While it’s extremely difficult to link cancer rates to military service, researchers are starting to get some initial inklings of possible connections, a US Department of Veterans Affairs (VA) oncologist told an audience at the 2023 annual meeting of the Association of VA Hematology/Oncology.

One study found surprising levels of abnormal proteins and cancer in the blood of service members, said Christin DeStefano, MD, of David Grant US Air Force Medical Center at Travis Air Force Base in California. Another may have uncovered a link between military trauma and lymphoma. And an analysis of pilots found they have higher rates of certain kinds of cancer— but lower levels of other cancer types.

“It is hard to tell if service-related exposures heighten the risk of cancer. Some aspects of military service might increase cancer risk,” DeStefano said. “But other aspects of military service might decrease cancer risk.”

The VA has been especially focused on the possible link between military service and cancer since the passage of the PACT Act in 2022. The legislation prioritizes claims for cancer, terminal illnesses, and homelessness, and it’s sparked more than 4.1 million free toxic-exposure screenings for veterans.

VA Under Secretary for Health Shereef Elnahal, MD, MBA, noted in the keynote address at the 2023 AVAHO annual meeting that “Every type of solid tumor is now considered a presumptive condition associated with burden of exposure to veterans deployed anywhere in Central Command, either in the Persian Gulf War or the post-9/11 conflicts.”

DeStefano noted that there are a variety of challenges to analyzing data regarding connections between military exposure and cancer. For one, “it’s hard to include people from the time they enter the military to postmilitary service. Some are getting their health care in the civilian health care systems.” In addition, “There are a lot of problems with ICD-9 and ICD-10 codes, which can be very erroneous. Maybe somebody came in with a mass, the doctor or the nurse practitioner was busy and they put down ‘suspected cancer,’ and now they have that ICD code in their chart where they never actually had cancer.” This is why more reliable cancer registries are so important, she said.

Another challenge is figuring out when exposures occurred and whether they actually occurred in the military at all. “There are multiple studies suggesting that a first driver event is often acquired 20 to 40 years before a cancer diagnosis, often in one’s 20s and 30s,” she said. “It's hard to quantify an exposure, since there can be exposures before military service and exposures after military service. The amount of exposure and duration of exposure might differ, and individuals might metabolize the exposures differently from each other.”

To make matters more complicated, research is pointing in surprising directions. DeStefano highlighted her not-yet-published study of monoclonal gammopathy (MG), a condition in which abnormal proteins are found in the blood, in 534 service members. MG can be a cancer precursor. Those exposed to burn pits in Iraq had similar risks of MG (6.7%) vs an unexposed, matched control group (5.4%; P = .22), Dr. DeStefano said. Over a mean follow-up of 14 years and 10 years, respectively, 7% of participants in each group developed cancer.

“You might think, ‘this is a negative study. There's no difference.’ However, it is very notable that the prevalence of monoclonal gammopathy was 6.1%. That is 3 times as high as we would expect in somebody in their 40s,” she said. “Also, 7% having a cancer diagnosis is not insignificant.” She added: “It is very possible that many of these service members already have full-blown multiple myeloma or something associated with monoclonal gammopathy that just has not been diagnosed yet.”

In another study, this one published in 2021, Dr. DeStefano and colleagues tracked 8834 injured Iraq/Afghanistan veterans and compared them with matched controls to see if there was a link between severe trauma and cancer. There wasn’t  except for lymphoma (22 vs 7 cases, respectively; odds ratio = 3.1; 95% CI, 1.34-7.37; P = .008). The connection remained after adjustment for confounders.

What’s going on? “It’s possible that blast injury might induce some alterations to the immune system that might set the stage for lymphoma genesis,” she said. “Or maybe that blast injury is a surrogate for a toxic exposure: Maybe carcinogens are released during a blast injury.”

Dr. DeStefano also highlighted a 2022 study that tracked 386,190 Air Force officers. The study found that combat pilots (9.1% of the total) had greater adjusted odds of testicular and prostate cancers and melanoma than the other officers. Why? “Military pilots have exposure to cosmic ionizing radiation as well as ultraviolet radiation,” she said.

But while “these are scary, sobering things,” she noted that combat pilots were less likely to develop several cancers than the general population, including kidney, testicular, colorectal, bladder and thyroid cancer, and they were less likely to die from colorectal cancer.

CHICAGO—While it’s extremely difficult to link cancer rates to military service, researchers are starting to get some initial inklings of possible connections, a US Department of Veterans Affairs (VA) oncologist told an audience at the 2023 annual meeting of the Association of VA Hematology/Oncology.

One study found surprising levels of abnormal proteins and cancer in the blood of service members, said Christin DeStefano, MD, of David Grant US Air Force Medical Center at Travis Air Force Base in California. Another may have uncovered a link between military trauma and lymphoma. And an analysis of pilots found they have higher rates of certain kinds of cancer— but lower levels of other cancer types.

“It is hard to tell if service-related exposures heighten the risk of cancer. Some aspects of military service might increase cancer risk,” DeStefano said. “But other aspects of military service might decrease cancer risk.”

The VA has been especially focused on the possible link between military service and cancer since the passage of the PACT Act in 2022. The legislation prioritizes claims for cancer, terminal illnesses, and homelessness, and it’s sparked more than 4.1 million free toxic-exposure screenings for veterans.

VA Under Secretary for Health Shereef Elnahal, MD, MBA, noted in the keynote address at the 2023 AVAHO annual meeting that “Every type of solid tumor is now considered a presumptive condition associated with burden of exposure to veterans deployed anywhere in Central Command, either in the Persian Gulf War or the post-9/11 conflicts.”

DeStefano noted that there are a variety of challenges to analyzing data regarding connections between military exposure and cancer. For one, “it’s hard to include people from the time they enter the military to postmilitary service. Some are getting their health care in the civilian health care systems.” In addition, “There are a lot of problems with ICD-9 and ICD-10 codes, which can be very erroneous. Maybe somebody came in with a mass, the doctor or the nurse practitioner was busy and they put down ‘suspected cancer,’ and now they have that ICD code in their chart where they never actually had cancer.” This is why more reliable cancer registries are so important, she said.

Another challenge is figuring out when exposures occurred and whether they actually occurred in the military at all. “There are multiple studies suggesting that a first driver event is often acquired 20 to 40 years before a cancer diagnosis, often in one’s 20s and 30s,” she said. “It's hard to quantify an exposure, since there can be exposures before military service and exposures after military service. The amount of exposure and duration of exposure might differ, and individuals might metabolize the exposures differently from each other.”

To make matters more complicated, research is pointing in surprising directions. DeStefano highlighted her not-yet-published study of monoclonal gammopathy (MG), a condition in which abnormal proteins are found in the blood, in 534 service members. MG can be a cancer precursor. Those exposed to burn pits in Iraq had similar risks of MG (6.7%) vs an unexposed, matched control group (5.4%; P = .22), Dr. DeStefano said. Over a mean follow-up of 14 years and 10 years, respectively, 7% of participants in each group developed cancer.

“You might think, ‘this is a negative study. There's no difference.’ However, it is very notable that the prevalence of monoclonal gammopathy was 6.1%. That is 3 times as high as we would expect in somebody in their 40s,” she said. “Also, 7% having a cancer diagnosis is not insignificant.” She added: “It is very possible that many of these service members already have full-blown multiple myeloma or something associated with monoclonal gammopathy that just has not been diagnosed yet.”

In another study, this one published in 2021, Dr. DeStefano and colleagues tracked 8834 injured Iraq/Afghanistan veterans and compared them with matched controls to see if there was a link between severe trauma and cancer. There wasn’t  except for lymphoma (22 vs 7 cases, respectively; odds ratio = 3.1; 95% CI, 1.34-7.37; P = .008). The connection remained after adjustment for confounders.

What’s going on? “It’s possible that blast injury might induce some alterations to the immune system that might set the stage for lymphoma genesis,” she said. “Or maybe that blast injury is a surrogate for a toxic exposure: Maybe carcinogens are released during a blast injury.”

Dr. DeStefano also highlighted a 2022 study that tracked 386,190 Air Force officers. The study found that combat pilots (9.1% of the total) had greater adjusted odds of testicular and prostate cancers and melanoma than the other officers. Why? “Military pilots have exposure to cosmic ionizing radiation as well as ultraviolet radiation,” she said.

But while “these are scary, sobering things,” she noted that combat pilots were less likely to develop several cancers than the general population, including kidney, testicular, colorectal, bladder and thyroid cancer, and they were less likely to die from colorectal cancer.

CHICAGO—While it’s extremely difficult to link cancer rates to military service, researchers are starting to get some initial inklings of possible connections, a US Department of Veterans Affairs (VA) oncologist told an audience at the 2023 annual meeting of the Association of VA Hematology/Oncology.

One study found surprising levels of abnormal proteins and cancer in the blood of service members, said Christin DeStefano, MD, of David Grant US Air Force Medical Center at Travis Air Force Base in California. Another may have uncovered a link between military trauma and lymphoma. And an analysis of pilots found they have higher rates of certain kinds of cancer— but lower levels of other cancer types.

“It is hard to tell if service-related exposures heighten the risk of cancer. Some aspects of military service might increase cancer risk,” DeStefano said. “But other aspects of military service might decrease cancer risk.”

The VA has been especially focused on the possible link between military service and cancer since the passage of the PACT Act in 2022. The legislation prioritizes claims for cancer, terminal illnesses, and homelessness, and it’s sparked more than 4.1 million free toxic-exposure screenings for veterans.

VA Under Secretary for Health Shereef Elnahal, MD, MBA, noted in the keynote address at the 2023 AVAHO annual meeting that “Every type of solid tumor is now considered a presumptive condition associated with burden of exposure to veterans deployed anywhere in Central Command, either in the Persian Gulf War or the post-9/11 conflicts.”

DeStefano noted that there are a variety of challenges to analyzing data regarding connections between military exposure and cancer. For one, “it’s hard to include people from the time they enter the military to postmilitary service. Some are getting their health care in the civilian health care systems.” In addition, “There are a lot of problems with ICD-9 and ICD-10 codes, which can be very erroneous. Maybe somebody came in with a mass, the doctor or the nurse practitioner was busy and they put down ‘suspected cancer,’ and now they have that ICD code in their chart where they never actually had cancer.” This is why more reliable cancer registries are so important, she said.

Another challenge is figuring out when exposures occurred and whether they actually occurred in the military at all. “There are multiple studies suggesting that a first driver event is often acquired 20 to 40 years before a cancer diagnosis, often in one’s 20s and 30s,” she said. “It's hard to quantify an exposure, since there can be exposures before military service and exposures after military service. The amount of exposure and duration of exposure might differ, and individuals might metabolize the exposures differently from each other.”

To make matters more complicated, research is pointing in surprising directions. DeStefano highlighted her not-yet-published study of monoclonal gammopathy (MG), a condition in which abnormal proteins are found in the blood, in 534 service members. MG can be a cancer precursor. Those exposed to burn pits in Iraq had similar risks of MG (6.7%) vs an unexposed, matched control group (5.4%; P = .22), Dr. DeStefano said. Over a mean follow-up of 14 years and 10 years, respectively, 7% of participants in each group developed cancer.

“You might think, ‘this is a negative study. There's no difference.’ However, it is very notable that the prevalence of monoclonal gammopathy was 6.1%. That is 3 times as high as we would expect in somebody in their 40s,” she said. “Also, 7% having a cancer diagnosis is not insignificant.” She added: “It is very possible that many of these service members already have full-blown multiple myeloma or something associated with monoclonal gammopathy that just has not been diagnosed yet.”

In another study, this one published in 2021, Dr. DeStefano and colleagues tracked 8834 injured Iraq/Afghanistan veterans and compared them with matched controls to see if there was a link between severe trauma and cancer. There wasn’t  except for lymphoma (22 vs 7 cases, respectively; odds ratio = 3.1; 95% CI, 1.34-7.37; P = .008). The connection remained after adjustment for confounders.

What’s going on? “It’s possible that blast injury might induce some alterations to the immune system that might set the stage for lymphoma genesis,” she said. “Or maybe that blast injury is a surrogate for a toxic exposure: Maybe carcinogens are released during a blast injury.”

Dr. DeStefano also highlighted a 2022 study that tracked 386,190 Air Force officers. The study found that combat pilots (9.1% of the total) had greater adjusted odds of testicular and prostate cancers and melanoma than the other officers. Why? “Military pilots have exposure to cosmic ionizing radiation as well as ultraviolet radiation,” she said.

But while “these are scary, sobering things,” she noted that combat pilots were less likely to develop several cancers than the general population, including kidney, testicular, colorectal, bladder and thyroid cancer, and they were less likely to die from colorectal cancer.

TOPLINE:

Older adults with limited life expectancy are just as likely to undergo colorectal cancer (CRC) screening as those with longer life expectancy, a new study shows.

METHODOLOGY:

• Researchers used national survey data to estimate the prevalence and factors associated with CRC screening in 25,888 community-dwelling adults aged 65-84 according to their predicted 10-year mortality risk.
• They estimated 10-year mortality risk using a validated index. From the lowest to highest quintiles, mortality risk was 12%, 24%, 39%, 58%, and 79%, respectively.
• Investigators determined the proportion of screening performed in adults with life expectancy less than 10 years, defined as 10-year mortality risk ≥ 50% (that is, quintiles 4 and 5).

TAKEAWAY:

• In this cohort of older adults previously not up to date with CRC screening, the overall prevalence of past-year screening was 38.5%.
• The prevalence of past-year CRC screening decreased with advancing age but did not differ significantly by 10-year mortality risk. From lowest to highest quintile, prevalence was 39.5%, 40.6%, 38.7%, 36.4%, and 35.4%, respectively.
• The likelihood of CRC screening did not differ between adults in the lowest vs. highest quintile of 10-year mortality risk (adjusted odds ratio, 1.05).
• More than one-quarter (27.9%) of past-year screening occurred in adults with life expectancy less than 10 years, and 50.7% of adults aged 75-84 years had life expectancy less than 10 years at the time of screening.
• Paradoxically, the prevalence of invasive screening increased with lowered life expectancy among adults aged 70-79 years.

IN PRACTICE:

“Our results suggest that health status and life expectancy may be overlooked in current CRC screening programs, and personalized screening incorporating individual life expectancy may improve the value of screening,” the authors write.

SOURCE:

The study, with first author Po-Hong Liu, MD, MPH, division of digestive and liver diseases, University of Texas Southwestern Medical Center, Dallas, was published online in the American Journal of Gastroenterology.

LIMITATIONS:

The survey data were self-reported and were not validated by medical records. The data did not include information to identify individuals who were at higher risk for CRC or to trace prior CRC screening history. It was not possible to reliably classify test indication (screening vs. surveillance vs. diagnostic).

DISCLOSURES:

The study was supported by the National Institutes of Health. One author disclosed serving as a consultant or on advisory boards for Exact Sciences, Universal Dx, Roche, and Freenome. Another disclosed consulting for Freenome.

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

TOPLINE:

Older adults with limited life expectancy are just as likely to undergo colorectal cancer (CRC) screening as those with longer life expectancy, a new study shows.

METHODOLOGY:

• Researchers used national survey data to estimate the prevalence and factors associated with CRC screening in 25,888 community-dwelling adults aged 65-84 according to their predicted 10-year mortality risk.
• They estimated 10-year mortality risk using a validated index. From the lowest to highest quintiles, mortality risk was 12%, 24%, 39%, 58%, and 79%, respectively.
• Investigators determined the proportion of screening performed in adults with life expectancy less than 10 years, defined as 10-year mortality risk ≥ 50% (that is, quintiles 4 and 5).

TAKEAWAY:

• In this cohort of older adults previously not up to date with CRC screening, the overall prevalence of past-year screening was 38.5%.
• The prevalence of past-year CRC screening decreased with advancing age but did not differ significantly by 10-year mortality risk. From lowest to highest quintile, prevalence was 39.5%, 40.6%, 38.7%, 36.4%, and 35.4%, respectively.
• The likelihood of CRC screening did not differ between adults in the lowest vs. highest quintile of 10-year mortality risk (adjusted odds ratio, 1.05).
• More than one-quarter (27.9%) of past-year screening occurred in adults with life expectancy less than 10 years, and 50.7% of adults aged 75-84 years had life expectancy less than 10 years at the time of screening.
• Paradoxically, the prevalence of invasive screening increased with lowered life expectancy among adults aged 70-79 years.

IN PRACTICE:

“Our results suggest that health status and life expectancy may be overlooked in current CRC screening programs, and personalized screening incorporating individual life expectancy may improve the value of screening,” the authors write.

SOURCE:

The study, with first author Po-Hong Liu, MD, MPH, division of digestive and liver diseases, University of Texas Southwestern Medical Center, Dallas, was published online in the American Journal of Gastroenterology.

LIMITATIONS:

The survey data were self-reported and were not validated by medical records. The data did not include information to identify individuals who were at higher risk for CRC or to trace prior CRC screening history. It was not possible to reliably classify test indication (screening vs. surveillance vs. diagnostic).

DISCLOSURES:

The study was supported by the National Institutes of Health. One author disclosed serving as a consultant or on advisory boards for Exact Sciences, Universal Dx, Roche, and Freenome. Another disclosed consulting for Freenome.

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

TOPLINE:

Older adults with limited life expectancy are just as likely to undergo colorectal cancer (CRC) screening as those with longer life expectancy, a new study shows.

METHODOLOGY:

• Researchers used national survey data to estimate the prevalence and factors associated with CRC screening in 25,888 community-dwelling adults aged 65-84 according to their predicted 10-year mortality risk.
• They estimated 10-year mortality risk using a validated index. From the lowest to highest quintiles, mortality risk was 12%, 24%, 39%, 58%, and 79%, respectively.
• Investigators determined the proportion of screening performed in adults with life expectancy less than 10 years, defined as 10-year mortality risk ≥ 50% (that is, quintiles 4 and 5).

TAKEAWAY:

• In this cohort of older adults previously not up to date with CRC screening, the overall prevalence of past-year screening was 38.5%.
• The prevalence of past-year CRC screening decreased with advancing age but did not differ significantly by 10-year mortality risk. From lowest to highest quintile, prevalence was 39.5%, 40.6%, 38.7%, 36.4%, and 35.4%, respectively.
• The likelihood of CRC screening did not differ between adults in the lowest vs. highest quintile of 10-year mortality risk (adjusted odds ratio, 1.05).
• More than one-quarter (27.9%) of past-year screening occurred in adults with life expectancy less than 10 years, and 50.7% of adults aged 75-84 years had life expectancy less than 10 years at the time of screening.
• Paradoxically, the prevalence of invasive screening increased with lowered life expectancy among adults aged 70-79 years.

IN PRACTICE:

“Our results suggest that health status and life expectancy may be overlooked in current CRC screening programs, and personalized screening incorporating individual life expectancy may improve the value of screening,” the authors write.

SOURCE:

The study, with first author Po-Hong Liu, MD, MPH, division of digestive and liver diseases, University of Texas Southwestern Medical Center, Dallas, was published online in the American Journal of Gastroenterology.

LIMITATIONS:

The survey data were self-reported and were not validated by medical records. The data did not include information to identify individuals who were at higher risk for CRC or to trace prior CRC screening history. It was not possible to reliably classify test indication (screening vs. surveillance vs. diagnostic).

DISCLOSURES:

The study was supported by the National Institutes of Health. One author disclosed serving as a consultant or on advisory boards for Exact Sciences, Universal Dx, Roche, and Freenome. Another disclosed consulting for Freenome.

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

MADRID – Research presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 underline the benefit of adding immunotherapy to chemotherapy in advanced or recurrent endometrial cancer, and question whether adding the PARP inhibitor olaparib to the chemo-immunotherapy combination could provide further benefit.

In the AtTEnd trial, presented on Oct. 21, more than 550 patients with advanced newly diagnosed or recurrent disease were randomized to the antiprogrammed death–ligand 1 (PD-L1) antibody atezolizumab (Tecentriq) or placebo plus chemotherapy followed by maintenance atezolizumab or placebo.

Adding immunotherapy to chemotherapy improved progression-free survival (PFS) among all-comers – 28.1% vs. 17% at 2 years. The PFS benefit was much more pronounced among patients with mismatch repair-deficient (dMMR) disease – 50.4% vs. 16% at 2 years. Mismatch repair-deficient disease patients receiving atezolizumab also demonstrated an early overall survival benefit, according to findings from the interim analysis.

In the DUO-E trial, presented during the same Oct. 21 session, nearly 720 patients with newly diagnosed advanced or recurrent endometrial cancer were randomized to one of three groups: Chemotherapy alone with maintenance placebo, chemotherapy plus durvalumab (Imfinzi) with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab and the PARP inhibitor olaparib.

The results, published simultaneously in the Journal of Clinical Oncology, showed that adding durvalumab to chemotherapy followed by maintenance durvalumab with or without olaparib led to a significant improvement in PFS, compared with chemotherapy alone. As in the AtTEnd trial, this PFS was also more pronounced in dMMR patients.

Overall, Andrés Cervantes, MD, PhD, from the University of Valencia, Spain, and president of ESMO, explained that this research marks “very positive data for women with gynecological cancers,” with immunotherapy now incorporated into the standard of care.

However, an expert questioned whether the DUO-E trial clearly demonstrated the benefit of adding olaparib to immuno- and chemotherapy and whether certain subsets of patients may be more likely to benefit from the PARP inhibitor.
 

Inside AtTEnd

A growing body of research has shown that single agent immunotherapy is effective in treating endometrial cancer, particularly in tumors with dMMR, and that immunotherapy and chemotherapy may have a synergistic effect.

David S. P. Tan, MD, PhD, National University Cancer Institute, Singapore, who was not involved in the studies, commented that “the molecular classification of endometrial cancer is now leading us to areas that we didn’t think before [were] possible.”

The rationale for combining immunotherapy with chemotherapy, Dr. Tan explained, is that “the cytotoxicity you get from chemotherapy is partly dependent on immune activity within the tumor, and so it makes sense” to combine them.

This approach was borne out by recent positive PFS results from the NRG-GY018 trial of pembrolizumab plus chemotherapy in advanced endometrial cancer as well as from the RUBY trial of dostarlimab in primary advanced or recurrent disease.

To further investigate this chemo-immunotherapy strategy, the AtTEnd team enrolled patients with newly diagnosed or recurrent stage III-IV disease who had received no prior systemic chemotherapy for recurrence within the previous 6 months.

Overall, 551 patients from 89 sites across 10 countries were randomized to standard first-line chemotherapy – carboplatin plus paclitaxel – with either atezolizumab or placebo, followed by maintenance atezolizumab or placebo, which continued until confirmed disease progression.

The median age in the intention-to-treat population was 64-67 years. Nearly 23% of patients had dMMR tumors, and 67.2% had recurrent disease.

The baseline characteristics were well balanced and distributed between arms in the dMMR and all-comers population, said Nicoletta Colombo, MD, University of Milan–Bicocca, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico, Italy, who presented the findings at ESMO.

Over a median follow up of 26.2 months, Dr. Colombo and colleagues observed a statistically significant improvement in PFS in the dMMR arm in favor of atezolizumab (hazard ratio, 0.36; P = .0005). At 2 years, 50.4% of patients receiving the immunotherapy were progression-free, compared with 16.0% in the placebo arm.

In all-comers, the PFS improvement with atezolizumab was less pronounced but remained significant (HR, 0.74; P = .0219).

A secondary analysis revealed, among dMMR patients, atezolizumab was associated with an overall survival advantage over placebo (HR, 0.41), with 75% of patients still alive at 2 years vs. 54.2% in the placebo arm. Dr. Colombo also noted a “clear trend” for improved overall survival with atezolizumab as well (HR, 0.82; P = .0483), but no PFS or overall survival benefit was seen with atezolizumab in MMR proficient (pMMR) patients.

Dr. Colombo said the safety profile of atezolizumab plus chemotherapy was “manageable,” with no differences in the rates of “major side effects,” although there was an increase in the rate of treatment-related grade ≥ 3 adverse events in the atezolizumab group (25.8% vs. 14.1%).

Dr. Tan noted that the AtTEnd trial revealed comparable results to earlier trials in this space but underlined that the survival curves in the interim analysis revealed a “red zone” of dMMR patients who do not respond to the combination and in whom immunotherapy is “not sufficient.”

Alongside this, Dr. Tan flagged a “blue zone” of dMMR patients who plateaued in both PFS and overall survival after 2 years. The question for these patients at this point is whether they need to continue immunotherapy beyond 24 months, he said.

But overall, Dr. Tan noted, the AtTEnd data “continue to validate practice-changing therapy for dMMR endometrial cancer patients” with immunotherapy plus chemotherapy, with the lack of benefit in pMMR disease underscoring an “unmet medical need.”
 

Inside DUO-E

The burning question, however, was whether adding a PARP inhibitor to immunotherapy and chemotherapy would boost the survival outcomes further.

The DUO-E trial involved patients with newly diagnosed stage III/IV or recurrent endometrial cancer who had not received systematic therapy for advanced disease and were naive to both PARP inhibitors and immune-mediated therapy.

Overall, 718 patients were randomized to one of three arms: Chemotherapy alone followed by maintenance placebo, chemotherapy plus durvalumab with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab plus olaparib.

Maintenance was continued until disease progression or unacceptable toxicity, or the patients met another discontinuation criteria.

About half of patients were newly diagnosed, half had recurrent disease, and approximately one-fifth had dMMR disease, said Shannon Westin, MD, from the University of Texas MD Anderson Cancer Center, Houston, who presented the findings.

Compared with placebo plus chemotherapy, patients in both the durvalumab alone and durvalumab plus olaparib arms experienced a significant improvement in PFS (HR, 0.71; P = .003; and HR, 0.55; P < .0001, respectively).

This effect was amplified in dMMR patients with durvalumab (HR, 0.42) as well as with durvalumab plus olaparib (HR, 0.41).

In pMMR patients, PFS benefit was stronger in the durvalumab-olaparib arm vs. durvalumab (HR, 0.57 vs. 0.77).

Although the overall survival analysis remains exploratory, Dr. Westin noted a trend toward better overall survival in the two treatment arms vs. placebo (HR, 0.77 with durvalumab, and HR, 0.59 with durvalumab plus olaparib).

However, adding olaparib to the equation increased the rate of grade ≥ 3 adverse events – 67.2% vs. 54.9% with durvalumab and 56.4% with chemotherapy alone in the overall analysis. The addition of olaparib also led to treatment discontinuation in 24.4% of patients vs. 20.9% in the durvalumab arm and 18.6% in the chemotherapy alone arm.

Domenica Lorusso, MD, PhD, who was not involved in the study, commented that the marginal PFS benefit of adding olaparib in DUO-E is “not surprising” because the bar set by immunotherapy is “so high in this population that it’s very difficult” to go any higher.

But the results in pMMR patients reveal “a clear additional benefit” to olaparib, said Dr. Lorusso, from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

“The main limitation of the trial,” she continued, “is that it was not powered to make a formal comparison between the two experimental arms.”

So, what then is the added benefit of olaparib? “Unfortunately, that remains an unanswered question,” Dr. Lorusso said.

AtTEnd was sponsored by the Mario Negri Institute for Pharmacological Research.

DUO-E was funded by AstraZeneca.

Dr. Colombo declares relationships with AstraZeneca, Clovis Oncology, Esai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Roche, and Novocure.

Dr. Tan declares relationships with AstraZeneca, Karyopharm Therapeutics, Bayer, Roche, MSD, Genmab, Esai, PMV, BioNTech, Ellipses Pharma, Boehringer Ingelheim, Merck Serono, Takeda, and Clovis.

Dr. Westin declares relationships with AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis, Genentech/Roche, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, and Zentalis; and consulting and advisory roles for AstraZeneca, Caris, Clovis, Eisai, EQRx, Genentech/Roche, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mersana, Mereo, NGM Bio, Nuvectis, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.

Dr. Lorusso declares relationships with PharmaMar, Merck Serono, Novartis, AstraZeneca, Clovis, Tesaro/GSK, Genmab, Immunogen, and Roche.

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

MADRID – Research presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 underline the benefit of adding immunotherapy to chemotherapy in advanced or recurrent endometrial cancer, and question whether adding the PARP inhibitor olaparib to the chemo-immunotherapy combination could provide further benefit.

In the AtTEnd trial, presented on Oct. 21, more than 550 patients with advanced newly diagnosed or recurrent disease were randomized to the antiprogrammed death–ligand 1 (PD-L1) antibody atezolizumab (Tecentriq) or placebo plus chemotherapy followed by maintenance atezolizumab or placebo.

Adding immunotherapy to chemotherapy improved progression-free survival (PFS) among all-comers – 28.1% vs. 17% at 2 years. The PFS benefit was much more pronounced among patients with mismatch repair-deficient (dMMR) disease – 50.4% vs. 16% at 2 years. Mismatch repair-deficient disease patients receiving atezolizumab also demonstrated an early overall survival benefit, according to findings from the interim analysis.

In the DUO-E trial, presented during the same Oct. 21 session, nearly 720 patients with newly diagnosed advanced or recurrent endometrial cancer were randomized to one of three groups: Chemotherapy alone with maintenance placebo, chemotherapy plus durvalumab (Imfinzi) with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab and the PARP inhibitor olaparib.

The results, published simultaneously in the Journal of Clinical Oncology, showed that adding durvalumab to chemotherapy followed by maintenance durvalumab with or without olaparib led to a significant improvement in PFS, compared with chemotherapy alone. As in the AtTEnd trial, this PFS was also more pronounced in dMMR patients.

Overall, Andrés Cervantes, MD, PhD, from the University of Valencia, Spain, and president of ESMO, explained that this research marks “very positive data for women with gynecological cancers,” with immunotherapy now incorporated into the standard of care.

However, an expert questioned whether the DUO-E trial clearly demonstrated the benefit of adding olaparib to immuno- and chemotherapy and whether certain subsets of patients may be more likely to benefit from the PARP inhibitor.
 

Inside AtTEnd

A growing body of research has shown that single agent immunotherapy is effective in treating endometrial cancer, particularly in tumors with dMMR, and that immunotherapy and chemotherapy may have a synergistic effect.

David S. P. Tan, MD, PhD, National University Cancer Institute, Singapore, who was not involved in the studies, commented that “the molecular classification of endometrial cancer is now leading us to areas that we didn’t think before [were] possible.”

The rationale for combining immunotherapy with chemotherapy, Dr. Tan explained, is that “the cytotoxicity you get from chemotherapy is partly dependent on immune activity within the tumor, and so it makes sense” to combine them.

This approach was borne out by recent positive PFS results from the NRG-GY018 trial of pembrolizumab plus chemotherapy in advanced endometrial cancer as well as from the RUBY trial of dostarlimab in primary advanced or recurrent disease.

To further investigate this chemo-immunotherapy strategy, the AtTEnd team enrolled patients with newly diagnosed or recurrent stage III-IV disease who had received no prior systemic chemotherapy for recurrence within the previous 6 months.

Overall, 551 patients from 89 sites across 10 countries were randomized to standard first-line chemotherapy – carboplatin plus paclitaxel – with either atezolizumab or placebo, followed by maintenance atezolizumab or placebo, which continued until confirmed disease progression.

The median age in the intention-to-treat population was 64-67 years. Nearly 23% of patients had dMMR tumors, and 67.2% had recurrent disease.

The baseline characteristics were well balanced and distributed between arms in the dMMR and all-comers population, said Nicoletta Colombo, MD, University of Milan–Bicocca, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico, Italy, who presented the findings at ESMO.

Over a median follow up of 26.2 months, Dr. Colombo and colleagues observed a statistically significant improvement in PFS in the dMMR arm in favor of atezolizumab (hazard ratio, 0.36; P = .0005). At 2 years, 50.4% of patients receiving the immunotherapy were progression-free, compared with 16.0% in the placebo arm.

In all-comers, the PFS improvement with atezolizumab was less pronounced but remained significant (HR, 0.74; P = .0219).

A secondary analysis revealed, among dMMR patients, atezolizumab was associated with an overall survival advantage over placebo (HR, 0.41), with 75% of patients still alive at 2 years vs. 54.2% in the placebo arm. Dr. Colombo also noted a “clear trend” for improved overall survival with atezolizumab as well (HR, 0.82; P = .0483), but no PFS or overall survival benefit was seen with atezolizumab in MMR proficient (pMMR) patients.

Dr. Colombo said the safety profile of atezolizumab plus chemotherapy was “manageable,” with no differences in the rates of “major side effects,” although there was an increase in the rate of treatment-related grade ≥ 3 adverse events in the atezolizumab group (25.8% vs. 14.1%).

Dr. Tan noted that the AtTEnd trial revealed comparable results to earlier trials in this space but underlined that the survival curves in the interim analysis revealed a “red zone” of dMMR patients who do not respond to the combination and in whom immunotherapy is “not sufficient.”

Alongside this, Dr. Tan flagged a “blue zone” of dMMR patients who plateaued in both PFS and overall survival after 2 years. The question for these patients at this point is whether they need to continue immunotherapy beyond 24 months, he said.

But overall, Dr. Tan noted, the AtTEnd data “continue to validate practice-changing therapy for dMMR endometrial cancer patients” with immunotherapy plus chemotherapy, with the lack of benefit in pMMR disease underscoring an “unmet medical need.”
 

Inside DUO-E

The burning question, however, was whether adding a PARP inhibitor to immunotherapy and chemotherapy would boost the survival outcomes further.

The DUO-E trial involved patients with newly diagnosed stage III/IV or recurrent endometrial cancer who had not received systematic therapy for advanced disease and were naive to both PARP inhibitors and immune-mediated therapy.

Overall, 718 patients were randomized to one of three arms: Chemotherapy alone followed by maintenance placebo, chemotherapy plus durvalumab with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab plus olaparib.

Maintenance was continued until disease progression or unacceptable toxicity, or the patients met another discontinuation criteria.

About half of patients were newly diagnosed, half had recurrent disease, and approximately one-fifth had dMMR disease, said Shannon Westin, MD, from the University of Texas MD Anderson Cancer Center, Houston, who presented the findings.

Compared with placebo plus chemotherapy, patients in both the durvalumab alone and durvalumab plus olaparib arms experienced a significant improvement in PFS (HR, 0.71; P = .003; and HR, 0.55; P < .0001, respectively).

This effect was amplified in dMMR patients with durvalumab (HR, 0.42) as well as with durvalumab plus olaparib (HR, 0.41).

In pMMR patients, PFS benefit was stronger in the durvalumab-olaparib arm vs. durvalumab (HR, 0.57 vs. 0.77).

Although the overall survival analysis remains exploratory, Dr. Westin noted a trend toward better overall survival in the two treatment arms vs. placebo (HR, 0.77 with durvalumab, and HR, 0.59 with durvalumab plus olaparib).

However, adding olaparib to the equation increased the rate of grade ≥ 3 adverse events – 67.2% vs. 54.9% with durvalumab and 56.4% with chemotherapy alone in the overall analysis. The addition of olaparib also led to treatment discontinuation in 24.4% of patients vs. 20.9% in the durvalumab arm and 18.6% in the chemotherapy alone arm.

Domenica Lorusso, MD, PhD, who was not involved in the study, commented that the marginal PFS benefit of adding olaparib in DUO-E is “not surprising” because the bar set by immunotherapy is “so high in this population that it’s very difficult” to go any higher.

But the results in pMMR patients reveal “a clear additional benefit” to olaparib, said Dr. Lorusso, from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

“The main limitation of the trial,” she continued, “is that it was not powered to make a formal comparison between the two experimental arms.”

So, what then is the added benefit of olaparib? “Unfortunately, that remains an unanswered question,” Dr. Lorusso said.

AtTEnd was sponsored by the Mario Negri Institute for Pharmacological Research.

DUO-E was funded by AstraZeneca.

Dr. Colombo declares relationships with AstraZeneca, Clovis Oncology, Esai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Roche, and Novocure.

Dr. Tan declares relationships with AstraZeneca, Karyopharm Therapeutics, Bayer, Roche, MSD, Genmab, Esai, PMV, BioNTech, Ellipses Pharma, Boehringer Ingelheim, Merck Serono, Takeda, and Clovis.

Dr. Westin declares relationships with AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis, Genentech/Roche, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, and Zentalis; and consulting and advisory roles for AstraZeneca, Caris, Clovis, Eisai, EQRx, Genentech/Roche, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mersana, Mereo, NGM Bio, Nuvectis, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.

Dr. Lorusso declares relationships with PharmaMar, Merck Serono, Novartis, AstraZeneca, Clovis, Tesaro/GSK, Genmab, Immunogen, and Roche.

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

MADRID – Research presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 underline the benefit of adding immunotherapy to chemotherapy in advanced or recurrent endometrial cancer, and question whether adding the PARP inhibitor olaparib to the chemo-immunotherapy combination could provide further benefit.

In the AtTEnd trial, presented on Oct. 21, more than 550 patients with advanced newly diagnosed or recurrent disease were randomized to the antiprogrammed death–ligand 1 (PD-L1) antibody atezolizumab (Tecentriq) or placebo plus chemotherapy followed by maintenance atezolizumab or placebo.

Adding immunotherapy to chemotherapy improved progression-free survival (PFS) among all-comers – 28.1% vs. 17% at 2 years. The PFS benefit was much more pronounced among patients with mismatch repair-deficient (dMMR) disease – 50.4% vs. 16% at 2 years. Mismatch repair-deficient disease patients receiving atezolizumab also demonstrated an early overall survival benefit, according to findings from the interim analysis.

In the DUO-E trial, presented during the same Oct. 21 session, nearly 720 patients with newly diagnosed advanced or recurrent endometrial cancer were randomized to one of three groups: Chemotherapy alone with maintenance placebo, chemotherapy plus durvalumab (Imfinzi) with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab and the PARP inhibitor olaparib.

The results, published simultaneously in the Journal of Clinical Oncology, showed that adding durvalumab to chemotherapy followed by maintenance durvalumab with or without olaparib led to a significant improvement in PFS, compared with chemotherapy alone. As in the AtTEnd trial, this PFS was also more pronounced in dMMR patients.

Overall, Andrés Cervantes, MD, PhD, from the University of Valencia, Spain, and president of ESMO, explained that this research marks “very positive data for women with gynecological cancers,” with immunotherapy now incorporated into the standard of care.

However, an expert questioned whether the DUO-E trial clearly demonstrated the benefit of adding olaparib to immuno- and chemotherapy and whether certain subsets of patients may be more likely to benefit from the PARP inhibitor.
 

Inside AtTEnd

A growing body of research has shown that single agent immunotherapy is effective in treating endometrial cancer, particularly in tumors with dMMR, and that immunotherapy and chemotherapy may have a synergistic effect.

David S. P. Tan, MD, PhD, National University Cancer Institute, Singapore, who was not involved in the studies, commented that “the molecular classification of endometrial cancer is now leading us to areas that we didn’t think before [were] possible.”

The rationale for combining immunotherapy with chemotherapy, Dr. Tan explained, is that “the cytotoxicity you get from chemotherapy is partly dependent on immune activity within the tumor, and so it makes sense” to combine them.

This approach was borne out by recent positive PFS results from the NRG-GY018 trial of pembrolizumab plus chemotherapy in advanced endometrial cancer as well as from the RUBY trial of dostarlimab in primary advanced or recurrent disease.

To further investigate this chemo-immunotherapy strategy, the AtTEnd team enrolled patients with newly diagnosed or recurrent stage III-IV disease who had received no prior systemic chemotherapy for recurrence within the previous 6 months.

Overall, 551 patients from 89 sites across 10 countries were randomized to standard first-line chemotherapy – carboplatin plus paclitaxel – with either atezolizumab or placebo, followed by maintenance atezolizumab or placebo, which continued until confirmed disease progression.

The median age in the intention-to-treat population was 64-67 years. Nearly 23% of patients had dMMR tumors, and 67.2% had recurrent disease.

The baseline characteristics were well balanced and distributed between arms in the dMMR and all-comers population, said Nicoletta Colombo, MD, University of Milan–Bicocca, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico, Italy, who presented the findings at ESMO.

Over a median follow up of 26.2 months, Dr. Colombo and colleagues observed a statistically significant improvement in PFS in the dMMR arm in favor of atezolizumab (hazard ratio, 0.36; P = .0005). At 2 years, 50.4% of patients receiving the immunotherapy were progression-free, compared with 16.0% in the placebo arm.

In all-comers, the PFS improvement with atezolizumab was less pronounced but remained significant (HR, 0.74; P = .0219).

A secondary analysis revealed, among dMMR patients, atezolizumab was associated with an overall survival advantage over placebo (HR, 0.41), with 75% of patients still alive at 2 years vs. 54.2% in the placebo arm. Dr. Colombo also noted a “clear trend” for improved overall survival with atezolizumab as well (HR, 0.82; P = .0483), but no PFS or overall survival benefit was seen with atezolizumab in MMR proficient (pMMR) patients.

Dr. Colombo said the safety profile of atezolizumab plus chemotherapy was “manageable,” with no differences in the rates of “major side effects,” although there was an increase in the rate of treatment-related grade ≥ 3 adverse events in the atezolizumab group (25.8% vs. 14.1%).

Dr. Tan noted that the AtTEnd trial revealed comparable results to earlier trials in this space but underlined that the survival curves in the interim analysis revealed a “red zone” of dMMR patients who do not respond to the combination and in whom immunotherapy is “not sufficient.”

Alongside this, Dr. Tan flagged a “blue zone” of dMMR patients who plateaued in both PFS and overall survival after 2 years. The question for these patients at this point is whether they need to continue immunotherapy beyond 24 months, he said.

But overall, Dr. Tan noted, the AtTEnd data “continue to validate practice-changing therapy for dMMR endometrial cancer patients” with immunotherapy plus chemotherapy, with the lack of benefit in pMMR disease underscoring an “unmet medical need.”
 

Inside DUO-E

The burning question, however, was whether adding a PARP inhibitor to immunotherapy and chemotherapy would boost the survival outcomes further.

The DUO-E trial involved patients with newly diagnosed stage III/IV or recurrent endometrial cancer who had not received systematic therapy for advanced disease and were naive to both PARP inhibitors and immune-mediated therapy.

Overall, 718 patients were randomized to one of three arms: Chemotherapy alone followed by maintenance placebo, chemotherapy plus durvalumab with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab plus olaparib.

Maintenance was continued until disease progression or unacceptable toxicity, or the patients met another discontinuation criteria.

About half of patients were newly diagnosed, half had recurrent disease, and approximately one-fifth had dMMR disease, said Shannon Westin, MD, from the University of Texas MD Anderson Cancer Center, Houston, who presented the findings.

Compared with placebo plus chemotherapy, patients in both the durvalumab alone and durvalumab plus olaparib arms experienced a significant improvement in PFS (HR, 0.71; P = .003; and HR, 0.55; P < .0001, respectively).

This effect was amplified in dMMR patients with durvalumab (HR, 0.42) as well as with durvalumab plus olaparib (HR, 0.41).

In pMMR patients, PFS benefit was stronger in the durvalumab-olaparib arm vs. durvalumab (HR, 0.57 vs. 0.77).

Although the overall survival analysis remains exploratory, Dr. Westin noted a trend toward better overall survival in the two treatment arms vs. placebo (HR, 0.77 with durvalumab, and HR, 0.59 with durvalumab plus olaparib).

However, adding olaparib to the equation increased the rate of grade ≥ 3 adverse events – 67.2% vs. 54.9% with durvalumab and 56.4% with chemotherapy alone in the overall analysis. The addition of olaparib also led to treatment discontinuation in 24.4% of patients vs. 20.9% in the durvalumab arm and 18.6% in the chemotherapy alone arm.

Domenica Lorusso, MD, PhD, who was not involved in the study, commented that the marginal PFS benefit of adding olaparib in DUO-E is “not surprising” because the bar set by immunotherapy is “so high in this population that it’s very difficult” to go any higher.

But the results in pMMR patients reveal “a clear additional benefit” to olaparib, said Dr. Lorusso, from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

“The main limitation of the trial,” she continued, “is that it was not powered to make a formal comparison between the two experimental arms.”

So, what then is the added benefit of olaparib? “Unfortunately, that remains an unanswered question,” Dr. Lorusso said.

AtTEnd was sponsored by the Mario Negri Institute for Pharmacological Research.

DUO-E was funded by AstraZeneca.

Dr. Colombo declares relationships with AstraZeneca, Clovis Oncology, Esai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Roche, and Novocure.

Dr. Tan declares relationships with AstraZeneca, Karyopharm Therapeutics, Bayer, Roche, MSD, Genmab, Esai, PMV, BioNTech, Ellipses Pharma, Boehringer Ingelheim, Merck Serono, Takeda, and Clovis.

Dr. Westin declares relationships with AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis, Genentech/Roche, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, and Zentalis; and consulting and advisory roles for AstraZeneca, Caris, Clovis, Eisai, EQRx, Genentech/Roche, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mersana, Mereo, NGM Bio, Nuvectis, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.

Dr. Lorusso declares relationships with PharmaMar, Merck Serono, Novartis, AstraZeneca, Clovis, Tesaro/GSK, Genmab, Immunogen, and Roche.

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

Sirisha Manyam, DO, shares highlights at the AVAHO 2023 conference, including the keynote address by Under Secretary for Health Shereef Elnahal, MD, and a presentation on the Close to Me program that services veterans residing in rural areas.  

Dr Manyam found Dr Elnahal's address particularly compelling, with its emphasis on not only developing but also retaining an oncologic workforce formidable in its evidence-based approach and determined in its commitment to meet the current and coming challenges of veterans' healthcare.  

Sirisha Manyam, DO, shares highlights at the AVAHO 2023 conference, including the keynote address by Under Secretary for Health Shereef Elnahal, MD, and a presentation on the Close to Me program that services veterans residing in rural areas.  

Dr Manyam found Dr Elnahal's address particularly compelling, with its emphasis on not only developing but also retaining an oncologic workforce formidable in its evidence-based approach and determined in its commitment to meet the current and coming challenges of veterans' healthcare.  

Sirisha Manyam, DO, shares highlights at the AVAHO 2023 conference, including the keynote address by Under Secretary for Health Shereef Elnahal, MD, and a presentation on the Close to Me program that services veterans residing in rural areas.  

Dr Manyam found Dr Elnahal's address particularly compelling, with its emphasis on not only developing but also retaining an oncologic workforce formidable in its evidence-based approach and determined in its commitment to meet the current and coming challenges of veterans' healthcare.  

Soo Park, MD, reflects on the experience of attending the AVAHO 2023 conference and highlights several key takeaways. Dr Park emphasizes the progressive nature of the VA healthcare system, its impact on elevating cancer care for veterans, and the importance of teleoncology in reaching all veterans across the United States.

Dr Park details various presentations, such as the keynote address from Dr Shereef Elnahal, under secretary for health in the US Department of Veterans Affairs, and Dr Michael Kelley's discussion on the significance of clinical pathways for standardized care. Dr Park also highlights learnings from the conference, such as the VA's leadership in research efforts, particularly in prostate and lung cancer.

Soo Park, MD, reflects on the experience of attending the AVAHO 2023 conference and highlights several key takeaways. Dr Park emphasizes the progressive nature of the VA healthcare system, its impact on elevating cancer care for veterans, and the importance of teleoncology in reaching all veterans across the United States.

Dr Park details various presentations, such as the keynote address from Dr Shereef Elnahal, under secretary for health in the US Department of Veterans Affairs, and Dr Michael Kelley's discussion on the significance of clinical pathways for standardized care. Dr Park also highlights learnings from the conference, such as the VA's leadership in research efforts, particularly in prostate and lung cancer.

Soo Park, MD, reflects on the experience of attending the AVAHO 2023 conference and highlights several key takeaways. Dr Park emphasizes the progressive nature of the VA healthcare system, its impact on elevating cancer care for veterans, and the importance of teleoncology in reaching all veterans across the United States.

Dr Park details various presentations, such as the keynote address from Dr Shereef Elnahal, under secretary for health in the US Department of Veterans Affairs, and Dr Michael Kelley's discussion on the significance of clinical pathways for standardized care. Dr Park also highlights learnings from the conference, such as the VA's leadership in research efforts, particularly in prostate and lung cancer.

Timothy O'Brien, MD, highlights several key updates from AVAHO 2023 in the areas of toxin-exposure assessment, cancer screening programs, and the expansion of cancer care delivery to remote areas. 

Dr O'Brien shares notable examples from these areas like the PACT Act for veterans, successful lung cancer screening programs, the availability of new tests that measure minimal residual disease in patients with multiple myeloma, and initiatives like the Close to Me  infusion program to improve healthcare access for veterans in rural areas. 

Timothy O'Brien, MD, highlights several key updates from AVAHO 2023 in the areas of toxin-exposure assessment, cancer screening programs, and the expansion of cancer care delivery to remote areas. 

Dr O'Brien shares notable examples from these areas like the PACT Act for veterans, successful lung cancer screening programs, the availability of new tests that measure minimal residual disease in patients with multiple myeloma, and initiatives like the Close to Me  infusion program to improve healthcare access for veterans in rural areas. 

Timothy O'Brien, MD, highlights several key updates from AVAHO 2023 in the areas of toxin-exposure assessment, cancer screening programs, and the expansion of cancer care delivery to remote areas. 

Dr O'Brien shares notable examples from these areas like the PACT Act for veterans, successful lung cancer screening programs, the availability of new tests that measure minimal residual disease in patients with multiple myeloma, and initiatives like the Close to Me  infusion program to improve healthcare access for veterans in rural areas. 

Alectinib, a potent anaplastic lymphoma kinase (ALK) inhibitor, significantly improved disease-free survival (DFS) at 2 years, compared with chemotherapy, in patients with completely resected ALK+ non–small cell lung cancer (NSCLC), according to interim findings from the open-label phase 3 ALINA trial.

The results suggest that alectinib, which is currently the first-line treatment choice in more advanced NSCLC, also provides an effective new treatment strategy for patients with resected ALK+ NSCLC, said Ben Solomon, MBBS, PhD, who presented late-breaking data from the trial at the annual meeting of the European Society for Medical Oncology.

ALINA is the first phase 3 trial of an ALK inhibitor to show a DFS benefit in completely resected stage IB-IIIA disease, said Dr. Solomon, professor and medical oncologist at Peter MacCallum Cancer Centre, Melbourne.

The current treatment recommendation for after surgery in this patient population is platinum-based chemotherapy, which is associated with modest improvements in overall survival. But multiple trials looking at alectinib in stage I-III NSCLC are underway given the unmet need for treatment in the 4%-5% of NSCLC patients with ALK rearrangements, Dr. Solomon explained.

The ALINA trial enrolled adults with good performance status and completely resected stage IB-IIIA ALK+ NSCLC. Patients were randomized 1:1 to 600 mg of oral alectinib twice daily for up to 24 months or until disease recurrence, or up to four 21-day cycles of intravenous platinum-based chemotherapy.

At median follow-up of 27.8 months, Dr. Solomon and colleagues observed an overall DFS benefit in 130 patients with stage II-IIIA disease randomized to receive alectinib, compared with the 127 patients who received chemotherapy (median DFS not reached vs. 44.4 months; hazard ratio, 0.24). The benefit was observed in the overall intention-to-treat (ITT) population of patients with stage IB-IIIA disease (median DFS not reached vs. 41.3 months; HR, 0.24).

Two-year DFS was also improved with alectinib vs. chemotherapy for stage IB (HR, 0.21), stage II (HR, 0.24), and stage IIIA disease (HR, 0.25).

The investigators observed a clinically meaningful central nervous system DFS benefit in the ITT population as well (HR, 0.22). This finding is important, given that patients with ALK+ disease have a high risk of brain metastases, which occurs in 50%-60% of patients over the course of disease, Dr. Solomon noted.

Over the treatment duration in each arm, 23.4% of patients in the alectinib arm and 25.8% in the chemotherapy arm experienced grade 3 or 4 adverse events; 5 patients in the alectinib arm and 13 in the chemotherapy arm had adverse events that led to treatment discontinuation.

“Adjuvant alectinib was tolerable and in line with the known safety profile of alectinib,” Dr. Solomon concluded, but noted that the overall survival data were not yet mature.

Invited discussant Marina Garassino, MBBS, however, cautioned against rushing to judgment, calling the DFS findings “interesting, but early.”

“Are 2 years of alectinib enough to impact overall survival? We don’t know yet,” said Dr. Garassino, professor of medicine and director of the thoracic oncology program at the University of Chicago.

Chemotherapy, conversely, has been shown to improve overall survival, she noted.

Toxicity of alectinib in the adjuvant setting may be a concern as well, she said, explaining that patients have reported numerous side effects that can affect quality of life, such as sun sensitivity, difficulty focusing, neuropathy, lower back muscle soreness, and constipation.

“So, I think we should still wait for more results from this trial,” she said.

In the meantime, she said she will ask patients “if they want this kind of toxicity in the absence of a clear overall survival benefit.”

The ALINA trial is funded by F. Hoffmann-La Roche. Dr. Solomon and Dr. Garassino each reported numerous relationships with pharmaceutical companies and other entities.

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

Alectinib, a potent anaplastic lymphoma kinase (ALK) inhibitor, significantly improved disease-free survival (DFS) at 2 years, compared with chemotherapy, in patients with completely resected ALK+ non–small cell lung cancer (NSCLC), according to interim findings from the open-label phase 3 ALINA trial.

The results suggest that alectinib, which is currently the first-line treatment choice in more advanced NSCLC, also provides an effective new treatment strategy for patients with resected ALK+ NSCLC, said Ben Solomon, MBBS, PhD, who presented late-breaking data from the trial at the annual meeting of the European Society for Medical Oncology.

ALINA is the first phase 3 trial of an ALK inhibitor to show a DFS benefit in completely resected stage IB-IIIA disease, said Dr. Solomon, professor and medical oncologist at Peter MacCallum Cancer Centre, Melbourne.

The current treatment recommendation for after surgery in this patient population is platinum-based chemotherapy, which is associated with modest improvements in overall survival. But multiple trials looking at alectinib in stage I-III NSCLC are underway given the unmet need for treatment in the 4%-5% of NSCLC patients with ALK rearrangements, Dr. Solomon explained.

The ALINA trial enrolled adults with good performance status and completely resected stage IB-IIIA ALK+ NSCLC. Patients were randomized 1:1 to 600 mg of oral alectinib twice daily for up to 24 months or until disease recurrence, or up to four 21-day cycles of intravenous platinum-based chemotherapy.

At median follow-up of 27.8 months, Dr. Solomon and colleagues observed an overall DFS benefit in 130 patients with stage II-IIIA disease randomized to receive alectinib, compared with the 127 patients who received chemotherapy (median DFS not reached vs. 44.4 months; hazard ratio, 0.24). The benefit was observed in the overall intention-to-treat (ITT) population of patients with stage IB-IIIA disease (median DFS not reached vs. 41.3 months; HR, 0.24).

Two-year DFS was also improved with alectinib vs. chemotherapy for stage IB (HR, 0.21), stage II (HR, 0.24), and stage IIIA disease (HR, 0.25).

The investigators observed a clinically meaningful central nervous system DFS benefit in the ITT population as well (HR, 0.22). This finding is important, given that patients with ALK+ disease have a high risk of brain metastases, which occurs in 50%-60% of patients over the course of disease, Dr. Solomon noted.

Over the treatment duration in each arm, 23.4% of patients in the alectinib arm and 25.8% in the chemotherapy arm experienced grade 3 or 4 adverse events; 5 patients in the alectinib arm and 13 in the chemotherapy arm had adverse events that led to treatment discontinuation.

“Adjuvant alectinib was tolerable and in line with the known safety profile of alectinib,” Dr. Solomon concluded, but noted that the overall survival data were not yet mature.

Invited discussant Marina Garassino, MBBS, however, cautioned against rushing to judgment, calling the DFS findings “interesting, but early.”

“Are 2 years of alectinib enough to impact overall survival? We don’t know yet,” said Dr. Garassino, professor of medicine and director of the thoracic oncology program at the University of Chicago.

Chemotherapy, conversely, has been shown to improve overall survival, she noted.

Toxicity of alectinib in the adjuvant setting may be a concern as well, she said, explaining that patients have reported numerous side effects that can affect quality of life, such as sun sensitivity, difficulty focusing, neuropathy, lower back muscle soreness, and constipation.

“So, I think we should still wait for more results from this trial,” she said.

In the meantime, she said she will ask patients “if they want this kind of toxicity in the absence of a clear overall survival benefit.”

The ALINA trial is funded by F. Hoffmann-La Roche. Dr. Solomon and Dr. Garassino each reported numerous relationships with pharmaceutical companies and other entities.

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

Alectinib, a potent anaplastic lymphoma kinase (ALK) inhibitor, significantly improved disease-free survival (DFS) at 2 years, compared with chemotherapy, in patients with completely resected ALK+ non–small cell lung cancer (NSCLC), according to interim findings from the open-label phase 3 ALINA trial.

The results suggest that alectinib, which is currently the first-line treatment choice in more advanced NSCLC, also provides an effective new treatment strategy for patients with resected ALK+ NSCLC, said Ben Solomon, MBBS, PhD, who presented late-breaking data from the trial at the annual meeting of the European Society for Medical Oncology.

ALINA is the first phase 3 trial of an ALK inhibitor to show a DFS benefit in completely resected stage IB-IIIA disease, said Dr. Solomon, professor and medical oncologist at Peter MacCallum Cancer Centre, Melbourne.

The current treatment recommendation for after surgery in this patient population is platinum-based chemotherapy, which is associated with modest improvements in overall survival. But multiple trials looking at alectinib in stage I-III NSCLC are underway given the unmet need for treatment in the 4%-5% of NSCLC patients with ALK rearrangements, Dr. Solomon explained.

The ALINA trial enrolled adults with good performance status and completely resected stage IB-IIIA ALK+ NSCLC. Patients were randomized 1:1 to 600 mg of oral alectinib twice daily for up to 24 months or until disease recurrence, or up to four 21-day cycles of intravenous platinum-based chemotherapy.

At median follow-up of 27.8 months, Dr. Solomon and colleagues observed an overall DFS benefit in 130 patients with stage II-IIIA disease randomized to receive alectinib, compared with the 127 patients who received chemotherapy (median DFS not reached vs. 44.4 months; hazard ratio, 0.24). The benefit was observed in the overall intention-to-treat (ITT) population of patients with stage IB-IIIA disease (median DFS not reached vs. 41.3 months; HR, 0.24).

Two-year DFS was also improved with alectinib vs. chemotherapy for stage IB (HR, 0.21), stage II (HR, 0.24), and stage IIIA disease (HR, 0.25).

The investigators observed a clinically meaningful central nervous system DFS benefit in the ITT population as well (HR, 0.22). This finding is important, given that patients with ALK+ disease have a high risk of brain metastases, which occurs in 50%-60% of patients over the course of disease, Dr. Solomon noted.

Over the treatment duration in each arm, 23.4% of patients in the alectinib arm and 25.8% in the chemotherapy arm experienced grade 3 or 4 adverse events; 5 patients in the alectinib arm and 13 in the chemotherapy arm had adverse events that led to treatment discontinuation.

“Adjuvant alectinib was tolerable and in line with the known safety profile of alectinib,” Dr. Solomon concluded, but noted that the overall survival data were not yet mature.

Invited discussant Marina Garassino, MBBS, however, cautioned against rushing to judgment, calling the DFS findings “interesting, but early.”

“Are 2 years of alectinib enough to impact overall survival? We don’t know yet,” said Dr. Garassino, professor of medicine and director of the thoracic oncology program at the University of Chicago.

Chemotherapy, conversely, has been shown to improve overall survival, she noted.

Toxicity of alectinib in the adjuvant setting may be a concern as well, she said, explaining that patients have reported numerous side effects that can affect quality of life, such as sun sensitivity, difficulty focusing, neuropathy, lower back muscle soreness, and constipation.

“So, I think we should still wait for more results from this trial,” she said.

In the meantime, she said she will ask patients “if they want this kind of toxicity in the absence of a clear overall survival benefit.”

The ALINA trial is funded by F. Hoffmann-La Roche. Dr. Solomon and Dr. Garassino each reported numerous relationships with pharmaceutical companies and other entities.

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

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

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

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

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

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

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

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.