Neil Osterweil

Patients with COVID-19 and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer, according to data from the COVID-19 and Cancer Consortium (CCC19) registry.

Mongkolchon Akesin/Shutterstock

Other independent risk factors for death in patients with COVID-19 and cancer were older age, male sex, former smoking, number of comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, and treatment with hydroxychloroquine plus azithromycin.

In fact, patients who received hydroxychloroquine and azithromycin had a nearly threefold higher risk of death than did patients who had not received the combination. However, this finding was of “uncertain validity due to a high risk of residual confounding; for example, patients receiving this combination were more likely to have severe disease or more likely to be hospitalized,” said Jeremy L. Warner, MD, of Vanderbilt University Medical Center in Nashville, Tennessee.

Dr. Warner presented these findings in an online press briefing. Additional findings from the CCC19 registry are set to be presented as part of the American Society of Clinical Oncology (ASCO) virtual scientific program. The findings were also published in The Lancet.

‘Severe impact’ in cancer patients

“For people with cancer, the impact of COVID-19 is especially severe, whether they have been exposed to the virus or not. Patients with cancer are typically older adults, often with other underlying conditions, and their immune systems may be suppressed by the cancer, or due to chemotherapy, radiation, or other treatment,” commented ASCO President Howard A. Burris III, MD, who moderated the press briefing but was not involved in the study of CCC19 registry data.

“ASCO members tell us that they have had to delay or modify treatment plans to reduce patients’ risk of infection, and we’re unclear what the impact of these changes will be. Delays in cancer screening and diagnosis are also a major concern,” Dr. Burris continued.

“This does confirm reports that have come out from other centers, including other parts of the world, where they have found that people who have cancer and COVID-19 have a worse outcome,” said Andrew T. Chan, MD, MPH, of Massachusetts General Hospital in Boston, who was not involved in the research.

Dr. Chan’s group has developed a COVID-19 symptom study app with the aim of defining whether people living with cancer are at increased risk for infections, in addition to whether cancer is an independent risk factor for COVID-19 severity or mortality.

“Using data from our app, we were able to show that people who reported living with cancer did have a higher risk of developing COVID and were more likely to be hospitalized related to COVID,” Dr. Chan said in an interview.
 

Study details

The CCC19 registry collects information from 104 participating institutions in the United States and Canada, as well as anonymous data from individuals in the United States, Argentina, Canada, the European Union, and the United Kingdom.

The sample of 928 patients Dr. Warner presented was evenly balanced by sex. The median age was 66 years, and 30% of patients were aged 75 years or older.

In all, 39% of patients were on active anticancer therapy, and 43% had measurable disease. Breast cancer was the most common diagnosis, followed by prostate cancer, gastrointestinal cancers, lymphomas, and thoracic cancers.

Two-thirds of the patients (68%) had an ECOG performance status of 0 or 1, 8% had a performance status of 2, and 5% a status of 3 or 4. The remaining patients had unknown performance status.

Slightly more than half of patients (52%) were never smokers, 37% were former smokers, and 5% were current smokers. The remaining 6% of patients had unknown smoking status.

At a median follow-up of 21 days, 121 patients (13%) had died. All deaths occurred within 30 days of COVID-19 diagnosis. Among patients who died, 78 were male, 64 were former smokers, 70 were aged 75 years or older, 41 had active stable or responding cancer, 25 had progressing cancer, and 42 had an ECOG performance status of 2 or higher.

In all, 466 patients were hospitalized, and 106 in this group (23%) died. Among the 132 patients admitted to an ICU, 50 (38%) died, including 27 patients aged 75 years or older, and 15 with an ECOG performance status of 2 or greater. Of the 116 patients who required intubation, 50 (43%) died, including 26 who were 75 years or older, and 11 who had a performance status of 2 or greater.

It’s early days yet, and a larger sample size with longer follow-up will be needed to get a more complete picture of how COVID-19 affects specific patient subsets over time, Dr. Warner said.

ASCO has established its own COVID-19 registry to collect both near-term and longitudinal data during the pandemic.

“We’ll be able to learn about both how the pandemic has impacted delivery of cancer care, as well as the longer-term effects of COVID-19 on cancer patients and understand what care approaches are working best,” said Richard L. Schilsky, MD, chief medical officer and executive vice president of ASCO, during the briefing.

The study of CCC19 registry data was supported in part by the National Institutes of Health and the American Cancer Society. Dr. Warner disclosed stock/ownership in HemOnc.org, consulting for IBM and Westat, and travel expenses from IBM. Dr. Burris, Dr. Schilsky, and Dr. Chan reported no disclosures relevant to the study.
 

SOURCE: Warner J L et al. ASCO 2020, Abstract LBA110.

Patients with COVID-19 and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer, according to data from the COVID-19 and Cancer Consortium (CCC19) registry.

Mongkolchon Akesin/Shutterstock

Other independent risk factors for death in patients with COVID-19 and cancer were older age, male sex, former smoking, number of comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, and treatment with hydroxychloroquine plus azithromycin.

In fact, patients who received hydroxychloroquine and azithromycin had a nearly threefold higher risk of death than did patients who had not received the combination. However, this finding was of “uncertain validity due to a high risk of residual confounding; for example, patients receiving this combination were more likely to have severe disease or more likely to be hospitalized,” said Jeremy L. Warner, MD, of Vanderbilt University Medical Center in Nashville, Tennessee.

Dr. Warner presented these findings in an online press briefing. Additional findings from the CCC19 registry are set to be presented as part of the American Society of Clinical Oncology (ASCO) virtual scientific program. The findings were also published in The Lancet.

‘Severe impact’ in cancer patients

“For people with cancer, the impact of COVID-19 is especially severe, whether they have been exposed to the virus or not. Patients with cancer are typically older adults, often with other underlying conditions, and their immune systems may be suppressed by the cancer, or due to chemotherapy, radiation, or other treatment,” commented ASCO President Howard A. Burris III, MD, who moderated the press briefing but was not involved in the study of CCC19 registry data.

“ASCO members tell us that they have had to delay or modify treatment plans to reduce patients’ risk of infection, and we’re unclear what the impact of these changes will be. Delays in cancer screening and diagnosis are also a major concern,” Dr. Burris continued.

“This does confirm reports that have come out from other centers, including other parts of the world, where they have found that people who have cancer and COVID-19 have a worse outcome,” said Andrew T. Chan, MD, MPH, of Massachusetts General Hospital in Boston, who was not involved in the research.

Dr. Chan’s group has developed a COVID-19 symptom study app with the aim of defining whether people living with cancer are at increased risk for infections, in addition to whether cancer is an independent risk factor for COVID-19 severity or mortality.

“Using data from our app, we were able to show that people who reported living with cancer did have a higher risk of developing COVID and were more likely to be hospitalized related to COVID,” Dr. Chan said in an interview.
 

Study details

The CCC19 registry collects information from 104 participating institutions in the United States and Canada, as well as anonymous data from individuals in the United States, Argentina, Canada, the European Union, and the United Kingdom.

The sample of 928 patients Dr. Warner presented was evenly balanced by sex. The median age was 66 years, and 30% of patients were aged 75 years or older.

In all, 39% of patients were on active anticancer therapy, and 43% had measurable disease. Breast cancer was the most common diagnosis, followed by prostate cancer, gastrointestinal cancers, lymphomas, and thoracic cancers.

Two-thirds of the patients (68%) had an ECOG performance status of 0 or 1, 8% had a performance status of 2, and 5% a status of 3 or 4. The remaining patients had unknown performance status.

Slightly more than half of patients (52%) were never smokers, 37% were former smokers, and 5% were current smokers. The remaining 6% of patients had unknown smoking status.

At a median follow-up of 21 days, 121 patients (13%) had died. All deaths occurred within 30 days of COVID-19 diagnosis. Among patients who died, 78 were male, 64 were former smokers, 70 were aged 75 years or older, 41 had active stable or responding cancer, 25 had progressing cancer, and 42 had an ECOG performance status of 2 or higher.

In all, 466 patients were hospitalized, and 106 in this group (23%) died. Among the 132 patients admitted to an ICU, 50 (38%) died, including 27 patients aged 75 years or older, and 15 with an ECOG performance status of 2 or greater. Of the 116 patients who required intubation, 50 (43%) died, including 26 who were 75 years or older, and 11 who had a performance status of 2 or greater.

It’s early days yet, and a larger sample size with longer follow-up will be needed to get a more complete picture of how COVID-19 affects specific patient subsets over time, Dr. Warner said.

ASCO has established its own COVID-19 registry to collect both near-term and longitudinal data during the pandemic.

“We’ll be able to learn about both how the pandemic has impacted delivery of cancer care, as well as the longer-term effects of COVID-19 on cancer patients and understand what care approaches are working best,” said Richard L. Schilsky, MD, chief medical officer and executive vice president of ASCO, during the briefing.

The study of CCC19 registry data was supported in part by the National Institutes of Health and the American Cancer Society. Dr. Warner disclosed stock/ownership in HemOnc.org, consulting for IBM and Westat, and travel expenses from IBM. Dr. Burris, Dr. Schilsky, and Dr. Chan reported no disclosures relevant to the study.
 

SOURCE: Warner J L et al. ASCO 2020, Abstract LBA110.

Patients with COVID-19 and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer, according to data from the COVID-19 and Cancer Consortium (CCC19) registry.

Mongkolchon Akesin/Shutterstock

Other independent risk factors for death in patients with COVID-19 and cancer were older age, male sex, former smoking, number of comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, and treatment with hydroxychloroquine plus azithromycin.

In fact, patients who received hydroxychloroquine and azithromycin had a nearly threefold higher risk of death than did patients who had not received the combination. However, this finding was of “uncertain validity due to a high risk of residual confounding; for example, patients receiving this combination were more likely to have severe disease or more likely to be hospitalized,” said Jeremy L. Warner, MD, of Vanderbilt University Medical Center in Nashville, Tennessee.

Dr. Warner presented these findings in an online press briefing. Additional findings from the CCC19 registry are set to be presented as part of the American Society of Clinical Oncology (ASCO) virtual scientific program. The findings were also published in The Lancet.

‘Severe impact’ in cancer patients

“For people with cancer, the impact of COVID-19 is especially severe, whether they have been exposed to the virus or not. Patients with cancer are typically older adults, often with other underlying conditions, and their immune systems may be suppressed by the cancer, or due to chemotherapy, radiation, or other treatment,” commented ASCO President Howard A. Burris III, MD, who moderated the press briefing but was not involved in the study of CCC19 registry data.

“ASCO members tell us that they have had to delay or modify treatment plans to reduce patients’ risk of infection, and we’re unclear what the impact of these changes will be. Delays in cancer screening and diagnosis are also a major concern,” Dr. Burris continued.

“This does confirm reports that have come out from other centers, including other parts of the world, where they have found that people who have cancer and COVID-19 have a worse outcome,” said Andrew T. Chan, MD, MPH, of Massachusetts General Hospital in Boston, who was not involved in the research.

Dr. Chan’s group has developed a COVID-19 symptom study app with the aim of defining whether people living with cancer are at increased risk for infections, in addition to whether cancer is an independent risk factor for COVID-19 severity or mortality.

“Using data from our app, we were able to show that people who reported living with cancer did have a higher risk of developing COVID and were more likely to be hospitalized related to COVID,” Dr. Chan said in an interview.
 

Study details

The CCC19 registry collects information from 104 participating institutions in the United States and Canada, as well as anonymous data from individuals in the United States, Argentina, Canada, the European Union, and the United Kingdom.

The sample of 928 patients Dr. Warner presented was evenly balanced by sex. The median age was 66 years, and 30% of patients were aged 75 years or older.

In all, 39% of patients were on active anticancer therapy, and 43% had measurable disease. Breast cancer was the most common diagnosis, followed by prostate cancer, gastrointestinal cancers, lymphomas, and thoracic cancers.

Two-thirds of the patients (68%) had an ECOG performance status of 0 or 1, 8% had a performance status of 2, and 5% a status of 3 or 4. The remaining patients had unknown performance status.

Slightly more than half of patients (52%) were never smokers, 37% were former smokers, and 5% were current smokers. The remaining 6% of patients had unknown smoking status.

At a median follow-up of 21 days, 121 patients (13%) had died. All deaths occurred within 30 days of COVID-19 diagnosis. Among patients who died, 78 were male, 64 were former smokers, 70 were aged 75 years or older, 41 had active stable or responding cancer, 25 had progressing cancer, and 42 had an ECOG performance status of 2 or higher.

In all, 466 patients were hospitalized, and 106 in this group (23%) died. Among the 132 patients admitted to an ICU, 50 (38%) died, including 27 patients aged 75 years or older, and 15 with an ECOG performance status of 2 or greater. Of the 116 patients who required intubation, 50 (43%) died, including 26 who were 75 years or older, and 11 who had a performance status of 2 or greater.

It’s early days yet, and a larger sample size with longer follow-up will be needed to get a more complete picture of how COVID-19 affects specific patient subsets over time, Dr. Warner said.

ASCO has established its own COVID-19 registry to collect both near-term and longitudinal data during the pandemic.

“We’ll be able to learn about both how the pandemic has impacted delivery of cancer care, as well as the longer-term effects of COVID-19 on cancer patients and understand what care approaches are working best,” said Richard L. Schilsky, MD, chief medical officer and executive vice president of ASCO, during the briefing.

The study of CCC19 registry data was supported in part by the National Institutes of Health and the American Cancer Society. Dr. Warner disclosed stock/ownership in HemOnc.org, consulting for IBM and Westat, and travel expenses from IBM. Dr. Burris, Dr. Schilsky, and Dr. Chan reported no disclosures relevant to the study.
 

SOURCE: Warner J L et al. ASCO 2020, Abstract LBA110.

Adjuvant therapy with osimertinib was associated with a nearly 80% reduction in the risk of disease recurrence or death in patients with stage IB-IIIA non–small cell lung cancer (NSCLC) bearing EGFR mutations, results of the ADAURA trial showed.

The randomized, phase 3 trial was a comparison of osimertinib treatment with placebo following complete resection of localized or locally advanced NSCLC with negative margins. The trial was unblinded early and halted on the recommendation of the independent data-monitoring committee, due to the efficacy of osimertinib.

“If I were on the committee, I would have done the same thing. These are extraordinary results,” said study investigator Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center and Smilow Cancer Center at Yale University in New Haven, Conn.

Dr. Herbst is scheduled to present results from ADAURA as part of the American Society of Clinical Oncology virtual scientific program.

In an online briefing prior to the meeting, Dr. Herbst said the impressive results reminded him of a lesson imparted by his mentor, the late Isaiah Fidler, DVM, PhD.

“He taught me, he taught all of us, that metastasis is a spread of tumor that kills patients,” Dr. Herbst said. “Drugs such as this, based on biology, given to patients at the earliest possible time, prevent those metastases and allow patients to live longer and with a better quality of life.”

Results from the ADAURA trial provide compelling evidence of the benefit of adjuvant osimertinib for a select group of patients, according to Tina Cascone, MD, PhD, assistant professor in the department of thoracic head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. She was not involved in the study.

“These are unprecedented results for a potentially curable, resected population of patients,” Dr. Cascone said in an interview. “This definitely has the potential to shift the paradigm in the treatments that we have available for patients with resected disease. It’s very important to emphasize how much we’ve learned from the metastatic setting and how we’re bringing what we’ve learned into early stage disease.”

 

High recurrence rates

An estimated 30% of patients with NSCLC present with resectable disease at diagnosis, but 5-year recurrence rates following surgery and cisplatin-based adjuvant chemotherapy remain high, ranging from 45% among patients with stage IB disease to 62% for patients with stage II NSCLC and 76% for patients with stage III disease, Dr. Herbst noted.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) targeted to EGFR. It has been shown to offer improvements in both progression-free survival and overall survival compared with the EGFR-TKIs erlotinib and gefitinib for patients with advanced EGFR-mutated NSCLC, as well as in patients with central nervous system metastases.

Osimertinib’s efficacy and safety profile against advanced disease suggests it may also be effective against early stage disease, a hypothesis the ADAURA trial was designed to test.
 

Study details

The phase 3, randomized, double-blind trial was conducted at centers in the United States, Europe, Asia, and Australia. A total of 682 patients with completely resected stage IB, II, or IIIA NSCLC, with or without planned adjuvant chemotherapy, were enrolled.

After stratification by stage, EGFR mutation, and race (Asian vs. non-Asian), patients were randomized on a 1:1 basis to receive either osimertinib at 80 mg once daily or placebo. The planned treatment duration was a maximum of 3 years.

Members of the independent data-monitoring committee held a meeting in April 2020. Although they had not planned an efficacy analysis at that time, they decided the results were clearly in favor of osimertinib. So they recommended unblinding and halting of the trial.

At the time of unblinding, the study had completed enrollment, and all patients had been followed for at least 1 year.
 

Efficacy and safety

For the primary endpoint of disease-free survival (DFS) in patients with stage II to IIIA disease, the median DFS was not reached for patients assigned to osimertinib, but it was 20.4 months for patients assigned to placebo (hazard ratio, 0.17; P < .0001).

The numbers were similar for the secondary endpoint of DFS in the overall population, including patients with stage IB disease. The median DFS was not reached for patients on osimertinib but was 28.1 months for patients on placebo (HR, 0.21; P < .0001).

DFS was significantly superior with osimertinib across all subgroups in the overall population, including sex, age, smoking status, race, stage, EGFR mutation, and adjuvant chemotherapy (yes or no).

Dr. Herbst said patients tolerated osimertinib well, and the drug’s safety profile was consistent with that already known. There were no adverse events leading to death in the osimertinib arm, and the incidence of grade 3 or 4 adverse events of any kind was low.

In all, 10 patients (3%) in the osimertinib arm were reported to have interstitial lung disease. Prolongation of the QT interval was reported in 22 patients (7%) on osimertinib and 4 patients (1%) in the placebo arm.

The results show that “adjuvant osimertinib provides a highly effective, practice-changing treatment for patients with stage IB, II, IIIA, EGFR mutation-positive non–small cell lung cancer after complete tumor resection,” Dr. Herbst said.

Dr. Herbst disclosed relationships with AstraZeneca, which funded the study, as well as Jun Shi Pharmaceuticals and other companies. Dr. Cascone is the international principal investigator of the NeoCOAST trial evaluating durvalumab, an AstraZeneca product.

SOURCE: Herbst RS et al. ASCO 2020, Abstract LBA5.

Adjuvant therapy with osimertinib was associated with a nearly 80% reduction in the risk of disease recurrence or death in patients with stage IB-IIIA non–small cell lung cancer (NSCLC) bearing EGFR mutations, results of the ADAURA trial showed.

The randomized, phase 3 trial was a comparison of osimertinib treatment with placebo following complete resection of localized or locally advanced NSCLC with negative margins. The trial was unblinded early and halted on the recommendation of the independent data-monitoring committee, due to the efficacy of osimertinib.

“If I were on the committee, I would have done the same thing. These are extraordinary results,” said study investigator Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center and Smilow Cancer Center at Yale University in New Haven, Conn.

Dr. Herbst is scheduled to present results from ADAURA as part of the American Society of Clinical Oncology virtual scientific program.

In an online briefing prior to the meeting, Dr. Herbst said the impressive results reminded him of a lesson imparted by his mentor, the late Isaiah Fidler, DVM, PhD.

“He taught me, he taught all of us, that metastasis is a spread of tumor that kills patients,” Dr. Herbst said. “Drugs such as this, based on biology, given to patients at the earliest possible time, prevent those metastases and allow patients to live longer and with a better quality of life.”

Results from the ADAURA trial provide compelling evidence of the benefit of adjuvant osimertinib for a select group of patients, according to Tina Cascone, MD, PhD, assistant professor in the department of thoracic head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. She was not involved in the study.

“These are unprecedented results for a potentially curable, resected population of patients,” Dr. Cascone said in an interview. “This definitely has the potential to shift the paradigm in the treatments that we have available for patients with resected disease. It’s very important to emphasize how much we’ve learned from the metastatic setting and how we’re bringing what we’ve learned into early stage disease.”

 

High recurrence rates

An estimated 30% of patients with NSCLC present with resectable disease at diagnosis, but 5-year recurrence rates following surgery and cisplatin-based adjuvant chemotherapy remain high, ranging from 45% among patients with stage IB disease to 62% for patients with stage II NSCLC and 76% for patients with stage III disease, Dr. Herbst noted.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) targeted to EGFR. It has been shown to offer improvements in both progression-free survival and overall survival compared with the EGFR-TKIs erlotinib and gefitinib for patients with advanced EGFR-mutated NSCLC, as well as in patients with central nervous system metastases.

Osimertinib’s efficacy and safety profile against advanced disease suggests it may also be effective against early stage disease, a hypothesis the ADAURA trial was designed to test.
 

Study details

The phase 3, randomized, double-blind trial was conducted at centers in the United States, Europe, Asia, and Australia. A total of 682 patients with completely resected stage IB, II, or IIIA NSCLC, with or without planned adjuvant chemotherapy, were enrolled.

After stratification by stage, EGFR mutation, and race (Asian vs. non-Asian), patients were randomized on a 1:1 basis to receive either osimertinib at 80 mg once daily or placebo. The planned treatment duration was a maximum of 3 years.

Members of the independent data-monitoring committee held a meeting in April 2020. Although they had not planned an efficacy analysis at that time, they decided the results were clearly in favor of osimertinib. So they recommended unblinding and halting of the trial.

At the time of unblinding, the study had completed enrollment, and all patients had been followed for at least 1 year.
 

Efficacy and safety

For the primary endpoint of disease-free survival (DFS) in patients with stage II to IIIA disease, the median DFS was not reached for patients assigned to osimertinib, but it was 20.4 months for patients assigned to placebo (hazard ratio, 0.17; P < .0001).

The numbers were similar for the secondary endpoint of DFS in the overall population, including patients with stage IB disease. The median DFS was not reached for patients on osimertinib but was 28.1 months for patients on placebo (HR, 0.21; P < .0001).

DFS was significantly superior with osimertinib across all subgroups in the overall population, including sex, age, smoking status, race, stage, EGFR mutation, and adjuvant chemotherapy (yes or no).

Dr. Herbst said patients tolerated osimertinib well, and the drug’s safety profile was consistent with that already known. There were no adverse events leading to death in the osimertinib arm, and the incidence of grade 3 or 4 adverse events of any kind was low.

In all, 10 patients (3%) in the osimertinib arm were reported to have interstitial lung disease. Prolongation of the QT interval was reported in 22 patients (7%) on osimertinib and 4 patients (1%) in the placebo arm.

The results show that “adjuvant osimertinib provides a highly effective, practice-changing treatment for patients with stage IB, II, IIIA, EGFR mutation-positive non–small cell lung cancer after complete tumor resection,” Dr. Herbst said.

Dr. Herbst disclosed relationships with AstraZeneca, which funded the study, as well as Jun Shi Pharmaceuticals and other companies. Dr. Cascone is the international principal investigator of the NeoCOAST trial evaluating durvalumab, an AstraZeneca product.

SOURCE: Herbst RS et al. ASCO 2020, Abstract LBA5.

Adjuvant therapy with osimertinib was associated with a nearly 80% reduction in the risk of disease recurrence or death in patients with stage IB-IIIA non–small cell lung cancer (NSCLC) bearing EGFR mutations, results of the ADAURA trial showed.

The randomized, phase 3 trial was a comparison of osimertinib treatment with placebo following complete resection of localized or locally advanced NSCLC with negative margins. The trial was unblinded early and halted on the recommendation of the independent data-monitoring committee, due to the efficacy of osimertinib.

“If I were on the committee, I would have done the same thing. These are extraordinary results,” said study investigator Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center and Smilow Cancer Center at Yale University in New Haven, Conn.

Dr. Herbst is scheduled to present results from ADAURA as part of the American Society of Clinical Oncology virtual scientific program.

In an online briefing prior to the meeting, Dr. Herbst said the impressive results reminded him of a lesson imparted by his mentor, the late Isaiah Fidler, DVM, PhD.

“He taught me, he taught all of us, that metastasis is a spread of tumor that kills patients,” Dr. Herbst said. “Drugs such as this, based on biology, given to patients at the earliest possible time, prevent those metastases and allow patients to live longer and with a better quality of life.”

Results from the ADAURA trial provide compelling evidence of the benefit of adjuvant osimertinib for a select group of patients, according to Tina Cascone, MD, PhD, assistant professor in the department of thoracic head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. She was not involved in the study.

“These are unprecedented results for a potentially curable, resected population of patients,” Dr. Cascone said in an interview. “This definitely has the potential to shift the paradigm in the treatments that we have available for patients with resected disease. It’s very important to emphasize how much we’ve learned from the metastatic setting and how we’re bringing what we’ve learned into early stage disease.”

 

High recurrence rates

An estimated 30% of patients with NSCLC present with resectable disease at diagnosis, but 5-year recurrence rates following surgery and cisplatin-based adjuvant chemotherapy remain high, ranging from 45% among patients with stage IB disease to 62% for patients with stage II NSCLC and 76% for patients with stage III disease, Dr. Herbst noted.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) targeted to EGFR. It has been shown to offer improvements in both progression-free survival and overall survival compared with the EGFR-TKIs erlotinib and gefitinib for patients with advanced EGFR-mutated NSCLC, as well as in patients with central nervous system metastases.

Osimertinib’s efficacy and safety profile against advanced disease suggests it may also be effective against early stage disease, a hypothesis the ADAURA trial was designed to test.
 

Study details

The phase 3, randomized, double-blind trial was conducted at centers in the United States, Europe, Asia, and Australia. A total of 682 patients with completely resected stage IB, II, or IIIA NSCLC, with or without planned adjuvant chemotherapy, were enrolled.

After stratification by stage, EGFR mutation, and race (Asian vs. non-Asian), patients were randomized on a 1:1 basis to receive either osimertinib at 80 mg once daily or placebo. The planned treatment duration was a maximum of 3 years.

Members of the independent data-monitoring committee held a meeting in April 2020. Although they had not planned an efficacy analysis at that time, they decided the results were clearly in favor of osimertinib. So they recommended unblinding and halting of the trial.

At the time of unblinding, the study had completed enrollment, and all patients had been followed for at least 1 year.
 

Efficacy and safety

For the primary endpoint of disease-free survival (DFS) in patients with stage II to IIIA disease, the median DFS was not reached for patients assigned to osimertinib, but it was 20.4 months for patients assigned to placebo (hazard ratio, 0.17; P < .0001).

The numbers were similar for the secondary endpoint of DFS in the overall population, including patients with stage IB disease. The median DFS was not reached for patients on osimertinib but was 28.1 months for patients on placebo (HR, 0.21; P < .0001).

DFS was significantly superior with osimertinib across all subgroups in the overall population, including sex, age, smoking status, race, stage, EGFR mutation, and adjuvant chemotherapy (yes or no).

Dr. Herbst said patients tolerated osimertinib well, and the drug’s safety profile was consistent with that already known. There were no adverse events leading to death in the osimertinib arm, and the incidence of grade 3 or 4 adverse events of any kind was low.

In all, 10 patients (3%) in the osimertinib arm were reported to have interstitial lung disease. Prolongation of the QT interval was reported in 22 patients (7%) on osimertinib and 4 patients (1%) in the placebo arm.

The results show that “adjuvant osimertinib provides a highly effective, practice-changing treatment for patients with stage IB, II, IIIA, EGFR mutation-positive non–small cell lung cancer after complete tumor resection,” Dr. Herbst said.

Dr. Herbst disclosed relationships with AstraZeneca, which funded the study, as well as Jun Shi Pharmaceuticals and other companies. Dr. Cascone is the international principal investigator of the NeoCOAST trial evaluating durvalumab, an AstraZeneca product.

SOURCE: Herbst RS et al. ASCO 2020, Abstract LBA5.

Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

“Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma,” said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician’s choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

“Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data,” said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Chemoresistant cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

“[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype’s relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so,” he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.
 

Trametinib study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m² for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m² on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.
 

Binimetinib study

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician’s choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m² on day 1 of each 28-day cycle; paclitaxel at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m² IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician’s choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.
 

Two MEKs, one ‘meh’

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that “with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success.”

Regarding the MILO/ENGOT-ov11 trial, she noted that “this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study.”

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician’s choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, ”especially in a rare tumor setting with limited options. This is a huge win for patients.”

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, Abbvie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

“Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma,” said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician’s choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

“Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data,” said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Chemoresistant cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

“[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype’s relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so,” he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.
 

Trametinib study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m² for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m² on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.
 

Binimetinib study

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician’s choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m² on day 1 of each 28-day cycle; paclitaxel at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m² IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician’s choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.
 

Two MEKs, one ‘meh’

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that “with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success.”

Regarding the MILO/ENGOT-ov11 trial, she noted that “this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study.”

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician’s choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, ”especially in a rare tumor setting with limited options. This is a huge win for patients.”

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, Abbvie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

“Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma,” said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician’s choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

“Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data,” said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Chemoresistant cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

“[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype’s relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so,” he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.
 

Trametinib study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m² for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m² on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.
 

Binimetinib study

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician’s choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m² on day 1 of each 28-day cycle; paclitaxel at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m² IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician’s choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.
 

Two MEKs, one ‘meh’

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that “with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success.”

Regarding the MILO/ENGOT-ov11 trial, she noted that “this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study.”

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician’s choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, ”especially in a rare tumor setting with limited options. This is a huge win for patients.”

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, Abbvie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

A triple-antiviral therapy regimen of interferon-beta1, lopinavir/ritonavir, and ribavirin shortened median time to COVID-19 viral negativity by 5 days in a small trial from Hong Kong.

Courtesy NIAID-RML

In an open-label, randomized phase 2 trial in patients with mild or moderate COVID-19 infections, the median time to viral negativity by nasopharyngeal swab was 7 days for 86 patients assigned to receive a 14-day course of lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million international units of interferon beta-1b on alternate days, compared with a median time to negativity of 12 days for patients treated with lopinavir/ritonavir alone (P = .0010), wrote Ivan Fan-Ngai Hung, MD, from Gleaneagles Hospital in Hong Kong, and colleagues.

“Triple-antiviral therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin were safe and superior to lopinavir/ritonavir alone in shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19,” they wrote in a study published online in The Lancet.

Patients who received the combination also had significantly shorter time to complete alleviation of symptoms as assessed by a National Early Warning Score 2 (NEWS2, a system for detecting clinical deterioration in patients with acute illnesses) score of 0 (4 vs. 8 days, respectively; hazard ratio 3.92, P < .0001), and to a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).

The median hospital stay was 9 days for patients treated with the combination, compared with 14.5 days for controls (HR 2.72, P = .016).

In most patients treated with the combination, SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat and posterior oropharyngeal saliva, and stool.

In addition, serum levels of interleukin 6 (IL-6) – an inflammatory cytokine implicated in the cytokine storm frequently seen in patients with severe COVID-19 infections – were significantly lower on treatment days 2, 6, and 8 in patients treated with the combination, compared with those treated with lopinavir/ritonavir alone.

“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to health care workers by reducing the duration and quantity of viral shedding (when the virus is detectable and potentially transmissible). Furthermore, the treatment combination appeared safe and well tolerated by patients,” said lead investigator Professor Kwok-Yung Yuen from the University of Hong Kong, in a statement.

“Despite these encouraging findings,” he continued, “we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness (in whom the virus has had more time to replicate).”

Plausible rationale

Benjamin Medoff, MD, chief of the division of pulmonary and critical care medicine at Massachusetts General Hospital in Boston, who was not involved in the study, said in an interview that the biologic rationale for the combination is plausible.

“I think this is a promising study that suggests that a regimen of interferon beta-1b, lopinavir/ritonavir, and ribavirin can shorten the duration of infection and improve symptoms in COVID-19 patients especially if started early in disease, in less than 7 days of symptom onset,” he said in reply to a request for expert analysis.

“The open-label nature and small size of the study limits the broad use of the regimen as noted by the authors, and it’s important to emphasize that the subjects enrolled did not have very severe disease (not in the ICU). However, the study does suggest that a larger truly randomized study is warranted,” he said.

AIDS drugs repurposed

Lopinavir/ritonavir is commonly used to treat HIV/AIDS throughout the world, and the investigators had previously reported that the antiviral agents combined with ribavirin reduced deaths and the need for intensive ventilator support among patients with SARS-CoV, the betacoronavirus that causes severe acute respiratory syndrome (SARS), and antivirals have shown in vitro activity against both SARS-CoV and MERS-CoV, the closely related pathogen that causes Middle East respiratory syndrome.

“ However the viral load of SARS and MERS peaks at around day 7-10 after symptom onset, whereas the viral load of COVID-19 peaks at the time of presentation, similar to influenza. Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single-drug treatments in this setting of patients with a high viral load at presentation,” the investigators wrote.

To test this, they enrolled adults patients admitted to one of six Hong Kong Hospitals for virologically confirmed COVID-19 infections from Feb. 10 through March 20, 2020.

A total of 86 patients were randomly assigned to the combination and 41 to lopinavir/ritonavir alone as controls, at doses described above.

Patients who entered the trial within less than 7 days of symptom onset received the triple combination, with interferon dosing adjusted according to the day that treatment started. Patients recruited 1 or 2 days after symptom onset received three doses of interferon, patients started on day 3 or 4 received two doses, and those started on days 5 or 6 received one interferon dose. Patients recruited 7 days or later from symptom onset did not receive interferon beta-1b because of its proinflammatory effects.

In post-hoc analysis by day of treatment initiation, clinical and virological outcomes (except stool samples) were superior in patients admitted less than 7 days after symptom onset for the 52 patients who received a least one interferon dose plus lopinavir/ritonavir and ribavirin, compared with 24 patients randomized to the control arm (lopinavir/ritonavir only). In contrast, among patients admitted and started on treatment at day 7 or later after symptom onset, there were no differences between those who received lopinavir/ritonavir alone or combined with ribavirin.

Adverse events were reported in 41 of 86 patients in the combination group and 20 of 41 patients in the control arm. The most common adverse events were diarrhea, occurring in 52 of all 127 patients, fever in 48, nausea in 43, and elevated alanine transaminase level in 18. The side effects generally resolved within 3 days of the start of treatments.

There were no serious adverse events reported in the combination group. One patient in the control group had impaired hepatic enzymes requiring discontinuation of treatment. No patients died during the study.

The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine. The authors and Dr. Medoff declared no competing interests.

SOURCE: Hung IFN et al. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31101-6.

A triple-antiviral therapy regimen of interferon-beta1, lopinavir/ritonavir, and ribavirin shortened median time to COVID-19 viral negativity by 5 days in a small trial from Hong Kong.

Courtesy NIAID-RML

In an open-label, randomized phase 2 trial in patients with mild or moderate COVID-19 infections, the median time to viral negativity by nasopharyngeal swab was 7 days for 86 patients assigned to receive a 14-day course of lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million international units of interferon beta-1b on alternate days, compared with a median time to negativity of 12 days for patients treated with lopinavir/ritonavir alone (P = .0010), wrote Ivan Fan-Ngai Hung, MD, from Gleaneagles Hospital in Hong Kong, and colleagues.

“Triple-antiviral therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin were safe and superior to lopinavir/ritonavir alone in shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19,” they wrote in a study published online in The Lancet.

Patients who received the combination also had significantly shorter time to complete alleviation of symptoms as assessed by a National Early Warning Score 2 (NEWS2, a system for detecting clinical deterioration in patients with acute illnesses) score of 0 (4 vs. 8 days, respectively; hazard ratio 3.92, P < .0001), and to a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).

The median hospital stay was 9 days for patients treated with the combination, compared with 14.5 days for controls (HR 2.72, P = .016).

In most patients treated with the combination, SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat and posterior oropharyngeal saliva, and stool.

In addition, serum levels of interleukin 6 (IL-6) – an inflammatory cytokine implicated in the cytokine storm frequently seen in patients with severe COVID-19 infections – were significantly lower on treatment days 2, 6, and 8 in patients treated with the combination, compared with those treated with lopinavir/ritonavir alone.

“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to health care workers by reducing the duration and quantity of viral shedding (when the virus is detectable and potentially transmissible). Furthermore, the treatment combination appeared safe and well tolerated by patients,” said lead investigator Professor Kwok-Yung Yuen from the University of Hong Kong, in a statement.

“Despite these encouraging findings,” he continued, “we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness (in whom the virus has had more time to replicate).”

Plausible rationale

Benjamin Medoff, MD, chief of the division of pulmonary and critical care medicine at Massachusetts General Hospital in Boston, who was not involved in the study, said in an interview that the biologic rationale for the combination is plausible.

“I think this is a promising study that suggests that a regimen of interferon beta-1b, lopinavir/ritonavir, and ribavirin can shorten the duration of infection and improve symptoms in COVID-19 patients especially if started early in disease, in less than 7 days of symptom onset,” he said in reply to a request for expert analysis.

“The open-label nature and small size of the study limits the broad use of the regimen as noted by the authors, and it’s important to emphasize that the subjects enrolled did not have very severe disease (not in the ICU). However, the study does suggest that a larger truly randomized study is warranted,” he said.

AIDS drugs repurposed

Lopinavir/ritonavir is commonly used to treat HIV/AIDS throughout the world, and the investigators had previously reported that the antiviral agents combined with ribavirin reduced deaths and the need for intensive ventilator support among patients with SARS-CoV, the betacoronavirus that causes severe acute respiratory syndrome (SARS), and antivirals have shown in vitro activity against both SARS-CoV and MERS-CoV, the closely related pathogen that causes Middle East respiratory syndrome.

“ However the viral load of SARS and MERS peaks at around day 7-10 after symptom onset, whereas the viral load of COVID-19 peaks at the time of presentation, similar to influenza. Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single-drug treatments in this setting of patients with a high viral load at presentation,” the investigators wrote.

To test this, they enrolled adults patients admitted to one of six Hong Kong Hospitals for virologically confirmed COVID-19 infections from Feb. 10 through March 20, 2020.

A total of 86 patients were randomly assigned to the combination and 41 to lopinavir/ritonavir alone as controls, at doses described above.

Patients who entered the trial within less than 7 days of symptom onset received the triple combination, with interferon dosing adjusted according to the day that treatment started. Patients recruited 1 or 2 days after symptom onset received three doses of interferon, patients started on day 3 or 4 received two doses, and those started on days 5 or 6 received one interferon dose. Patients recruited 7 days or later from symptom onset did not receive interferon beta-1b because of its proinflammatory effects.

In post-hoc analysis by day of treatment initiation, clinical and virological outcomes (except stool samples) were superior in patients admitted less than 7 days after symptom onset for the 52 patients who received a least one interferon dose plus lopinavir/ritonavir and ribavirin, compared with 24 patients randomized to the control arm (lopinavir/ritonavir only). In contrast, among patients admitted and started on treatment at day 7 or later after symptom onset, there were no differences between those who received lopinavir/ritonavir alone or combined with ribavirin.

Adverse events were reported in 41 of 86 patients in the combination group and 20 of 41 patients in the control arm. The most common adverse events were diarrhea, occurring in 52 of all 127 patients, fever in 48, nausea in 43, and elevated alanine transaminase level in 18. The side effects generally resolved within 3 days of the start of treatments.

There were no serious adverse events reported in the combination group. One patient in the control group had impaired hepatic enzymes requiring discontinuation of treatment. No patients died during the study.

The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine. The authors and Dr. Medoff declared no competing interests.

SOURCE: Hung IFN et al. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31101-6.

A triple-antiviral therapy regimen of interferon-beta1, lopinavir/ritonavir, and ribavirin shortened median time to COVID-19 viral negativity by 5 days in a small trial from Hong Kong.

Courtesy NIAID-RML

In an open-label, randomized phase 2 trial in patients with mild or moderate COVID-19 infections, the median time to viral negativity by nasopharyngeal swab was 7 days for 86 patients assigned to receive a 14-day course of lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million international units of interferon beta-1b on alternate days, compared with a median time to negativity of 12 days for patients treated with lopinavir/ritonavir alone (P = .0010), wrote Ivan Fan-Ngai Hung, MD, from Gleaneagles Hospital in Hong Kong, and colleagues.

“Triple-antiviral therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin were safe and superior to lopinavir/ritonavir alone in shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19,” they wrote in a study published online in The Lancet.

Patients who received the combination also had significantly shorter time to complete alleviation of symptoms as assessed by a National Early Warning Score 2 (NEWS2, a system for detecting clinical deterioration in patients with acute illnesses) score of 0 (4 vs. 8 days, respectively; hazard ratio 3.92, P < .0001), and to a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).

The median hospital stay was 9 days for patients treated with the combination, compared with 14.5 days for controls (HR 2.72, P = .016).

In most patients treated with the combination, SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat and posterior oropharyngeal saliva, and stool.

In addition, serum levels of interleukin 6 (IL-6) – an inflammatory cytokine implicated in the cytokine storm frequently seen in patients with severe COVID-19 infections – were significantly lower on treatment days 2, 6, and 8 in patients treated with the combination, compared with those treated with lopinavir/ritonavir alone.

“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to health care workers by reducing the duration and quantity of viral shedding (when the virus is detectable and potentially transmissible). Furthermore, the treatment combination appeared safe and well tolerated by patients,” said lead investigator Professor Kwok-Yung Yuen from the University of Hong Kong, in a statement.

“Despite these encouraging findings,” he continued, “we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness (in whom the virus has had more time to replicate).”

Plausible rationale

Benjamin Medoff, MD, chief of the division of pulmonary and critical care medicine at Massachusetts General Hospital in Boston, who was not involved in the study, said in an interview that the biologic rationale for the combination is plausible.

“I think this is a promising study that suggests that a regimen of interferon beta-1b, lopinavir/ritonavir, and ribavirin can shorten the duration of infection and improve symptoms in COVID-19 patients especially if started early in disease, in less than 7 days of symptom onset,” he said in reply to a request for expert analysis.

“The open-label nature and small size of the study limits the broad use of the regimen as noted by the authors, and it’s important to emphasize that the subjects enrolled did not have very severe disease (not in the ICU). However, the study does suggest that a larger truly randomized study is warranted,” he said.

AIDS drugs repurposed

Lopinavir/ritonavir is commonly used to treat HIV/AIDS throughout the world, and the investigators had previously reported that the antiviral agents combined with ribavirin reduced deaths and the need for intensive ventilator support among patients with SARS-CoV, the betacoronavirus that causes severe acute respiratory syndrome (SARS), and antivirals have shown in vitro activity against both SARS-CoV and MERS-CoV, the closely related pathogen that causes Middle East respiratory syndrome.

“ However the viral load of SARS and MERS peaks at around day 7-10 after symptom onset, whereas the viral load of COVID-19 peaks at the time of presentation, similar to influenza. Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single-drug treatments in this setting of patients with a high viral load at presentation,” the investigators wrote.

To test this, they enrolled adults patients admitted to one of six Hong Kong Hospitals for virologically confirmed COVID-19 infections from Feb. 10 through March 20, 2020.

A total of 86 patients were randomly assigned to the combination and 41 to lopinavir/ritonavir alone as controls, at doses described above.

Patients who entered the trial within less than 7 days of symptom onset received the triple combination, with interferon dosing adjusted according to the day that treatment started. Patients recruited 1 or 2 days after symptom onset received three doses of interferon, patients started on day 3 or 4 received two doses, and those started on days 5 or 6 received one interferon dose. Patients recruited 7 days or later from symptom onset did not receive interferon beta-1b because of its proinflammatory effects.

In post-hoc analysis by day of treatment initiation, clinical and virological outcomes (except stool samples) were superior in patients admitted less than 7 days after symptom onset for the 52 patients who received a least one interferon dose plus lopinavir/ritonavir and ribavirin, compared with 24 patients randomized to the control arm (lopinavir/ritonavir only). In contrast, among patients admitted and started on treatment at day 7 or later after symptom onset, there were no differences between those who received lopinavir/ritonavir alone or combined with ribavirin.

Adverse events were reported in 41 of 86 patients in the combination group and 20 of 41 patients in the control arm. The most common adverse events were diarrhea, occurring in 52 of all 127 patients, fever in 48, nausea in 43, and elevated alanine transaminase level in 18. The side effects generally resolved within 3 days of the start of treatments.

There were no serious adverse events reported in the combination group. One patient in the control group had impaired hepatic enzymes requiring discontinuation of treatment. No patients died during the study.

The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine. The authors and Dr. Medoff declared no competing interests.

SOURCE: Hung IFN et al. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31101-6.

Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.

“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.

Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).

“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
 

Study flaws harm conclusions

But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”

“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”

Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.

“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”

Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”

They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
 

Coagulation differences

Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.

“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.

Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.

To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.

Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.

Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.

Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.

“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.

When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.

They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).

There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)

“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.

They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.

“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.

The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.

The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.

SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.

Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.

“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.

Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).

“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
 

Study flaws harm conclusions

But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”

“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”

Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.

“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”

Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”

They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
 

Coagulation differences

Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.

“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.

Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.

To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.

Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.

Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.

Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.

“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.

When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.

They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).

There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)

“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.

They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.

“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.

The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.

The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.

SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.

Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.

“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.

Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).

“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
 

Study flaws harm conclusions

But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”

“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”

Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.

“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”

Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”

They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
 

Coagulation differences

Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.

“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.

Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.

To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.

Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.

Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.

Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.

“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.

When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.

They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).

There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)

“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.

They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.

“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.

The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.

The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.

SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.

Triple-negative breast cancer (TNBC) is a particularly aggressive form of this disease, with a poor prognosis, so there is great interest in any new treatment approach. Immunotherapy has raised hopes in TNBC, but more recently, studies have produced conflicting results.

New results show that adding a novel immune activator, Imprime PGG (Biothera), to immunotherapy with pembrolizumab (Keytruda, Merck) appears to improve the clinical benefit. The overall survival seen with the combination was twice that seen in a separate trial with pembrolizumab alone.

The new results were presented during the American Association for Cancer Research (AACR) virtual annual meeting I.

They come from the IMPRIME 1 trial, conducted in 44 women with metastatic TNBC who had anti-glucan antibodies.

“These were patients who had had prior chemotherapy and had extensive disease, including the majority with visceral disease and even liver metastasis,” said investigator Steven O’Day, MD, from the John Wayne Cancer Institute in Santa Monica, California.

All patients were treated with the combination. “We see encouraging clinical benefit evidence across all of our clinical measurements: response, durable response, and median and overall survival compared to historical single-agent [anti] PD-1 in a similar metastatic triple-negative breast cancer population,” he said.

At a median follow-up of 22.5 months, median overall survival with the combination among the 44 patients treated was 16.4 months.

In contrast, in the Keynote-086 trial of pembrolizumab monotherapy in patients with TNBC, median overall survival was 9 months, O’Day said.

He emphasized, however, that the IMPRIME 1 trial was not designed or powered to directly compare the combination therapy with pembrolizumab monotherapy.

Clinical benefit with the combination was particularly pronounced for patients who were so-called TNBC “converters” — that is, they originally had estrogen receptor (ER)-positive tumors that had progressed on endocrine therapy and, prior to starting treatment with Imprime PGG and pembrolizumab, they had biopsy results confirming TNBC, O’Day said.

The overall response rate (ORR) for all 44 patients included in the efficacy analysis was 15.9%. But among the 12 patients whose disease converted from ER-positive to TNBC after endocrine therapy, six had a response, for an ORR of 50% and a median overall survival of 17.1 months.

“It is not clear whether hormone resistance may have led to the increased responses versus secondary triple-negative status, but it is of great interest to us,” O’Day said.
 

Why This Special Benefit?

Invited discussant Ben Ho Park, MD, PhD, from Vanderbilt University Medical Center in Nashville, Tennessee, commented that the finding of special benefit among TNBC converters raises the question of biomarkers to determine which patients might most benefit from the combination.

“We already know that anti-beta-glucan antibodies were required to be actually eligible for this study, but is it that, in combination with immune activation, or prior ER-positive disease?” he said. “What about the role of PD-L1 staining? Can we actually combine all this data to come up with some sort of predictive score for whether or not a patient is more or less likely to respond, and more or less likely to have toxicities?”

Yeast-Derived Compound

Imprime PGG is a novel beta-glucan isolated from the cell walls of saccharomyces yeast that binds to endogenous anti-beta-glucan antibodies to form an immune complex.

The immune complex, which is the active drug, binds to a receptor known as dectin-1 to activate innate immunity and reprogram the immunosuppressive tumor microenvironment, enhance antigen presentation, and trigger T-cell activation to improve the efficacy of immune checkpoint inhibitor therapy, O’Day explained.

The complex has been administered to date to approximately 600 healthy volunteers and patients. In these studies, it was administered intravenously at doses of 2 mg/kg to 6 mg/kg weekly as monotherapy or in combination with anti-angiogenic antibodies or tumor-targeting antibodies, with or without chemotherapy.

Studies in volunteers showed that the complex activated innate immunity. Patients have tolerated it well, with no significant safety signals in either monotherapy or combination, with grade 1 or 2 infusion-related reactions being the most common adverse events to date, O’Day reported.

Study Details

Imprime 1 was a single-arm phase 2 trial enrolling 44 women with TNBC who had received at least one prior line of treatment, but not with an immune checkpoint inhibitor. They were all required to have anti-beta-glucan antibody levels of at least 20 mcg/mL.

All patients received the combination, which comprised Imprime PGG 4 mg/kg weekly plus pembrolizumab 200 mg IV every 3 weeks.

Twenty one patients were under age 50 years, and 23 were 50 years old and older. Seventeen patients were premenopausal, and 27 were postmenopausal. In all, 15 patients had more than three prior lines of therapy for metastatic disease, 30 had visceral disease, and 12 had liver metastases; only four had metastases confined to lymph nodes.

As noted above, median overall survival for all patients was 16.4 months. The ORR was 15.9%, and the disease control rate (a combination of complete and partial responses plus stable disease) was 25%. The median progression-free survival was 2.7 months (vs 2 months in Keynote-086).

In all, 39 of the 44 patients had treatment-related adverse events, with the most common being nausea, back pain, chills, fatigue, diarrhea, arthralgia, and headache. Four patients had grade 3 or 4 events, which included an infusion-related reaction, hyperglycemia, pericarditis, and pancreatitis.

Infusion-related reactions were seen in 27 patients, but only one of these reactions was grade 3 or 4.

The most common immune-mediated events were grade 1 or 2 thyroid dysfunction, which is commonly seen with PD-1 inhibitors, and there were single low-grade events of pancreatitis, pneumonitis, and pericarditis “most likely related to PD-1 inhibitor therapy,” O’Day said.

Translational data showed that innate and adaptive immunity in peripheral blood correlates with clinical benefit, with longer overall survival among patients with either monocyte activation (P = .0045) or T-cell activation (P = .012) compared with patients without activation of those components.

Taken together, the findings suggest that larger controlled studies of the combination are warranted, O’Day said.

The study was sponsored by Biothera and Merck. O’Day disclosed advisory board activities and research funding from both companies and others, and consulting for Biothera. Park disclosed royalties and consulting activities from several companies, not including the Imprime 1 sponsors.
 

This article first appeared on Medscape.com.

Triple-negative breast cancer (TNBC) is a particularly aggressive form of this disease, with a poor prognosis, so there is great interest in any new treatment approach. Immunotherapy has raised hopes in TNBC, but more recently, studies have produced conflicting results.

New results show that adding a novel immune activator, Imprime PGG (Biothera), to immunotherapy with pembrolizumab (Keytruda, Merck) appears to improve the clinical benefit. The overall survival seen with the combination was twice that seen in a separate trial with pembrolizumab alone.

The new results were presented during the American Association for Cancer Research (AACR) virtual annual meeting I.

They come from the IMPRIME 1 trial, conducted in 44 women with metastatic TNBC who had anti-glucan antibodies.

“These were patients who had had prior chemotherapy and had extensive disease, including the majority with visceral disease and even liver metastasis,” said investigator Steven O’Day, MD, from the John Wayne Cancer Institute in Santa Monica, California.

All patients were treated with the combination. “We see encouraging clinical benefit evidence across all of our clinical measurements: response, durable response, and median and overall survival compared to historical single-agent [anti] PD-1 in a similar metastatic triple-negative breast cancer population,” he said.

At a median follow-up of 22.5 months, median overall survival with the combination among the 44 patients treated was 16.4 months.

In contrast, in the Keynote-086 trial of pembrolizumab monotherapy in patients with TNBC, median overall survival was 9 months, O’Day said.

He emphasized, however, that the IMPRIME 1 trial was not designed or powered to directly compare the combination therapy with pembrolizumab monotherapy.

Clinical benefit with the combination was particularly pronounced for patients who were so-called TNBC “converters” — that is, they originally had estrogen receptor (ER)-positive tumors that had progressed on endocrine therapy and, prior to starting treatment with Imprime PGG and pembrolizumab, they had biopsy results confirming TNBC, O’Day said.

The overall response rate (ORR) for all 44 patients included in the efficacy analysis was 15.9%. But among the 12 patients whose disease converted from ER-positive to TNBC after endocrine therapy, six had a response, for an ORR of 50% and a median overall survival of 17.1 months.

“It is not clear whether hormone resistance may have led to the increased responses versus secondary triple-negative status, but it is of great interest to us,” O’Day said.
 

Why This Special Benefit?

Invited discussant Ben Ho Park, MD, PhD, from Vanderbilt University Medical Center in Nashville, Tennessee, commented that the finding of special benefit among TNBC converters raises the question of biomarkers to determine which patients might most benefit from the combination.

“We already know that anti-beta-glucan antibodies were required to be actually eligible for this study, but is it that, in combination with immune activation, or prior ER-positive disease?” he said. “What about the role of PD-L1 staining? Can we actually combine all this data to come up with some sort of predictive score for whether or not a patient is more or less likely to respond, and more or less likely to have toxicities?”

Yeast-Derived Compound

Imprime PGG is a novel beta-glucan isolated from the cell walls of saccharomyces yeast that binds to endogenous anti-beta-glucan antibodies to form an immune complex.

The immune complex, which is the active drug, binds to a receptor known as dectin-1 to activate innate immunity and reprogram the immunosuppressive tumor microenvironment, enhance antigen presentation, and trigger T-cell activation to improve the efficacy of immune checkpoint inhibitor therapy, O’Day explained.

The complex has been administered to date to approximately 600 healthy volunteers and patients. In these studies, it was administered intravenously at doses of 2 mg/kg to 6 mg/kg weekly as monotherapy or in combination with anti-angiogenic antibodies or tumor-targeting antibodies, with or without chemotherapy.

Studies in volunteers showed that the complex activated innate immunity. Patients have tolerated it well, with no significant safety signals in either monotherapy or combination, with grade 1 or 2 infusion-related reactions being the most common adverse events to date, O’Day reported.

Study Details

Imprime 1 was a single-arm phase 2 trial enrolling 44 women with TNBC who had received at least one prior line of treatment, but not with an immune checkpoint inhibitor. They were all required to have anti-beta-glucan antibody levels of at least 20 mcg/mL.

All patients received the combination, which comprised Imprime PGG 4 mg/kg weekly plus pembrolizumab 200 mg IV every 3 weeks.

Twenty one patients were under age 50 years, and 23 were 50 years old and older. Seventeen patients were premenopausal, and 27 were postmenopausal. In all, 15 patients had more than three prior lines of therapy for metastatic disease, 30 had visceral disease, and 12 had liver metastases; only four had metastases confined to lymph nodes.

As noted above, median overall survival for all patients was 16.4 months. The ORR was 15.9%, and the disease control rate (a combination of complete and partial responses plus stable disease) was 25%. The median progression-free survival was 2.7 months (vs 2 months in Keynote-086).

In all, 39 of the 44 patients had treatment-related adverse events, with the most common being nausea, back pain, chills, fatigue, diarrhea, arthralgia, and headache. Four patients had grade 3 or 4 events, which included an infusion-related reaction, hyperglycemia, pericarditis, and pancreatitis.

Infusion-related reactions were seen in 27 patients, but only one of these reactions was grade 3 or 4.

The most common immune-mediated events were grade 1 or 2 thyroid dysfunction, which is commonly seen with PD-1 inhibitors, and there were single low-grade events of pancreatitis, pneumonitis, and pericarditis “most likely related to PD-1 inhibitor therapy,” O’Day said.

Translational data showed that innate and adaptive immunity in peripheral blood correlates with clinical benefit, with longer overall survival among patients with either monocyte activation (P = .0045) or T-cell activation (P = .012) compared with patients without activation of those components.

Taken together, the findings suggest that larger controlled studies of the combination are warranted, O’Day said.

The study was sponsored by Biothera and Merck. O’Day disclosed advisory board activities and research funding from both companies and others, and consulting for Biothera. Park disclosed royalties and consulting activities from several companies, not including the Imprime 1 sponsors.
 

This article first appeared on Medscape.com.

Triple-negative breast cancer (TNBC) is a particularly aggressive form of this disease, with a poor prognosis, so there is great interest in any new treatment approach. Immunotherapy has raised hopes in TNBC, but more recently, studies have produced conflicting results.

New results show that adding a novel immune activator, Imprime PGG (Biothera), to immunotherapy with pembrolizumab (Keytruda, Merck) appears to improve the clinical benefit. The overall survival seen with the combination was twice that seen in a separate trial with pembrolizumab alone.

The new results were presented during the American Association for Cancer Research (AACR) virtual annual meeting I.

They come from the IMPRIME 1 trial, conducted in 44 women with metastatic TNBC who had anti-glucan antibodies.

“These were patients who had had prior chemotherapy and had extensive disease, including the majority with visceral disease and even liver metastasis,” said investigator Steven O’Day, MD, from the John Wayne Cancer Institute in Santa Monica, California.

All patients were treated with the combination. “We see encouraging clinical benefit evidence across all of our clinical measurements: response, durable response, and median and overall survival compared to historical single-agent [anti] PD-1 in a similar metastatic triple-negative breast cancer population,” he said.

At a median follow-up of 22.5 months, median overall survival with the combination among the 44 patients treated was 16.4 months.

In contrast, in the Keynote-086 trial of pembrolizumab monotherapy in patients with TNBC, median overall survival was 9 months, O’Day said.

He emphasized, however, that the IMPRIME 1 trial was not designed or powered to directly compare the combination therapy with pembrolizumab monotherapy.

Clinical benefit with the combination was particularly pronounced for patients who were so-called TNBC “converters” — that is, they originally had estrogen receptor (ER)-positive tumors that had progressed on endocrine therapy and, prior to starting treatment with Imprime PGG and pembrolizumab, they had biopsy results confirming TNBC, O’Day said.

The overall response rate (ORR) for all 44 patients included in the efficacy analysis was 15.9%. But among the 12 patients whose disease converted from ER-positive to TNBC after endocrine therapy, six had a response, for an ORR of 50% and a median overall survival of 17.1 months.

“It is not clear whether hormone resistance may have led to the increased responses versus secondary triple-negative status, but it is of great interest to us,” O’Day said.
 

Why This Special Benefit?

Invited discussant Ben Ho Park, MD, PhD, from Vanderbilt University Medical Center in Nashville, Tennessee, commented that the finding of special benefit among TNBC converters raises the question of biomarkers to determine which patients might most benefit from the combination.

“We already know that anti-beta-glucan antibodies were required to be actually eligible for this study, but is it that, in combination with immune activation, or prior ER-positive disease?” he said. “What about the role of PD-L1 staining? Can we actually combine all this data to come up with some sort of predictive score for whether or not a patient is more or less likely to respond, and more or less likely to have toxicities?”

Yeast-Derived Compound

Imprime PGG is a novel beta-glucan isolated from the cell walls of saccharomyces yeast that binds to endogenous anti-beta-glucan antibodies to form an immune complex.

The immune complex, which is the active drug, binds to a receptor known as dectin-1 to activate innate immunity and reprogram the immunosuppressive tumor microenvironment, enhance antigen presentation, and trigger T-cell activation to improve the efficacy of immune checkpoint inhibitor therapy, O’Day explained.

The complex has been administered to date to approximately 600 healthy volunteers and patients. In these studies, it was administered intravenously at doses of 2 mg/kg to 6 mg/kg weekly as monotherapy or in combination with anti-angiogenic antibodies or tumor-targeting antibodies, with or without chemotherapy.

Studies in volunteers showed that the complex activated innate immunity. Patients have tolerated it well, with no significant safety signals in either monotherapy or combination, with grade 1 or 2 infusion-related reactions being the most common adverse events to date, O’Day reported.

Study Details

Imprime 1 was a single-arm phase 2 trial enrolling 44 women with TNBC who had received at least one prior line of treatment, but not with an immune checkpoint inhibitor. They were all required to have anti-beta-glucan antibody levels of at least 20 mcg/mL.

All patients received the combination, which comprised Imprime PGG 4 mg/kg weekly plus pembrolizumab 200 mg IV every 3 weeks.

Twenty one patients were under age 50 years, and 23 were 50 years old and older. Seventeen patients were premenopausal, and 27 were postmenopausal. In all, 15 patients had more than three prior lines of therapy for metastatic disease, 30 had visceral disease, and 12 had liver metastases; only four had metastases confined to lymph nodes.

As noted above, median overall survival for all patients was 16.4 months. The ORR was 15.9%, and the disease control rate (a combination of complete and partial responses plus stable disease) was 25%. The median progression-free survival was 2.7 months (vs 2 months in Keynote-086).

In all, 39 of the 44 patients had treatment-related adverse events, with the most common being nausea, back pain, chills, fatigue, diarrhea, arthralgia, and headache. Four patients had grade 3 or 4 events, which included an infusion-related reaction, hyperglycemia, pericarditis, and pancreatitis.

Infusion-related reactions were seen in 27 patients, but only one of these reactions was grade 3 or 4.

The most common immune-mediated events were grade 1 or 2 thyroid dysfunction, which is commonly seen with PD-1 inhibitors, and there were single low-grade events of pancreatitis, pneumonitis, and pericarditis “most likely related to PD-1 inhibitor therapy,” O’Day said.

Translational data showed that innate and adaptive immunity in peripheral blood correlates with clinical benefit, with longer overall survival among patients with either monocyte activation (P = .0045) or T-cell activation (P = .012) compared with patients without activation of those components.

Taken together, the findings suggest that larger controlled studies of the combination are warranted, O’Day said.

The study was sponsored by Biothera and Merck. O’Day disclosed advisory board activities and research funding from both companies and others, and consulting for Biothera. Park disclosed royalties and consulting activities from several companies, not including the Imprime 1 sponsors.
 

This article first appeared on Medscape.com.

No clinical benefit was seen from adding the immune checkpoint inhibitor atezolizumab (Tecentriq, Genentech) to standard treatment with the androgen receptor inhibitor enzalutamide (Xtandi; Astellas Pharma) for men with metastatic castration-resistant prostate cancer (mCRPC).

Median overall survival, the trial’s primary endpoint, was numerically but not statistically longer among patients with mCRPC who were randomly assigned to receive treatment with enzalutamide alone, reported lead investigator Christopher J. Sweeney, MBBS, from the Dana-Farber Cancer Institute in Boston.

The finding comes from the phase 3 IMbassador250 trial.

This was “the first phase 3 trial to investigate a checkpoint inhibitor therapy combination in metastatic CRPC. It revealed no evidence of a difference in cancer control between arms, whether it be measured by radiographic progression-free survival or time to PSA [prostate-specific antigen] progression,” he said.

Adding insult to injury, the investigators could not identify, on the basis of expression of programmed death–ligand 1 (PD-L1), a subpopulation of patients who might have benefited from the combination therapy, and adverse events were more frequent than with enzalutamide alone, Sweeney said.

Sweeney presented the results online during the American Association for Cancer Research (AACR) 2020 virtual meeting.
 

What happened?

It sounded good on paper: the clinical rationale for combining an immune checkpoint inhibitor with enzalutamide was that there was evidence that immunotherapy with sipuleucel-T (Provenge, Dendreon Pharmaceuticals) had efficacy in CRPC, and initial investigations with ipilimumab (Yervoy, Bristol-Myers Squibb) that showed an increase in antigen-specific T cells following treatment with sipuleucel-T, Sweeney said.

In addition, there has been evidence that programmed death–1 (PD-1) blockade may have activity following the development of resistance to enzalutamide and that monotherapy with atezolizumab, an inhibitor of PD-1 and PD-L1, was associated with long-term disease control in mCRPC, he added.

However, these new results “indicate that neither anti-PD-1/PD-L1 monotherapy or the anti-PD-1/PD-L1 combination therapy with enzalutamide are likely to provide improved clinical benefit over standard-of-care agents for patients with mCRPC whose disease progressed on prior hormonal therapy and prior chemotherapy,” commented Padmanee Sharma, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant.

Discussing why the IMbassador250 trial may have failed, she noted that prostate cancer has few T cells, and therefore targeting PD-1 or PD-L1 would not have much of an effect.

“There are multiple immunosuppressive pathways within the prostate tumor microenvironment, and the PD-1/PD-L1-targeting agents may not sufficiently target all these immunosuppressive pathways,” she said.

In addition, “there are few mutations in prostate cancer, and as a result, the effector T cells may not be able to recognize an adequate number of antigens to lead to an antitumor response,” Sharma said.
 

Study details

The IMbassador250 study was a phase 3, multicenter, randomized, open-label study involving 759 men with metastatic, locally advanced, or incurable CRPC who had experienced disease progression with abiraterone (Zytiga, Janssen), were ineligible or refused a taxane-based regimen, or for whom a taxane regimen had failed.

After stratification on the basis of prior taxane therapy, presence of liver metastases, lactate dehydrogenase levels, and pain severity in the past 24 hours, the patients were randomly assigned to receive either enzalutamide 160 mg daily or the same regimen plus atezolizumab 1200 mg intravenously every 3 weeks. Treatment continued until loss of clinical benefit or unacceptable toxicity.

Median overall survival (OS) was 15.2 months with the combination, compared with 16.6 months for enzalutamide alone, which translated into a hazard ratio for death with the combination of 1.12 (P = .28).

The 12-month OS rates were 60.6% for enzalutamide alone versus 64.7% for the combination.

An analysis of OS by clinical subgroup found no advantage from the combination over enzalutamide alone for prior docetaxel exposure, prior local therapy, measurable disease status, the presence of visceral or nonvisceral metastases, or PD-L1 expression.

Radiographic progression-free survival was 4.2 months with atezolizumab/enzalutamide versus 4.1 months with enzalutamide alone (P = ns). Time to PSA progression was 2.8 months in each arm.

Among patients with measurable disease at baseline, the overall response rates were 14% in the combination group and 7% in the group that received enzalutamide alone. Two patients in the combination group and one in the enzalutamide-only group had complete responses.

Grade 3 or 4 treatment-related adverse events (AEs) occurred in 28% of patients who received the combination, versus 10% who received enzalutamide alone. Seven patients in the combination arm and one in the enzalutamide arm died from treatment-related causes. Treatment-related serious AEs were also more frequent with the combination (14% vs. 3%), and AEs that led to discontinuation of any treatment component occurred in 14% of patients in the combination arm, versus 6% in the enzalutamide-alone arm.

The study was sponsored by F. Hoffman–La Roche. Enzalutamide was provided by Astellas and Pfizer. Sweeny has advisory or consulting roles and/or has received research funding from the companies. Sharma has consulting roles, has engaged in advisory board activities, or owns stock in for various companies, not including the sponsors.

This article first appeared on Medscape.com.

No clinical benefit was seen from adding the immune checkpoint inhibitor atezolizumab (Tecentriq, Genentech) to standard treatment with the androgen receptor inhibitor enzalutamide (Xtandi; Astellas Pharma) for men with metastatic castration-resistant prostate cancer (mCRPC).

Median overall survival, the trial’s primary endpoint, was numerically but not statistically longer among patients with mCRPC who were randomly assigned to receive treatment with enzalutamide alone, reported lead investigator Christopher J. Sweeney, MBBS, from the Dana-Farber Cancer Institute in Boston.

The finding comes from the phase 3 IMbassador250 trial.

This was “the first phase 3 trial to investigate a checkpoint inhibitor therapy combination in metastatic CRPC. It revealed no evidence of a difference in cancer control between arms, whether it be measured by radiographic progression-free survival or time to PSA [prostate-specific antigen] progression,” he said.

Adding insult to injury, the investigators could not identify, on the basis of expression of programmed death–ligand 1 (PD-L1), a subpopulation of patients who might have benefited from the combination therapy, and adverse events were more frequent than with enzalutamide alone, Sweeney said.

Sweeney presented the results online during the American Association for Cancer Research (AACR) 2020 virtual meeting.
 

What happened?

It sounded good on paper: the clinical rationale for combining an immune checkpoint inhibitor with enzalutamide was that there was evidence that immunotherapy with sipuleucel-T (Provenge, Dendreon Pharmaceuticals) had efficacy in CRPC, and initial investigations with ipilimumab (Yervoy, Bristol-Myers Squibb) that showed an increase in antigen-specific T cells following treatment with sipuleucel-T, Sweeney said.

In addition, there has been evidence that programmed death–1 (PD-1) blockade may have activity following the development of resistance to enzalutamide and that monotherapy with atezolizumab, an inhibitor of PD-1 and PD-L1, was associated with long-term disease control in mCRPC, he added.

However, these new results “indicate that neither anti-PD-1/PD-L1 monotherapy or the anti-PD-1/PD-L1 combination therapy with enzalutamide are likely to provide improved clinical benefit over standard-of-care agents for patients with mCRPC whose disease progressed on prior hormonal therapy and prior chemotherapy,” commented Padmanee Sharma, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant.

Discussing why the IMbassador250 trial may have failed, she noted that prostate cancer has few T cells, and therefore targeting PD-1 or PD-L1 would not have much of an effect.

“There are multiple immunosuppressive pathways within the prostate tumor microenvironment, and the PD-1/PD-L1-targeting agents may not sufficiently target all these immunosuppressive pathways,” she said.

In addition, “there are few mutations in prostate cancer, and as a result, the effector T cells may not be able to recognize an adequate number of antigens to lead to an antitumor response,” Sharma said.
 

Study details

The IMbassador250 study was a phase 3, multicenter, randomized, open-label study involving 759 men with metastatic, locally advanced, or incurable CRPC who had experienced disease progression with abiraterone (Zytiga, Janssen), were ineligible or refused a taxane-based regimen, or for whom a taxane regimen had failed.

After stratification on the basis of prior taxane therapy, presence of liver metastases, lactate dehydrogenase levels, and pain severity in the past 24 hours, the patients were randomly assigned to receive either enzalutamide 160 mg daily or the same regimen plus atezolizumab 1200 mg intravenously every 3 weeks. Treatment continued until loss of clinical benefit or unacceptable toxicity.

Median overall survival (OS) was 15.2 months with the combination, compared with 16.6 months for enzalutamide alone, which translated into a hazard ratio for death with the combination of 1.12 (P = .28).

The 12-month OS rates were 60.6% for enzalutamide alone versus 64.7% for the combination.

An analysis of OS by clinical subgroup found no advantage from the combination over enzalutamide alone for prior docetaxel exposure, prior local therapy, measurable disease status, the presence of visceral or nonvisceral metastases, or PD-L1 expression.

Radiographic progression-free survival was 4.2 months with atezolizumab/enzalutamide versus 4.1 months with enzalutamide alone (P = ns). Time to PSA progression was 2.8 months in each arm.

Among patients with measurable disease at baseline, the overall response rates were 14% in the combination group and 7% in the group that received enzalutamide alone. Two patients in the combination group and one in the enzalutamide-only group had complete responses.

Grade 3 or 4 treatment-related adverse events (AEs) occurred in 28% of patients who received the combination, versus 10% who received enzalutamide alone. Seven patients in the combination arm and one in the enzalutamide arm died from treatment-related causes. Treatment-related serious AEs were also more frequent with the combination (14% vs. 3%), and AEs that led to discontinuation of any treatment component occurred in 14% of patients in the combination arm, versus 6% in the enzalutamide-alone arm.

The study was sponsored by F. Hoffman–La Roche. Enzalutamide was provided by Astellas and Pfizer. Sweeny has advisory or consulting roles and/or has received research funding from the companies. Sharma has consulting roles, has engaged in advisory board activities, or owns stock in for various companies, not including the sponsors.

This article first appeared on Medscape.com.

No clinical benefit was seen from adding the immune checkpoint inhibitor atezolizumab (Tecentriq, Genentech) to standard treatment with the androgen receptor inhibitor enzalutamide (Xtandi; Astellas Pharma) for men with metastatic castration-resistant prostate cancer (mCRPC).

Median overall survival, the trial’s primary endpoint, was numerically but not statistically longer among patients with mCRPC who were randomly assigned to receive treatment with enzalutamide alone, reported lead investigator Christopher J. Sweeney, MBBS, from the Dana-Farber Cancer Institute in Boston.

The finding comes from the phase 3 IMbassador250 trial.

This was “the first phase 3 trial to investigate a checkpoint inhibitor therapy combination in metastatic CRPC. It revealed no evidence of a difference in cancer control between arms, whether it be measured by radiographic progression-free survival or time to PSA [prostate-specific antigen] progression,” he said.

Adding insult to injury, the investigators could not identify, on the basis of expression of programmed death–ligand 1 (PD-L1), a subpopulation of patients who might have benefited from the combination therapy, and adverse events were more frequent than with enzalutamide alone, Sweeney said.

Sweeney presented the results online during the American Association for Cancer Research (AACR) 2020 virtual meeting.
 

What happened?

It sounded good on paper: the clinical rationale for combining an immune checkpoint inhibitor with enzalutamide was that there was evidence that immunotherapy with sipuleucel-T (Provenge, Dendreon Pharmaceuticals) had efficacy in CRPC, and initial investigations with ipilimumab (Yervoy, Bristol-Myers Squibb) that showed an increase in antigen-specific T cells following treatment with sipuleucel-T, Sweeney said.

In addition, there has been evidence that programmed death–1 (PD-1) blockade may have activity following the development of resistance to enzalutamide and that monotherapy with atezolizumab, an inhibitor of PD-1 and PD-L1, was associated with long-term disease control in mCRPC, he added.

However, these new results “indicate that neither anti-PD-1/PD-L1 monotherapy or the anti-PD-1/PD-L1 combination therapy with enzalutamide are likely to provide improved clinical benefit over standard-of-care agents for patients with mCRPC whose disease progressed on prior hormonal therapy and prior chemotherapy,” commented Padmanee Sharma, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant.

Discussing why the IMbassador250 trial may have failed, she noted that prostate cancer has few T cells, and therefore targeting PD-1 or PD-L1 would not have much of an effect.

“There are multiple immunosuppressive pathways within the prostate tumor microenvironment, and the PD-1/PD-L1-targeting agents may not sufficiently target all these immunosuppressive pathways,” she said.

In addition, “there are few mutations in prostate cancer, and as a result, the effector T cells may not be able to recognize an adequate number of antigens to lead to an antitumor response,” Sharma said.
 

Study details

The IMbassador250 study was a phase 3, multicenter, randomized, open-label study involving 759 men with metastatic, locally advanced, or incurable CRPC who had experienced disease progression with abiraterone (Zytiga, Janssen), were ineligible or refused a taxane-based regimen, or for whom a taxane regimen had failed.

After stratification on the basis of prior taxane therapy, presence of liver metastases, lactate dehydrogenase levels, and pain severity in the past 24 hours, the patients were randomly assigned to receive either enzalutamide 160 mg daily or the same regimen plus atezolizumab 1200 mg intravenously every 3 weeks. Treatment continued until loss of clinical benefit or unacceptable toxicity.

Median overall survival (OS) was 15.2 months with the combination, compared with 16.6 months for enzalutamide alone, which translated into a hazard ratio for death with the combination of 1.12 (P = .28).

The 12-month OS rates were 60.6% for enzalutamide alone versus 64.7% for the combination.

An analysis of OS by clinical subgroup found no advantage from the combination over enzalutamide alone for prior docetaxel exposure, prior local therapy, measurable disease status, the presence of visceral or nonvisceral metastases, or PD-L1 expression.

Radiographic progression-free survival was 4.2 months with atezolizumab/enzalutamide versus 4.1 months with enzalutamide alone (P = ns). Time to PSA progression was 2.8 months in each arm.

Among patients with measurable disease at baseline, the overall response rates were 14% in the combination group and 7% in the group that received enzalutamide alone. Two patients in the combination group and one in the enzalutamide-only group had complete responses.

Grade 3 or 4 treatment-related adverse events (AEs) occurred in 28% of patients who received the combination, versus 10% who received enzalutamide alone. Seven patients in the combination arm and one in the enzalutamide arm died from treatment-related causes. Treatment-related serious AEs were also more frequent with the combination (14% vs. 3%), and AEs that led to discontinuation of any treatment component occurred in 14% of patients in the combination arm, versus 6% in the enzalutamide-alone arm.

The study was sponsored by F. Hoffman–La Roche. Enzalutamide was provided by Astellas and Pfizer. Sweeny has advisory or consulting roles and/or has received research funding from the companies. Sharma has consulting roles, has engaged in advisory board activities, or owns stock in for various companies, not including the sponsors.

This article first appeared on Medscape.com.

A novel combination has boosted responses in women with high-risk, HER2-negative breast cancer.

The new combo comprises the immune checkpoint inhibitor durvalumab (Imfinzi, AstraZeneca) and the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca).

When this combo was added to standard neoadjuvant chemotherapy, it yielded a significantly higher pathologic complete response (pCR) rate at the time of surgery than was seen with chemotherapy alone.

The superior pCR rate was seen across all HER2-negative breast cancer subtypes, including HER2-negative, estrogen receptor–positive tumors (Mammaprint high risk), and in women with triple-negative breast cancer (TNBC), reported lead investigator Lajos Pusztai, MD, DPhil, from Yale Cancer Center in New Haven, Connecticut.

“These results provide further evidence for the clinical value of immunotherapy in early-stage breast cancer and suggest new avenues for how to exploit these drugs in hormone receptor [HR]–positive breast cancers,” said Pusztai.

He presented the results at the American Association for Cancer Research (AACR) virtual annual meeting, which took place online, owing to the COVID-19 pandemic.
 

Toxicities, including financial

“The benefits from immunotherapy are clearly emerging in early and metastatic triple-negative breast cancer, likely with PD-L1 expression. However, there’s much more uncertainty in patients with hormone-sensitive tumors whether there is benefit and who will benefit from immunotherapy,” commented Pamela N. Munster, MD, from the University of California, San Francisco, who was the invited discussant.

“The signal of a better pCR rate among patients in the ultra-high Mammaprint group may allow selection of patients with HR-positive disease who may benefit from immunotherapeutic agents and/or PARP inhibitors,” she said.

Munster noted that the approximately 10% higher rate of immune-related adverse events of grade 3 or greater that was seen with the combination appears similar to that seen in other studies, but anemia and fatigue appeared to be less frequent with durvalumab/olaparaib and paclitaxel in comparison with paclitaxel alone.

“In the absence of a clear delineation of the contribution of olaparib, some weight should be given to the financial burden of adding both durvalumab and olaparib to a preoperative regimen,” she said.

The additional cost of durvalumab is approximately $34,000, and adding olaparib boosts that by about $22,000 more, Munster said.
 

Ongoing platform trial

The new results come from one arm of the ongoing Investigation of Serial Studies to Predict Your Therapeutic Response Through Imaging and Molecular Analysis 2 (I-SPY-2) trial. This is an ongoing platform trial that is exploring the use of new drugs in combination with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

In this trial, women with stage II or III breast cancer with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 status, HR status, and genetic risk factors, as determined on the basis of a 70-gene assay. The patients within each biomarker subtype are randomly assigned to receive standard therapy either with or without an investigational agent.

For each subtrial, a primary endpoint is an improvement in pCR in comparison with the standard of care.

Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Those who are considered to have a high Bayesian predictive probability of success are eligible for moving on to phase 3 trials.

The I-SPY-2 trial was described in detail by principal investigator Laura J. Esserman, MD, MBA, from the Helen Diller Comprehensive Cancer Center at the University of California, San Francisco, in a 2017 interview from the annual meeting of the American Society of Clinical Oncology.

As previously reported, the first drugs to “graduate” from the trial were the HER2/HER4 inhibitor neratinib (Nerlynx, Puma Biotechnology) and the investigational PARP inhibitor veliparib (AbbVie).
 

Study details

The I-SPY-2 results that Pusztai reported at the AACR meeting were based on an analysis of 73 HER2-negative patients, including 21 patients with TNBC and 52 with HR-positive tumors with Mammaprint high-risk features. These patients underwent treatment with durvalumab 1500 mg every 4 weeks for three cycles, olaparib 100 mg twice daily for weeks 1 through 11, and paclitaxel 80 mg/m2 weekly for 12 weeks, followed by AC chemotherapy (doxorubicin and cyclophosphamide) for four cycles.

The 299 patients in the control arm received paclitaxel and chemotherapy only.

In all three biomarker subsets studied, durvalumab and olaparib increased pCR rates compared with controls, as shown in the table.

The probability that the combination was superior to control in each subgroup approached 100%, Pusztai noted.

Adverse events with the combination were consistent with known side effects of the drugs, he commented. Immune-related grade 3 adverse events occurred in 19% of patients in the combination therapy arm, compared with 1.6% in the control arm.

Higher pCR rates were seen in the subset of immune-rich tumors among all cancer subtypes and in both study arms.

“Exploratory analysis suggests several potential predictive markers of durvalumab/olaparib benefit over chemotherapy alone,” Pusztai reported.

These markers included Mammaprint MP2 (ultra high) versus MP1 in HR+/HER2– tumors, and low CD3/CD8 gene signature ratio, high macrophage/Tc-class 2 gene signature ratio, and high proliferation signature, all of which were associated with higher pCR rates in the experimental arm among patients with TNBC.

The trial was supported by the William K. Bowes Jr Foundation, Foundation for the NIH, Give Breast Cancer the Boot, UCSF, the Biomarkers Consortium, IQVIA, the Breast Cancer Research Foundation, Safeway, California Breast Cancer Research Program, Breast Cancer Research–Atwater Trust, and Stand Up to Cancer. Pusztai has received honoraria and consulting fees from AstraZeneca and other companies. Munster has received research and travel support from and has served on the scientific advisory boards of AstraZeneca and other companies.

This article first appeared on Medscape.com.

A novel combination has boosted responses in women with high-risk, HER2-negative breast cancer.

The new combo comprises the immune checkpoint inhibitor durvalumab (Imfinzi, AstraZeneca) and the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca).

When this combo was added to standard neoadjuvant chemotherapy, it yielded a significantly higher pathologic complete response (pCR) rate at the time of surgery than was seen with chemotherapy alone.

The superior pCR rate was seen across all HER2-negative breast cancer subtypes, including HER2-negative, estrogen receptor–positive tumors (Mammaprint high risk), and in women with triple-negative breast cancer (TNBC), reported lead investigator Lajos Pusztai, MD, DPhil, from Yale Cancer Center in New Haven, Connecticut.

“These results provide further evidence for the clinical value of immunotherapy in early-stage breast cancer and suggest new avenues for how to exploit these drugs in hormone receptor [HR]–positive breast cancers,” said Pusztai.

He presented the results at the American Association for Cancer Research (AACR) virtual annual meeting, which took place online, owing to the COVID-19 pandemic.
 

Toxicities, including financial

“The benefits from immunotherapy are clearly emerging in early and metastatic triple-negative breast cancer, likely with PD-L1 expression. However, there’s much more uncertainty in patients with hormone-sensitive tumors whether there is benefit and who will benefit from immunotherapy,” commented Pamela N. Munster, MD, from the University of California, San Francisco, who was the invited discussant.

“The signal of a better pCR rate among patients in the ultra-high Mammaprint group may allow selection of patients with HR-positive disease who may benefit from immunotherapeutic agents and/or PARP inhibitors,” she said.

Munster noted that the approximately 10% higher rate of immune-related adverse events of grade 3 or greater that was seen with the combination appears similar to that seen in other studies, but anemia and fatigue appeared to be less frequent with durvalumab/olaparaib and paclitaxel in comparison with paclitaxel alone.

“In the absence of a clear delineation of the contribution of olaparib, some weight should be given to the financial burden of adding both durvalumab and olaparib to a preoperative regimen,” she said.

The additional cost of durvalumab is approximately $34,000, and adding olaparib boosts that by about $22,000 more, Munster said.
 

Ongoing platform trial

The new results come from one arm of the ongoing Investigation of Serial Studies to Predict Your Therapeutic Response Through Imaging and Molecular Analysis 2 (I-SPY-2) trial. This is an ongoing platform trial that is exploring the use of new drugs in combination with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

In this trial, women with stage II or III breast cancer with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 status, HR status, and genetic risk factors, as determined on the basis of a 70-gene assay. The patients within each biomarker subtype are randomly assigned to receive standard therapy either with or without an investigational agent.

For each subtrial, a primary endpoint is an improvement in pCR in comparison with the standard of care.

Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Those who are considered to have a high Bayesian predictive probability of success are eligible for moving on to phase 3 trials.

The I-SPY-2 trial was described in detail by principal investigator Laura J. Esserman, MD, MBA, from the Helen Diller Comprehensive Cancer Center at the University of California, San Francisco, in a 2017 interview from the annual meeting of the American Society of Clinical Oncology.

As previously reported, the first drugs to “graduate” from the trial were the HER2/HER4 inhibitor neratinib (Nerlynx, Puma Biotechnology) and the investigational PARP inhibitor veliparib (AbbVie).
 

Study details

The I-SPY-2 results that Pusztai reported at the AACR meeting were based on an analysis of 73 HER2-negative patients, including 21 patients with TNBC and 52 with HR-positive tumors with Mammaprint high-risk features. These patients underwent treatment with durvalumab 1500 mg every 4 weeks for three cycles, olaparib 100 mg twice daily for weeks 1 through 11, and paclitaxel 80 mg/m2 weekly for 12 weeks, followed by AC chemotherapy (doxorubicin and cyclophosphamide) for four cycles.

The 299 patients in the control arm received paclitaxel and chemotherapy only.

In all three biomarker subsets studied, durvalumab and olaparib increased pCR rates compared with controls, as shown in the table.

The probability that the combination was superior to control in each subgroup approached 100%, Pusztai noted.

Adverse events with the combination were consistent with known side effects of the drugs, he commented. Immune-related grade 3 adverse events occurred in 19% of patients in the combination therapy arm, compared with 1.6% in the control arm.

Higher pCR rates were seen in the subset of immune-rich tumors among all cancer subtypes and in both study arms.

“Exploratory analysis suggests several potential predictive markers of durvalumab/olaparib benefit over chemotherapy alone,” Pusztai reported.

These markers included Mammaprint MP2 (ultra high) versus MP1 in HR+/HER2– tumors, and low CD3/CD8 gene signature ratio, high macrophage/Tc-class 2 gene signature ratio, and high proliferation signature, all of which were associated with higher pCR rates in the experimental arm among patients with TNBC.

The trial was supported by the William K. Bowes Jr Foundation, Foundation for the NIH, Give Breast Cancer the Boot, UCSF, the Biomarkers Consortium, IQVIA, the Breast Cancer Research Foundation, Safeway, California Breast Cancer Research Program, Breast Cancer Research–Atwater Trust, and Stand Up to Cancer. Pusztai has received honoraria and consulting fees from AstraZeneca and other companies. Munster has received research and travel support from and has served on the scientific advisory boards of AstraZeneca and other companies.

This article first appeared on Medscape.com.

A novel combination has boosted responses in women with high-risk, HER2-negative breast cancer.

The new combo comprises the immune checkpoint inhibitor durvalumab (Imfinzi, AstraZeneca) and the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca).

When this combo was added to standard neoadjuvant chemotherapy, it yielded a significantly higher pathologic complete response (pCR) rate at the time of surgery than was seen with chemotherapy alone.

The superior pCR rate was seen across all HER2-negative breast cancer subtypes, including HER2-negative, estrogen receptor–positive tumors (Mammaprint high risk), and in women with triple-negative breast cancer (TNBC), reported lead investigator Lajos Pusztai, MD, DPhil, from Yale Cancer Center in New Haven, Connecticut.

“These results provide further evidence for the clinical value of immunotherapy in early-stage breast cancer and suggest new avenues for how to exploit these drugs in hormone receptor [HR]–positive breast cancers,” said Pusztai.

He presented the results at the American Association for Cancer Research (AACR) virtual annual meeting, which took place online, owing to the COVID-19 pandemic.
 

Toxicities, including financial

“The benefits from immunotherapy are clearly emerging in early and metastatic triple-negative breast cancer, likely with PD-L1 expression. However, there’s much more uncertainty in patients with hormone-sensitive tumors whether there is benefit and who will benefit from immunotherapy,” commented Pamela N. Munster, MD, from the University of California, San Francisco, who was the invited discussant.

“The signal of a better pCR rate among patients in the ultra-high Mammaprint group may allow selection of patients with HR-positive disease who may benefit from immunotherapeutic agents and/or PARP inhibitors,” she said.

Munster noted that the approximately 10% higher rate of immune-related adverse events of grade 3 or greater that was seen with the combination appears similar to that seen in other studies, but anemia and fatigue appeared to be less frequent with durvalumab/olaparaib and paclitaxel in comparison with paclitaxel alone.

“In the absence of a clear delineation of the contribution of olaparib, some weight should be given to the financial burden of adding both durvalumab and olaparib to a preoperative regimen,” she said.

The additional cost of durvalumab is approximately $34,000, and adding olaparib boosts that by about $22,000 more, Munster said.
 

Ongoing platform trial

The new results come from one arm of the ongoing Investigation of Serial Studies to Predict Your Therapeutic Response Through Imaging and Molecular Analysis 2 (I-SPY-2) trial. This is an ongoing platform trial that is exploring the use of new drugs in combination with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

In this trial, women with stage II or III breast cancer with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 status, HR status, and genetic risk factors, as determined on the basis of a 70-gene assay. The patients within each biomarker subtype are randomly assigned to receive standard therapy either with or without an investigational agent.

For each subtrial, a primary endpoint is an improvement in pCR in comparison with the standard of care.

Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Those who are considered to have a high Bayesian predictive probability of success are eligible for moving on to phase 3 trials.

The I-SPY-2 trial was described in detail by principal investigator Laura J. Esserman, MD, MBA, from the Helen Diller Comprehensive Cancer Center at the University of California, San Francisco, in a 2017 interview from the annual meeting of the American Society of Clinical Oncology.

As previously reported, the first drugs to “graduate” from the trial were the HER2/HER4 inhibitor neratinib (Nerlynx, Puma Biotechnology) and the investigational PARP inhibitor veliparib (AbbVie).
 

Study details

The I-SPY-2 results that Pusztai reported at the AACR meeting were based on an analysis of 73 HER2-negative patients, including 21 patients with TNBC and 52 with HR-positive tumors with Mammaprint high-risk features. These patients underwent treatment with durvalumab 1500 mg every 4 weeks for three cycles, olaparib 100 mg twice daily for weeks 1 through 11, and paclitaxel 80 mg/m2 weekly for 12 weeks, followed by AC chemotherapy (doxorubicin and cyclophosphamide) for four cycles.

The 299 patients in the control arm received paclitaxel and chemotherapy only.

In all three biomarker subsets studied, durvalumab and olaparib increased pCR rates compared with controls, as shown in the table.

The probability that the combination was superior to control in each subgroup approached 100%, Pusztai noted.

Adverse events with the combination were consistent with known side effects of the drugs, he commented. Immune-related grade 3 adverse events occurred in 19% of patients in the combination therapy arm, compared with 1.6% in the control arm.

Higher pCR rates were seen in the subset of immune-rich tumors among all cancer subtypes and in both study arms.

“Exploratory analysis suggests several potential predictive markers of durvalumab/olaparib benefit over chemotherapy alone,” Pusztai reported.

These markers included Mammaprint MP2 (ultra high) versus MP1 in HR+/HER2– tumors, and low CD3/CD8 gene signature ratio, high macrophage/Tc-class 2 gene signature ratio, and high proliferation signature, all of which were associated with higher pCR rates in the experimental arm among patients with TNBC.

The trial was supported by the William K. Bowes Jr Foundation, Foundation for the NIH, Give Breast Cancer the Boot, UCSF, the Biomarkers Consortium, IQVIA, the Breast Cancer Research Foundation, Safeway, California Breast Cancer Research Program, Breast Cancer Research–Atwater Trust, and Stand Up to Cancer. Pusztai has received honoraria and consulting fees from AstraZeneca and other companies. Munster has received research and travel support from and has served on the scientific advisory boards of AstraZeneca and other companies.

This article first appeared on Medscape.com.

The COVID-19 pandemic continues to exact a heavy price on cancer patients, cancer care, and clinical trials, an expert panel reported during a presscast.

“Limited data available thus far are sobering: In Italy, about 20% of COVID-related deaths occurred in people with cancer, and, in China, COVID-19 patients who had cancer were about five times more likely than others to die or be placed on a ventilator in an intensive care unit,” said Howard A “Skip” Burris, MD, president of the American Society of Clinical Oncology and president and CEO of the Sarah Cannon Cancer Institute in Nashville, Tenn.

“We also have little evidence on returning COVID-19 patients with cancer. Physicians have to rely on limited data, anecdotal reports, and their own professional expertise” regarding the extent of increased risk to cancer patients with COVID-19, whether to interrupt or modify treatment, and the effects of cancer on recovery from COVID-19 infection, Dr. Burris said during the ASCO-sponsored online presscast.
 

Care of COVID-free patients

For cancer patients without COVID-19, the picture is equally dim, with the prospect of delayed surgery, chemotherapy, or screening; shortages of medications and equipment needed for critical care; the shift to telemedicine that may increase patient anxiety; and the potential loss of access to innovative therapies through clinical trials, Dr. Burris said.

“We’re concerned that some hospitals have effectively deemed all cancer surgeries to be elective, requiring them to be postponed. For patients with fast-moving or hard-to-treat cancer, this delay may be devastating,” he said.

Dr. Burris also cited concerns about delayed cancer diagnosis. “In a typical month, roughly 150,000 Americans are diagnosed with cancer. But right now, routine screening visits are postponed, and patients with pain or other warning signs may put off a doctor’s visit because of social distancing,” he said.

The pandemic has also exacerbated shortages of sedatives and opioid analgesics required for intubation and mechanical ventilation of patients.
 

Trials halted or slowed

Dr. Burris also briefly discussed results of a new survey, which were posted online ahead of publication in JCO Oncology Practice. The survey showed that, of 14 academic and 18 community-based cancer programs, 59.4% reported halting screening and/or enrollment for at least some clinical trials and suspending research-based clinical visits except for those where cancer treatment was delivered.

“Half of respondents reported ceasing research-only blood and/or tissue collections,” the authors of the article reported.

“Trial interruptions are devastating news for thousands of patients; in many cases, clinical trials are the best or only appropriate option for care,” Dr. Burris said.

The article authors, led by David Waterhouse, MD, of Oncology Hematology Care in Cincinnati, pointed to a silver lining in the pandemic cloud in the form of opportunities to improve clinical trials going forward.

“Nearly all respondents (90.3%) identified telehealth visits for participants as a potential improvement to clinical trial conduct, and more than three-quarters (77.4%) indicated that remote patient review of symptoms held similar potential,” the authors wrote.

Other potential improvements included remote site visits from trial sponsors and/or contract research organizations, more efficient study enrollment through secure electronic platforms, direct shipment of oral drugs to patients, remote assessments of adverse events, and streamlined data collection.
 

Lessons from the front lines

Another member of the presscast panel, Melissa Dillmon, MD, of the Harbin Clinic Cancer Center in Rome, Georgia, described the experience of community oncologists during the pandemic.

Her community, located in northeastern Georgia, experienced a COVID-19 outbreak in early March linked to services at two large churches. Community public health authorities issued a shelter-in-place order before the state government issued stay-at-home guidelines and shuttered all but essential business, some of which were allowed by state order to reopen as of April 24.

Dr. Dillmon’s center began screening patients for COVID-19 symptoms at the door, limited visitors or companions, instituted virtual visits and tumor boards, and set up a cancer treatment triage system that would allow essential surgeries to proceed and most infusions to continue, while delaying the start of chemotherapy when possible.

“We have encouraged patients to continue on treatment, especially if treatment is being given with curative intent, or if the cancer is responding well already to treatment,” she said.

The center, located in a community with a high prevalence of comorbidities and high incidence of lung cancer, has seen a sharp decline in colonoscopies, mammograms, and lung scans as patient shelter in place.

“We have great concerns about patients missing their screening lung scans, as this program has already proven to be finding earlier lung cancers that are curable,” Dr. Dillmon said.
 

A view from Washington state

Another panel member, Gary Lyman, MD, of the Fred Hutchinson Cancer Research Center in Seattle, described the response by the state of Washington, the initial epicenter of the COVID-19 outbreak in the United States.

Following identification of infections in hospitalized patients and at a nursing home in Kirkland, Washington, “our response, which began in early March and progressed through the second and third week in March at the state level, was to restrict large gatherings; progressively, schools were closed; larger businesses closed; and, by March 23, a stay-at-home policy was implemented, and all nonessential businesses were closed,” Dr. Lyman said.

“We believe, based on what has happened since that time, that this has considerably flattened the curve,” he continued.

Lessons from the Washington experience include the need to plan for a long-term disruption or alteration of cancer care, expand COVID-19 testing to all patients coming into hospitals or major clinics, institute aggressive supportive care measures, prepare for subsequent waves of infection, collect and share data, and, for remote or rural areas, identify lifelines to needed resources, Dr. Lyman said.
 

ASCO resources

Also speaking at the presscast, Jonathan Marron, MD, of Boston Children’s Hospital and Harvard Medical School, Boston, outlined ASCO’s guidance on allocation of scarce resources during the COVID-19 pandemic.

Richard L. Schilsky, MD, ASCO chief medical officer and executive vice president, outlined community-wide collaborations, data initiatives, and online resources for both clinicians and patients.

The COVID-19 pandemic continues to exact a heavy price on cancer patients, cancer care, and clinical trials, an expert panel reported during a presscast.

“Limited data available thus far are sobering: In Italy, about 20% of COVID-related deaths occurred in people with cancer, and, in China, COVID-19 patients who had cancer were about five times more likely than others to die or be placed on a ventilator in an intensive care unit,” said Howard A “Skip” Burris, MD, president of the American Society of Clinical Oncology and president and CEO of the Sarah Cannon Cancer Institute in Nashville, Tenn.

“We also have little evidence on returning COVID-19 patients with cancer. Physicians have to rely on limited data, anecdotal reports, and their own professional expertise” regarding the extent of increased risk to cancer patients with COVID-19, whether to interrupt or modify treatment, and the effects of cancer on recovery from COVID-19 infection, Dr. Burris said during the ASCO-sponsored online presscast.
 

Care of COVID-free patients

For cancer patients without COVID-19, the picture is equally dim, with the prospect of delayed surgery, chemotherapy, or screening; shortages of medications and equipment needed for critical care; the shift to telemedicine that may increase patient anxiety; and the potential loss of access to innovative therapies through clinical trials, Dr. Burris said.

“We’re concerned that some hospitals have effectively deemed all cancer surgeries to be elective, requiring them to be postponed. For patients with fast-moving or hard-to-treat cancer, this delay may be devastating,” he said.

Dr. Burris also cited concerns about delayed cancer diagnosis. “In a typical month, roughly 150,000 Americans are diagnosed with cancer. But right now, routine screening visits are postponed, and patients with pain or other warning signs may put off a doctor’s visit because of social distancing,” he said.

The pandemic has also exacerbated shortages of sedatives and opioid analgesics required for intubation and mechanical ventilation of patients.
 

Trials halted or slowed

Dr. Burris also briefly discussed results of a new survey, which were posted online ahead of publication in JCO Oncology Practice. The survey showed that, of 14 academic and 18 community-based cancer programs, 59.4% reported halting screening and/or enrollment for at least some clinical trials and suspending research-based clinical visits except for those where cancer treatment was delivered.

“Half of respondents reported ceasing research-only blood and/or tissue collections,” the authors of the article reported.

“Trial interruptions are devastating news for thousands of patients; in many cases, clinical trials are the best or only appropriate option for care,” Dr. Burris said.

The article authors, led by David Waterhouse, MD, of Oncology Hematology Care in Cincinnati, pointed to a silver lining in the pandemic cloud in the form of opportunities to improve clinical trials going forward.

“Nearly all respondents (90.3%) identified telehealth visits for participants as a potential improvement to clinical trial conduct, and more than three-quarters (77.4%) indicated that remote patient review of symptoms held similar potential,” the authors wrote.

Other potential improvements included remote site visits from trial sponsors and/or contract research organizations, more efficient study enrollment through secure electronic platforms, direct shipment of oral drugs to patients, remote assessments of adverse events, and streamlined data collection.
 

Lessons from the front lines

Another member of the presscast panel, Melissa Dillmon, MD, of the Harbin Clinic Cancer Center in Rome, Georgia, described the experience of community oncologists during the pandemic.

Her community, located in northeastern Georgia, experienced a COVID-19 outbreak in early March linked to services at two large churches. Community public health authorities issued a shelter-in-place order before the state government issued stay-at-home guidelines and shuttered all but essential business, some of which were allowed by state order to reopen as of April 24.

Dr. Dillmon’s center began screening patients for COVID-19 symptoms at the door, limited visitors or companions, instituted virtual visits and tumor boards, and set up a cancer treatment triage system that would allow essential surgeries to proceed and most infusions to continue, while delaying the start of chemotherapy when possible.

“We have encouraged patients to continue on treatment, especially if treatment is being given with curative intent, or if the cancer is responding well already to treatment,” she said.

The center, located in a community with a high prevalence of comorbidities and high incidence of lung cancer, has seen a sharp decline in colonoscopies, mammograms, and lung scans as patient shelter in place.

“We have great concerns about patients missing their screening lung scans, as this program has already proven to be finding earlier lung cancers that are curable,” Dr. Dillmon said.
 

A view from Washington state

Another panel member, Gary Lyman, MD, of the Fred Hutchinson Cancer Research Center in Seattle, described the response by the state of Washington, the initial epicenter of the COVID-19 outbreak in the United States.

Following identification of infections in hospitalized patients and at a nursing home in Kirkland, Washington, “our response, which began in early March and progressed through the second and third week in March at the state level, was to restrict large gatherings; progressively, schools were closed; larger businesses closed; and, by March 23, a stay-at-home policy was implemented, and all nonessential businesses were closed,” Dr. Lyman said.

“We believe, based on what has happened since that time, that this has considerably flattened the curve,” he continued.

Lessons from the Washington experience include the need to plan for a long-term disruption or alteration of cancer care, expand COVID-19 testing to all patients coming into hospitals or major clinics, institute aggressive supportive care measures, prepare for subsequent waves of infection, collect and share data, and, for remote or rural areas, identify lifelines to needed resources, Dr. Lyman said.
 

ASCO resources

Also speaking at the presscast, Jonathan Marron, MD, of Boston Children’s Hospital and Harvard Medical School, Boston, outlined ASCO’s guidance on allocation of scarce resources during the COVID-19 pandemic.

Richard L. Schilsky, MD, ASCO chief medical officer and executive vice president, outlined community-wide collaborations, data initiatives, and online resources for both clinicians and patients.

The COVID-19 pandemic continues to exact a heavy price on cancer patients, cancer care, and clinical trials, an expert panel reported during a presscast.

“Limited data available thus far are sobering: In Italy, about 20% of COVID-related deaths occurred in people with cancer, and, in China, COVID-19 patients who had cancer were about five times more likely than others to die or be placed on a ventilator in an intensive care unit,” said Howard A “Skip” Burris, MD, president of the American Society of Clinical Oncology and president and CEO of the Sarah Cannon Cancer Institute in Nashville, Tenn.

“We also have little evidence on returning COVID-19 patients with cancer. Physicians have to rely on limited data, anecdotal reports, and their own professional expertise” regarding the extent of increased risk to cancer patients with COVID-19, whether to interrupt or modify treatment, and the effects of cancer on recovery from COVID-19 infection, Dr. Burris said during the ASCO-sponsored online presscast.
 

Care of COVID-free patients

For cancer patients without COVID-19, the picture is equally dim, with the prospect of delayed surgery, chemotherapy, or screening; shortages of medications and equipment needed for critical care; the shift to telemedicine that may increase patient anxiety; and the potential loss of access to innovative therapies through clinical trials, Dr. Burris said.

“We’re concerned that some hospitals have effectively deemed all cancer surgeries to be elective, requiring them to be postponed. For patients with fast-moving or hard-to-treat cancer, this delay may be devastating,” he said.

Dr. Burris also cited concerns about delayed cancer diagnosis. “In a typical month, roughly 150,000 Americans are diagnosed with cancer. But right now, routine screening visits are postponed, and patients with pain or other warning signs may put off a doctor’s visit because of social distancing,” he said.

The pandemic has also exacerbated shortages of sedatives and opioid analgesics required for intubation and mechanical ventilation of patients.
 

Trials halted or slowed

Dr. Burris also briefly discussed results of a new survey, which were posted online ahead of publication in JCO Oncology Practice. The survey showed that, of 14 academic and 18 community-based cancer programs, 59.4% reported halting screening and/or enrollment for at least some clinical trials and suspending research-based clinical visits except for those where cancer treatment was delivered.

“Half of respondents reported ceasing research-only blood and/or tissue collections,” the authors of the article reported.

“Trial interruptions are devastating news for thousands of patients; in many cases, clinical trials are the best or only appropriate option for care,” Dr. Burris said.

The article authors, led by David Waterhouse, MD, of Oncology Hematology Care in Cincinnati, pointed to a silver lining in the pandemic cloud in the form of opportunities to improve clinical trials going forward.

“Nearly all respondents (90.3%) identified telehealth visits for participants as a potential improvement to clinical trial conduct, and more than three-quarters (77.4%) indicated that remote patient review of symptoms held similar potential,” the authors wrote.

Other potential improvements included remote site visits from trial sponsors and/or contract research organizations, more efficient study enrollment through secure electronic platforms, direct shipment of oral drugs to patients, remote assessments of adverse events, and streamlined data collection.
 

Lessons from the front lines

Another member of the presscast panel, Melissa Dillmon, MD, of the Harbin Clinic Cancer Center in Rome, Georgia, described the experience of community oncologists during the pandemic.

Her community, located in northeastern Georgia, experienced a COVID-19 outbreak in early March linked to services at two large churches. Community public health authorities issued a shelter-in-place order before the state government issued stay-at-home guidelines and shuttered all but essential business, some of which were allowed by state order to reopen as of April 24.

Dr. Dillmon’s center began screening patients for COVID-19 symptoms at the door, limited visitors or companions, instituted virtual visits and tumor boards, and set up a cancer treatment triage system that would allow essential surgeries to proceed and most infusions to continue, while delaying the start of chemotherapy when possible.

“We have encouraged patients to continue on treatment, especially if treatment is being given with curative intent, or if the cancer is responding well already to treatment,” she said.

The center, located in a community with a high prevalence of comorbidities and high incidence of lung cancer, has seen a sharp decline in colonoscopies, mammograms, and lung scans as patient shelter in place.

“We have great concerns about patients missing their screening lung scans, as this program has already proven to be finding earlier lung cancers that are curable,” Dr. Dillmon said.
 

A view from Washington state

Another panel member, Gary Lyman, MD, of the Fred Hutchinson Cancer Research Center in Seattle, described the response by the state of Washington, the initial epicenter of the COVID-19 outbreak in the United States.

Following identification of infections in hospitalized patients and at a nursing home in Kirkland, Washington, “our response, which began in early March and progressed through the second and third week in March at the state level, was to restrict large gatherings; progressively, schools were closed; larger businesses closed; and, by March 23, a stay-at-home policy was implemented, and all nonessential businesses were closed,” Dr. Lyman said.

“We believe, based on what has happened since that time, that this has considerably flattened the curve,” he continued.

Lessons from the Washington experience include the need to plan for a long-term disruption or alteration of cancer care, expand COVID-19 testing to all patients coming into hospitals or major clinics, institute aggressive supportive care measures, prepare for subsequent waves of infection, collect and share data, and, for remote or rural areas, identify lifelines to needed resources, Dr. Lyman said.
 

ASCO resources

Also speaking at the presscast, Jonathan Marron, MD, of Boston Children’s Hospital and Harvard Medical School, Boston, outlined ASCO’s guidance on allocation of scarce resources during the COVID-19 pandemic.

Richard L. Schilsky, MD, ASCO chief medical officer and executive vice president, outlined community-wide collaborations, data initiatives, and online resources for both clinicians and patients.

Rates of minimally invasive surgery for early-stage endometrial cancer may be higher than previously reported, results of a registry study suggest.

Of 3,730 women with endometrial cancer in the Society of Gynecologic Oncology Clinical Outcomes Registry (SGO-COR), 88.8% underwent minimally invasive procedures, reported Amanda Nickles Fader, MD, of Johns Hopkins Hospital, Baltimore, and colleagues.

“When you have surgery with a gyn-oncologist who is specially trained in this type of surgery, we see that women have a very high likelihood of having the appropriate surgery, the minimally invasive surgery, and we thought that this benchmark of an 80% rate of minimally invasive surgery in these patients is very feasible and should be recognized as the standard of care,” Dr. Nickles Fader said in an interview.

Coinvestigator Summer B. Dewdney, MD, of Rush University Medical Center, Chicago, who was instrumental in creating and running the SGO-COR registry, said these findings are encouraging.

“We’re happy to see that rate. It’s the rate that it should be because minimally invasive surgery is the standard of care for endometrial cancer,” Dr. Dewdney said. She added, however, that data supplied to the registry come from gynecologic oncologists who are highly motivated to participate and follow best practice guidelines, which could skew the results slightly toward more favorable outcomes.

Results of the registry-based study are detailed in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Assessing adherence to guidelines

In 2015, the SGO Clinical Practice Committee and the American College of Obstetricians and Gynecologists issued a practice bulletin, which stated that “minimally invasive surgery should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer.”

Similarly, National Comprehensive Cancer Network guidelines for uterine cancer state that “minimally invasive surgery is the preferred approach when technically feasible” for treatment of endometrial cancer confined to the uterus.

Despite these recommendations, the overall rate of minimally invasive endometrial cancer surgery in the United States is reported be around to 60%, Dr. Nickles Fader and colleagues wrote.

With this in mind, the investigators set out to determine the rate of minimally invasive surgery in women with apparent stage I, II, or III endometrial cancer who underwent hysterectomy with or without staging from 2012 to 2017 at a center reporting to SGO-COR.

The team identified 3,730 women treated at 25 SGO-COR centers; 12 of which were university-affiliated centers and 13 of which were nonuniversity based. Most patients (83.2%) had stage I disease, 4.7% had stage II cancer, and 12.1% had stage III disease. The median patient age was 57 years. Most patients (88%) were white, and two-thirds (67.1%) were obese. In all, 80.4% of samples had endometrioid histology, and 77.7% were either grade 1 or 2.
 

Factors associated with minimally invasive surgery

The data showed that 88.8% of patients underwent a minimally invasive hysterectomy, composed of robotic-assisted procedures in 73.9% of cases, laparoscopy in 13.4%, and vaginal access in 1.6%.

The proportion of patients who underwent a minimally invasive procedure was significantly higher at nonuniversity centers, compared with academic centers (92.6% vs. 82.7%; P < .0001), but rates of minimally invasive procedures did not differ significantly across U.S. geographic regions.

Dr. Dewdney said that the higher proportion of open surgeries performed at university centers may be attributable to those centers treating patients with more advanced disease or rare aggressive cancers that may not be amenable to a minimally invasive approach.

In a multivariate analysis, factors associated with a failure to perform minimally invasive surgery were black race of the patient (adjusted odds ratio, 0.57), body mass index over 35 kg/m² (aOR, 1.40), stage II disease (aOR, 0.49), stage III disease (aOR, 0.36), carcinosarcoma/leiomyosarcoma (aOR, 0.58), and university hospital (aOR, 3.46).

Looking at perioperative complications, the investigators found that laparotomy was associated with more in-hospital complications than minimally invasive procedures, including more unscheduled ICU stays (P < .001) and prolonged hospital stays (P = .0002).

Dr. Dewdney said that investigators are planning further registry-based studies focusing on ovarian cancer, uterine cancer, and cervical cancer.

Dr. Nickles Fader and Dr. Dewdney reported having no relevant conflicts of interest.

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 63.

Rates of minimally invasive surgery for early-stage endometrial cancer may be higher than previously reported, results of a registry study suggest.

Of 3,730 women with endometrial cancer in the Society of Gynecologic Oncology Clinical Outcomes Registry (SGO-COR), 88.8% underwent minimally invasive procedures, reported Amanda Nickles Fader, MD, of Johns Hopkins Hospital, Baltimore, and colleagues.

“When you have surgery with a gyn-oncologist who is specially trained in this type of surgery, we see that women have a very high likelihood of having the appropriate surgery, the minimally invasive surgery, and we thought that this benchmark of an 80% rate of minimally invasive surgery in these patients is very feasible and should be recognized as the standard of care,” Dr. Nickles Fader said in an interview.

Coinvestigator Summer B. Dewdney, MD, of Rush University Medical Center, Chicago, who was instrumental in creating and running the SGO-COR registry, said these findings are encouraging.

“We’re happy to see that rate. It’s the rate that it should be because minimally invasive surgery is the standard of care for endometrial cancer,” Dr. Dewdney said. She added, however, that data supplied to the registry come from gynecologic oncologists who are highly motivated to participate and follow best practice guidelines, which could skew the results slightly toward more favorable outcomes.

Results of the registry-based study are detailed in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Assessing adherence to guidelines

In 2015, the SGO Clinical Practice Committee and the American College of Obstetricians and Gynecologists issued a practice bulletin, which stated that “minimally invasive surgery should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer.”

Similarly, National Comprehensive Cancer Network guidelines for uterine cancer state that “minimally invasive surgery is the preferred approach when technically feasible” for treatment of endometrial cancer confined to the uterus.

Despite these recommendations, the overall rate of minimally invasive endometrial cancer surgery in the United States is reported be around to 60%, Dr. Nickles Fader and colleagues wrote.

With this in mind, the investigators set out to determine the rate of minimally invasive surgery in women with apparent stage I, II, or III endometrial cancer who underwent hysterectomy with or without staging from 2012 to 2017 at a center reporting to SGO-COR.

The team identified 3,730 women treated at 25 SGO-COR centers; 12 of which were university-affiliated centers and 13 of which were nonuniversity based. Most patients (83.2%) had stage I disease, 4.7% had stage II cancer, and 12.1% had stage III disease. The median patient age was 57 years. Most patients (88%) were white, and two-thirds (67.1%) were obese. In all, 80.4% of samples had endometrioid histology, and 77.7% were either grade 1 or 2.
 

Factors associated with minimally invasive surgery

The data showed that 88.8% of patients underwent a minimally invasive hysterectomy, composed of robotic-assisted procedures in 73.9% of cases, laparoscopy in 13.4%, and vaginal access in 1.6%.

The proportion of patients who underwent a minimally invasive procedure was significantly higher at nonuniversity centers, compared with academic centers (92.6% vs. 82.7%; P < .0001), but rates of minimally invasive procedures did not differ significantly across U.S. geographic regions.

Dr. Dewdney said that the higher proportion of open surgeries performed at university centers may be attributable to those centers treating patients with more advanced disease or rare aggressive cancers that may not be amenable to a minimally invasive approach.

In a multivariate analysis, factors associated with a failure to perform minimally invasive surgery were black race of the patient (adjusted odds ratio, 0.57), body mass index over 35 kg/m² (aOR, 1.40), stage II disease (aOR, 0.49), stage III disease (aOR, 0.36), carcinosarcoma/leiomyosarcoma (aOR, 0.58), and university hospital (aOR, 3.46).

Looking at perioperative complications, the investigators found that laparotomy was associated with more in-hospital complications than minimally invasive procedures, including more unscheduled ICU stays (P < .001) and prolonged hospital stays (P = .0002).

Dr. Dewdney said that investigators are planning further registry-based studies focusing on ovarian cancer, uterine cancer, and cervical cancer.

Dr. Nickles Fader and Dr. Dewdney reported having no relevant conflicts of interest.

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 63.

Rates of minimally invasive surgery for early-stage endometrial cancer may be higher than previously reported, results of a registry study suggest.

Of 3,730 women with endometrial cancer in the Society of Gynecologic Oncology Clinical Outcomes Registry (SGO-COR), 88.8% underwent minimally invasive procedures, reported Amanda Nickles Fader, MD, of Johns Hopkins Hospital, Baltimore, and colleagues.

“When you have surgery with a gyn-oncologist who is specially trained in this type of surgery, we see that women have a very high likelihood of having the appropriate surgery, the minimally invasive surgery, and we thought that this benchmark of an 80% rate of minimally invasive surgery in these patients is very feasible and should be recognized as the standard of care,” Dr. Nickles Fader said in an interview.

Coinvestigator Summer B. Dewdney, MD, of Rush University Medical Center, Chicago, who was instrumental in creating and running the SGO-COR registry, said these findings are encouraging.

“We’re happy to see that rate. It’s the rate that it should be because minimally invasive surgery is the standard of care for endometrial cancer,” Dr. Dewdney said. She added, however, that data supplied to the registry come from gynecologic oncologists who are highly motivated to participate and follow best practice guidelines, which could skew the results slightly toward more favorable outcomes.

Results of the registry-based study are detailed in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Assessing adherence to guidelines

In 2015, the SGO Clinical Practice Committee and the American College of Obstetricians and Gynecologists issued a practice bulletin, which stated that “minimally invasive surgery should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer.”

Similarly, National Comprehensive Cancer Network guidelines for uterine cancer state that “minimally invasive surgery is the preferred approach when technically feasible” for treatment of endometrial cancer confined to the uterus.

Despite these recommendations, the overall rate of minimally invasive endometrial cancer surgery in the United States is reported be around to 60%, Dr. Nickles Fader and colleagues wrote.

With this in mind, the investigators set out to determine the rate of minimally invasive surgery in women with apparent stage I, II, or III endometrial cancer who underwent hysterectomy with or without staging from 2012 to 2017 at a center reporting to SGO-COR.

The team identified 3,730 women treated at 25 SGO-COR centers; 12 of which were university-affiliated centers and 13 of which were nonuniversity based. Most patients (83.2%) had stage I disease, 4.7% had stage II cancer, and 12.1% had stage III disease. The median patient age was 57 years. Most patients (88%) were white, and two-thirds (67.1%) were obese. In all, 80.4% of samples had endometrioid histology, and 77.7% were either grade 1 or 2.
 

Factors associated with minimally invasive surgery

The data showed that 88.8% of patients underwent a minimally invasive hysterectomy, composed of robotic-assisted procedures in 73.9% of cases, laparoscopy in 13.4%, and vaginal access in 1.6%.

The proportion of patients who underwent a minimally invasive procedure was significantly higher at nonuniversity centers, compared with academic centers (92.6% vs. 82.7%; P < .0001), but rates of minimally invasive procedures did not differ significantly across U.S. geographic regions.

Dr. Dewdney said that the higher proportion of open surgeries performed at university centers may be attributable to those centers treating patients with more advanced disease or rare aggressive cancers that may not be amenable to a minimally invasive approach.

In a multivariate analysis, factors associated with a failure to perform minimally invasive surgery were black race of the patient (adjusted odds ratio, 0.57), body mass index over 35 kg/m² (aOR, 1.40), stage II disease (aOR, 0.49), stage III disease (aOR, 0.36), carcinosarcoma/leiomyosarcoma (aOR, 0.58), and university hospital (aOR, 3.46).

Looking at perioperative complications, the investigators found that laparotomy was associated with more in-hospital complications than minimally invasive procedures, including more unscheduled ICU stays (P < .001) and prolonged hospital stays (P = .0002).

Dr. Dewdney said that investigators are planning further registry-based studies focusing on ovarian cancer, uterine cancer, and cervical cancer.

Dr. Nickles Fader and Dr. Dewdney reported having no relevant conflicts of interest.

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 63.