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No benefit with adjuvant sorafenib in intermediate-/high-risk RCC
“The results of the SORCE trial will end the debate about adjuvant tyrosine kinase inhibitors in renal cell carcinoma for most investigators,” Tim Eisen, MBBChir, PhD, of Cambridge (England) University Hospitals NHS Foundation Trust, said in an interview.
Dr. Eisen and colleagues reported results from SORCE in the Journal of Clinical Oncology.
Patients with intermediate- or high-risk RCC after surgical resection have 5-year relapse rates of 30%-40% and 5-year survival of 74.8% that declines steeply to 16% with metastatic disease, Dr. Eisen and colleagues wrote.
While adjuvant strategies – including cytokines, radiotherapy, and hormone therapy – have not yielded success, oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor have shown efficacy in metastatic RCC.
With inconsistent results in randomized trials of TKIs in the adjuvant RCC setting, however, active surveillance after nephrectomy has remained the international standard of care. SORCE was conducted “to settle the question of adjuvant TKI therapy” in RCC, according to Dr. Eisen and colleagues.
The investigators enrolled 1,711 patients with completely resected, clear cell or non–clear cell RCC at intermediate or high risk of relapse. The patients’ mean age was 58 years, 71% of patients were men, and 84% had clear cell histology.
Patients were randomized (2:3:3) to 3 years of placebo, 1 year of sorafenib followed by 2 years of placebo, or 3 years of sorafenib.
The initial sorafenib dose was 400 mg twice per day orally, but it was amended to 400 mg daily.
The primary outcome was investigator-reported disease-free survival comparing 3 years of sorafenib with placebo.
No survival benefit, more adverse events
Survival outcomes were similar across the study arms. The median disease-free survival was not reached for 3 years of sorafenib or for 3 years of placebo (hazard ratio, 1.01; 95% confidence interval, 0.82-1.23; P = .946).
The restricted mean survival time over 10 years was 6.81 years for 3 years of sorafenib and 6.82 years for 3 years of placebo (P = .988).
As for overall survival, the hazard ratio for 3 years of sorafenib versus 3 years of placebo was 1.06 (95% CI, 0.82-1.38; P = .638), and the hazard ratio for 1 year of sorafenib versus 3 years of placebo was 0.92 (95% CI, 0.71-1.20; P = .541).
Adverse events of grade 3 or higher were reported by 58.6% of patients receiving 1 year of sorafenib, 63.9% of patients receiving 3 years of sorafenib, and 29.2% of patients receiving placebo. Serious adverse events were reported at rates of 19.1% for placebo, 21.6% for 1 year of sorafenib, and 24% for 3 years of sorafenib.
Despite being offered treatment adaptations, more than half of participants had stopped treatment by 12 months because of toxicity.
Results undermine TKI use
“The significant toxicity observed with TKI monotherapy, despite pragmatic dose reductions, together with lack of evidence of a survival benefit, fundamentally undermines the use of TKIs in the adjuvant treatment of RCC,” Dr. Eisen and colleagues concluded.
In an interview, Dr. Eisen noted: “We are now asking whether adjuvant PD-1/PD-L1, with or without CTLA4 checkpoint inhibitors, are of benefit for patients who have had a high- or intermediate-risk RCC resected. A more challenging question is whether neoadjuvant checkpoint inhibitors may add further benefit. There are many such studies, which will report over the next few years and have the potential to change the treatment landscape enormously.”
“Interest in the field in general has shifted to immunotherapy and immunotherapy/TKI combinations,” observed Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute in Bethesda, Md., who was not involved in this study.
“The majority in the field probably had a fairly good idea that sorafenib was unlikely to show any benefit, whether given over 1 or 3 years. SORCE results were not unexpected. They do cement our belief that TKIs such as sorafenib do not have a real role in managing patients with kidney cancer in the adjuvant setting,” Dr. Srinivasan said.
The SORCE trial was supported by Bayer, Cancer Research UK, the Medical Research Council, University College London, Cancer Australia, and the Australian National Health and Medical Research Council. Dr. Eisen disclosed relationships with AstraZeneca, Roche, EUSA, Bayer, Pfizer, Macmillan Cancer Support, and Kidney Cancer UK. His coauthors disclosed relationships with many companies. Dr. Srinivasan disclosed that the National Cancer Institute has received funds from Calithera Biosciences and Peloton/Merck for clinical trials on which he was the principal investigator.
SOURCE: Eisen T et al. J Clin Oncol. 2020 Oct 14. J Clin Oncol. 2020 Oct 14. doi: 10.1200/JCO.20.01800.
“The results of the SORCE trial will end the debate about adjuvant tyrosine kinase inhibitors in renal cell carcinoma for most investigators,” Tim Eisen, MBBChir, PhD, of Cambridge (England) University Hospitals NHS Foundation Trust, said in an interview.
Dr. Eisen and colleagues reported results from SORCE in the Journal of Clinical Oncology.
Patients with intermediate- or high-risk RCC after surgical resection have 5-year relapse rates of 30%-40% and 5-year survival of 74.8% that declines steeply to 16% with metastatic disease, Dr. Eisen and colleagues wrote.
While adjuvant strategies – including cytokines, radiotherapy, and hormone therapy – have not yielded success, oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor have shown efficacy in metastatic RCC.
With inconsistent results in randomized trials of TKIs in the adjuvant RCC setting, however, active surveillance after nephrectomy has remained the international standard of care. SORCE was conducted “to settle the question of adjuvant TKI therapy” in RCC, according to Dr. Eisen and colleagues.
The investigators enrolled 1,711 patients with completely resected, clear cell or non–clear cell RCC at intermediate or high risk of relapse. The patients’ mean age was 58 years, 71% of patients were men, and 84% had clear cell histology.
Patients were randomized (2:3:3) to 3 years of placebo, 1 year of sorafenib followed by 2 years of placebo, or 3 years of sorafenib.
The initial sorafenib dose was 400 mg twice per day orally, but it was amended to 400 mg daily.
The primary outcome was investigator-reported disease-free survival comparing 3 years of sorafenib with placebo.
No survival benefit, more adverse events
Survival outcomes were similar across the study arms. The median disease-free survival was not reached for 3 years of sorafenib or for 3 years of placebo (hazard ratio, 1.01; 95% confidence interval, 0.82-1.23; P = .946).
The restricted mean survival time over 10 years was 6.81 years for 3 years of sorafenib and 6.82 years for 3 years of placebo (P = .988).
As for overall survival, the hazard ratio for 3 years of sorafenib versus 3 years of placebo was 1.06 (95% CI, 0.82-1.38; P = .638), and the hazard ratio for 1 year of sorafenib versus 3 years of placebo was 0.92 (95% CI, 0.71-1.20; P = .541).
Adverse events of grade 3 or higher were reported by 58.6% of patients receiving 1 year of sorafenib, 63.9% of patients receiving 3 years of sorafenib, and 29.2% of patients receiving placebo. Serious adverse events were reported at rates of 19.1% for placebo, 21.6% for 1 year of sorafenib, and 24% for 3 years of sorafenib.
Despite being offered treatment adaptations, more than half of participants had stopped treatment by 12 months because of toxicity.
Results undermine TKI use
“The significant toxicity observed with TKI monotherapy, despite pragmatic dose reductions, together with lack of evidence of a survival benefit, fundamentally undermines the use of TKIs in the adjuvant treatment of RCC,” Dr. Eisen and colleagues concluded.
In an interview, Dr. Eisen noted: “We are now asking whether adjuvant PD-1/PD-L1, with or without CTLA4 checkpoint inhibitors, are of benefit for patients who have had a high- or intermediate-risk RCC resected. A more challenging question is whether neoadjuvant checkpoint inhibitors may add further benefit. There are many such studies, which will report over the next few years and have the potential to change the treatment landscape enormously.”
“Interest in the field in general has shifted to immunotherapy and immunotherapy/TKI combinations,” observed Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute in Bethesda, Md., who was not involved in this study.
“The majority in the field probably had a fairly good idea that sorafenib was unlikely to show any benefit, whether given over 1 or 3 years. SORCE results were not unexpected. They do cement our belief that TKIs such as sorafenib do not have a real role in managing patients with kidney cancer in the adjuvant setting,” Dr. Srinivasan said.
The SORCE trial was supported by Bayer, Cancer Research UK, the Medical Research Council, University College London, Cancer Australia, and the Australian National Health and Medical Research Council. Dr. Eisen disclosed relationships with AstraZeneca, Roche, EUSA, Bayer, Pfizer, Macmillan Cancer Support, and Kidney Cancer UK. His coauthors disclosed relationships with many companies. Dr. Srinivasan disclosed that the National Cancer Institute has received funds from Calithera Biosciences and Peloton/Merck for clinical trials on which he was the principal investigator.
SOURCE: Eisen T et al. J Clin Oncol. 2020 Oct 14. J Clin Oncol. 2020 Oct 14. doi: 10.1200/JCO.20.01800.
“The results of the SORCE trial will end the debate about adjuvant tyrosine kinase inhibitors in renal cell carcinoma for most investigators,” Tim Eisen, MBBChir, PhD, of Cambridge (England) University Hospitals NHS Foundation Trust, said in an interview.
Dr. Eisen and colleagues reported results from SORCE in the Journal of Clinical Oncology.
Patients with intermediate- or high-risk RCC after surgical resection have 5-year relapse rates of 30%-40% and 5-year survival of 74.8% that declines steeply to 16% with metastatic disease, Dr. Eisen and colleagues wrote.
While adjuvant strategies – including cytokines, radiotherapy, and hormone therapy – have not yielded success, oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor have shown efficacy in metastatic RCC.
With inconsistent results in randomized trials of TKIs in the adjuvant RCC setting, however, active surveillance after nephrectomy has remained the international standard of care. SORCE was conducted “to settle the question of adjuvant TKI therapy” in RCC, according to Dr. Eisen and colleagues.
The investigators enrolled 1,711 patients with completely resected, clear cell or non–clear cell RCC at intermediate or high risk of relapse. The patients’ mean age was 58 years, 71% of patients were men, and 84% had clear cell histology.
Patients were randomized (2:3:3) to 3 years of placebo, 1 year of sorafenib followed by 2 years of placebo, or 3 years of sorafenib.
The initial sorafenib dose was 400 mg twice per day orally, but it was amended to 400 mg daily.
The primary outcome was investigator-reported disease-free survival comparing 3 years of sorafenib with placebo.
No survival benefit, more adverse events
Survival outcomes were similar across the study arms. The median disease-free survival was not reached for 3 years of sorafenib or for 3 years of placebo (hazard ratio, 1.01; 95% confidence interval, 0.82-1.23; P = .946).
The restricted mean survival time over 10 years was 6.81 years for 3 years of sorafenib and 6.82 years for 3 years of placebo (P = .988).
As for overall survival, the hazard ratio for 3 years of sorafenib versus 3 years of placebo was 1.06 (95% CI, 0.82-1.38; P = .638), and the hazard ratio for 1 year of sorafenib versus 3 years of placebo was 0.92 (95% CI, 0.71-1.20; P = .541).
Adverse events of grade 3 or higher were reported by 58.6% of patients receiving 1 year of sorafenib, 63.9% of patients receiving 3 years of sorafenib, and 29.2% of patients receiving placebo. Serious adverse events were reported at rates of 19.1% for placebo, 21.6% for 1 year of sorafenib, and 24% for 3 years of sorafenib.
Despite being offered treatment adaptations, more than half of participants had stopped treatment by 12 months because of toxicity.
Results undermine TKI use
“The significant toxicity observed with TKI monotherapy, despite pragmatic dose reductions, together with lack of evidence of a survival benefit, fundamentally undermines the use of TKIs in the adjuvant treatment of RCC,” Dr. Eisen and colleagues concluded.
In an interview, Dr. Eisen noted: “We are now asking whether adjuvant PD-1/PD-L1, with or without CTLA4 checkpoint inhibitors, are of benefit for patients who have had a high- or intermediate-risk RCC resected. A more challenging question is whether neoadjuvant checkpoint inhibitors may add further benefit. There are many such studies, which will report over the next few years and have the potential to change the treatment landscape enormously.”
“Interest in the field in general has shifted to immunotherapy and immunotherapy/TKI combinations,” observed Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute in Bethesda, Md., who was not involved in this study.
“The majority in the field probably had a fairly good idea that sorafenib was unlikely to show any benefit, whether given over 1 or 3 years. SORCE results were not unexpected. They do cement our belief that TKIs such as sorafenib do not have a real role in managing patients with kidney cancer in the adjuvant setting,” Dr. Srinivasan said.
The SORCE trial was supported by Bayer, Cancer Research UK, the Medical Research Council, University College London, Cancer Australia, and the Australian National Health and Medical Research Council. Dr. Eisen disclosed relationships with AstraZeneca, Roche, EUSA, Bayer, Pfizer, Macmillan Cancer Support, and Kidney Cancer UK. His coauthors disclosed relationships with many companies. Dr. Srinivasan disclosed that the National Cancer Institute has received funds from Calithera Biosciences and Peloton/Merck for clinical trials on which he was the principal investigator.
SOURCE: Eisen T et al. J Clin Oncol. 2020 Oct 14. J Clin Oncol. 2020 Oct 14. doi: 10.1200/JCO.20.01800.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Baricitinib reduces adult atopic dermatitis severity in phase 3 study
in the phase 3, double-blind, placebo-controlled, BREEZE-AD7 study.
The study enrolled patients with inadequate responses to topical corticosteroids, according to Kristian Reich, MD, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and his coauthors.
First test of baricitinib plus topical steroids
Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, inhibits several cytokines in AD pathogenesis, and in two monotherapy studies (BREEZE-AD1 and BREEZE-AD2), it was superior to placebo for reducing several AD clinical signs and symptoms. The current BREEZE-AD7 study is the first to test baricitinib plus background topical corticosteroid therapy, more closely mirroring clinical practice, the authors noted.
BREEZE-AD7 was conducted at 68 centers in 10 countries in Asia, Australia, Europe, and South America. It included 329 adults with moderate to severe AD (mean age around 34 years, and around 34% were female) with inadequate responses to topical corticosteroids documented within the last 6 months. They were randomized 1:1:1 to daily baricitinib 4 mg, daily baricitinib 2 mg, or placebo for 16 weeks. All patients received moderate- and/or low-potency topical corticosteroids (such as 0.1%triamcinolone cream and 2.5% hydrocortisone ointment, respectively) for active lesions.
Significant benefit at 4 mg
At week 16, 31% of AD patients receiving baricitinib 4 mg achieved Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 (clear) or 1 (almost clear) versus 15% in the placebo group (odds ratio, 2.8; 95% confidence interval, 1.4-5.6; P = .004). Among patients receiving baricitinib 2 mg, 24% achieved vI-GA-AD scores of 0 or 1 (OR, 1.9; 95% CI, 0.9-3.9; P = .08).
The same pattern of improving scores from placebo to baricitinib 2 mg to baricitinib 4 mg persisted, as reflected with secondary endpoints at week 16. Among patients receiving baricitinib 4 mg, 48% achieved Eczema Area Severity Index (EASI) 75 responses, versus 43% and 23% in 2 mg and placebo groups, respectively. Percent changes from baseline in total EASI score were –67%, –58%, –45% for baricitinib 4 mg, baricitinib 2 mg, and placebo, respectively; the proportion of patients achieving 4-point or greater improvements in Itch Numeric Rating Scale (NRS) was 44%, 38%, and 20% for baricitinib 4 mg, baricitinib 2 mg and placebo, respectively.
Similarly, mean change from baseline on the Skin Pain numeric rating scale was –3.7, –3.2, and –2.1 for baricitinib 4 mg, baricitinib 2 mg and placebo. Nighttime itch awakenings were also reduced in a similar progression from placebo to the higher baricitinib dose.
Adverse events dose related
Treatment-related adverse events were reported more frequently in the baricitinib groups (58% baricitinib 4 mg, 56% baricitinib 2 mg) versus placebo 38%. Nasopharyngitis was most common, followed by oral herpes, upper respiratory tract infection, acne, diarrhea, and back pain. Serious adverse event rates were similar across treatment groups. Permanent discontinuation rates were low at 5% for baricitinib 4 mg, 0% for baricitinib 2 mg, and 1% for placebo. The side-effect profile for baricitinib was consistent with prior studies, Dr. Reich and his coauthors reported.
The authors noted further, “data in this study suggest that patients with AD treated with baricitinib may be able to reduce the frequency and total quantity of concomitant TCSs [topical corticosteroids] used, thus mitigating concerns associated with continual or sustained application of topical treatments.”
“Overall, this study provides further evidence to support the efficacy and safety profile of baricitinib for the treatment of moderate-severe AD,” commented one of the authors, Jonathan I. Silverberg, MD, PhD, MPH, of the department of dermatology at George Washington University in Washington.
“In particular, this study shows that adding topical corticosteroids to baricitinib increases the rate of treatment success compared with the efficacy seen in baricitinib monotherapy studies. These data will be important to guide the use of baricitinib with topical corticosteroids in clinical practice. I think these data are also important because they show that baricitinib 4 mg may be more effective than 2 mg in some patients,” he said in an interview.
In late September, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval of oral baricitinib for adults with moderate to severe AD who are candidates for systemic therapy. Baricitinib is approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis. If approved in Europe, it will be the first JAK inhibitor and first oral medication indicated to treat patients with AD.
The study was funded by Eli Lilly and Company under license from Incyte Corporation. Dr. Reich reported receiving fees to the institution for participation in clinical trials from Eli Lilly and Company during the conduct of the study and personal fees for lectures. Dr. Silverberg reported receiving fees from Eli Lilly and Company during the conduct of the study, and fees from companies outside of this work. Other authors also reported disclosures related to Eli Lilly and other pharmaceutical companies, and several authors were Eli Lilly employees.
SOURCE: Reich K et al. JAMA Dermatol. 2020 Sep 30. doi: 10.1001/jamadermatol.2020.3260.
in the phase 3, double-blind, placebo-controlled, BREEZE-AD7 study.
The study enrolled patients with inadequate responses to topical corticosteroids, according to Kristian Reich, MD, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and his coauthors.
First test of baricitinib plus topical steroids
Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, inhibits several cytokines in AD pathogenesis, and in two monotherapy studies (BREEZE-AD1 and BREEZE-AD2), it was superior to placebo for reducing several AD clinical signs and symptoms. The current BREEZE-AD7 study is the first to test baricitinib plus background topical corticosteroid therapy, more closely mirroring clinical practice, the authors noted.
BREEZE-AD7 was conducted at 68 centers in 10 countries in Asia, Australia, Europe, and South America. It included 329 adults with moderate to severe AD (mean age around 34 years, and around 34% were female) with inadequate responses to topical corticosteroids documented within the last 6 months. They were randomized 1:1:1 to daily baricitinib 4 mg, daily baricitinib 2 mg, or placebo for 16 weeks. All patients received moderate- and/or low-potency topical corticosteroids (such as 0.1%triamcinolone cream and 2.5% hydrocortisone ointment, respectively) for active lesions.
Significant benefit at 4 mg
At week 16, 31% of AD patients receiving baricitinib 4 mg achieved Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 (clear) or 1 (almost clear) versus 15% in the placebo group (odds ratio, 2.8; 95% confidence interval, 1.4-5.6; P = .004). Among patients receiving baricitinib 2 mg, 24% achieved vI-GA-AD scores of 0 or 1 (OR, 1.9; 95% CI, 0.9-3.9; P = .08).
The same pattern of improving scores from placebo to baricitinib 2 mg to baricitinib 4 mg persisted, as reflected with secondary endpoints at week 16. Among patients receiving baricitinib 4 mg, 48% achieved Eczema Area Severity Index (EASI) 75 responses, versus 43% and 23% in 2 mg and placebo groups, respectively. Percent changes from baseline in total EASI score were –67%, –58%, –45% for baricitinib 4 mg, baricitinib 2 mg, and placebo, respectively; the proportion of patients achieving 4-point or greater improvements in Itch Numeric Rating Scale (NRS) was 44%, 38%, and 20% for baricitinib 4 mg, baricitinib 2 mg and placebo, respectively.
Similarly, mean change from baseline on the Skin Pain numeric rating scale was –3.7, –3.2, and –2.1 for baricitinib 4 mg, baricitinib 2 mg and placebo. Nighttime itch awakenings were also reduced in a similar progression from placebo to the higher baricitinib dose.
Adverse events dose related
Treatment-related adverse events were reported more frequently in the baricitinib groups (58% baricitinib 4 mg, 56% baricitinib 2 mg) versus placebo 38%. Nasopharyngitis was most common, followed by oral herpes, upper respiratory tract infection, acne, diarrhea, and back pain. Serious adverse event rates were similar across treatment groups. Permanent discontinuation rates were low at 5% for baricitinib 4 mg, 0% for baricitinib 2 mg, and 1% for placebo. The side-effect profile for baricitinib was consistent with prior studies, Dr. Reich and his coauthors reported.
The authors noted further, “data in this study suggest that patients with AD treated with baricitinib may be able to reduce the frequency and total quantity of concomitant TCSs [topical corticosteroids] used, thus mitigating concerns associated with continual or sustained application of topical treatments.”
“Overall, this study provides further evidence to support the efficacy and safety profile of baricitinib for the treatment of moderate-severe AD,” commented one of the authors, Jonathan I. Silverberg, MD, PhD, MPH, of the department of dermatology at George Washington University in Washington.
“In particular, this study shows that adding topical corticosteroids to baricitinib increases the rate of treatment success compared with the efficacy seen in baricitinib monotherapy studies. These data will be important to guide the use of baricitinib with topical corticosteroids in clinical practice. I think these data are also important because they show that baricitinib 4 mg may be more effective than 2 mg in some patients,” he said in an interview.
In late September, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval of oral baricitinib for adults with moderate to severe AD who are candidates for systemic therapy. Baricitinib is approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis. If approved in Europe, it will be the first JAK inhibitor and first oral medication indicated to treat patients with AD.
The study was funded by Eli Lilly and Company under license from Incyte Corporation. Dr. Reich reported receiving fees to the institution for participation in clinical trials from Eli Lilly and Company during the conduct of the study and personal fees for lectures. Dr. Silverberg reported receiving fees from Eli Lilly and Company during the conduct of the study, and fees from companies outside of this work. Other authors also reported disclosures related to Eli Lilly and other pharmaceutical companies, and several authors were Eli Lilly employees.
SOURCE: Reich K et al. JAMA Dermatol. 2020 Sep 30. doi: 10.1001/jamadermatol.2020.3260.
in the phase 3, double-blind, placebo-controlled, BREEZE-AD7 study.
The study enrolled patients with inadequate responses to topical corticosteroids, according to Kristian Reich, MD, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and his coauthors.
First test of baricitinib plus topical steroids
Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, inhibits several cytokines in AD pathogenesis, and in two monotherapy studies (BREEZE-AD1 and BREEZE-AD2), it was superior to placebo for reducing several AD clinical signs and symptoms. The current BREEZE-AD7 study is the first to test baricitinib plus background topical corticosteroid therapy, more closely mirroring clinical practice, the authors noted.
BREEZE-AD7 was conducted at 68 centers in 10 countries in Asia, Australia, Europe, and South America. It included 329 adults with moderate to severe AD (mean age around 34 years, and around 34% were female) with inadequate responses to topical corticosteroids documented within the last 6 months. They were randomized 1:1:1 to daily baricitinib 4 mg, daily baricitinib 2 mg, or placebo for 16 weeks. All patients received moderate- and/or low-potency topical corticosteroids (such as 0.1%triamcinolone cream and 2.5% hydrocortisone ointment, respectively) for active lesions.
Significant benefit at 4 mg
At week 16, 31% of AD patients receiving baricitinib 4 mg achieved Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 (clear) or 1 (almost clear) versus 15% in the placebo group (odds ratio, 2.8; 95% confidence interval, 1.4-5.6; P = .004). Among patients receiving baricitinib 2 mg, 24% achieved vI-GA-AD scores of 0 or 1 (OR, 1.9; 95% CI, 0.9-3.9; P = .08).
The same pattern of improving scores from placebo to baricitinib 2 mg to baricitinib 4 mg persisted, as reflected with secondary endpoints at week 16. Among patients receiving baricitinib 4 mg, 48% achieved Eczema Area Severity Index (EASI) 75 responses, versus 43% and 23% in 2 mg and placebo groups, respectively. Percent changes from baseline in total EASI score were –67%, –58%, –45% for baricitinib 4 mg, baricitinib 2 mg, and placebo, respectively; the proportion of patients achieving 4-point or greater improvements in Itch Numeric Rating Scale (NRS) was 44%, 38%, and 20% for baricitinib 4 mg, baricitinib 2 mg and placebo, respectively.
Similarly, mean change from baseline on the Skin Pain numeric rating scale was –3.7, –3.2, and –2.1 for baricitinib 4 mg, baricitinib 2 mg and placebo. Nighttime itch awakenings were also reduced in a similar progression from placebo to the higher baricitinib dose.
Adverse events dose related
Treatment-related adverse events were reported more frequently in the baricitinib groups (58% baricitinib 4 mg, 56% baricitinib 2 mg) versus placebo 38%. Nasopharyngitis was most common, followed by oral herpes, upper respiratory tract infection, acne, diarrhea, and back pain. Serious adverse event rates were similar across treatment groups. Permanent discontinuation rates were low at 5% for baricitinib 4 mg, 0% for baricitinib 2 mg, and 1% for placebo. The side-effect profile for baricitinib was consistent with prior studies, Dr. Reich and his coauthors reported.
The authors noted further, “data in this study suggest that patients with AD treated with baricitinib may be able to reduce the frequency and total quantity of concomitant TCSs [topical corticosteroids] used, thus mitigating concerns associated with continual or sustained application of topical treatments.”
“Overall, this study provides further evidence to support the efficacy and safety profile of baricitinib for the treatment of moderate-severe AD,” commented one of the authors, Jonathan I. Silverberg, MD, PhD, MPH, of the department of dermatology at George Washington University in Washington.
“In particular, this study shows that adding topical corticosteroids to baricitinib increases the rate of treatment success compared with the efficacy seen in baricitinib monotherapy studies. These data will be important to guide the use of baricitinib with topical corticosteroids in clinical practice. I think these data are also important because they show that baricitinib 4 mg may be more effective than 2 mg in some patients,” he said in an interview.
In late September, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval of oral baricitinib for adults with moderate to severe AD who are candidates for systemic therapy. Baricitinib is approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis. If approved in Europe, it will be the first JAK inhibitor and first oral medication indicated to treat patients with AD.
The study was funded by Eli Lilly and Company under license from Incyte Corporation. Dr. Reich reported receiving fees to the institution for participation in clinical trials from Eli Lilly and Company during the conduct of the study and personal fees for lectures. Dr. Silverberg reported receiving fees from Eli Lilly and Company during the conduct of the study, and fees from companies outside of this work. Other authors also reported disclosures related to Eli Lilly and other pharmaceutical companies, and several authors were Eli Lilly employees.
SOURCE: Reich K et al. JAMA Dermatol. 2020 Sep 30. doi: 10.1001/jamadermatol.2020.3260.
FROM JAMA DERMATOLOGY
Durable efficacy with MK-6482 in VHL-associated RCC
according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.
MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.
Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.
The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.
The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).
The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
Efficacy and safety
At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.
By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.
The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.
“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.
Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.
In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.
“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.
Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
Remaining questions and next steps
The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.
“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.
While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.
“These are the best response rates reported in non-RCC lesions,” she noted.
However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?
Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.
The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.
SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.
according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.
MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.
Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.
The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.
The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).
The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
Efficacy and safety
At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.
By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.
The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.
“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.
Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.
In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.
“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.
Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
Remaining questions and next steps
The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.
“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.
While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.
“These are the best response rates reported in non-RCC lesions,” she noted.
However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?
Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.
The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.
SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.
according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.
MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.
Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.
The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.
The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).
The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
Efficacy and safety
At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.
By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.
The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.
“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.
Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.
In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.
“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.
Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
Remaining questions and next steps
The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.
“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.
While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.
“These are the best response rates reported in non-RCC lesions,” she noted.
However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?
Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.
The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.
SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.
ESMO 2020
Clinical factors and treatment tied to COVID-19 mortality in cancer patients
according to two presentations at the European Society for Medical Oncology Virtual Congress 2020.
Two analyses of data from the COVID-19 and Cancer Consortium (CCC19) were presented at the meeting.
The data suggest that older age, male sex, more comorbidities, poor performance status, progressive cancer or multiple cancers, hematologic malignancy, and recent cancer therapy are all associated with higher mortality among patients with cancer and COVID-19. Anti-CD20 therapy is associated with an especially high mortality rate, according to an investigator.
Among hospitalized patients, increased absolute neutrophil count as well as abnormal D-dimer, high-sensitivity troponin, and C-reactive protein are associated with a higher risk of mortality.
Prior analyses of CCC19 data pointed to several factors associated with higher COVID-19 death rates, according to Petros Grivas, MD, PhD, of University of Washington, Seattle, who presented some CCC19 data at the meeting. However, the prior analyses were limited by weak statistical power and low event rates, Dr. Grivas said.
Clinical and laboratory factors: Abstract LBA72
The aim of Dr. Grivas’s analysis was to validate a priori identified demographic and clinicopathologic factors associated with 30-day all-cause mortality in patients with COVID-19 and cancer. Dr. Grivas and colleagues also explored the potential association between laboratory parameters and 30-day all-cause mortality.
The analysis included 3,899 patients with cancer and COVID-19 from 124 centers. Most centers are in the United States, but 4% are in Canada, and 2% are in Spain. About two-thirds of patients were 60 years of age or younger at baseline, half were men, 79% had solid tumors, and 21% had hematologic malignancies.
Cancer-specific factors associated with an increased risk of 30-day all-cause mortality were having progressive cancer (adjusted odds ratio, 2.9), receiving cancer therapy within 3 months (aOR, 1.2), having a hematologic versus solid tumor (aOR, 1.7), and having multiple malignancies (aOR, 1.5).
Clinical factors associated with an increased risk of 30-day all-cause mortality were Black versus White race (aOR, 1.5), older age (aOR, 1.7 per 10 years), three or more actively treated comorbidities (versus none; aOR, 2.1), and Eastern Cooperative Oncology Group performance status of 2 or more (versus 0; aOR, 4.6).
In hospitalized patients, several laboratory variables were associated with an increased risk of 30-day all-cause mortality. Having an absolute neutrophil count above the upper limit of normal doubled the risk (aOR, 2.0), while abnormal D-dimer, high-sensitivity troponin, and C-reactive protein all more than doubled the risk of mortality (aORs of 2.5, 2.5, and 2.4, respectively).
Further risk modeling with multivariable analysis will be performed after longer follow-up, Dr. Grivas noted.
Treatment-related outcomes: Abstract LBA71
An additional analysis of CCC19 data encompassed 3,654 patients. In this analysis, researchers investigated the correlation between timing of cancer treatment and COVID-19–related complications and 30-day mortality.
Mortality was highest among cancer patients treated 1-3 months prior to COVID-19 diagnosis, with all-cause mortality at 28%, said Trisha M. Wise-Draper, MD, PhD, of University of Cincinnati, when presenting the data at the meeting.
Rates for other complications (hospitalization, oxygen required, ICU admission, and mechanical ventilation) were similar regardless of treatment timing.
The unadjusted 30-day mortality rate was highest for patients treated most recently with chemoimmunotherapy (30%), followed by chemotherapy (18%), chemoradiotherapy (18%), and targeted therapy (17%).
The mortality rate was “particularly high,” at 50%, in patients receiving anti-CD20 therapy 1-3 months prior to COVID-19 diagnosis – the time period for which significant B-cell depletion develops, Dr. Wise-Draper observed.
An analysis of disease status among 1,449 patients treated within 3 months of COVID-19 diagnosis showed mortality risk increasing from 6% among patients in remission or with newly emergent disease, to 22% in patients with any active cancer, to 34% in those with progressing disease, Dr. Wise-Draper said.
Discussant Benjamin Solomon, MD, PhD, of Peter MacCallum Cancer Centre in Melbourne, made note of the high 30-day mortality rate seen in patients receiving anti-CD20 therapy as well as the elevated standardized mortality ratios with recent chemoimmunotherapy and targeted therapy.
“Although there are some limitations of this analysis, it provides the best data we have to date about the effects of treatment on early mortality in patients with COVID-19 and cancer. It points to a modest but heterogeneous effect of treatment on outcome, one which is likely to become clearer with larger cohorts and additional analysis,” Dr. Solomon said.
This research was funded by the American Cancer Society, Hope Foundation for Cancer Research, Jim and Carol O’Hare Fund, National Cancer Institute, National Human Genome Research Institute, Vanderbilt Institute for Clinical and Translational Research, and Fonds de Recherche du Quebec-Sante. Dr. Grivas disclosed relationships with many companies, but none are related to this work. Dr. Wise-Draper disclosed relationships with Merck, Bristol-Myers Squibb, Tesaro, GlaxoSmithKline, AstraZeneca, Shattuck Labs, and Rakuten. Dr. Solomon disclosed relationships with Amgen, AstraZeneca, Merck, Bristol-Myers Squibb, Novartis, Pfizer, and Roche-Genentech.
SOURCES: Grivas P et al. ESMO 2020, Abstract LBA72; Wise-Draper TM et al. ESMO 2020, Abstract LBA71.
according to two presentations at the European Society for Medical Oncology Virtual Congress 2020.
Two analyses of data from the COVID-19 and Cancer Consortium (CCC19) were presented at the meeting.
The data suggest that older age, male sex, more comorbidities, poor performance status, progressive cancer or multiple cancers, hematologic malignancy, and recent cancer therapy are all associated with higher mortality among patients with cancer and COVID-19. Anti-CD20 therapy is associated with an especially high mortality rate, according to an investigator.
Among hospitalized patients, increased absolute neutrophil count as well as abnormal D-dimer, high-sensitivity troponin, and C-reactive protein are associated with a higher risk of mortality.
Prior analyses of CCC19 data pointed to several factors associated with higher COVID-19 death rates, according to Petros Grivas, MD, PhD, of University of Washington, Seattle, who presented some CCC19 data at the meeting. However, the prior analyses were limited by weak statistical power and low event rates, Dr. Grivas said.
Clinical and laboratory factors: Abstract LBA72
The aim of Dr. Grivas’s analysis was to validate a priori identified demographic and clinicopathologic factors associated with 30-day all-cause mortality in patients with COVID-19 and cancer. Dr. Grivas and colleagues also explored the potential association between laboratory parameters and 30-day all-cause mortality.
The analysis included 3,899 patients with cancer and COVID-19 from 124 centers. Most centers are in the United States, but 4% are in Canada, and 2% are in Spain. About two-thirds of patients were 60 years of age or younger at baseline, half were men, 79% had solid tumors, and 21% had hematologic malignancies.
Cancer-specific factors associated with an increased risk of 30-day all-cause mortality were having progressive cancer (adjusted odds ratio, 2.9), receiving cancer therapy within 3 months (aOR, 1.2), having a hematologic versus solid tumor (aOR, 1.7), and having multiple malignancies (aOR, 1.5).
Clinical factors associated with an increased risk of 30-day all-cause mortality were Black versus White race (aOR, 1.5), older age (aOR, 1.7 per 10 years), three or more actively treated comorbidities (versus none; aOR, 2.1), and Eastern Cooperative Oncology Group performance status of 2 or more (versus 0; aOR, 4.6).
In hospitalized patients, several laboratory variables were associated with an increased risk of 30-day all-cause mortality. Having an absolute neutrophil count above the upper limit of normal doubled the risk (aOR, 2.0), while abnormal D-dimer, high-sensitivity troponin, and C-reactive protein all more than doubled the risk of mortality (aORs of 2.5, 2.5, and 2.4, respectively).
Further risk modeling with multivariable analysis will be performed after longer follow-up, Dr. Grivas noted.
Treatment-related outcomes: Abstract LBA71
An additional analysis of CCC19 data encompassed 3,654 patients. In this analysis, researchers investigated the correlation between timing of cancer treatment and COVID-19–related complications and 30-day mortality.
Mortality was highest among cancer patients treated 1-3 months prior to COVID-19 diagnosis, with all-cause mortality at 28%, said Trisha M. Wise-Draper, MD, PhD, of University of Cincinnati, when presenting the data at the meeting.
Rates for other complications (hospitalization, oxygen required, ICU admission, and mechanical ventilation) were similar regardless of treatment timing.
The unadjusted 30-day mortality rate was highest for patients treated most recently with chemoimmunotherapy (30%), followed by chemotherapy (18%), chemoradiotherapy (18%), and targeted therapy (17%).
The mortality rate was “particularly high,” at 50%, in patients receiving anti-CD20 therapy 1-3 months prior to COVID-19 diagnosis – the time period for which significant B-cell depletion develops, Dr. Wise-Draper observed.
An analysis of disease status among 1,449 patients treated within 3 months of COVID-19 diagnosis showed mortality risk increasing from 6% among patients in remission or with newly emergent disease, to 22% in patients with any active cancer, to 34% in those with progressing disease, Dr. Wise-Draper said.
Discussant Benjamin Solomon, MD, PhD, of Peter MacCallum Cancer Centre in Melbourne, made note of the high 30-day mortality rate seen in patients receiving anti-CD20 therapy as well as the elevated standardized mortality ratios with recent chemoimmunotherapy and targeted therapy.
“Although there are some limitations of this analysis, it provides the best data we have to date about the effects of treatment on early mortality in patients with COVID-19 and cancer. It points to a modest but heterogeneous effect of treatment on outcome, one which is likely to become clearer with larger cohorts and additional analysis,” Dr. Solomon said.
This research was funded by the American Cancer Society, Hope Foundation for Cancer Research, Jim and Carol O’Hare Fund, National Cancer Institute, National Human Genome Research Institute, Vanderbilt Institute for Clinical and Translational Research, and Fonds de Recherche du Quebec-Sante. Dr. Grivas disclosed relationships with many companies, but none are related to this work. Dr. Wise-Draper disclosed relationships with Merck, Bristol-Myers Squibb, Tesaro, GlaxoSmithKline, AstraZeneca, Shattuck Labs, and Rakuten. Dr. Solomon disclosed relationships with Amgen, AstraZeneca, Merck, Bristol-Myers Squibb, Novartis, Pfizer, and Roche-Genentech.
SOURCES: Grivas P et al. ESMO 2020, Abstract LBA72; Wise-Draper TM et al. ESMO 2020, Abstract LBA71.
according to two presentations at the European Society for Medical Oncology Virtual Congress 2020.
Two analyses of data from the COVID-19 and Cancer Consortium (CCC19) were presented at the meeting.
The data suggest that older age, male sex, more comorbidities, poor performance status, progressive cancer or multiple cancers, hematologic malignancy, and recent cancer therapy are all associated with higher mortality among patients with cancer and COVID-19. Anti-CD20 therapy is associated with an especially high mortality rate, according to an investigator.
Among hospitalized patients, increased absolute neutrophil count as well as abnormal D-dimer, high-sensitivity troponin, and C-reactive protein are associated with a higher risk of mortality.
Prior analyses of CCC19 data pointed to several factors associated with higher COVID-19 death rates, according to Petros Grivas, MD, PhD, of University of Washington, Seattle, who presented some CCC19 data at the meeting. However, the prior analyses were limited by weak statistical power and low event rates, Dr. Grivas said.
Clinical and laboratory factors: Abstract LBA72
The aim of Dr. Grivas’s analysis was to validate a priori identified demographic and clinicopathologic factors associated with 30-day all-cause mortality in patients with COVID-19 and cancer. Dr. Grivas and colleagues also explored the potential association between laboratory parameters and 30-day all-cause mortality.
The analysis included 3,899 patients with cancer and COVID-19 from 124 centers. Most centers are in the United States, but 4% are in Canada, and 2% are in Spain. About two-thirds of patients were 60 years of age or younger at baseline, half were men, 79% had solid tumors, and 21% had hematologic malignancies.
Cancer-specific factors associated with an increased risk of 30-day all-cause mortality were having progressive cancer (adjusted odds ratio, 2.9), receiving cancer therapy within 3 months (aOR, 1.2), having a hematologic versus solid tumor (aOR, 1.7), and having multiple malignancies (aOR, 1.5).
Clinical factors associated with an increased risk of 30-day all-cause mortality were Black versus White race (aOR, 1.5), older age (aOR, 1.7 per 10 years), three or more actively treated comorbidities (versus none; aOR, 2.1), and Eastern Cooperative Oncology Group performance status of 2 or more (versus 0; aOR, 4.6).
In hospitalized patients, several laboratory variables were associated with an increased risk of 30-day all-cause mortality. Having an absolute neutrophil count above the upper limit of normal doubled the risk (aOR, 2.0), while abnormal D-dimer, high-sensitivity troponin, and C-reactive protein all more than doubled the risk of mortality (aORs of 2.5, 2.5, and 2.4, respectively).
Further risk modeling with multivariable analysis will be performed after longer follow-up, Dr. Grivas noted.
Treatment-related outcomes: Abstract LBA71
An additional analysis of CCC19 data encompassed 3,654 patients. In this analysis, researchers investigated the correlation between timing of cancer treatment and COVID-19–related complications and 30-day mortality.
Mortality was highest among cancer patients treated 1-3 months prior to COVID-19 diagnosis, with all-cause mortality at 28%, said Trisha M. Wise-Draper, MD, PhD, of University of Cincinnati, when presenting the data at the meeting.
Rates for other complications (hospitalization, oxygen required, ICU admission, and mechanical ventilation) were similar regardless of treatment timing.
The unadjusted 30-day mortality rate was highest for patients treated most recently with chemoimmunotherapy (30%), followed by chemotherapy (18%), chemoradiotherapy (18%), and targeted therapy (17%).
The mortality rate was “particularly high,” at 50%, in patients receiving anti-CD20 therapy 1-3 months prior to COVID-19 diagnosis – the time period for which significant B-cell depletion develops, Dr. Wise-Draper observed.
An analysis of disease status among 1,449 patients treated within 3 months of COVID-19 diagnosis showed mortality risk increasing from 6% among patients in remission or with newly emergent disease, to 22% in patients with any active cancer, to 34% in those with progressing disease, Dr. Wise-Draper said.
Discussant Benjamin Solomon, MD, PhD, of Peter MacCallum Cancer Centre in Melbourne, made note of the high 30-day mortality rate seen in patients receiving anti-CD20 therapy as well as the elevated standardized mortality ratios with recent chemoimmunotherapy and targeted therapy.
“Although there are some limitations of this analysis, it provides the best data we have to date about the effects of treatment on early mortality in patients with COVID-19 and cancer. It points to a modest but heterogeneous effect of treatment on outcome, one which is likely to become clearer with larger cohorts and additional analysis,” Dr. Solomon said.
This research was funded by the American Cancer Society, Hope Foundation for Cancer Research, Jim and Carol O’Hare Fund, National Cancer Institute, National Human Genome Research Institute, Vanderbilt Institute for Clinical and Translational Research, and Fonds de Recherche du Quebec-Sante. Dr. Grivas disclosed relationships with many companies, but none are related to this work. Dr. Wise-Draper disclosed relationships with Merck, Bristol-Myers Squibb, Tesaro, GlaxoSmithKline, AstraZeneca, Shattuck Labs, and Rakuten. Dr. Solomon disclosed relationships with Amgen, AstraZeneca, Merck, Bristol-Myers Squibb, Novartis, Pfizer, and Roche-Genentech.
SOURCES: Grivas P et al. ESMO 2020, Abstract LBA72; Wise-Draper TM et al. ESMO 2020, Abstract LBA71.
FROM ESMO 2020
Apatinib plus gefitinib: Better PFS but more toxicity
ACTIVE is the first phase 3 trial of an oral vascular epidermal growth factor receptor–2 (VEGFR2) tyrosine kinase inhibitor (TKI) added to an EGFR-TKI as first-line therapy in this population, according to Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China.
Dr. Zhang presented results from ACTIVE at the European Society for Medical Oncology Virtual Congress 2020.
“This dual oral regimen will provide more convenient treatment for patients who require long-term administration,” Dr. Zhang said. He added that apatinib plus gefitinib “is expected to become a new first-line treatment option for EGFR-mutant NSCLC.”
A discussant for the ACTIVE study was less optimistic, however, noting that the regimen proved tough to tolerate for some patients, and the PFS benefit may not translate to overall survival.
Study rationale and details
Sensitizing EGFR mutations occur in about 10% of White patients and up to 50% of Asian patients, Dr. Zhang noted. Unfortunately, most patients progress after first-line treatment with EGFR-TKIs because of acquired resistance.
Blocking VEGF receptor pathways has been shown to enhance EGFR-TKIs in EGFR-mutated NSCLC, and pilot study results have shown apatinib – an oral VEGFR2–TKI – to be safe and well-tolerated with promising efficacy in combination with gefitinib, Dr. Zhang added.
To expand upon those results, he and his colleagues tested apatinib with gefitinib in the phase 3, double-blind, placebo-controlled ACTIVE trial (CTONG1706).
The trial included 313 patients (median age, 58.5 years) with locally advanced, metastatic, or recurrent nonsquamous NSCLC. All were chemotherapy-naive and EGFR mutation-positive (exon 19 deletion or exon 21 L858R).
Patients were randomized 1:1 to first-line apatinib at 500 mg daily plus gefitinib at 250 mg daily (n = 157) or placebo plus gefitinib at 250 mg daily (n = 156) until progressive disease or unacceptable toxicity.
Efficacy and safety
The primary endpoint was PFS by independent review. The median follow-up was 15.8 months.
The median PFS was 13.7 months in the apatinib group and 10.2 months in the placebo group (hazard ratio, 0.71; P = .0189).
Objective response rates were similar for both groups – 77.1% with apatinib and 73.7% with placebo. However, depth of response ≥30% and depth of response ≥50% both favored the apatinib arm – 89.2% versus 79.5% for ≥ 30% (P = .0209) and 64.3% versus 52.6% for ≥50% (P = .0238).
In addition, the median duration of response was longer for the apatinib group – 12.9 months versus 9.3 months (HR, 0.64; P = .005).
Exploratory biomarker analyses showed the benefit of apatinib was more common in patients with TP53 exon 8 mutations.
The rate of grade 3 or higher treatment-emergent adverse events was 84.1% in the apatinib arm and 37.7% in the placebo arm. Diarrhea (73.2%) and hypertension (68.2%) were the most common treatment-emergent adverse events in the apatinib group.
Dose interruptions were more common in the apatinib group (59.5% vs. 22.7%) as were dose reductions (48.4% vs. 4.5%). However, treatment discontinuations attributable to treatment-emergent adverse events were few in both arms (5.1% in the apatinib arm and 3.2% in the placebo arm).
Cause for hesitation
“VEGFR-TKIs have not yet found a solid home in lung cancer,” said study discussant Lecia V. Sequist, MD, of Massachusetts General Hospital in Boston.
Listing 10 VEGFR-TKIs, Dr. Sequist noted: “None of them have changed practice.”
She added that, while an all-oral regimen is appealing, the benefit of adding apatinib to gefitinib was modest, and the regimen was “fairly difficult” to tolerate. “The PFS with apatinib plus gefitinib is well below what we see with other EGFR/VEGF first-line studies,” she said.
Dr. Sequist also observed that most studies have shown a PFS benefit but no overall survival benefit. “That, in combination with the toxicity, makes me a little hesitant about this regimen. The role of VEGF remains unclear in EGFR mutation–positive lung cancer in 2020,” she concluded.
The ACTIVE study was funded by Jiangsu HengRui Medicine, the Chinese Thoracic Oncology Group, and grants from Sun Yat-sen University and the National Key R&D Program of China. Dr. Zhang disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Pfizer, and Roche. Dr. Sequist disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Blueprint Medicines, and many other companies.
SOURCE: Zhang L et al. ESMO 2020, Abstract LBA50.
ACTIVE is the first phase 3 trial of an oral vascular epidermal growth factor receptor–2 (VEGFR2) tyrosine kinase inhibitor (TKI) added to an EGFR-TKI as first-line therapy in this population, according to Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China.
Dr. Zhang presented results from ACTIVE at the European Society for Medical Oncology Virtual Congress 2020.
“This dual oral regimen will provide more convenient treatment for patients who require long-term administration,” Dr. Zhang said. He added that apatinib plus gefitinib “is expected to become a new first-line treatment option for EGFR-mutant NSCLC.”
A discussant for the ACTIVE study was less optimistic, however, noting that the regimen proved tough to tolerate for some patients, and the PFS benefit may not translate to overall survival.
Study rationale and details
Sensitizing EGFR mutations occur in about 10% of White patients and up to 50% of Asian patients, Dr. Zhang noted. Unfortunately, most patients progress after first-line treatment with EGFR-TKIs because of acquired resistance.
Blocking VEGF receptor pathways has been shown to enhance EGFR-TKIs in EGFR-mutated NSCLC, and pilot study results have shown apatinib – an oral VEGFR2–TKI – to be safe and well-tolerated with promising efficacy in combination with gefitinib, Dr. Zhang added.
To expand upon those results, he and his colleagues tested apatinib with gefitinib in the phase 3, double-blind, placebo-controlled ACTIVE trial (CTONG1706).
The trial included 313 patients (median age, 58.5 years) with locally advanced, metastatic, or recurrent nonsquamous NSCLC. All were chemotherapy-naive and EGFR mutation-positive (exon 19 deletion or exon 21 L858R).
Patients were randomized 1:1 to first-line apatinib at 500 mg daily plus gefitinib at 250 mg daily (n = 157) or placebo plus gefitinib at 250 mg daily (n = 156) until progressive disease or unacceptable toxicity.
Efficacy and safety
The primary endpoint was PFS by independent review. The median follow-up was 15.8 months.
The median PFS was 13.7 months in the apatinib group and 10.2 months in the placebo group (hazard ratio, 0.71; P = .0189).
Objective response rates were similar for both groups – 77.1% with apatinib and 73.7% with placebo. However, depth of response ≥30% and depth of response ≥50% both favored the apatinib arm – 89.2% versus 79.5% for ≥ 30% (P = .0209) and 64.3% versus 52.6% for ≥50% (P = .0238).
In addition, the median duration of response was longer for the apatinib group – 12.9 months versus 9.3 months (HR, 0.64; P = .005).
Exploratory biomarker analyses showed the benefit of apatinib was more common in patients with TP53 exon 8 mutations.
The rate of grade 3 or higher treatment-emergent adverse events was 84.1% in the apatinib arm and 37.7% in the placebo arm. Diarrhea (73.2%) and hypertension (68.2%) were the most common treatment-emergent adverse events in the apatinib group.
Dose interruptions were more common in the apatinib group (59.5% vs. 22.7%) as were dose reductions (48.4% vs. 4.5%). However, treatment discontinuations attributable to treatment-emergent adverse events were few in both arms (5.1% in the apatinib arm and 3.2% in the placebo arm).
Cause for hesitation
“VEGFR-TKIs have not yet found a solid home in lung cancer,” said study discussant Lecia V. Sequist, MD, of Massachusetts General Hospital in Boston.
Listing 10 VEGFR-TKIs, Dr. Sequist noted: “None of them have changed practice.”
She added that, while an all-oral regimen is appealing, the benefit of adding apatinib to gefitinib was modest, and the regimen was “fairly difficult” to tolerate. “The PFS with apatinib plus gefitinib is well below what we see with other EGFR/VEGF first-line studies,” she said.
Dr. Sequist also observed that most studies have shown a PFS benefit but no overall survival benefit. “That, in combination with the toxicity, makes me a little hesitant about this regimen. The role of VEGF remains unclear in EGFR mutation–positive lung cancer in 2020,” she concluded.
The ACTIVE study was funded by Jiangsu HengRui Medicine, the Chinese Thoracic Oncology Group, and grants from Sun Yat-sen University and the National Key R&D Program of China. Dr. Zhang disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Pfizer, and Roche. Dr. Sequist disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Blueprint Medicines, and many other companies.
SOURCE: Zhang L et al. ESMO 2020, Abstract LBA50.
ACTIVE is the first phase 3 trial of an oral vascular epidermal growth factor receptor–2 (VEGFR2) tyrosine kinase inhibitor (TKI) added to an EGFR-TKI as first-line therapy in this population, according to Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China.
Dr. Zhang presented results from ACTIVE at the European Society for Medical Oncology Virtual Congress 2020.
“This dual oral regimen will provide more convenient treatment for patients who require long-term administration,” Dr. Zhang said. He added that apatinib plus gefitinib “is expected to become a new first-line treatment option for EGFR-mutant NSCLC.”
A discussant for the ACTIVE study was less optimistic, however, noting that the regimen proved tough to tolerate for some patients, and the PFS benefit may not translate to overall survival.
Study rationale and details
Sensitizing EGFR mutations occur in about 10% of White patients and up to 50% of Asian patients, Dr. Zhang noted. Unfortunately, most patients progress after first-line treatment with EGFR-TKIs because of acquired resistance.
Blocking VEGF receptor pathways has been shown to enhance EGFR-TKIs in EGFR-mutated NSCLC, and pilot study results have shown apatinib – an oral VEGFR2–TKI – to be safe and well-tolerated with promising efficacy in combination with gefitinib, Dr. Zhang added.
To expand upon those results, he and his colleagues tested apatinib with gefitinib in the phase 3, double-blind, placebo-controlled ACTIVE trial (CTONG1706).
The trial included 313 patients (median age, 58.5 years) with locally advanced, metastatic, or recurrent nonsquamous NSCLC. All were chemotherapy-naive and EGFR mutation-positive (exon 19 deletion or exon 21 L858R).
Patients were randomized 1:1 to first-line apatinib at 500 mg daily plus gefitinib at 250 mg daily (n = 157) or placebo plus gefitinib at 250 mg daily (n = 156) until progressive disease or unacceptable toxicity.
Efficacy and safety
The primary endpoint was PFS by independent review. The median follow-up was 15.8 months.
The median PFS was 13.7 months in the apatinib group and 10.2 months in the placebo group (hazard ratio, 0.71; P = .0189).
Objective response rates were similar for both groups – 77.1% with apatinib and 73.7% with placebo. However, depth of response ≥30% and depth of response ≥50% both favored the apatinib arm – 89.2% versus 79.5% for ≥ 30% (P = .0209) and 64.3% versus 52.6% for ≥50% (P = .0238).
In addition, the median duration of response was longer for the apatinib group – 12.9 months versus 9.3 months (HR, 0.64; P = .005).
Exploratory biomarker analyses showed the benefit of apatinib was more common in patients with TP53 exon 8 mutations.
The rate of grade 3 or higher treatment-emergent adverse events was 84.1% in the apatinib arm and 37.7% in the placebo arm. Diarrhea (73.2%) and hypertension (68.2%) were the most common treatment-emergent adverse events in the apatinib group.
Dose interruptions were more common in the apatinib group (59.5% vs. 22.7%) as were dose reductions (48.4% vs. 4.5%). However, treatment discontinuations attributable to treatment-emergent adverse events were few in both arms (5.1% in the apatinib arm and 3.2% in the placebo arm).
Cause for hesitation
“VEGFR-TKIs have not yet found a solid home in lung cancer,” said study discussant Lecia V. Sequist, MD, of Massachusetts General Hospital in Boston.
Listing 10 VEGFR-TKIs, Dr. Sequist noted: “None of them have changed practice.”
She added that, while an all-oral regimen is appealing, the benefit of adding apatinib to gefitinib was modest, and the regimen was “fairly difficult” to tolerate. “The PFS with apatinib plus gefitinib is well below what we see with other EGFR/VEGF first-line studies,” she said.
Dr. Sequist also observed that most studies have shown a PFS benefit but no overall survival benefit. “That, in combination with the toxicity, makes me a little hesitant about this regimen. The role of VEGF remains unclear in EGFR mutation–positive lung cancer in 2020,” she concluded.
The ACTIVE study was funded by Jiangsu HengRui Medicine, the Chinese Thoracic Oncology Group, and grants from Sun Yat-sen University and the National Key R&D Program of China. Dr. Zhang disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Pfizer, and Roche. Dr. Sequist disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Blueprint Medicines, and many other companies.
SOURCE: Zhang L et al. ESMO 2020, Abstract LBA50.
FROM ESMO 2020
Divergent findings with paclitaxel and nab-paclitaxel in TNBC
The trials, IMpassion130 and IMpassion131, both enrolled patients with metastatic or unresectable, locally advanced TNBC.
In IMpassion131, adding atezolizumab to paclitaxel did not improve progression-free survival (PFS) or overall survival (OS), regardless of programmed death–ligand 1 (PD-L1) expression.
In IMpassion130, adding atezolizumab to nab-paclitaxel did not improve OS in the intention-to-treat (ITT) population but did provide a “clinically meaningful” improvement in OS among PD-L1-positive patients, according to investigators.
IMpassion130 and IMpassion131 were presented during the same session at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.
Potential reasons for the different outcomes in the two studies require further exploration, according to David Miles, MD, of Mount Vernon Cancer Centre in Northwood, England, who presented the findings from IMpassion131.
ESMO discussant Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill, posited three possible explanations for the divergent findings. The steroids necessary with paclitaxel dosing may have had a negative effect on immune checkpoint inhibitor activity, differences in study populations may have played a role, or the divergent findings could be caused by chance.
Steroid use in IMpassion131 could have played a negative role because of its lympholytic activity, but other indications with steroid use have not demonstrated attenuated benefits, said Leisha A. Emens, MD, PhD, of the University of Pittsburgh Medical Center, who presented the findings from IMpassion130 at ESMO 2020.
“If I were a patient, based on the data to date, I would want nab-paclitaxel with atezolizumab,” Dr. Emens said.
Trial details
Both trials are phase 3, double-blind, placebo-controlled studies of women with metastatic or unresectable locally advanced TNBC who had received no prior therapy for advanced TNBC.
IMpassion130 included 451 patients randomized to atezolizumab plus nab-paclitaxel and 451 randomized to placebo plus nab-paclitaxel. Patients received nab-paclitaxel at a starting dose of 100 mg/m2 via IV infusion on days 1, 8, and 15 of each 28-day cycle for at least six cycles.
In both studies, patients received atezolizumab at 840 mg on days 1 and 15 of a 28-day cycle in their active treatment arms.
IMpassion131 included 651 patients randomized 2:1 to atezolizumab plus paclitaxel (n = 431) or placebo plus paclitaxel (n = 220). Patients received paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity.
Baseline characteristics were well balanced between the treatment arms in both studies. Less than half of patients – 45% in IMpassion131 and 41% in IMpassion130 – were PD-L1 positive.
Results of IMpassion131
The primary endpoint in IMpassion131 was PFS, and there was no significant difference in PFS between the treatment arms.
“The primary objective of IMpassion131 was not met,” Dr. Miles said. “[The] addition of atezolizumab to paclitaxel did not significantly improve PFS in patients with PD-L1-positive metastatic triple-negative breast cancer.”
In the PD-L1-positive population, the median PFS was 5.7 months in the placebo arm and 6.0 months in the atezolizumab arm (stratified hazard ratio, 0.82, P = .20).
In the ITT population, the median PFS was 5.6 months in the control arm and 5.7 months in the atezolizumab arm (HR, 0.86).
In subgroup analyses, Dr. Miles noted, “There was no clue about adverse or beneficial effects in any subgroup.”
The updated OS analysis demonstrated no benefit with atezolizumab in the ITT population or the PD-L1-positive population. In fact, there was a trend toward better OS for the control group in the latter analysis.
In the PD-L1-positive population, the median OS was 28.3 months in the control arm and 22.1 months in the atezolizumab arm (HR, 1.12). The 2-year OS rates were 51% and 49%, respectively.
In the ITT population, the median OS was 22.8 months in the control arm and 19.2 months in the atezolizumab arm (HR, 1.11). The 2-year OS rates were 45% and 42%, respectively.
The safety profile of the atezolizumab-paclitaxel combination was consistent with known side effects of the individual drugs, Dr. Miles said. There were four fatal treatment-related adverse events in the atezolizumab arm.
Results of IMpassion130
Presenting the final OS analysis from IMpassion130, Dr. Emens noted that the study’s findings have led to recommendations for atezolizumab plus nab-paclitaxel as first-line treatment of PD-L1-positive TNBC in international guidelines.
The median OS in the ITT population was 18.7 months in the placebo arm and 21.0 months in the atezolizumab arm (stratified HR, 0.87, P = .077). The 3-year OS rates were 25% and 28%, respectively.
The median OS in the PD-L1-positive population was 17.9 months in the placebo arm and 25.4 months in the atezolizumab arm (HR, 0.67). The 3-year OS rates were 22% and 36%, respectively.
A P value is not available for the between-arm OS comparison in the PD-L1-positive population. OS was not formally tested in this group because the OS boundary for statistical significance was not crossed in the ITT population. However, Dr. Emens said there was a “clinically meaningful” OS benefit observed with atezolizumab in the PD-L1-positive patients.
Treatment withdrawals caused by adverse events were more common in the atezolizumab arm (19% vs. 8%). The most common of these was neuropathy, Dr. Emens said. However, she noted that atezolizumab-related adverse events were generally low grade and easily managed.
“These results support a positive benefit-risk profile for atezolizumab plus nab-paclitaxel as first-line therapy in patients with PD-L1-positive metastatic triple-negative breast cancer,” Dr. Emens concluded.
Both studies were funded by F. Hoffman–La Roche. Dr. Miles, Dr. Emens, and Dr. Carey disclosed financial relationships with Roche and other companies.
SOURCES: Miles D et al. ESMO 2020, Abstract LBA15; Emens LA et al. ESMO 2020, Abstract LBA16.
The trials, IMpassion130 and IMpassion131, both enrolled patients with metastatic or unresectable, locally advanced TNBC.
In IMpassion131, adding atezolizumab to paclitaxel did not improve progression-free survival (PFS) or overall survival (OS), regardless of programmed death–ligand 1 (PD-L1) expression.
In IMpassion130, adding atezolizumab to nab-paclitaxel did not improve OS in the intention-to-treat (ITT) population but did provide a “clinically meaningful” improvement in OS among PD-L1-positive patients, according to investigators.
IMpassion130 and IMpassion131 were presented during the same session at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.
Potential reasons for the different outcomes in the two studies require further exploration, according to David Miles, MD, of Mount Vernon Cancer Centre in Northwood, England, who presented the findings from IMpassion131.
ESMO discussant Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill, posited three possible explanations for the divergent findings. The steroids necessary with paclitaxel dosing may have had a negative effect on immune checkpoint inhibitor activity, differences in study populations may have played a role, or the divergent findings could be caused by chance.
Steroid use in IMpassion131 could have played a negative role because of its lympholytic activity, but other indications with steroid use have not demonstrated attenuated benefits, said Leisha A. Emens, MD, PhD, of the University of Pittsburgh Medical Center, who presented the findings from IMpassion130 at ESMO 2020.
“If I were a patient, based on the data to date, I would want nab-paclitaxel with atezolizumab,” Dr. Emens said.
Trial details
Both trials are phase 3, double-blind, placebo-controlled studies of women with metastatic or unresectable locally advanced TNBC who had received no prior therapy for advanced TNBC.
IMpassion130 included 451 patients randomized to atezolizumab plus nab-paclitaxel and 451 randomized to placebo plus nab-paclitaxel. Patients received nab-paclitaxel at a starting dose of 100 mg/m2 via IV infusion on days 1, 8, and 15 of each 28-day cycle for at least six cycles.
In both studies, patients received atezolizumab at 840 mg on days 1 and 15 of a 28-day cycle in their active treatment arms.
IMpassion131 included 651 patients randomized 2:1 to atezolizumab plus paclitaxel (n = 431) or placebo plus paclitaxel (n = 220). Patients received paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity.
Baseline characteristics were well balanced between the treatment arms in both studies. Less than half of patients – 45% in IMpassion131 and 41% in IMpassion130 – were PD-L1 positive.
Results of IMpassion131
The primary endpoint in IMpassion131 was PFS, and there was no significant difference in PFS between the treatment arms.
“The primary objective of IMpassion131 was not met,” Dr. Miles said. “[The] addition of atezolizumab to paclitaxel did not significantly improve PFS in patients with PD-L1-positive metastatic triple-negative breast cancer.”
In the PD-L1-positive population, the median PFS was 5.7 months in the placebo arm and 6.0 months in the atezolizumab arm (stratified hazard ratio, 0.82, P = .20).
In the ITT population, the median PFS was 5.6 months in the control arm and 5.7 months in the atezolizumab arm (HR, 0.86).
In subgroup analyses, Dr. Miles noted, “There was no clue about adverse or beneficial effects in any subgroup.”
The updated OS analysis demonstrated no benefit with atezolizumab in the ITT population or the PD-L1-positive population. In fact, there was a trend toward better OS for the control group in the latter analysis.
In the PD-L1-positive population, the median OS was 28.3 months in the control arm and 22.1 months in the atezolizumab arm (HR, 1.12). The 2-year OS rates were 51% and 49%, respectively.
In the ITT population, the median OS was 22.8 months in the control arm and 19.2 months in the atezolizumab arm (HR, 1.11). The 2-year OS rates were 45% and 42%, respectively.
The safety profile of the atezolizumab-paclitaxel combination was consistent with known side effects of the individual drugs, Dr. Miles said. There were four fatal treatment-related adverse events in the atezolizumab arm.
Results of IMpassion130
Presenting the final OS analysis from IMpassion130, Dr. Emens noted that the study’s findings have led to recommendations for atezolizumab plus nab-paclitaxel as first-line treatment of PD-L1-positive TNBC in international guidelines.
The median OS in the ITT population was 18.7 months in the placebo arm and 21.0 months in the atezolizumab arm (stratified HR, 0.87, P = .077). The 3-year OS rates were 25% and 28%, respectively.
The median OS in the PD-L1-positive population was 17.9 months in the placebo arm and 25.4 months in the atezolizumab arm (HR, 0.67). The 3-year OS rates were 22% and 36%, respectively.
A P value is not available for the between-arm OS comparison in the PD-L1-positive population. OS was not formally tested in this group because the OS boundary for statistical significance was not crossed in the ITT population. However, Dr. Emens said there was a “clinically meaningful” OS benefit observed with atezolizumab in the PD-L1-positive patients.
Treatment withdrawals caused by adverse events were more common in the atezolizumab arm (19% vs. 8%). The most common of these was neuropathy, Dr. Emens said. However, she noted that atezolizumab-related adverse events were generally low grade and easily managed.
“These results support a positive benefit-risk profile for atezolizumab plus nab-paclitaxel as first-line therapy in patients with PD-L1-positive metastatic triple-negative breast cancer,” Dr. Emens concluded.
Both studies were funded by F. Hoffman–La Roche. Dr. Miles, Dr. Emens, and Dr. Carey disclosed financial relationships with Roche and other companies.
SOURCES: Miles D et al. ESMO 2020, Abstract LBA15; Emens LA et al. ESMO 2020, Abstract LBA16.
The trials, IMpassion130 and IMpassion131, both enrolled patients with metastatic or unresectable, locally advanced TNBC.
In IMpassion131, adding atezolizumab to paclitaxel did not improve progression-free survival (PFS) or overall survival (OS), regardless of programmed death–ligand 1 (PD-L1) expression.
In IMpassion130, adding atezolizumab to nab-paclitaxel did not improve OS in the intention-to-treat (ITT) population but did provide a “clinically meaningful” improvement in OS among PD-L1-positive patients, according to investigators.
IMpassion130 and IMpassion131 were presented during the same session at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.
Potential reasons for the different outcomes in the two studies require further exploration, according to David Miles, MD, of Mount Vernon Cancer Centre in Northwood, England, who presented the findings from IMpassion131.
ESMO discussant Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill, posited three possible explanations for the divergent findings. The steroids necessary with paclitaxel dosing may have had a negative effect on immune checkpoint inhibitor activity, differences in study populations may have played a role, or the divergent findings could be caused by chance.
Steroid use in IMpassion131 could have played a negative role because of its lympholytic activity, but other indications with steroid use have not demonstrated attenuated benefits, said Leisha A. Emens, MD, PhD, of the University of Pittsburgh Medical Center, who presented the findings from IMpassion130 at ESMO 2020.
“If I were a patient, based on the data to date, I would want nab-paclitaxel with atezolizumab,” Dr. Emens said.
Trial details
Both trials are phase 3, double-blind, placebo-controlled studies of women with metastatic or unresectable locally advanced TNBC who had received no prior therapy for advanced TNBC.
IMpassion130 included 451 patients randomized to atezolizumab plus nab-paclitaxel and 451 randomized to placebo plus nab-paclitaxel. Patients received nab-paclitaxel at a starting dose of 100 mg/m2 via IV infusion on days 1, 8, and 15 of each 28-day cycle for at least six cycles.
In both studies, patients received atezolizumab at 840 mg on days 1 and 15 of a 28-day cycle in their active treatment arms.
IMpassion131 included 651 patients randomized 2:1 to atezolizumab plus paclitaxel (n = 431) or placebo plus paclitaxel (n = 220). Patients received paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity.
Baseline characteristics were well balanced between the treatment arms in both studies. Less than half of patients – 45% in IMpassion131 and 41% in IMpassion130 – were PD-L1 positive.
Results of IMpassion131
The primary endpoint in IMpassion131 was PFS, and there was no significant difference in PFS between the treatment arms.
“The primary objective of IMpassion131 was not met,” Dr. Miles said. “[The] addition of atezolizumab to paclitaxel did not significantly improve PFS in patients with PD-L1-positive metastatic triple-negative breast cancer.”
In the PD-L1-positive population, the median PFS was 5.7 months in the placebo arm and 6.0 months in the atezolizumab arm (stratified hazard ratio, 0.82, P = .20).
In the ITT population, the median PFS was 5.6 months in the control arm and 5.7 months in the atezolizumab arm (HR, 0.86).
In subgroup analyses, Dr. Miles noted, “There was no clue about adverse or beneficial effects in any subgroup.”
The updated OS analysis demonstrated no benefit with atezolizumab in the ITT population or the PD-L1-positive population. In fact, there was a trend toward better OS for the control group in the latter analysis.
In the PD-L1-positive population, the median OS was 28.3 months in the control arm and 22.1 months in the atezolizumab arm (HR, 1.12). The 2-year OS rates were 51% and 49%, respectively.
In the ITT population, the median OS was 22.8 months in the control arm and 19.2 months in the atezolizumab arm (HR, 1.11). The 2-year OS rates were 45% and 42%, respectively.
The safety profile of the atezolizumab-paclitaxel combination was consistent with known side effects of the individual drugs, Dr. Miles said. There were four fatal treatment-related adverse events in the atezolizumab arm.
Results of IMpassion130
Presenting the final OS analysis from IMpassion130, Dr. Emens noted that the study’s findings have led to recommendations for atezolizumab plus nab-paclitaxel as first-line treatment of PD-L1-positive TNBC in international guidelines.
The median OS in the ITT population was 18.7 months in the placebo arm and 21.0 months in the atezolizumab arm (stratified HR, 0.87, P = .077). The 3-year OS rates were 25% and 28%, respectively.
The median OS in the PD-L1-positive population was 17.9 months in the placebo arm and 25.4 months in the atezolizumab arm (HR, 0.67). The 3-year OS rates were 22% and 36%, respectively.
A P value is not available for the between-arm OS comparison in the PD-L1-positive population. OS was not formally tested in this group because the OS boundary for statistical significance was not crossed in the ITT population. However, Dr. Emens said there was a “clinically meaningful” OS benefit observed with atezolizumab in the PD-L1-positive patients.
Treatment withdrawals caused by adverse events were more common in the atezolizumab arm (19% vs. 8%). The most common of these was neuropathy, Dr. Emens said. However, she noted that atezolizumab-related adverse events were generally low grade and easily managed.
“These results support a positive benefit-risk profile for atezolizumab plus nab-paclitaxel as first-line therapy in patients with PD-L1-positive metastatic triple-negative breast cancer,” Dr. Emens concluded.
Both studies were funded by F. Hoffman–La Roche. Dr. Miles, Dr. Emens, and Dr. Carey disclosed financial relationships with Roche and other companies.
SOURCES: Miles D et al. ESMO 2020, Abstract LBA15; Emens LA et al. ESMO 2020, Abstract LBA16.
FROM ESMO 2020
Palbociclib plus letrozole improves PFS in advanced endometrial cancer
Adding palbociclib to letrozole significantly prolonged progression-free survival (PFS) in a phase 2 trial of patients with advanced or recurrent estrogen receptor (ER)–positive endometrial cancer.
This was the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor in patients with advanced or recurrent ER-positive endometrial cancer, noted study investigator Mansoor Raza Mirza, MD, PhD, of Rigshospitalet Copenhagen University Hospital.
Dr. Mirza presented results from this study, ENGOT-EN3-NSGO/PALEO, at the European Society for Medical Oncology Virtual Congress 2020.
Palbociclib is a selective inhibitor of CDK4/, both of which are involved in cell-cycle transitions, Dr. Mirza explained. He observed that endometrial endometrioid adenocarcinomas are hormone dependent, and endocrine treatment with an aromatase inhibitor is well established. Palbociclib has been shown to be superior, when combined with letrozole, to letrozole alone in ER-positive breast cancer.
For the ENGOT-EN3-NSGO/PALEO study, investigators enrolled 77 patients with ER-positive advanced/recurrent endometrial cancer. Patients had received at least one prior systemic therapy, no prior endocrine therapy (except medroxyprogesterone acetate and megestrol acetate), and no prior CDK inhibitor.
Patients were randomized 1:1 to receive oral letrozole (2.5 mg on days 1-28) and either palbociclib (125 mg on days 1-21) or placebo (125 mg on days 1-21) in a 28-day cycle until progression. Baseline characteristics were similar between the treatment arms.
Efficacy
Of the 77 patients enrolled, 73 were evaluable. The primary endpoint was PFS.
The median PFS in the intention-to-treat population was 3.0 months in the placebo arm and 8.3 months in the palbociclib arm (hazard ratio, 0.56; 95% confidence interval, 0.32-0.98; P = .0376).
Looking at stratification factors, PFS was higher in the palbociclib arm among the large majority (about 85%) of patients who had received no prior medroxyprogesterone acetate or megestrol acetate (HR, 0.55; 95% CI, 0.29-01.04; P = .0615) and among patients with relapsed disease (HR, 0.61; 95% CI, 0.34-1.09; P = .0916).
The disease control rate at 24 weeks, a secondary endpoint, was 63.6% in the palbociclib arm and 37.8% in the placebo arm.
Safety
Adverse events were more frequent in the palbociclib arm, with neutropenia being the most common.
Rates of adverse event–related dose reduction (to 100 mg or 75 mg) were 36% in the palbociclib arm and 3% in the placebo arm.
Adverse event–related discontinuation rates were 25% and 19% for palbociclib and letrozole, respectively, in the palbociclib arm and 14% and 11% for placebo and letrozole, respectively, in the placebo arm.
“The toxicity of palbociclib plus letrozole combination therapy was manageable, with most patients remaining on treatment until disease progression,” Dr. Mirza said.
He noted that an analysis of patient-reported outcomes revealed no detrimental effect on quality of life with the combination therapy.
Next steps
“Compared with placebo plus letrozole, the combination of palbociclib plus letrozole demonstrated clinically meaningful improvement in PFS,” Dr. Mirza said. “These results merit a phase 3 validation trial.”
“There is a huge rationale for using this drug in endometrial cancer,” commented study discussant Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Hearth in Rome.
Dr. Lorusso said hormone receptor expression, which has been identified as a strong predictor of CDK4/6 inhibitor activity, is present in up to 90% of patients with type 1 and in about 65% of patients with type 2 endometrial cancer.
Response rates, in experience with aromatase inhibitors, have been “quite disappointing, in the 10%-20% range,” Dr. Lorusso said, with “dismal prognosis” and guidelines stating that “no standard second-line treatment has been identified.”
This research was sponsored by investigators, but Pfizer provided a study grant. Dr. Mirza disclosed relationships with Pfizer, AstraZeneca, Biocad, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Oncology Adventure, Roche, Seattle Genetics, Sera Prognostics, Sotio, GlaxoSmithKline, Zai Lab, and Boehringer Ingelheim. Dr. Lorusso disclosed relationships with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, Roche, Tesaro, Amgen, Immunogen, and Pharma Mar.
SOURCE: Mirza MR et al. ESMO 2020, Abstract LBA28.
Adding palbociclib to letrozole significantly prolonged progression-free survival (PFS) in a phase 2 trial of patients with advanced or recurrent estrogen receptor (ER)–positive endometrial cancer.
This was the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor in patients with advanced or recurrent ER-positive endometrial cancer, noted study investigator Mansoor Raza Mirza, MD, PhD, of Rigshospitalet Copenhagen University Hospital.
Dr. Mirza presented results from this study, ENGOT-EN3-NSGO/PALEO, at the European Society for Medical Oncology Virtual Congress 2020.
Palbociclib is a selective inhibitor of CDK4/, both of which are involved in cell-cycle transitions, Dr. Mirza explained. He observed that endometrial endometrioid adenocarcinomas are hormone dependent, and endocrine treatment with an aromatase inhibitor is well established. Palbociclib has been shown to be superior, when combined with letrozole, to letrozole alone in ER-positive breast cancer.
For the ENGOT-EN3-NSGO/PALEO study, investigators enrolled 77 patients with ER-positive advanced/recurrent endometrial cancer. Patients had received at least one prior systemic therapy, no prior endocrine therapy (except medroxyprogesterone acetate and megestrol acetate), and no prior CDK inhibitor.
Patients were randomized 1:1 to receive oral letrozole (2.5 mg on days 1-28) and either palbociclib (125 mg on days 1-21) or placebo (125 mg on days 1-21) in a 28-day cycle until progression. Baseline characteristics were similar between the treatment arms.
Efficacy
Of the 77 patients enrolled, 73 were evaluable. The primary endpoint was PFS.
The median PFS in the intention-to-treat population was 3.0 months in the placebo arm and 8.3 months in the palbociclib arm (hazard ratio, 0.56; 95% confidence interval, 0.32-0.98; P = .0376).
Looking at stratification factors, PFS was higher in the palbociclib arm among the large majority (about 85%) of patients who had received no prior medroxyprogesterone acetate or megestrol acetate (HR, 0.55; 95% CI, 0.29-01.04; P = .0615) and among patients with relapsed disease (HR, 0.61; 95% CI, 0.34-1.09; P = .0916).
The disease control rate at 24 weeks, a secondary endpoint, was 63.6% in the palbociclib arm and 37.8% in the placebo arm.
Safety
Adverse events were more frequent in the palbociclib arm, with neutropenia being the most common.
Rates of adverse event–related dose reduction (to 100 mg or 75 mg) were 36% in the palbociclib arm and 3% in the placebo arm.
Adverse event–related discontinuation rates were 25% and 19% for palbociclib and letrozole, respectively, in the palbociclib arm and 14% and 11% for placebo and letrozole, respectively, in the placebo arm.
“The toxicity of palbociclib plus letrozole combination therapy was manageable, with most patients remaining on treatment until disease progression,” Dr. Mirza said.
He noted that an analysis of patient-reported outcomes revealed no detrimental effect on quality of life with the combination therapy.
Next steps
“Compared with placebo plus letrozole, the combination of palbociclib plus letrozole demonstrated clinically meaningful improvement in PFS,” Dr. Mirza said. “These results merit a phase 3 validation trial.”
“There is a huge rationale for using this drug in endometrial cancer,” commented study discussant Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Hearth in Rome.
Dr. Lorusso said hormone receptor expression, which has been identified as a strong predictor of CDK4/6 inhibitor activity, is present in up to 90% of patients with type 1 and in about 65% of patients with type 2 endometrial cancer.
Response rates, in experience with aromatase inhibitors, have been “quite disappointing, in the 10%-20% range,” Dr. Lorusso said, with “dismal prognosis” and guidelines stating that “no standard second-line treatment has been identified.”
This research was sponsored by investigators, but Pfizer provided a study grant. Dr. Mirza disclosed relationships with Pfizer, AstraZeneca, Biocad, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Oncology Adventure, Roche, Seattle Genetics, Sera Prognostics, Sotio, GlaxoSmithKline, Zai Lab, and Boehringer Ingelheim. Dr. Lorusso disclosed relationships with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, Roche, Tesaro, Amgen, Immunogen, and Pharma Mar.
SOURCE: Mirza MR et al. ESMO 2020, Abstract LBA28.
Adding palbociclib to letrozole significantly prolonged progression-free survival (PFS) in a phase 2 trial of patients with advanced or recurrent estrogen receptor (ER)–positive endometrial cancer.
This was the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor in patients with advanced or recurrent ER-positive endometrial cancer, noted study investigator Mansoor Raza Mirza, MD, PhD, of Rigshospitalet Copenhagen University Hospital.
Dr. Mirza presented results from this study, ENGOT-EN3-NSGO/PALEO, at the European Society for Medical Oncology Virtual Congress 2020.
Palbociclib is a selective inhibitor of CDK4/, both of which are involved in cell-cycle transitions, Dr. Mirza explained. He observed that endometrial endometrioid adenocarcinomas are hormone dependent, and endocrine treatment with an aromatase inhibitor is well established. Palbociclib has been shown to be superior, when combined with letrozole, to letrozole alone in ER-positive breast cancer.
For the ENGOT-EN3-NSGO/PALEO study, investigators enrolled 77 patients with ER-positive advanced/recurrent endometrial cancer. Patients had received at least one prior systemic therapy, no prior endocrine therapy (except medroxyprogesterone acetate and megestrol acetate), and no prior CDK inhibitor.
Patients were randomized 1:1 to receive oral letrozole (2.5 mg on days 1-28) and either palbociclib (125 mg on days 1-21) or placebo (125 mg on days 1-21) in a 28-day cycle until progression. Baseline characteristics were similar between the treatment arms.
Efficacy
Of the 77 patients enrolled, 73 were evaluable. The primary endpoint was PFS.
The median PFS in the intention-to-treat population was 3.0 months in the placebo arm and 8.3 months in the palbociclib arm (hazard ratio, 0.56; 95% confidence interval, 0.32-0.98; P = .0376).
Looking at stratification factors, PFS was higher in the palbociclib arm among the large majority (about 85%) of patients who had received no prior medroxyprogesterone acetate or megestrol acetate (HR, 0.55; 95% CI, 0.29-01.04; P = .0615) and among patients with relapsed disease (HR, 0.61; 95% CI, 0.34-1.09; P = .0916).
The disease control rate at 24 weeks, a secondary endpoint, was 63.6% in the palbociclib arm and 37.8% in the placebo arm.
Safety
Adverse events were more frequent in the palbociclib arm, with neutropenia being the most common.
Rates of adverse event–related dose reduction (to 100 mg or 75 mg) were 36% in the palbociclib arm and 3% in the placebo arm.
Adverse event–related discontinuation rates were 25% and 19% for palbociclib and letrozole, respectively, in the palbociclib arm and 14% and 11% for placebo and letrozole, respectively, in the placebo arm.
“The toxicity of palbociclib plus letrozole combination therapy was manageable, with most patients remaining on treatment until disease progression,” Dr. Mirza said.
He noted that an analysis of patient-reported outcomes revealed no detrimental effect on quality of life with the combination therapy.
Next steps
“Compared with placebo plus letrozole, the combination of palbociclib plus letrozole demonstrated clinically meaningful improvement in PFS,” Dr. Mirza said. “These results merit a phase 3 validation trial.”
“There is a huge rationale for using this drug in endometrial cancer,” commented study discussant Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Hearth in Rome.
Dr. Lorusso said hormone receptor expression, which has been identified as a strong predictor of CDK4/6 inhibitor activity, is present in up to 90% of patients with type 1 and in about 65% of patients with type 2 endometrial cancer.
Response rates, in experience with aromatase inhibitors, have been “quite disappointing, in the 10%-20% range,” Dr. Lorusso said, with “dismal prognosis” and guidelines stating that “no standard second-line treatment has been identified.”
This research was sponsored by investigators, but Pfizer provided a study grant. Dr. Mirza disclosed relationships with Pfizer, AstraZeneca, Biocad, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Oncology Adventure, Roche, Seattle Genetics, Sera Prognostics, Sotio, GlaxoSmithKline, Zai Lab, and Boehringer Ingelheim. Dr. Lorusso disclosed relationships with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, Roche, Tesaro, Amgen, Immunogen, and Pharma Mar.
SOURCE: Mirza MR et al. ESMO 2020, Abstract LBA28.
FROM ESMO 2020
No benefit with postoperative radiotherapy in stage IIIAN2 NSCLC
In patients with completely resected non–small cell lung cancer and proven N2 disease, postoperative radiotherapy (PORT) provided no significant improvement in disease-free survival (DFS) at 3 years, according to a phase 3 trial.
Investigator Cécile Le Péchoux, MD, a radiation oncologist from Institut Gustave Roussy in Paris, presented the results of the Lung ART trial at the European Society for Medical Oncology Virtual Congress 2020.
The results resolve what ESMO commentator Rafal Dziadziuszko, MD, PhD, of Medical University of Gdansk (Poland), called “perhaps the longest ongoing debate in thoracic oncology,” on whether or not to irradiate patients with mediastinal lymph node involvement after surgery.
Dr. Dziadziuszko noted that some past studies have suggested PORT may provide improved local control and a survival benefit, but other studies have shown no survival benefit and evidence of harm with PORT.
“So here is an academic study with the answer,” Dr. Dziadziuszko said.
Study details
The intention-to-treat population of Lung ART included 252 patients randomized to receive 5.5 weeks of PORT (54 Gy) and 249 patients randomized to the control arm without PORT.
The patients’ median age was 61 years, 66% were men, and adenocarcinoma was the predominant histology (76% of patients in the control arm and 70% in the PORT arm). All patients had received adjuvant or neoadjuvant chemotherapy.
The median follow-up was 4.8 years. The 3-year DFS rate was 47.1% in the PORT arm and 43.8% in the control arm (hazard ratio, 0.85; 95% confidence interval, 0.67-1.07, P = .16). The median DFS was 30.5 months with PORT and 22.8 months in the control group. As for DFS components, the rate for death as a first event was 14.6% in the PORT arm and 5.3% among controls.
The mediastinal relapse rate was higher among controls, at 46.1% versus 25.0% with PORT.
The 3-year overall survival rate was 66.5% among patients in the PORT arm and 68.5% in the control arm.
At least one grade 3-4 toxicity was reported in 23.7% of the PORT group and in 15.0% of controls. The grade 3-4 cardiopulmonary toxicity rate of 10.8% in the PORT arm and 4.9% in the control arm needs to be further explored, Dr. Le Péchoux said.
Applying the results to practice
In response to a question as to which patients might benefit from PORT, Dr. Le Péchoux pointed out that, among patients who have nodes in the inferior part of the mediastinum closer to the heart, PORT might be more toxic.
“For the moment, we did not see anything that would give us a clue,” Dr. Le Péchoux said. “We have a lot to investigate.”
Further analyses looking at patterns of failure, predictive factors of efficacy and toxicity, quality of radiotherapy, and quality of surgery are planned, she added.
Dr. Le Péchoux concluded: “Conformal PORT cannot be recommended as standard of care in all completely resected stage IIIAN2 [non–small cell lung cancer] patients.”
Dr. Dziadziuszko commented further: “For my practice, this is a clear message that routine PORT should not be used in these patients. We are looking for more effective systemic therapies.”
He added that “over 50% 5-year survival in these patients is a great result, and is made possible by modern staging and modern surgery.”
The Lung ART study was sponsored by Gustave Roussy and supported by the French National Cancer Institute, French Health Ministry, and a Cancer Research UK grant. Dr. Le Péchoux and Dr. Dziadziuszko reported no conflicts of interest related to the presentation.
SOURCE: Le Péchoux C et al. ESMO 2020, Abstract LBA3_PR.
In patients with completely resected non–small cell lung cancer and proven N2 disease, postoperative radiotherapy (PORT) provided no significant improvement in disease-free survival (DFS) at 3 years, according to a phase 3 trial.
Investigator Cécile Le Péchoux, MD, a radiation oncologist from Institut Gustave Roussy in Paris, presented the results of the Lung ART trial at the European Society for Medical Oncology Virtual Congress 2020.
The results resolve what ESMO commentator Rafal Dziadziuszko, MD, PhD, of Medical University of Gdansk (Poland), called “perhaps the longest ongoing debate in thoracic oncology,” on whether or not to irradiate patients with mediastinal lymph node involvement after surgery.
Dr. Dziadziuszko noted that some past studies have suggested PORT may provide improved local control and a survival benefit, but other studies have shown no survival benefit and evidence of harm with PORT.
“So here is an academic study with the answer,” Dr. Dziadziuszko said.
Study details
The intention-to-treat population of Lung ART included 252 patients randomized to receive 5.5 weeks of PORT (54 Gy) and 249 patients randomized to the control arm without PORT.
The patients’ median age was 61 years, 66% were men, and adenocarcinoma was the predominant histology (76% of patients in the control arm and 70% in the PORT arm). All patients had received adjuvant or neoadjuvant chemotherapy.
The median follow-up was 4.8 years. The 3-year DFS rate was 47.1% in the PORT arm and 43.8% in the control arm (hazard ratio, 0.85; 95% confidence interval, 0.67-1.07, P = .16). The median DFS was 30.5 months with PORT and 22.8 months in the control group. As for DFS components, the rate for death as a first event was 14.6% in the PORT arm and 5.3% among controls.
The mediastinal relapse rate was higher among controls, at 46.1% versus 25.0% with PORT.
The 3-year overall survival rate was 66.5% among patients in the PORT arm and 68.5% in the control arm.
At least one grade 3-4 toxicity was reported in 23.7% of the PORT group and in 15.0% of controls. The grade 3-4 cardiopulmonary toxicity rate of 10.8% in the PORT arm and 4.9% in the control arm needs to be further explored, Dr. Le Péchoux said.
Applying the results to practice
In response to a question as to which patients might benefit from PORT, Dr. Le Péchoux pointed out that, among patients who have nodes in the inferior part of the mediastinum closer to the heart, PORT might be more toxic.
“For the moment, we did not see anything that would give us a clue,” Dr. Le Péchoux said. “We have a lot to investigate.”
Further analyses looking at patterns of failure, predictive factors of efficacy and toxicity, quality of radiotherapy, and quality of surgery are planned, she added.
Dr. Le Péchoux concluded: “Conformal PORT cannot be recommended as standard of care in all completely resected stage IIIAN2 [non–small cell lung cancer] patients.”
Dr. Dziadziuszko commented further: “For my practice, this is a clear message that routine PORT should not be used in these patients. We are looking for more effective systemic therapies.”
He added that “over 50% 5-year survival in these patients is a great result, and is made possible by modern staging and modern surgery.”
The Lung ART study was sponsored by Gustave Roussy and supported by the French National Cancer Institute, French Health Ministry, and a Cancer Research UK grant. Dr. Le Péchoux and Dr. Dziadziuszko reported no conflicts of interest related to the presentation.
SOURCE: Le Péchoux C et al. ESMO 2020, Abstract LBA3_PR.
In patients with completely resected non–small cell lung cancer and proven N2 disease, postoperative radiotherapy (PORT) provided no significant improvement in disease-free survival (DFS) at 3 years, according to a phase 3 trial.
Investigator Cécile Le Péchoux, MD, a radiation oncologist from Institut Gustave Roussy in Paris, presented the results of the Lung ART trial at the European Society for Medical Oncology Virtual Congress 2020.
The results resolve what ESMO commentator Rafal Dziadziuszko, MD, PhD, of Medical University of Gdansk (Poland), called “perhaps the longest ongoing debate in thoracic oncology,” on whether or not to irradiate patients with mediastinal lymph node involvement after surgery.
Dr. Dziadziuszko noted that some past studies have suggested PORT may provide improved local control and a survival benefit, but other studies have shown no survival benefit and evidence of harm with PORT.
“So here is an academic study with the answer,” Dr. Dziadziuszko said.
Study details
The intention-to-treat population of Lung ART included 252 patients randomized to receive 5.5 weeks of PORT (54 Gy) and 249 patients randomized to the control arm without PORT.
The patients’ median age was 61 years, 66% were men, and adenocarcinoma was the predominant histology (76% of patients in the control arm and 70% in the PORT arm). All patients had received adjuvant or neoadjuvant chemotherapy.
The median follow-up was 4.8 years. The 3-year DFS rate was 47.1% in the PORT arm and 43.8% in the control arm (hazard ratio, 0.85; 95% confidence interval, 0.67-1.07, P = .16). The median DFS was 30.5 months with PORT and 22.8 months in the control group. As for DFS components, the rate for death as a first event was 14.6% in the PORT arm and 5.3% among controls.
The mediastinal relapse rate was higher among controls, at 46.1% versus 25.0% with PORT.
The 3-year overall survival rate was 66.5% among patients in the PORT arm and 68.5% in the control arm.
At least one grade 3-4 toxicity was reported in 23.7% of the PORT group and in 15.0% of controls. The grade 3-4 cardiopulmonary toxicity rate of 10.8% in the PORT arm and 4.9% in the control arm needs to be further explored, Dr. Le Péchoux said.
Applying the results to practice
In response to a question as to which patients might benefit from PORT, Dr. Le Péchoux pointed out that, among patients who have nodes in the inferior part of the mediastinum closer to the heart, PORT might be more toxic.
“For the moment, we did not see anything that would give us a clue,” Dr. Le Péchoux said. “We have a lot to investigate.”
Further analyses looking at patterns of failure, predictive factors of efficacy and toxicity, quality of radiotherapy, and quality of surgery are planned, she added.
Dr. Le Péchoux concluded: “Conformal PORT cannot be recommended as standard of care in all completely resected stage IIIAN2 [non–small cell lung cancer] patients.”
Dr. Dziadziuszko commented further: “For my practice, this is a clear message that routine PORT should not be used in these patients. We are looking for more effective systemic therapies.”
He added that “over 50% 5-year survival in these patients is a great result, and is made possible by modern staging and modern surgery.”
The Lung ART study was sponsored by Gustave Roussy and supported by the French National Cancer Institute, French Health Ministry, and a Cancer Research UK grant. Dr. Le Péchoux and Dr. Dziadziuszko reported no conflicts of interest related to the presentation.
SOURCE: Le Péchoux C et al. ESMO 2020, Abstract LBA3_PR.
FROM ESMO 2020
Survey quantifies COVID-19’s impact on oncology
An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.
The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).
Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.
The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.
The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.
The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).
The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
Impact on treatment
The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).
Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).
Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.
On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.
Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.
“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.
“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.
Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.
Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
Telehealth, meetings, and trials
The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).
Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).
While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.
Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.
Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.
He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”
This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.
SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.
An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.
The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).
Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.
The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.
The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.
The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).
The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
Impact on treatment
The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).
Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).
Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.
On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.
Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.
“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.
“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.
Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.
Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
Telehealth, meetings, and trials
The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).
Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).
While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.
Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.
Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.
He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”
This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.
SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.
An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.
The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).
Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.
The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.
The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.
The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).
The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
Impact on treatment
The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).
Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).
Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.
On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.
Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.
“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.
“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.
Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.
Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
Telehealth, meetings, and trials
The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).
Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).
While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.
Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.
Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.
He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”
This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.
SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.
FROM ESMO 2020
Subgroups predict adjuvant chemoradiotherapy benefits in low-grade glioma
Adjuvant chemoradiotherapy beat radiotherapy alone for treatment of certain patients with World Health Organization (WHO)–defined low-grade glioma (LGG), according to researchers.
Prior results from this trial, NRG Oncology/RTOG 9802 (NCT00003375), demonstrated an increase in progression-free survival (PFS) and overall survival (OS) when procarbazine, lomustine, and vincristine (PCV) chemotherapy was added to radiation in patients with high-risk LGG.
The current results, published in the Journal of Clinical Oncology, displayed highly variable survival outcomes depending on molecular subgroup.
The initial report included only IDH1 R132H immunohistochemistry data because of limited tissue availability. However, retrospective retrieval of additional tissues subsequently enabled rigorous examination of the prognostic and predictive significance of these genetic biomarkers.
Prognostic and predictive
The trial included 251 patients with LGG (grade 2). Among the 106 eligible patients with WHO-defined molecular groups successfully profiled, 26 (24%) were IDH wild-type, 43 (41%) were IDH-mutant/non-codeleted, and 37 (35%) were IDH-mutant/codeleted.
After adjustment for clinical variables and treatment, multivariate analysis confirmed WHO-defined subgroup was a significant predictor of survival. All predictive analyses, however, were considered exploratory because of small sample sizes for patients with specific biomarker features in most cases.
In prognostic multivariable analyses, significantly favorable molecular subgroup associations were observed for OS in the IDH-mutant subgroups versus that in the wild type group (IDH-mutant/codeleted group HR, 0.18; P < .0001; IDH mutant/non-codeleleted group HR, 0.56; P = .048). Individually, the statistical significance was maintained for favorable OS for IDH1/2 mutations and 1p/19q codeletions.
In the predictive analyses, OS was longer for patients harboring IDH mutant/codeleted tumors receiving radiotherapy plus PCV than for those receiving radiotherapy alone (HR, 0.21; P = .029). The median OS was 13.9 years for radiotherapy and was not reached for PCV and radiotherapy.
PFS in the IDH-mutant/codeleted subgroup also was longer for patients receiving PCV (HR, 0.13; P < .001). The median PFS was 5.8 years for radiotherapy alone and was not reached for added PCV.
In the IDH-mutant/non-codeleted subgroup, OS was longer with PCV (HR, 0.38; P = .013). The median OS was 4.3 years for radiotherapy alone and 11.4 years when PCV was added.
PFS was also longer in the IDH-mutant/non-codeleted subgroup (HR, 0.32; P = .003). The median PFS was 3.3 years for radiotherapy and 10.4 years with PCV added.
IDH–wild type patients displayed no significant clinical benefit from the addition of PCV.
“Historically, many have thought that primarily patients with codeletions received benefit from PCV,” study author Erica H. Bell, PhD, of The Ohio State University in Columbus, said in an interview. “But we showed here that there is benefit in both IDH-mutant groups.”
Primary predictor
“Our evidence suggests that IDH mutation status could serve as the primary predictor of response to PCV in addition to radiotherapy in high-risk, low-grade gliomas and is a more accurate predictor of response than historical histopathological classifications,” Dr. Bell and colleagues wrote. “Consideration should be given for adjuvant PCV in the setting of high-risk, low-grade glioma patients harboring IDH mutations.”
High-risk was defined as being 40 years or older or having a subtotal resection biopsy.
“While both IDH mutant subgroups received benefit from the addition of PCV for both overall survival and PFS, the patients in the wild-type subgroup did not do well," Dr. Bell said. "We need to treat them more aggressively. We need to determine exactly what therapy modality they should receive. This is an active question in our field.”
“Another conclusion from the study,” she added, “is that upfront tissue collection and molecular subtyping are absolutely necessary for moving our field forward.”
Finding novel biomarkers and novel therapeutic targets remain as a further goal.
Dr. Bell commented that results of the CODEL trial of temozolomide in newly diagnosed 1p/19q-codeleted anaplastic glioma are widely anticipated.
“PCV is a very toxic treatment," she said. "If another agent that is less toxic, but just as efficacious, becomes available, we would rather use that. At this point, though, there are no head-to-head trials comparing temozolomide with PCV in codeleted populations.”
The current study was sponsored by the National Cancer Institute and The Ohio State University. The authors disclosed patents, royalties, and other intellectual property.
SOURCE: Bell EH et al. J Clin Oncol. 2020. doi: 10.1200/JCO.19.02983.
Adjuvant chemoradiotherapy beat radiotherapy alone for treatment of certain patients with World Health Organization (WHO)–defined low-grade glioma (LGG), according to researchers.
Prior results from this trial, NRG Oncology/RTOG 9802 (NCT00003375), demonstrated an increase in progression-free survival (PFS) and overall survival (OS) when procarbazine, lomustine, and vincristine (PCV) chemotherapy was added to radiation in patients with high-risk LGG.
The current results, published in the Journal of Clinical Oncology, displayed highly variable survival outcomes depending on molecular subgroup.
The initial report included only IDH1 R132H immunohistochemistry data because of limited tissue availability. However, retrospective retrieval of additional tissues subsequently enabled rigorous examination of the prognostic and predictive significance of these genetic biomarkers.
Prognostic and predictive
The trial included 251 patients with LGG (grade 2). Among the 106 eligible patients with WHO-defined molecular groups successfully profiled, 26 (24%) were IDH wild-type, 43 (41%) were IDH-mutant/non-codeleted, and 37 (35%) were IDH-mutant/codeleted.
After adjustment for clinical variables and treatment, multivariate analysis confirmed WHO-defined subgroup was a significant predictor of survival. All predictive analyses, however, were considered exploratory because of small sample sizes for patients with specific biomarker features in most cases.
In prognostic multivariable analyses, significantly favorable molecular subgroup associations were observed for OS in the IDH-mutant subgroups versus that in the wild type group (IDH-mutant/codeleted group HR, 0.18; P < .0001; IDH mutant/non-codeleleted group HR, 0.56; P = .048). Individually, the statistical significance was maintained for favorable OS for IDH1/2 mutations and 1p/19q codeletions.
In the predictive analyses, OS was longer for patients harboring IDH mutant/codeleted tumors receiving radiotherapy plus PCV than for those receiving radiotherapy alone (HR, 0.21; P = .029). The median OS was 13.9 years for radiotherapy and was not reached for PCV and radiotherapy.
PFS in the IDH-mutant/codeleted subgroup also was longer for patients receiving PCV (HR, 0.13; P < .001). The median PFS was 5.8 years for radiotherapy alone and was not reached for added PCV.
In the IDH-mutant/non-codeleted subgroup, OS was longer with PCV (HR, 0.38; P = .013). The median OS was 4.3 years for radiotherapy alone and 11.4 years when PCV was added.
PFS was also longer in the IDH-mutant/non-codeleted subgroup (HR, 0.32; P = .003). The median PFS was 3.3 years for radiotherapy and 10.4 years with PCV added.
IDH–wild type patients displayed no significant clinical benefit from the addition of PCV.
“Historically, many have thought that primarily patients with codeletions received benefit from PCV,” study author Erica H. Bell, PhD, of The Ohio State University in Columbus, said in an interview. “But we showed here that there is benefit in both IDH-mutant groups.”
Primary predictor
“Our evidence suggests that IDH mutation status could serve as the primary predictor of response to PCV in addition to radiotherapy in high-risk, low-grade gliomas and is a more accurate predictor of response than historical histopathological classifications,” Dr. Bell and colleagues wrote. “Consideration should be given for adjuvant PCV in the setting of high-risk, low-grade glioma patients harboring IDH mutations.”
High-risk was defined as being 40 years or older or having a subtotal resection biopsy.
“While both IDH mutant subgroups received benefit from the addition of PCV for both overall survival and PFS, the patients in the wild-type subgroup did not do well," Dr. Bell said. "We need to treat them more aggressively. We need to determine exactly what therapy modality they should receive. This is an active question in our field.”
“Another conclusion from the study,” she added, “is that upfront tissue collection and molecular subtyping are absolutely necessary for moving our field forward.”
Finding novel biomarkers and novel therapeutic targets remain as a further goal.
Dr. Bell commented that results of the CODEL trial of temozolomide in newly diagnosed 1p/19q-codeleted anaplastic glioma are widely anticipated.
“PCV is a very toxic treatment," she said. "If another agent that is less toxic, but just as efficacious, becomes available, we would rather use that. At this point, though, there are no head-to-head trials comparing temozolomide with PCV in codeleted populations.”
The current study was sponsored by the National Cancer Institute and The Ohio State University. The authors disclosed patents, royalties, and other intellectual property.
SOURCE: Bell EH et al. J Clin Oncol. 2020. doi: 10.1200/JCO.19.02983.
Adjuvant chemoradiotherapy beat radiotherapy alone for treatment of certain patients with World Health Organization (WHO)–defined low-grade glioma (LGG), according to researchers.
Prior results from this trial, NRG Oncology/RTOG 9802 (NCT00003375), demonstrated an increase in progression-free survival (PFS) and overall survival (OS) when procarbazine, lomustine, and vincristine (PCV) chemotherapy was added to radiation in patients with high-risk LGG.
The current results, published in the Journal of Clinical Oncology, displayed highly variable survival outcomes depending on molecular subgroup.
The initial report included only IDH1 R132H immunohistochemistry data because of limited tissue availability. However, retrospective retrieval of additional tissues subsequently enabled rigorous examination of the prognostic and predictive significance of these genetic biomarkers.
Prognostic and predictive
The trial included 251 patients with LGG (grade 2). Among the 106 eligible patients with WHO-defined molecular groups successfully profiled, 26 (24%) were IDH wild-type, 43 (41%) were IDH-mutant/non-codeleted, and 37 (35%) were IDH-mutant/codeleted.
After adjustment for clinical variables and treatment, multivariate analysis confirmed WHO-defined subgroup was a significant predictor of survival. All predictive analyses, however, were considered exploratory because of small sample sizes for patients with specific biomarker features in most cases.
In prognostic multivariable analyses, significantly favorable molecular subgroup associations were observed for OS in the IDH-mutant subgroups versus that in the wild type group (IDH-mutant/codeleted group HR, 0.18; P < .0001; IDH mutant/non-codeleleted group HR, 0.56; P = .048). Individually, the statistical significance was maintained for favorable OS for IDH1/2 mutations and 1p/19q codeletions.
In the predictive analyses, OS was longer for patients harboring IDH mutant/codeleted tumors receiving radiotherapy plus PCV than for those receiving radiotherapy alone (HR, 0.21; P = .029). The median OS was 13.9 years for radiotherapy and was not reached for PCV and radiotherapy.
PFS in the IDH-mutant/codeleted subgroup also was longer for patients receiving PCV (HR, 0.13; P < .001). The median PFS was 5.8 years for radiotherapy alone and was not reached for added PCV.
In the IDH-mutant/non-codeleted subgroup, OS was longer with PCV (HR, 0.38; P = .013). The median OS was 4.3 years for radiotherapy alone and 11.4 years when PCV was added.
PFS was also longer in the IDH-mutant/non-codeleted subgroup (HR, 0.32; P = .003). The median PFS was 3.3 years for radiotherapy and 10.4 years with PCV added.
IDH–wild type patients displayed no significant clinical benefit from the addition of PCV.
“Historically, many have thought that primarily patients with codeletions received benefit from PCV,” study author Erica H. Bell, PhD, of The Ohio State University in Columbus, said in an interview. “But we showed here that there is benefit in both IDH-mutant groups.”
Primary predictor
“Our evidence suggests that IDH mutation status could serve as the primary predictor of response to PCV in addition to radiotherapy in high-risk, low-grade gliomas and is a more accurate predictor of response than historical histopathological classifications,” Dr. Bell and colleagues wrote. “Consideration should be given for adjuvant PCV in the setting of high-risk, low-grade glioma patients harboring IDH mutations.”
High-risk was defined as being 40 years or older or having a subtotal resection biopsy.
“While both IDH mutant subgroups received benefit from the addition of PCV for both overall survival and PFS, the patients in the wild-type subgroup did not do well," Dr. Bell said. "We need to treat them more aggressively. We need to determine exactly what therapy modality they should receive. This is an active question in our field.”
“Another conclusion from the study,” she added, “is that upfront tissue collection and molecular subtyping are absolutely necessary for moving our field forward.”
Finding novel biomarkers and novel therapeutic targets remain as a further goal.
Dr. Bell commented that results of the CODEL trial of temozolomide in newly diagnosed 1p/19q-codeleted anaplastic glioma are widely anticipated.
“PCV is a very toxic treatment," she said. "If another agent that is less toxic, but just as efficacious, becomes available, we would rather use that. At this point, though, there are no head-to-head trials comparing temozolomide with PCV in codeleted populations.”
The current study was sponsored by the National Cancer Institute and The Ohio State University. The authors disclosed patents, royalties, and other intellectual property.
SOURCE: Bell EH et al. J Clin Oncol. 2020. doi: 10.1200/JCO.19.02983.
FROM THE JOURNAL OF CLINICAL ONCOLOGY