User login
Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
PCI safely improves iPFS and OS in advanced NSCLC
TORONTO – Prophylactic cranial irradiation, which is standard-of-care practice in patients with small cell lung cancer, also appears to improve intracranial progression-free survival (iPFS) and overall survival in patients with stage IV non–small cell lung cancer (NSCLC), according to findings from a randomized study.
The cumulative incidence of brain metastases at 2 years was 22% in 41 patients who received prophylactic cranial irradiation (PCI), compared with 52% in 43 patients who received standard care with first- and second-generation tyrosine kinase inhibitors (TKIs) without PCI, Oscar Arrieta, MD, reported at the World Conference on Lung Cancer.
PCI was associated with lower odds of progression to the CNS (odds ratio, 0.16), Dr. Arrieta, of the National Cancer Institute of Mexico, Mexico City, said at the meeting sponsored by the International Association for the Study of Lung Cancer. Further, the relative risk for iPFS in patients with an epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase mutation (ALK), who comprised 70% of patients in both groups, was 0.29 with PCI.
Median overall survival in the groups was 42.8 months versus 25.9 months (HR, 0.48).
The burden of brain metastases can impact the quality and length of survival in patients with NSCLC, and because of an aging population and advances in detection and treatment of primary cancers, patients are living longer and thus are more likely to experience brain metastases, Dr. Arrieta said, noting that this is particularly true for patients at high risk, such as those with elevated carcinoembryonic antigen levels.
Although PCI is standard in small cell lung cancer, its role in NSCLC remains controversial because of concerns about neurologic morbidity and lack of overall survival benefit, he explained.
“The objective of this study was to determine if the use of PCI reduced the development of brain metastases and improved the survival in this population without impairing quality of life,” he said.
Study participants were patients with confirmed stage IV NSCLC and adenocarcinoma histology at high risk for developing brain metastasis. PCI in the treatment group was delivered at 25 Gy/10 fractions.
The findings suggest that in NSCLC with a high risk of developing brain metastases who are treated with a first- or second-generation TKI – particularly those with EGFR and ALK mutations – PCI increases iPFS, Dr. Arrieta said.
“The findings can be extrapolated to those treated with third-generation TKIs, which have higher CNS penetration,” he said, noting, however, that access to third-generation TKIs is limited in most developing countries and cost barriers are high.
Of note, the relatively low dose of PCI used in this study was not associated with significant differences in Mini-Mental State Examination or quality of life scores in the short-term. Long-term assessments are needed, he said, concluding that, while additional study is needed to confirm the findings, the results, including the overall survival benefit seen with PCI, “highlight the benefits of this approach, particularly among patients with a high risk of developing brain metastases.”
Invited discussant Nasser Hanna, MD, the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at Indiana University, Indianapolis, said the findings of this “interesting and important study,” are intriguing, but agreed that additional study is needed.
“The study is far too small ... to definitively make this conclusion [that PCI improves iPFS in this population]; I would not recommend PCI without confirmatory data from larger, randomized trials,” he said.
Dr. Arrieta reported advisory roles or provision of expert testimony for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Merck, Takeda, and Bristol-Myers Squibb, and receipt of honoraria and/or research funding from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Bristol-Myers Squibb. Dr. Nasser reported receiving research grants from Bristol-Myers Squibb, AstraZeneca, Genentech, and Merck.
SOURCE: Arrieta O et al. WCLC 2018, Abstract MA08.02.
TORONTO – Prophylactic cranial irradiation, which is standard-of-care practice in patients with small cell lung cancer, also appears to improve intracranial progression-free survival (iPFS) and overall survival in patients with stage IV non–small cell lung cancer (NSCLC), according to findings from a randomized study.
The cumulative incidence of brain metastases at 2 years was 22% in 41 patients who received prophylactic cranial irradiation (PCI), compared with 52% in 43 patients who received standard care with first- and second-generation tyrosine kinase inhibitors (TKIs) without PCI, Oscar Arrieta, MD, reported at the World Conference on Lung Cancer.
PCI was associated with lower odds of progression to the CNS (odds ratio, 0.16), Dr. Arrieta, of the National Cancer Institute of Mexico, Mexico City, said at the meeting sponsored by the International Association for the Study of Lung Cancer. Further, the relative risk for iPFS in patients with an epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase mutation (ALK), who comprised 70% of patients in both groups, was 0.29 with PCI.
Median overall survival in the groups was 42.8 months versus 25.9 months (HR, 0.48).
The burden of brain metastases can impact the quality and length of survival in patients with NSCLC, and because of an aging population and advances in detection and treatment of primary cancers, patients are living longer and thus are more likely to experience brain metastases, Dr. Arrieta said, noting that this is particularly true for patients at high risk, such as those with elevated carcinoembryonic antigen levels.
Although PCI is standard in small cell lung cancer, its role in NSCLC remains controversial because of concerns about neurologic morbidity and lack of overall survival benefit, he explained.
“The objective of this study was to determine if the use of PCI reduced the development of brain metastases and improved the survival in this population without impairing quality of life,” he said.
Study participants were patients with confirmed stage IV NSCLC and adenocarcinoma histology at high risk for developing brain metastasis. PCI in the treatment group was delivered at 25 Gy/10 fractions.
The findings suggest that in NSCLC with a high risk of developing brain metastases who are treated with a first- or second-generation TKI – particularly those with EGFR and ALK mutations – PCI increases iPFS, Dr. Arrieta said.
“The findings can be extrapolated to those treated with third-generation TKIs, which have higher CNS penetration,” he said, noting, however, that access to third-generation TKIs is limited in most developing countries and cost barriers are high.
Of note, the relatively low dose of PCI used in this study was not associated with significant differences in Mini-Mental State Examination or quality of life scores in the short-term. Long-term assessments are needed, he said, concluding that, while additional study is needed to confirm the findings, the results, including the overall survival benefit seen with PCI, “highlight the benefits of this approach, particularly among patients with a high risk of developing brain metastases.”
Invited discussant Nasser Hanna, MD, the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at Indiana University, Indianapolis, said the findings of this “interesting and important study,” are intriguing, but agreed that additional study is needed.
“The study is far too small ... to definitively make this conclusion [that PCI improves iPFS in this population]; I would not recommend PCI without confirmatory data from larger, randomized trials,” he said.
Dr. Arrieta reported advisory roles or provision of expert testimony for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Merck, Takeda, and Bristol-Myers Squibb, and receipt of honoraria and/or research funding from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Bristol-Myers Squibb. Dr. Nasser reported receiving research grants from Bristol-Myers Squibb, AstraZeneca, Genentech, and Merck.
SOURCE: Arrieta O et al. WCLC 2018, Abstract MA08.02.
TORONTO – Prophylactic cranial irradiation, which is standard-of-care practice in patients with small cell lung cancer, also appears to improve intracranial progression-free survival (iPFS) and overall survival in patients with stage IV non–small cell lung cancer (NSCLC), according to findings from a randomized study.
The cumulative incidence of brain metastases at 2 years was 22% in 41 patients who received prophylactic cranial irradiation (PCI), compared with 52% in 43 patients who received standard care with first- and second-generation tyrosine kinase inhibitors (TKIs) without PCI, Oscar Arrieta, MD, reported at the World Conference on Lung Cancer.
PCI was associated with lower odds of progression to the CNS (odds ratio, 0.16), Dr. Arrieta, of the National Cancer Institute of Mexico, Mexico City, said at the meeting sponsored by the International Association for the Study of Lung Cancer. Further, the relative risk for iPFS in patients with an epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase mutation (ALK), who comprised 70% of patients in both groups, was 0.29 with PCI.
Median overall survival in the groups was 42.8 months versus 25.9 months (HR, 0.48).
The burden of brain metastases can impact the quality and length of survival in patients with NSCLC, and because of an aging population and advances in detection and treatment of primary cancers, patients are living longer and thus are more likely to experience brain metastases, Dr. Arrieta said, noting that this is particularly true for patients at high risk, such as those with elevated carcinoembryonic antigen levels.
Although PCI is standard in small cell lung cancer, its role in NSCLC remains controversial because of concerns about neurologic morbidity and lack of overall survival benefit, he explained.
“The objective of this study was to determine if the use of PCI reduced the development of brain metastases and improved the survival in this population without impairing quality of life,” he said.
Study participants were patients with confirmed stage IV NSCLC and adenocarcinoma histology at high risk for developing brain metastasis. PCI in the treatment group was delivered at 25 Gy/10 fractions.
The findings suggest that in NSCLC with a high risk of developing brain metastases who are treated with a first- or second-generation TKI – particularly those with EGFR and ALK mutations – PCI increases iPFS, Dr. Arrieta said.
“The findings can be extrapolated to those treated with third-generation TKIs, which have higher CNS penetration,” he said, noting, however, that access to third-generation TKIs is limited in most developing countries and cost barriers are high.
Of note, the relatively low dose of PCI used in this study was not associated with significant differences in Mini-Mental State Examination or quality of life scores in the short-term. Long-term assessments are needed, he said, concluding that, while additional study is needed to confirm the findings, the results, including the overall survival benefit seen with PCI, “highlight the benefits of this approach, particularly among patients with a high risk of developing brain metastases.”
Invited discussant Nasser Hanna, MD, the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at Indiana University, Indianapolis, said the findings of this “interesting and important study,” are intriguing, but agreed that additional study is needed.
“The study is far too small ... to definitively make this conclusion [that PCI improves iPFS in this population]; I would not recommend PCI without confirmatory data from larger, randomized trials,” he said.
Dr. Arrieta reported advisory roles or provision of expert testimony for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Merck, Takeda, and Bristol-Myers Squibb, and receipt of honoraria and/or research funding from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Bristol-Myers Squibb. Dr. Nasser reported receiving research grants from Bristol-Myers Squibb, AstraZeneca, Genentech, and Merck.
SOURCE: Arrieta O et al. WCLC 2018, Abstract MA08.02.
REPORTING FROM WCLC 2018
Key clinical point: Prophylactic cranial irradiation improves intracranial progression-free survival and overall survival in non–small cell lung cancer.
Major finding: Prophylactic cranial irradiation reduced the risk of CNS progression (odds ratio, 0.16).
Study details: A randomized study of 84 patients with non–small cell lung cancer.
Disclosures: Dr. Arrieta reported advisory roles or provision of expert testimony for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Merck, Takeda, and Bristol-Myers Squibb, and receipt of honoraria and/or research funding from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Bristol-Myers Squibb. Dr. Nasser reported receiving research grants from Bristol-Myers Squibb, AstraZeneca, Genentech, and Merck.
Source: Arrieta O et al. WCLC 2018, Abstract MA08.02.
High-dose flu vaccine in RA patients beats standard dose
CHICAGO – The administration of high-dose vs. standard-dose influenza vaccine provided substantially better immune responses in seropositive rheumatoid arthritis patients in a randomized, active-controlled trial.
High-dose trivalent influenza vaccine is known to improve immune responses in the elderly, but the current findings, which were presented at the annual meeting of the American College of Rheumatology, are the first to document a successful intervention to enhance vaccine responses in immunocompromised patients, according to Inés Colmegna, MD, of McGill University, Montreal.
Dr. Colmegna and her colleagues assessed antibody responses to either standard-dose (15 mcg of hemagglutinin per strain) quadrivalent inactivated influenza vaccine (SD-QIV) or high-dose (60 mcg of hemagglutinin per strain) trivalent inactivated influenza vaccine (HD-TIV) in 140 and 139 patients, respectively.
Seroprotection rates prior to vaccination were comparable in the two groups, but the high-dose recipients had consistently higher overall responses to vaccination.
Seroconversion rates were 22.3% vs. 8.6% (odds ratio, 2.93) for the H3N2 strain (A/HongKong/4801/2014), and 44.6% vs. 28.6% (OR, 1.93) for the B Victoria Lin strain (B/Brisbane/60/2008). For the H1N1 strain A/California/7/2009 in 2016-2017 and closely related A/Michigan/45/2015 in 2017-2018, the seroconversion rates were 51.1% vs. 30.0% (OR, 2.91) and 46.4% vs. 24.6% (OR, 2.79), respectively. Seroprotection rates for the H3N2 strain were 48.5% vs. 30.9%, and for the B Victoria Lin strain, 60.0% vs. 50.7%. The seroprotection rates for the H1N1 strains together were and 80.4% vs. 73.5%, Dr. Colmegna said.
Seroconversion was defined as at least a fourfold serum hemagglutination inhibition (HI) antibody increase from prevaccination level (day 0), and seroprotection was defined as percent with HI titers of 1:40 or greater at postvaccination day 28.
After the researchers controlled for age, vaccine type, treatment type in the 3 months prior to vaccination and during the study period, Charlson comorbidity index, and RA duration, the only significant predictors of vaccine seroresponse were vaccine dose and age.
The findings are notable because RA patients have a nearly threefold increase in the risk of contracting influenza infection or related illness, compared with age-matched healthy controls, because of “inherent immune dysfunction associated with RA, comorbidities, the age of our patients, and immunosuppressive therapy,” Dr. Colmegna said.
For this reason, RA patients are a priority group for annual vaccination. However, while vaccination remains the most effective method for preventing influenza and its associated complications, vaccine-induced antibody responses and protection in RA are suboptimal, she explained, noting that this puts them at increased risk for severe influenza.
“There is a high priority to develop new approaches to try to decrease this risk,” she said.
It was unknown whether HD-TIV – the only currently available high-dose influenza vaccine – would safely enhance antibody production in RA as it does in the elderly, so she and her colleagues recruited patients from a tertiary care center during the 2016-2017 and 2017-2018 Northern Hemisphere influenza seasons for this study.
The mean age of the patients was 61 years, and 80% were women. All were on stable treatment with either disease-modifying antirheumatic drugs (DMARDs) or biologics for at least 3 months prior to vaccination; treatment types included DMARDs in 138 patients (49.5%), anticytokine therapy in 92 patients (33%), and anti-B-cell therapy and small molecules in 49 patients (17.6%). An analysis by treatment type showed a possible reduction in the rate of seroconversion in patients who received anti-B-cell therapy and small molecules, but the number of patients in the group was too small to make definitive conclusions, Dr. Colmegna said.
Treatment in all groups was safe, with no differences in adverse events between those receiving high- or standard-dose vaccine, and none of the adverse events were related to treatment.
Further, the high-dose vaccine was not associated with an increase in disease activity.
“We believe that these results will likely change clinical practice,” she concluded.
Dr. Colmegna reported having no disclosures.
SOURCE: Colmegna I et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 837.
CHICAGO – The administration of high-dose vs. standard-dose influenza vaccine provided substantially better immune responses in seropositive rheumatoid arthritis patients in a randomized, active-controlled trial.
High-dose trivalent influenza vaccine is known to improve immune responses in the elderly, but the current findings, which were presented at the annual meeting of the American College of Rheumatology, are the first to document a successful intervention to enhance vaccine responses in immunocompromised patients, according to Inés Colmegna, MD, of McGill University, Montreal.
Dr. Colmegna and her colleagues assessed antibody responses to either standard-dose (15 mcg of hemagglutinin per strain) quadrivalent inactivated influenza vaccine (SD-QIV) or high-dose (60 mcg of hemagglutinin per strain) trivalent inactivated influenza vaccine (HD-TIV) in 140 and 139 patients, respectively.
Seroprotection rates prior to vaccination were comparable in the two groups, but the high-dose recipients had consistently higher overall responses to vaccination.
Seroconversion rates were 22.3% vs. 8.6% (odds ratio, 2.93) for the H3N2 strain (A/HongKong/4801/2014), and 44.6% vs. 28.6% (OR, 1.93) for the B Victoria Lin strain (B/Brisbane/60/2008). For the H1N1 strain A/California/7/2009 in 2016-2017 and closely related A/Michigan/45/2015 in 2017-2018, the seroconversion rates were 51.1% vs. 30.0% (OR, 2.91) and 46.4% vs. 24.6% (OR, 2.79), respectively. Seroprotection rates for the H3N2 strain were 48.5% vs. 30.9%, and for the B Victoria Lin strain, 60.0% vs. 50.7%. The seroprotection rates for the H1N1 strains together were and 80.4% vs. 73.5%, Dr. Colmegna said.
Seroconversion was defined as at least a fourfold serum hemagglutination inhibition (HI) antibody increase from prevaccination level (day 0), and seroprotection was defined as percent with HI titers of 1:40 or greater at postvaccination day 28.
After the researchers controlled for age, vaccine type, treatment type in the 3 months prior to vaccination and during the study period, Charlson comorbidity index, and RA duration, the only significant predictors of vaccine seroresponse were vaccine dose and age.
The findings are notable because RA patients have a nearly threefold increase in the risk of contracting influenza infection or related illness, compared with age-matched healthy controls, because of “inherent immune dysfunction associated with RA, comorbidities, the age of our patients, and immunosuppressive therapy,” Dr. Colmegna said.
For this reason, RA patients are a priority group for annual vaccination. However, while vaccination remains the most effective method for preventing influenza and its associated complications, vaccine-induced antibody responses and protection in RA are suboptimal, she explained, noting that this puts them at increased risk for severe influenza.
“There is a high priority to develop new approaches to try to decrease this risk,” she said.
It was unknown whether HD-TIV – the only currently available high-dose influenza vaccine – would safely enhance antibody production in RA as it does in the elderly, so she and her colleagues recruited patients from a tertiary care center during the 2016-2017 and 2017-2018 Northern Hemisphere influenza seasons for this study.
The mean age of the patients was 61 years, and 80% were women. All were on stable treatment with either disease-modifying antirheumatic drugs (DMARDs) or biologics for at least 3 months prior to vaccination; treatment types included DMARDs in 138 patients (49.5%), anticytokine therapy in 92 patients (33%), and anti-B-cell therapy and small molecules in 49 patients (17.6%). An analysis by treatment type showed a possible reduction in the rate of seroconversion in patients who received anti-B-cell therapy and small molecules, but the number of patients in the group was too small to make definitive conclusions, Dr. Colmegna said.
Treatment in all groups was safe, with no differences in adverse events between those receiving high- or standard-dose vaccine, and none of the adverse events were related to treatment.
Further, the high-dose vaccine was not associated with an increase in disease activity.
“We believe that these results will likely change clinical practice,” she concluded.
Dr. Colmegna reported having no disclosures.
SOURCE: Colmegna I et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 837.
CHICAGO – The administration of high-dose vs. standard-dose influenza vaccine provided substantially better immune responses in seropositive rheumatoid arthritis patients in a randomized, active-controlled trial.
High-dose trivalent influenza vaccine is known to improve immune responses in the elderly, but the current findings, which were presented at the annual meeting of the American College of Rheumatology, are the first to document a successful intervention to enhance vaccine responses in immunocompromised patients, according to Inés Colmegna, MD, of McGill University, Montreal.
Dr. Colmegna and her colleagues assessed antibody responses to either standard-dose (15 mcg of hemagglutinin per strain) quadrivalent inactivated influenza vaccine (SD-QIV) or high-dose (60 mcg of hemagglutinin per strain) trivalent inactivated influenza vaccine (HD-TIV) in 140 and 139 patients, respectively.
Seroprotection rates prior to vaccination were comparable in the two groups, but the high-dose recipients had consistently higher overall responses to vaccination.
Seroconversion rates were 22.3% vs. 8.6% (odds ratio, 2.93) for the H3N2 strain (A/HongKong/4801/2014), and 44.6% vs. 28.6% (OR, 1.93) for the B Victoria Lin strain (B/Brisbane/60/2008). For the H1N1 strain A/California/7/2009 in 2016-2017 and closely related A/Michigan/45/2015 in 2017-2018, the seroconversion rates were 51.1% vs. 30.0% (OR, 2.91) and 46.4% vs. 24.6% (OR, 2.79), respectively. Seroprotection rates for the H3N2 strain were 48.5% vs. 30.9%, and for the B Victoria Lin strain, 60.0% vs. 50.7%. The seroprotection rates for the H1N1 strains together were and 80.4% vs. 73.5%, Dr. Colmegna said.
Seroconversion was defined as at least a fourfold serum hemagglutination inhibition (HI) antibody increase from prevaccination level (day 0), and seroprotection was defined as percent with HI titers of 1:40 or greater at postvaccination day 28.
After the researchers controlled for age, vaccine type, treatment type in the 3 months prior to vaccination and during the study period, Charlson comorbidity index, and RA duration, the only significant predictors of vaccine seroresponse were vaccine dose and age.
The findings are notable because RA patients have a nearly threefold increase in the risk of contracting influenza infection or related illness, compared with age-matched healthy controls, because of “inherent immune dysfunction associated with RA, comorbidities, the age of our patients, and immunosuppressive therapy,” Dr. Colmegna said.
For this reason, RA patients are a priority group for annual vaccination. However, while vaccination remains the most effective method for preventing influenza and its associated complications, vaccine-induced antibody responses and protection in RA are suboptimal, she explained, noting that this puts them at increased risk for severe influenza.
“There is a high priority to develop new approaches to try to decrease this risk,” she said.
It was unknown whether HD-TIV – the only currently available high-dose influenza vaccine – would safely enhance antibody production in RA as it does in the elderly, so she and her colleagues recruited patients from a tertiary care center during the 2016-2017 and 2017-2018 Northern Hemisphere influenza seasons for this study.
The mean age of the patients was 61 years, and 80% were women. All were on stable treatment with either disease-modifying antirheumatic drugs (DMARDs) or biologics for at least 3 months prior to vaccination; treatment types included DMARDs in 138 patients (49.5%), anticytokine therapy in 92 patients (33%), and anti-B-cell therapy and small molecules in 49 patients (17.6%). An analysis by treatment type showed a possible reduction in the rate of seroconversion in patients who received anti-B-cell therapy and small molecules, but the number of patients in the group was too small to make definitive conclusions, Dr. Colmegna said.
Treatment in all groups was safe, with no differences in adverse events between those receiving high- or standard-dose vaccine, and none of the adverse events were related to treatment.
Further, the high-dose vaccine was not associated with an increase in disease activity.
“We believe that these results will likely change clinical practice,” she concluded.
Dr. Colmegna reported having no disclosures.
SOURCE: Colmegna I et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 837.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: High- vs. standard-dose flu vaccine improves immune responses in RA patients.
Major finding: High-dose trivalent inactivated influenza vaccine was associated with greater odds of H3N2, B Victoria Lin, and H1N1 seroconversion.
Study details: A randomized, active-controlled trial of 279 RA patients
Disclosures: Dr. Colmegna reported having no disclosures.
Source: Colmegna I et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 837.
PET/CT has good accuracy for diagnosing GCA
CHICAGO – Combined PET/CT has good diagnostic accuracy, including a 98% negative predictive value, when compared with temporal artery biopsy for suspected giant cell arteritis, according to findings from a study of 64 patients.
Study participants included patients with newly suspected giant cell arteritis (GCA) and all underwent PET/CT from the vertex to the diaphragm within 72 hours of starting corticosteroid therapy and prior to undergoing temporal artery biopsy (TAB). Two nuclear medicine physicians blinded to clinical and biopsy data identified GCA in the scans of 12 of 58 patients (21%) who ultimately underwent both PET/CT and TAB, Anthony M. Sammel, MBBS, reported at the annual meeting of the American College of Rheumatology.
Compared with TAB, which is the standard of care for diagnosing GCA in most centers, global GCA assessment by PET/CT had a sensitivity of 92%, specificity of 85%, and positive predictive value of 61%, said Dr. Sammel, a rheumatologist at Royal North Shore Hospital in Sydney.
The findings, and particularly the 98% negative predictive value, suggest that PET/CT could be used first line to rule out suspected GCA, although the sample size in the study was modest, he noted.
“I believe [the findings] would support PET/CT, when we include the head, neck, and chest, as a first-line test for patients newly suspected of having giant cell arteritis. I think we do need to be mindful that it’s not perfect,” he said, explaining that a TAB is warranted in a patient with a negative scan despite a clinician’s sense that there is a high likelihood of GCA.
However, the findings suggest that a negative study in a low to moderate risk patient would be “very, very reassuring,” and as such patients probably do not need a biopsy, he said in a video interview in which he also discussed cost-benefit issues with respect to PET/CT in this setting.
Of note, PET/CT diagnosed alternative conditions, including cancer and infections, that can mimic GCA in 13 study participants. At least one of those patients “may well have come to serious harm” on immunosuppressive therapy had his cervical spine infection gone undiagnosed, he said.
This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
SOURCE: Sammel AM et al. ACR Annual Meeting, Abstract L15.
CHICAGO – Combined PET/CT has good diagnostic accuracy, including a 98% negative predictive value, when compared with temporal artery biopsy for suspected giant cell arteritis, according to findings from a study of 64 patients.
Study participants included patients with newly suspected giant cell arteritis (GCA) and all underwent PET/CT from the vertex to the diaphragm within 72 hours of starting corticosteroid therapy and prior to undergoing temporal artery biopsy (TAB). Two nuclear medicine physicians blinded to clinical and biopsy data identified GCA in the scans of 12 of 58 patients (21%) who ultimately underwent both PET/CT and TAB, Anthony M. Sammel, MBBS, reported at the annual meeting of the American College of Rheumatology.
Compared with TAB, which is the standard of care for diagnosing GCA in most centers, global GCA assessment by PET/CT had a sensitivity of 92%, specificity of 85%, and positive predictive value of 61%, said Dr. Sammel, a rheumatologist at Royal North Shore Hospital in Sydney.
The findings, and particularly the 98% negative predictive value, suggest that PET/CT could be used first line to rule out suspected GCA, although the sample size in the study was modest, he noted.
“I believe [the findings] would support PET/CT, when we include the head, neck, and chest, as a first-line test for patients newly suspected of having giant cell arteritis. I think we do need to be mindful that it’s not perfect,” he said, explaining that a TAB is warranted in a patient with a negative scan despite a clinician’s sense that there is a high likelihood of GCA.
However, the findings suggest that a negative study in a low to moderate risk patient would be “very, very reassuring,” and as such patients probably do not need a biopsy, he said in a video interview in which he also discussed cost-benefit issues with respect to PET/CT in this setting.
Of note, PET/CT diagnosed alternative conditions, including cancer and infections, that can mimic GCA in 13 study participants. At least one of those patients “may well have come to serious harm” on immunosuppressive therapy had his cervical spine infection gone undiagnosed, he said.
This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
SOURCE: Sammel AM et al. ACR Annual Meeting, Abstract L15.
CHICAGO – Combined PET/CT has good diagnostic accuracy, including a 98% negative predictive value, when compared with temporal artery biopsy for suspected giant cell arteritis, according to findings from a study of 64 patients.
Study participants included patients with newly suspected giant cell arteritis (GCA) and all underwent PET/CT from the vertex to the diaphragm within 72 hours of starting corticosteroid therapy and prior to undergoing temporal artery biopsy (TAB). Two nuclear medicine physicians blinded to clinical and biopsy data identified GCA in the scans of 12 of 58 patients (21%) who ultimately underwent both PET/CT and TAB, Anthony M. Sammel, MBBS, reported at the annual meeting of the American College of Rheumatology.
Compared with TAB, which is the standard of care for diagnosing GCA in most centers, global GCA assessment by PET/CT had a sensitivity of 92%, specificity of 85%, and positive predictive value of 61%, said Dr. Sammel, a rheumatologist at Royal North Shore Hospital in Sydney.
The findings, and particularly the 98% negative predictive value, suggest that PET/CT could be used first line to rule out suspected GCA, although the sample size in the study was modest, he noted.
“I believe [the findings] would support PET/CT, when we include the head, neck, and chest, as a first-line test for patients newly suspected of having giant cell arteritis. I think we do need to be mindful that it’s not perfect,” he said, explaining that a TAB is warranted in a patient with a negative scan despite a clinician’s sense that there is a high likelihood of GCA.
However, the findings suggest that a negative study in a low to moderate risk patient would be “very, very reassuring,” and as such patients probably do not need a biopsy, he said in a video interview in which he also discussed cost-benefit issues with respect to PET/CT in this setting.
Of note, PET/CT diagnosed alternative conditions, including cancer and infections, that can mimic GCA in 13 study participants. At least one of those patients “may well have come to serious harm” on immunosuppressive therapy had his cervical spine infection gone undiagnosed, he said.
This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
SOURCE: Sammel AM et al. ACR Annual Meeting, Abstract L15.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: PET/CT had 92% sensitivity, 85% specificity, 61% positive predictive value, and 98% negative predictive value.
Study details: A study of diagnostic accuracy of PET/CT for giant cell arteritis in 64 patients.
Disclosures: This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
Source: Sammel AM et al. ACR Annual Meeting, Abstract L15.
Researchers consider R/R ALL drugs in the first-line setting
CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.
“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.
At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
Blinatumomab
“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.
“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”
The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).
Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.
“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.
The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.
Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.
Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).
“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”
One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.
“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.
Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.
“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.
Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.
“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
Inotuzumab
Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.
Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.
“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.
The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).
The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.
Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.
“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.
The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.
It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
CAR T-cell therapy
As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.
Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.
“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
Overall outcomes
“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”
Two trials seek to address this, she said.
The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.
The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.
The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.
“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.
“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.
At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
Blinatumomab
“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.
“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”
The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).
Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.
“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.
The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.
Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.
Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).
“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”
One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.
“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.
Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.
“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.
Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.
“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
Inotuzumab
Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.
Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.
“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.
The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).
The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.
Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.
“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.
The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.
It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
CAR T-cell therapy
As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.
Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.
“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
Overall outcomes
“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”
Two trials seek to address this, she said.
The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.
The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.
The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.
“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.
“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.
At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
Blinatumomab
“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.
“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”
The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).
Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.
“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.
The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.
Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.
Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).
“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”
One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.
“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.
Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.
“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.
Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.
“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
Inotuzumab
Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.
Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.
“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.
The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).
The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.
Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.
“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.
The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.
It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
CAR T-cell therapy
As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.
Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.
“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
Overall outcomes
“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”
Two trials seek to address this, she said.
The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.
The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.
The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.
“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
EXPERT ANALYSIS FROM MHM 2018
DETERRED trial: Concurrent atezolizumab, CRT shows promise in LA-NSCLC
TORONTO – (LA-NSCLC) in the phase 2 DETERRED trial.
In part 1 of the single-institution study, 10 patients underwent chemoradiation therapy (CRT) with low-dose carboplatin/paclitaxel followed by high-dose consolidation chemotherapy plus atezolizumab and atezolizumab maintenance for 1 year. Six patients in this group (60%) experienced grade 3 or higher adverse events (AEs). In part 2 of the study, 30 patients received concurrent atezolizumab and CRT followed by the same consolidation and maintenance used in part 1, and 17 (57%) experienced grade 3 or higher AEs, Steven H. Lin, MD, reported at the World Conference on Lung Cancer.
Grade 3 or higher AEs were associated with atezolizumab in 30% and 23% of patients in part 1 and part 2, respectively. In part 1 these included dyspnea, arthralgia, and a grade 5 tracheoesophageal fistula, and in part 2 included diarrhea, pneumonitis, nephritis, fatigue, respiratory failure, and heart failure in one patient each, and fatigue in three patients.
Grade 2 radiation pneumonitis was seen in two patients in each group, Dr. Lin of the University of Texas MD Anderson Cancer Center, Houston, said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
Withdrawals caused by toxicity occurred in three and four patients in part 1 and 2, respectively.
Four patients in part 1 progressed with disease during atezolizumab maintenance and five have died from either tracheoesophageal fistula or grade 5 toxicity. In part 2, six have progressed and five have died, most caused by cancer progression, he said.
Preliminary survival data show a median progression-free survival of 20.1 months in part 1, whereas progression-free survival was not reached in part 2. Median overall survival at 1 year was 60% versus 77% in parts 1 and 2, respectively.
Consolidation immunotherapy with durvalumab after CRT has been the standard of care for LA-NSCLC as established by the phase 3 PACIFIC trial, but evidence from that trial also suggested timing of the start of immunotherapy may be important.
“If patients were randomized less than 14 days after starting durvalumab there was a trend, or suggestion, that there was potentially an improvement in progression-free survival, compared with patients who started durvalumab outside of this window,” Dr. Lin said, noting that this is also supported by some preclinical evidence showing that the effectiveness of immunotherapies may be enhanced when combined with concurrent CRT.
The DETERRED trial evaluated the safety and preliminary efficacy of this approach followed by consolidation full-dose carboplatin/paclitaxel with atezolizumab and maintenance atezolizumab for up to 1 year for LA-NSCLC.
Patients, who had a median age of 66.5 years, were enrolled between February 2016 and April 2018; 15% had stage II disease, 50% had stage IIIA, and 35% had stage IIIB. Most (58%) had adenocarcinoma.
In part 1, standard chemoradiation including low-dose carboplatin/paclitaxel was given for 6 weeks. After CRT completion, patients were given consolidated high-dose chemotherapy with carboplatin/paclitaxel and intravenous atezolizumab was started at that point at a dose of 1,200 mg every 3 weeks for up to 1 year from the first dose. Part 2 was initiated based on the safety data in part 1 showing no concerning toxicities. In part 2, atezolizumab was given concurrently with CRT followed by the same consolidated regimen and maintenance.
“So the take-home message from this study is that the concurrent immunotherapy with atezolizumab and chemoradiation therapy can be administered safely,” Dr. Lin said, adding that grade 3+ pneumonitis is low and not significantly increased with the addition of concurrent atezolizumab with CRT.
Early efficacy analyses also show promising results, but further follow-up is needed, he said.
Trials now being planned include a phase 3 trial comparing the DETERRED and PACIFIC regimens, a phase 1 study comparing durvalumab with radiation to replace chemotherapy in programmed death–ligand 1–high locoregionally advanced NSCLC, and a phase 1 study of nivolumab with radiation to replace chemotherapy in locoregionally advanced NSCLC, he noted.
The DETERRED trial was supported by Genentech. Dr. Lin has received research grants from STCube Pharmaceuticals, Hitachi Chemical Diagnostics, Genentech, New River Labs, and BeyondSpring Pharmaceuticals, and is an advisory board member for AstraZeneca and New River Labs.
SOURCE: Lin SH et al. WCLC 2018, Abstract OA01.06.
TORONTO – (LA-NSCLC) in the phase 2 DETERRED trial.
In part 1 of the single-institution study, 10 patients underwent chemoradiation therapy (CRT) with low-dose carboplatin/paclitaxel followed by high-dose consolidation chemotherapy plus atezolizumab and atezolizumab maintenance for 1 year. Six patients in this group (60%) experienced grade 3 or higher adverse events (AEs). In part 2 of the study, 30 patients received concurrent atezolizumab and CRT followed by the same consolidation and maintenance used in part 1, and 17 (57%) experienced grade 3 or higher AEs, Steven H. Lin, MD, reported at the World Conference on Lung Cancer.
Grade 3 or higher AEs were associated with atezolizumab in 30% and 23% of patients in part 1 and part 2, respectively. In part 1 these included dyspnea, arthralgia, and a grade 5 tracheoesophageal fistula, and in part 2 included diarrhea, pneumonitis, nephritis, fatigue, respiratory failure, and heart failure in one patient each, and fatigue in three patients.
Grade 2 radiation pneumonitis was seen in two patients in each group, Dr. Lin of the University of Texas MD Anderson Cancer Center, Houston, said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
Withdrawals caused by toxicity occurred in three and four patients in part 1 and 2, respectively.
Four patients in part 1 progressed with disease during atezolizumab maintenance and five have died from either tracheoesophageal fistula or grade 5 toxicity. In part 2, six have progressed and five have died, most caused by cancer progression, he said.
Preliminary survival data show a median progression-free survival of 20.1 months in part 1, whereas progression-free survival was not reached in part 2. Median overall survival at 1 year was 60% versus 77% in parts 1 and 2, respectively.
Consolidation immunotherapy with durvalumab after CRT has been the standard of care for LA-NSCLC as established by the phase 3 PACIFIC trial, but evidence from that trial also suggested timing of the start of immunotherapy may be important.
“If patients were randomized less than 14 days after starting durvalumab there was a trend, or suggestion, that there was potentially an improvement in progression-free survival, compared with patients who started durvalumab outside of this window,” Dr. Lin said, noting that this is also supported by some preclinical evidence showing that the effectiveness of immunotherapies may be enhanced when combined with concurrent CRT.
The DETERRED trial evaluated the safety and preliminary efficacy of this approach followed by consolidation full-dose carboplatin/paclitaxel with atezolizumab and maintenance atezolizumab for up to 1 year for LA-NSCLC.
Patients, who had a median age of 66.5 years, were enrolled between February 2016 and April 2018; 15% had stage II disease, 50% had stage IIIA, and 35% had stage IIIB. Most (58%) had adenocarcinoma.
In part 1, standard chemoradiation including low-dose carboplatin/paclitaxel was given for 6 weeks. After CRT completion, patients were given consolidated high-dose chemotherapy with carboplatin/paclitaxel and intravenous atezolizumab was started at that point at a dose of 1,200 mg every 3 weeks for up to 1 year from the first dose. Part 2 was initiated based on the safety data in part 1 showing no concerning toxicities. In part 2, atezolizumab was given concurrently with CRT followed by the same consolidated regimen and maintenance.
“So the take-home message from this study is that the concurrent immunotherapy with atezolizumab and chemoradiation therapy can be administered safely,” Dr. Lin said, adding that grade 3+ pneumonitis is low and not significantly increased with the addition of concurrent atezolizumab with CRT.
Early efficacy analyses also show promising results, but further follow-up is needed, he said.
Trials now being planned include a phase 3 trial comparing the DETERRED and PACIFIC regimens, a phase 1 study comparing durvalumab with radiation to replace chemotherapy in programmed death–ligand 1–high locoregionally advanced NSCLC, and a phase 1 study of nivolumab with radiation to replace chemotherapy in locoregionally advanced NSCLC, he noted.
The DETERRED trial was supported by Genentech. Dr. Lin has received research grants from STCube Pharmaceuticals, Hitachi Chemical Diagnostics, Genentech, New River Labs, and BeyondSpring Pharmaceuticals, and is an advisory board member for AstraZeneca and New River Labs.
SOURCE: Lin SH et al. WCLC 2018, Abstract OA01.06.
TORONTO – (LA-NSCLC) in the phase 2 DETERRED trial.
In part 1 of the single-institution study, 10 patients underwent chemoradiation therapy (CRT) with low-dose carboplatin/paclitaxel followed by high-dose consolidation chemotherapy plus atezolizumab and atezolizumab maintenance for 1 year. Six patients in this group (60%) experienced grade 3 or higher adverse events (AEs). In part 2 of the study, 30 patients received concurrent atezolizumab and CRT followed by the same consolidation and maintenance used in part 1, and 17 (57%) experienced grade 3 or higher AEs, Steven H. Lin, MD, reported at the World Conference on Lung Cancer.
Grade 3 or higher AEs were associated with atezolizumab in 30% and 23% of patients in part 1 and part 2, respectively. In part 1 these included dyspnea, arthralgia, and a grade 5 tracheoesophageal fistula, and in part 2 included diarrhea, pneumonitis, nephritis, fatigue, respiratory failure, and heart failure in one patient each, and fatigue in three patients.
Grade 2 radiation pneumonitis was seen in two patients in each group, Dr. Lin of the University of Texas MD Anderson Cancer Center, Houston, said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
Withdrawals caused by toxicity occurred in three and four patients in part 1 and 2, respectively.
Four patients in part 1 progressed with disease during atezolizumab maintenance and five have died from either tracheoesophageal fistula or grade 5 toxicity. In part 2, six have progressed and five have died, most caused by cancer progression, he said.
Preliminary survival data show a median progression-free survival of 20.1 months in part 1, whereas progression-free survival was not reached in part 2. Median overall survival at 1 year was 60% versus 77% in parts 1 and 2, respectively.
Consolidation immunotherapy with durvalumab after CRT has been the standard of care for LA-NSCLC as established by the phase 3 PACIFIC trial, but evidence from that trial also suggested timing of the start of immunotherapy may be important.
“If patients were randomized less than 14 days after starting durvalumab there was a trend, or suggestion, that there was potentially an improvement in progression-free survival, compared with patients who started durvalumab outside of this window,” Dr. Lin said, noting that this is also supported by some preclinical evidence showing that the effectiveness of immunotherapies may be enhanced when combined with concurrent CRT.
The DETERRED trial evaluated the safety and preliminary efficacy of this approach followed by consolidation full-dose carboplatin/paclitaxel with atezolizumab and maintenance atezolizumab for up to 1 year for LA-NSCLC.
Patients, who had a median age of 66.5 years, were enrolled between February 2016 and April 2018; 15% had stage II disease, 50% had stage IIIA, and 35% had stage IIIB. Most (58%) had adenocarcinoma.
In part 1, standard chemoradiation including low-dose carboplatin/paclitaxel was given for 6 weeks. After CRT completion, patients were given consolidated high-dose chemotherapy with carboplatin/paclitaxel and intravenous atezolizumab was started at that point at a dose of 1,200 mg every 3 weeks for up to 1 year from the first dose. Part 2 was initiated based on the safety data in part 1 showing no concerning toxicities. In part 2, atezolizumab was given concurrently with CRT followed by the same consolidated regimen and maintenance.
“So the take-home message from this study is that the concurrent immunotherapy with atezolizumab and chemoradiation therapy can be administered safely,” Dr. Lin said, adding that grade 3+ pneumonitis is low and not significantly increased with the addition of concurrent atezolizumab with CRT.
Early efficacy analyses also show promising results, but further follow-up is needed, he said.
Trials now being planned include a phase 3 trial comparing the DETERRED and PACIFIC regimens, a phase 1 study comparing durvalumab with radiation to replace chemotherapy in programmed death–ligand 1–high locoregionally advanced NSCLC, and a phase 1 study of nivolumab with radiation to replace chemotherapy in locoregionally advanced NSCLC, he noted.
The DETERRED trial was supported by Genentech. Dr. Lin has received research grants from STCube Pharmaceuticals, Hitachi Chemical Diagnostics, Genentech, New River Labs, and BeyondSpring Pharmaceuticals, and is an advisory board member for AstraZeneca and New River Labs.
SOURCE: Lin SH et al. WCLC 2018, Abstract OA01.06.
REPORTING FROM WCLC 2018
Key clinical point: Concurrent atezolizumab and chemoradiation therapy is safe and shows promising efficacy in locally advanced non–small cell lung cancer.
Major finding: A total of 60% and 57% of part 1 and 2 patients, respectively, experienced grade 3 or higher adverse events.
Study details: The phase 2 DETERRED trial of 40 patients.
Disclosures: The DETERRED trial was supported by Genentech. Dr. Lin has received research grants from STCube Pharmaceuticals, Hitachi Chemical Diagnostics, Genentech, New River Labs, and BeyondSpring Pharmaceuticals, and is an advisory board member for AstraZeneca and New River Labs.
Source: Lin SH et al. WCLC 2018, Abstract OA01.06.
MCL treatment choices depend partly on age
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
EXPERT ANALYSIS FROM MHM 2018
ALTA-1L: Brigatinib beats crizotinib for PFS in ALK-positive NSCLC
TORONTO – in the first interim results from the multicenter, open-label, phase 3 ALTA-1L trial.
In fact, the primary endpoint of the study – blinded independent review committee–assessed progression-free survival (PFS) – was met at this first analysis. The next-generation ALK inhibitor brigatinib reduced the chance of progression or death by 51% as compared with crizotinib – the current first-line standard of care in this population, D. Ross Camidge, MD, reported at the World Conference on Lung Cancer.
“At a median follow-up of 9-11 months, 26% [of 137 patients] on the brigatinib arm and 46% [of 138 patients] on the crizotinib arm had experienced a PFS event. Median PFS was not reached for the brigatinib arm and was 9.8 months for the crizotinib arm; the hazard ratio for progression or death was 0.49 and highly statistically significant,” said Dr. Camidge, director of thoracic oncology and the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, Aurora, at the meeting sponsored by the International Association for the Study of Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The 12-month PFS rate estimate was 67% for brigatinib and 43% for crizotinib, and the investigator-assessed hazard ratio for PFS was 0.45. Overall survival data are immature, Dr. Camidge added, noting that the PFS hazard ratios for those with versus those without prior chemotherapy were 0.35 and 0.55, respectively.
“PFS consistently favored brigatinib across all other subgroups,” he said. “Although the confidence intervals overlap, the effect size appears greater among those with baseline [CNS] disease than among those without [HR, 0.2 vs. 0.72].”
Data suggest that CNS progression among those with CNS disease at baseline tends to be an earlier event than either extra-CNS progression in general or CNS progression in those without baseline CNS disease. “Consequently, this first interim analysis may be preferentially emphasizing drug efficacy differences within the subgroup in whom the earlier progression events are occurring,” Dr. Camidge said.
As for overall objective responses, the rates were numerically higher with brigatinib versus crizotinib (70% vs. 60%), but were not statistically different in the two groups. “However, the median duration of confirmed responses was not reached for brigatinib and [was] 11.1 months with crizotinib, with the 12-month [probability] of sustained response being 75% for brigatinib and 41% for crizotinib,” he added.
Further, among those with measurable CNS lesions, brigatinib demonstrated a significantly higher intracranial response rate of 78% versus 29% (odds ratio, 10.42), and when those with nonmeasurable CNS disease were included in the intracranial response assessment, the odds ratio was 13.
Median intracranial PFS among those with CNS involvement at baseline was not reached in the brigatinib arm versus 5.6 months with crizotinib, for a highly statistically significant hazard ratio of 0.27. “Which, given that the median PFS for crizotinib in the overall population ... was 9.8 months, again emphasizes how CNS events in this subgroup tend to occur early,” he noted.
Study subjects had stage IIIB/IV ALK-positive non–small cell lung cancer (NSCLC) based on local ALK testing, Eastern Cooperative Oncology Group performance status of 0-2, no more than one prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor therapy, Dr. Camidge said, noting that asymptomatic, untreated brain metastases were allowed and crossover to the brigatinib arm was permitted for those with blinded independent review committee–assessed progression on crizotinib.
Those randomized to the brigatinib arm had a median age of 58 years and received 180 mg daily with a 7-day lead-in at 90 mg. Those randomized to the crizotinib group had a median age of 60 years and received 250 mg twice daily. Prior chemotherapy for advanced disease was received by 26% and 27% and brain metastasis was present in 29% and 30% of patients in the arms, respectively.
The most common treatment-emergent adverse events of grade 3 or higher in the brigatinib patients were laboratory abnormalities such as creatinine phosphokinase, lipase, and amylase increases, and the most common in the crizotinib group were gastrointestinal effects, transaminitis, bradycardia, peripheral edema, and vision disturbances.
Discontinuations caused by adverse events occurred in 12% and 9% of the brigatinib and crizotinib patients, respectively, he said. No clinical cases of pancreatitis occurred in either arm, there was no difference in the incidence of any grade myalgia or musculoskeletal pain between arms, and there was no grade 3 or greater myalgia or musculoskeletal pain reported.
Early-onset interstitial lung disease, however, “appears to be a unique side effect of brigatinib,” Dr. Camidge noted.
Although interstitial lung disease/pneumonitis occurred in both groups, onset at days 3-8 after treatment initiation occurred only with brigatinib, he said, adding that “it only occurred in 3% of cases – half the rate seen in the postcrizotinib setting.”
The PROFILE 1014 study established crizotinib as the standard first-line therapy for advanced ALK-rearranged NSCLC, showing superior PFS versus pemetrexed doublet chemotherapy (HR, 0.45), but median PFS with crizotinib in that trial was only 10.9 months, Dr. Camidge said.
The next-generation ALK inhibitor brigatinib, however, has demonstrated broad preclinical activity against ALK resistance mutations, has excellent CNS penetration, and is the only ALK inhibitor with marked activity against multiple epidermal growth factor receptor–mutant cell lines, he said. “It has already shown significant activity both within the CNS and extracranially in the postcrizotinib setting, where it has consistently demonstrated the longest reported median PFS [up to 16.7 months] of any licensed or experimental ALK inhibitor.”
The ALTA-1L study provides a head-to-head comparison of brigatinib and crizotinib in a real-world setting, and the findings demonstrate that “brigatinib represents a promising new treatment for inhibitor-naive, ALK-rearranged NSCLC,” he said.
In a press statement, Dr. Camidge further stated that, based on these findings, brigatinib is set to become a first-line treatment option for ALK-positive lung cancer, adding that, “even with only 9-11 months of follow-up, the efficacy of brigatinib is clearly superior to crizotinib. A lot of the initial difference is driven by an effect on brain metastases, which tend to be an earlier progression event. However, once differences in control of disease outside the brain have time to manifest, it is possible the PFS improvement may increase.”
Both Dr. Camidge and invited discussant Fiona Blackhall, PhD, noted that the tolerability of brigatinib may be “even better in the real world,” as most of the 29% of patients on the brigatinib arm with adverse event–related dose reductions had “paper toxicities” for which the clinical impact is not well understood.
The rate of dose reductions for adverse events with brigatinib was higher in ALTA-1L than that seen in earlier studies of the second-generation ALK inhibitor alectinib, said Dr. Blackhall, professor and chair in thoracic oncology at the University of Manchester (England).
“We need to be sure that these dose reductions are appropriate and not potentially compromising efficacy,” she added.
Dr. Blackhall also suggested that sequential use of crizotinib and other ALK inhibitors like brigatinib should be evaluated and that the potential impact of ALK inhibitor selection “on the spectrum and type of resistance mutations and mechanisms” should be considered.
“Brigatinib is a new first-line treatment option for patients with ALK-positive non–small cell lung cancer. ... But in the absence of direct comparison of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed – if there ever will be – a ‘best’ ALK inhibitor for our patients,” she said.
Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIADTakeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
SOURCE: Camidge DR et al. WCLC 2018, Abstract PL02.03.
TORONTO – in the first interim results from the multicenter, open-label, phase 3 ALTA-1L trial.
In fact, the primary endpoint of the study – blinded independent review committee–assessed progression-free survival (PFS) – was met at this first analysis. The next-generation ALK inhibitor brigatinib reduced the chance of progression or death by 51% as compared with crizotinib – the current first-line standard of care in this population, D. Ross Camidge, MD, reported at the World Conference on Lung Cancer.
“At a median follow-up of 9-11 months, 26% [of 137 patients] on the brigatinib arm and 46% [of 138 patients] on the crizotinib arm had experienced a PFS event. Median PFS was not reached for the brigatinib arm and was 9.8 months for the crizotinib arm; the hazard ratio for progression or death was 0.49 and highly statistically significant,” said Dr. Camidge, director of thoracic oncology and the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, Aurora, at the meeting sponsored by the International Association for the Study of Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The 12-month PFS rate estimate was 67% for brigatinib and 43% for crizotinib, and the investigator-assessed hazard ratio for PFS was 0.45. Overall survival data are immature, Dr. Camidge added, noting that the PFS hazard ratios for those with versus those without prior chemotherapy were 0.35 and 0.55, respectively.
“PFS consistently favored brigatinib across all other subgroups,” he said. “Although the confidence intervals overlap, the effect size appears greater among those with baseline [CNS] disease than among those without [HR, 0.2 vs. 0.72].”
Data suggest that CNS progression among those with CNS disease at baseline tends to be an earlier event than either extra-CNS progression in general or CNS progression in those without baseline CNS disease. “Consequently, this first interim analysis may be preferentially emphasizing drug efficacy differences within the subgroup in whom the earlier progression events are occurring,” Dr. Camidge said.
As for overall objective responses, the rates were numerically higher with brigatinib versus crizotinib (70% vs. 60%), but were not statistically different in the two groups. “However, the median duration of confirmed responses was not reached for brigatinib and [was] 11.1 months with crizotinib, with the 12-month [probability] of sustained response being 75% for brigatinib and 41% for crizotinib,” he added.
Further, among those with measurable CNS lesions, brigatinib demonstrated a significantly higher intracranial response rate of 78% versus 29% (odds ratio, 10.42), and when those with nonmeasurable CNS disease were included in the intracranial response assessment, the odds ratio was 13.
Median intracranial PFS among those with CNS involvement at baseline was not reached in the brigatinib arm versus 5.6 months with crizotinib, for a highly statistically significant hazard ratio of 0.27. “Which, given that the median PFS for crizotinib in the overall population ... was 9.8 months, again emphasizes how CNS events in this subgroup tend to occur early,” he noted.
Study subjects had stage IIIB/IV ALK-positive non–small cell lung cancer (NSCLC) based on local ALK testing, Eastern Cooperative Oncology Group performance status of 0-2, no more than one prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor therapy, Dr. Camidge said, noting that asymptomatic, untreated brain metastases were allowed and crossover to the brigatinib arm was permitted for those with blinded independent review committee–assessed progression on crizotinib.
Those randomized to the brigatinib arm had a median age of 58 years and received 180 mg daily with a 7-day lead-in at 90 mg. Those randomized to the crizotinib group had a median age of 60 years and received 250 mg twice daily. Prior chemotherapy for advanced disease was received by 26% and 27% and brain metastasis was present in 29% and 30% of patients in the arms, respectively.
The most common treatment-emergent adverse events of grade 3 or higher in the brigatinib patients were laboratory abnormalities such as creatinine phosphokinase, lipase, and amylase increases, and the most common in the crizotinib group were gastrointestinal effects, transaminitis, bradycardia, peripheral edema, and vision disturbances.
Discontinuations caused by adverse events occurred in 12% and 9% of the brigatinib and crizotinib patients, respectively, he said. No clinical cases of pancreatitis occurred in either arm, there was no difference in the incidence of any grade myalgia or musculoskeletal pain between arms, and there was no grade 3 or greater myalgia or musculoskeletal pain reported.
Early-onset interstitial lung disease, however, “appears to be a unique side effect of brigatinib,” Dr. Camidge noted.
Although interstitial lung disease/pneumonitis occurred in both groups, onset at days 3-8 after treatment initiation occurred only with brigatinib, he said, adding that “it only occurred in 3% of cases – half the rate seen in the postcrizotinib setting.”
The PROFILE 1014 study established crizotinib as the standard first-line therapy for advanced ALK-rearranged NSCLC, showing superior PFS versus pemetrexed doublet chemotherapy (HR, 0.45), but median PFS with crizotinib in that trial was only 10.9 months, Dr. Camidge said.
The next-generation ALK inhibitor brigatinib, however, has demonstrated broad preclinical activity against ALK resistance mutations, has excellent CNS penetration, and is the only ALK inhibitor with marked activity against multiple epidermal growth factor receptor–mutant cell lines, he said. “It has already shown significant activity both within the CNS and extracranially in the postcrizotinib setting, where it has consistently demonstrated the longest reported median PFS [up to 16.7 months] of any licensed or experimental ALK inhibitor.”
The ALTA-1L study provides a head-to-head comparison of brigatinib and crizotinib in a real-world setting, and the findings demonstrate that “brigatinib represents a promising new treatment for inhibitor-naive, ALK-rearranged NSCLC,” he said.
In a press statement, Dr. Camidge further stated that, based on these findings, brigatinib is set to become a first-line treatment option for ALK-positive lung cancer, adding that, “even with only 9-11 months of follow-up, the efficacy of brigatinib is clearly superior to crizotinib. A lot of the initial difference is driven by an effect on brain metastases, which tend to be an earlier progression event. However, once differences in control of disease outside the brain have time to manifest, it is possible the PFS improvement may increase.”
Both Dr. Camidge and invited discussant Fiona Blackhall, PhD, noted that the tolerability of brigatinib may be “even better in the real world,” as most of the 29% of patients on the brigatinib arm with adverse event–related dose reductions had “paper toxicities” for which the clinical impact is not well understood.
The rate of dose reductions for adverse events with brigatinib was higher in ALTA-1L than that seen in earlier studies of the second-generation ALK inhibitor alectinib, said Dr. Blackhall, professor and chair in thoracic oncology at the University of Manchester (England).
“We need to be sure that these dose reductions are appropriate and not potentially compromising efficacy,” she added.
Dr. Blackhall also suggested that sequential use of crizotinib and other ALK inhibitors like brigatinib should be evaluated and that the potential impact of ALK inhibitor selection “on the spectrum and type of resistance mutations and mechanisms” should be considered.
“Brigatinib is a new first-line treatment option for patients with ALK-positive non–small cell lung cancer. ... But in the absence of direct comparison of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed – if there ever will be – a ‘best’ ALK inhibitor for our patients,” she said.
Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIADTakeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
SOURCE: Camidge DR et al. WCLC 2018, Abstract PL02.03.
TORONTO – in the first interim results from the multicenter, open-label, phase 3 ALTA-1L trial.
In fact, the primary endpoint of the study – blinded independent review committee–assessed progression-free survival (PFS) – was met at this first analysis. The next-generation ALK inhibitor brigatinib reduced the chance of progression or death by 51% as compared with crizotinib – the current first-line standard of care in this population, D. Ross Camidge, MD, reported at the World Conference on Lung Cancer.
“At a median follow-up of 9-11 months, 26% [of 137 patients] on the brigatinib arm and 46% [of 138 patients] on the crizotinib arm had experienced a PFS event. Median PFS was not reached for the brigatinib arm and was 9.8 months for the crizotinib arm; the hazard ratio for progression or death was 0.49 and highly statistically significant,” said Dr. Camidge, director of thoracic oncology and the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, Aurora, at the meeting sponsored by the International Association for the Study of Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The 12-month PFS rate estimate was 67% for brigatinib and 43% for crizotinib, and the investigator-assessed hazard ratio for PFS was 0.45. Overall survival data are immature, Dr. Camidge added, noting that the PFS hazard ratios for those with versus those without prior chemotherapy were 0.35 and 0.55, respectively.
“PFS consistently favored brigatinib across all other subgroups,” he said. “Although the confidence intervals overlap, the effect size appears greater among those with baseline [CNS] disease than among those without [HR, 0.2 vs. 0.72].”
Data suggest that CNS progression among those with CNS disease at baseline tends to be an earlier event than either extra-CNS progression in general or CNS progression in those without baseline CNS disease. “Consequently, this first interim analysis may be preferentially emphasizing drug efficacy differences within the subgroup in whom the earlier progression events are occurring,” Dr. Camidge said.
As for overall objective responses, the rates were numerically higher with brigatinib versus crizotinib (70% vs. 60%), but were not statistically different in the two groups. “However, the median duration of confirmed responses was not reached for brigatinib and [was] 11.1 months with crizotinib, with the 12-month [probability] of sustained response being 75% for brigatinib and 41% for crizotinib,” he added.
Further, among those with measurable CNS lesions, brigatinib demonstrated a significantly higher intracranial response rate of 78% versus 29% (odds ratio, 10.42), and when those with nonmeasurable CNS disease were included in the intracranial response assessment, the odds ratio was 13.
Median intracranial PFS among those with CNS involvement at baseline was not reached in the brigatinib arm versus 5.6 months with crizotinib, for a highly statistically significant hazard ratio of 0.27. “Which, given that the median PFS for crizotinib in the overall population ... was 9.8 months, again emphasizes how CNS events in this subgroup tend to occur early,” he noted.
Study subjects had stage IIIB/IV ALK-positive non–small cell lung cancer (NSCLC) based on local ALK testing, Eastern Cooperative Oncology Group performance status of 0-2, no more than one prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor therapy, Dr. Camidge said, noting that asymptomatic, untreated brain metastases were allowed and crossover to the brigatinib arm was permitted for those with blinded independent review committee–assessed progression on crizotinib.
Those randomized to the brigatinib arm had a median age of 58 years and received 180 mg daily with a 7-day lead-in at 90 mg. Those randomized to the crizotinib group had a median age of 60 years and received 250 mg twice daily. Prior chemotherapy for advanced disease was received by 26% and 27% and brain metastasis was present in 29% and 30% of patients in the arms, respectively.
The most common treatment-emergent adverse events of grade 3 or higher in the brigatinib patients were laboratory abnormalities such as creatinine phosphokinase, lipase, and amylase increases, and the most common in the crizotinib group were gastrointestinal effects, transaminitis, bradycardia, peripheral edema, and vision disturbances.
Discontinuations caused by adverse events occurred in 12% and 9% of the brigatinib and crizotinib patients, respectively, he said. No clinical cases of pancreatitis occurred in either arm, there was no difference in the incidence of any grade myalgia or musculoskeletal pain between arms, and there was no grade 3 or greater myalgia or musculoskeletal pain reported.
Early-onset interstitial lung disease, however, “appears to be a unique side effect of brigatinib,” Dr. Camidge noted.
Although interstitial lung disease/pneumonitis occurred in both groups, onset at days 3-8 after treatment initiation occurred only with brigatinib, he said, adding that “it only occurred in 3% of cases – half the rate seen in the postcrizotinib setting.”
The PROFILE 1014 study established crizotinib as the standard first-line therapy for advanced ALK-rearranged NSCLC, showing superior PFS versus pemetrexed doublet chemotherapy (HR, 0.45), but median PFS with crizotinib in that trial was only 10.9 months, Dr. Camidge said.
The next-generation ALK inhibitor brigatinib, however, has demonstrated broad preclinical activity against ALK resistance mutations, has excellent CNS penetration, and is the only ALK inhibitor with marked activity against multiple epidermal growth factor receptor–mutant cell lines, he said. “It has already shown significant activity both within the CNS and extracranially in the postcrizotinib setting, where it has consistently demonstrated the longest reported median PFS [up to 16.7 months] of any licensed or experimental ALK inhibitor.”
The ALTA-1L study provides a head-to-head comparison of brigatinib and crizotinib in a real-world setting, and the findings demonstrate that “brigatinib represents a promising new treatment for inhibitor-naive, ALK-rearranged NSCLC,” he said.
In a press statement, Dr. Camidge further stated that, based on these findings, brigatinib is set to become a first-line treatment option for ALK-positive lung cancer, adding that, “even with only 9-11 months of follow-up, the efficacy of brigatinib is clearly superior to crizotinib. A lot of the initial difference is driven by an effect on brain metastases, which tend to be an earlier progression event. However, once differences in control of disease outside the brain have time to manifest, it is possible the PFS improvement may increase.”
Both Dr. Camidge and invited discussant Fiona Blackhall, PhD, noted that the tolerability of brigatinib may be “even better in the real world,” as most of the 29% of patients on the brigatinib arm with adverse event–related dose reductions had “paper toxicities” for which the clinical impact is not well understood.
The rate of dose reductions for adverse events with brigatinib was higher in ALTA-1L than that seen in earlier studies of the second-generation ALK inhibitor alectinib, said Dr. Blackhall, professor and chair in thoracic oncology at the University of Manchester (England).
“We need to be sure that these dose reductions are appropriate and not potentially compromising efficacy,” she added.
Dr. Blackhall also suggested that sequential use of crizotinib and other ALK inhibitors like brigatinib should be evaluated and that the potential impact of ALK inhibitor selection “on the spectrum and type of resistance mutations and mechanisms” should be considered.
“Brigatinib is a new first-line treatment option for patients with ALK-positive non–small cell lung cancer. ... But in the absence of direct comparison of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed – if there ever will be – a ‘best’ ALK inhibitor for our patients,” she said.
Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIADTakeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
SOURCE: Camidge DR et al. WCLC 2018, Abstract PL02.03.
REPORTING FROM WCLC 2018
Key clinical point: Brigatinib improves progression-free survival versus crizotinib in anaplastic lymphoma kinase–positive non–small cell lung cancer.
Major finding: Brigatinib reduced the chance of progression or death by 51% versus crizotinib.
Study details: The multicenter, open-label, phase 3 ALTA-1L trial of 275 patients.
Disclosures: Dr. Camidge has received honoraria from Arrys/Kyn, AstraZeneca, Biothera, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, Genoptix, Hansoh, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Revolution Medicines, Roche/Genentech, and Takeda, and has received research funding from ARIAD/Takeda. Dr. Blackhall reported research funding from Amgen, AstraZeneca, Novartis, and Pfizer, and has served has an advisory board member, consultant, or speaker for AbbVie, Boehringer Ingelheim, Cell Medica, Medivation, Merck, Regeneron, Roche, and Takeda.
Source: Camidge DR et al. WCLC 2018, Abstract PL02.03.
Some mutation testing can be useful at CLL diagnosis
CHICAGO – A number of mutation tests – including immunoglobulin heavy chain gene (IgVH), fluorescence in situ hybridization (FISH), and TP53 – provide useful prognostic information at the time of chronic lymphocytic leukemia (CLL) diagnosis, according to Paul M. Barr, MD.
“It’s understood that IgVH mutation status is certainly prognostic,” Dr. Barr, associate professor of hematology/oncology at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
The B-cell receptor of the CLL cells uses IgVH genes that may or may not have undergone somatic mutations, with unmutated being defined as 98% or more sequence homology to germline.
“This is indicative of stronger signaling through the B-cell receptor and, as we all know, predicts for an inferior prognosis,” he explained, citing a study that demonstrated superior survival rates with mutated IgVH genes (Blood. 1999;94[6]:1840-7).
“It’s also well understood and accepted that we should perform a FISH panel; we should look for interphase cytogenetics based on FISH in our patients,” Dr. Barr said. “Having said that, we, as medical oncologists, do not do a very good job of using this testing appropriately. Patterns of care studies have suggested that a significant number of patients don’t get FISH testing at diagnosis or before first-line therapy.”
In fact, a typical interphase FISH panel identifies cytogenetic lesions, including del(17p), del(11q), del(13q), and trisomy 12 in more than 80% of CLL cases, with del(13q) being the most common.
Another marker that can be assessed in CLL patients and has maintained prognostic value across multiple analyses is serum beta-2 microglobulin, Dr. Barr noted.
TP53 sequencing is valuable as well and has been associated with outcomes similar to those seen in patients with del(17p), he said, citing data from a study that found similarly poor outcomes with TP53 mutations or deletions and del(17p), even when minor subclones are identified using next-generation sequencing (Blood. 2014;123:2139-47).
“One of the primary reasons for this is that the two aberrations go together. Most often, if you have del(17p) you’re also going to find a TP53 mutation, but in about 30% of patients or so, only one allele is affected, so this is why it’s still important to test for TP53 mutations when you’re looking for a 17p deletion,” he said.
Numerous other recurrent mutations in CLL have been associated with poor overall survival and/or progression-free survival, including SF3B1, ATM, NOTCH1, POT1, BIRC3, and NFKBIE.
“The gut instinct is that maybe we should start testing for all of these mutations now, but I would caution everybody that we still need further validation before we can apply these to the majority of patients,” Dr. Barr said. “We still don’t know exactly what to do with all of these mutations – when and how often we should test for them, if the novel agents are truly better – so while, again, they can predict for inferior outcomes, I would say these are not yet standard of care to be tested in all patients.”
It is likely, though, that new prognostic systems will evolve as more is learned about how to use these molecular aberrations. Attempts are already being made to incorporate novel mutations into a prognostic system. Dr. Barr pointed to a report that looked at the integration of mutations and cytogenetic lesions to improve the accuracy of survival prediction in CLL (Blood. 2013;121:1403-12).
“But this still requires prospective testing, especially in patients getting the novel agents,” he said.
Conventional karyotyping also has potential, though a limited role in this setting, he said, noting that it can be reliably performed with stimulation of CLL cells.
“We also know additional aberrations are prognostic and that a complex karyotype predicts for a very poor outcome,” he said. The International Workshop on CLL (iwCLL) guidelines, which were recently updated for the first time in a decade, state that further validation is needed.
“I think it’s potentially useful in a very young patient you are considering taking to transplant, but again, I agree with the stance that this is not something that should be performed in every patient across the board,” he said.
The tests currently recommended by iwCLL before CLL treatment include IgVH mutation status; FISH for del(13q), del(11q), del(17p), and trisomy 12 in peripheral blood lymphocytes; and TP53.
“Some folks... don’t check a lot of these markers at diagnosis, but wait for patients to require therapy, and that’s a reasonable way to practice,” Dr. Barr said, noting, however, that he prefers knowing patients’ risk up front – especially for those patients he will see just once before they are “managed closer to home for the majority of their course.
“But if you [wait], then knowing what to repeat later is important,” he added. Namely, the FISH and TP53 tests are worth repeating as patients can acquire additional molecular aberrations over time.
Dr. Barr reported serving as a consultant for Pharmacyclics, AbbVie, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Novartis, and Seattle Genetics. He also reported receiving research funding from Pharmacyclics and AbbVie.
CHICAGO – A number of mutation tests – including immunoglobulin heavy chain gene (IgVH), fluorescence in situ hybridization (FISH), and TP53 – provide useful prognostic information at the time of chronic lymphocytic leukemia (CLL) diagnosis, according to Paul M. Barr, MD.
“It’s understood that IgVH mutation status is certainly prognostic,” Dr. Barr, associate professor of hematology/oncology at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
The B-cell receptor of the CLL cells uses IgVH genes that may or may not have undergone somatic mutations, with unmutated being defined as 98% or more sequence homology to germline.
“This is indicative of stronger signaling through the B-cell receptor and, as we all know, predicts for an inferior prognosis,” he explained, citing a study that demonstrated superior survival rates with mutated IgVH genes (Blood. 1999;94[6]:1840-7).
“It’s also well understood and accepted that we should perform a FISH panel; we should look for interphase cytogenetics based on FISH in our patients,” Dr. Barr said. “Having said that, we, as medical oncologists, do not do a very good job of using this testing appropriately. Patterns of care studies have suggested that a significant number of patients don’t get FISH testing at diagnosis or before first-line therapy.”
In fact, a typical interphase FISH panel identifies cytogenetic lesions, including del(17p), del(11q), del(13q), and trisomy 12 in more than 80% of CLL cases, with del(13q) being the most common.
Another marker that can be assessed in CLL patients and has maintained prognostic value across multiple analyses is serum beta-2 microglobulin, Dr. Barr noted.
TP53 sequencing is valuable as well and has been associated with outcomes similar to those seen in patients with del(17p), he said, citing data from a study that found similarly poor outcomes with TP53 mutations or deletions and del(17p), even when minor subclones are identified using next-generation sequencing (Blood. 2014;123:2139-47).
“One of the primary reasons for this is that the two aberrations go together. Most often, if you have del(17p) you’re also going to find a TP53 mutation, but in about 30% of patients or so, only one allele is affected, so this is why it’s still important to test for TP53 mutations when you’re looking for a 17p deletion,” he said.
Numerous other recurrent mutations in CLL have been associated with poor overall survival and/or progression-free survival, including SF3B1, ATM, NOTCH1, POT1, BIRC3, and NFKBIE.
“The gut instinct is that maybe we should start testing for all of these mutations now, but I would caution everybody that we still need further validation before we can apply these to the majority of patients,” Dr. Barr said. “We still don’t know exactly what to do with all of these mutations – when and how often we should test for them, if the novel agents are truly better – so while, again, they can predict for inferior outcomes, I would say these are not yet standard of care to be tested in all patients.”
It is likely, though, that new prognostic systems will evolve as more is learned about how to use these molecular aberrations. Attempts are already being made to incorporate novel mutations into a prognostic system. Dr. Barr pointed to a report that looked at the integration of mutations and cytogenetic lesions to improve the accuracy of survival prediction in CLL (Blood. 2013;121:1403-12).
“But this still requires prospective testing, especially in patients getting the novel agents,” he said.
Conventional karyotyping also has potential, though a limited role in this setting, he said, noting that it can be reliably performed with stimulation of CLL cells.
“We also know additional aberrations are prognostic and that a complex karyotype predicts for a very poor outcome,” he said. The International Workshop on CLL (iwCLL) guidelines, which were recently updated for the first time in a decade, state that further validation is needed.
“I think it’s potentially useful in a very young patient you are considering taking to transplant, but again, I agree with the stance that this is not something that should be performed in every patient across the board,” he said.
The tests currently recommended by iwCLL before CLL treatment include IgVH mutation status; FISH for del(13q), del(11q), del(17p), and trisomy 12 in peripheral blood lymphocytes; and TP53.
“Some folks... don’t check a lot of these markers at diagnosis, but wait for patients to require therapy, and that’s a reasonable way to practice,” Dr. Barr said, noting, however, that he prefers knowing patients’ risk up front – especially for those patients he will see just once before they are “managed closer to home for the majority of their course.
“But if you [wait], then knowing what to repeat later is important,” he added. Namely, the FISH and TP53 tests are worth repeating as patients can acquire additional molecular aberrations over time.
Dr. Barr reported serving as a consultant for Pharmacyclics, AbbVie, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Novartis, and Seattle Genetics. He also reported receiving research funding from Pharmacyclics and AbbVie.
CHICAGO – A number of mutation tests – including immunoglobulin heavy chain gene (IgVH), fluorescence in situ hybridization (FISH), and TP53 – provide useful prognostic information at the time of chronic lymphocytic leukemia (CLL) diagnosis, according to Paul M. Barr, MD.
“It’s understood that IgVH mutation status is certainly prognostic,” Dr. Barr, associate professor of hematology/oncology at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
The B-cell receptor of the CLL cells uses IgVH genes that may or may not have undergone somatic mutations, with unmutated being defined as 98% or more sequence homology to germline.
“This is indicative of stronger signaling through the B-cell receptor and, as we all know, predicts for an inferior prognosis,” he explained, citing a study that demonstrated superior survival rates with mutated IgVH genes (Blood. 1999;94[6]:1840-7).
“It’s also well understood and accepted that we should perform a FISH panel; we should look for interphase cytogenetics based on FISH in our patients,” Dr. Barr said. “Having said that, we, as medical oncologists, do not do a very good job of using this testing appropriately. Patterns of care studies have suggested that a significant number of patients don’t get FISH testing at diagnosis or before first-line therapy.”
In fact, a typical interphase FISH panel identifies cytogenetic lesions, including del(17p), del(11q), del(13q), and trisomy 12 in more than 80% of CLL cases, with del(13q) being the most common.
Another marker that can be assessed in CLL patients and has maintained prognostic value across multiple analyses is serum beta-2 microglobulin, Dr. Barr noted.
TP53 sequencing is valuable as well and has been associated with outcomes similar to those seen in patients with del(17p), he said, citing data from a study that found similarly poor outcomes with TP53 mutations or deletions and del(17p), even when minor subclones are identified using next-generation sequencing (Blood. 2014;123:2139-47).
“One of the primary reasons for this is that the two aberrations go together. Most often, if you have del(17p) you’re also going to find a TP53 mutation, but in about 30% of patients or so, only one allele is affected, so this is why it’s still important to test for TP53 mutations when you’re looking for a 17p deletion,” he said.
Numerous other recurrent mutations in CLL have been associated with poor overall survival and/or progression-free survival, including SF3B1, ATM, NOTCH1, POT1, BIRC3, and NFKBIE.
“The gut instinct is that maybe we should start testing for all of these mutations now, but I would caution everybody that we still need further validation before we can apply these to the majority of patients,” Dr. Barr said. “We still don’t know exactly what to do with all of these mutations – when and how often we should test for them, if the novel agents are truly better – so while, again, they can predict for inferior outcomes, I would say these are not yet standard of care to be tested in all patients.”
It is likely, though, that new prognostic systems will evolve as more is learned about how to use these molecular aberrations. Attempts are already being made to incorporate novel mutations into a prognostic system. Dr. Barr pointed to a report that looked at the integration of mutations and cytogenetic lesions to improve the accuracy of survival prediction in CLL (Blood. 2013;121:1403-12).
“But this still requires prospective testing, especially in patients getting the novel agents,” he said.
Conventional karyotyping also has potential, though a limited role in this setting, he said, noting that it can be reliably performed with stimulation of CLL cells.
“We also know additional aberrations are prognostic and that a complex karyotype predicts for a very poor outcome,” he said. The International Workshop on CLL (iwCLL) guidelines, which were recently updated for the first time in a decade, state that further validation is needed.
“I think it’s potentially useful in a very young patient you are considering taking to transplant, but again, I agree with the stance that this is not something that should be performed in every patient across the board,” he said.
The tests currently recommended by iwCLL before CLL treatment include IgVH mutation status; FISH for del(13q), del(11q), del(17p), and trisomy 12 in peripheral blood lymphocytes; and TP53.
“Some folks... don’t check a lot of these markers at diagnosis, but wait for patients to require therapy, and that’s a reasonable way to practice,” Dr. Barr said, noting, however, that he prefers knowing patients’ risk up front – especially for those patients he will see just once before they are “managed closer to home for the majority of their course.
“But if you [wait], then knowing what to repeat later is important,” he added. Namely, the FISH and TP53 tests are worth repeating as patients can acquire additional molecular aberrations over time.
Dr. Barr reported serving as a consultant for Pharmacyclics, AbbVie, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Novartis, and Seattle Genetics. He also reported receiving research funding from Pharmacyclics and AbbVie.
EXPERT ANALYSIS FROM MHM 2018
IMPower132 trial: Atezolizumab improves PFS in advanced nonsquamous NSCLC
TORONTO – Adding the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to standard first-line chemotherapy and maintenance therapy in patients with advanced nonsquamous non–small-cell lung cancer significantly improved progression-free survival (PFS), in the randomized, open-label IMpower132 trial.
At a minimum follow-up of 11.7 months (median, 14.8 months), investigator-assessed median PFS in 292 patients enrolled in the atezolizumab arm of the global study was 7.6 months, compared with 5.2 months – a 40% reduction in risk of disease progression – in 286 patients who received only first-line carboplatin plus pemetrexed and pemetrexed maintenance therapy (hazard ratio, 0.60), Vassiliki A Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.
“The landmark PFS at 12-months showed almost a doubling for the investigational arm [at] 33.7% vs. 17%,” said Dr. Papadimitrakopoulou, professor of medicine and chief of the section of thoracic medical oncology at MD Anderson Cancer Center in Houston. “PFS benefit was seen across all key subgroups, [and was] especially pronounced for female patients (HR, 0.51), Asian patients (HR, 0.42), never-smokers (HR, 0.49), and patients who didn’t have liver metastases (HR, 0.56).”
PFS was also looked at – as an exploratory endpoint – by PD-L1 status in biomarker-evaluable patients, and “again, benefit was seen across all PD-L1-defined subgroups with a consistent trend for most benefit among the highest expressers,” she noted.
Median PFS was 10.8 months in 25 atezolizumab-treated patients with high PD-L1 expression, vs. 6.5 months in 20 control group patients with high PD-L1 expression; 6.2 vs. 5.7 months in 63 and 73 patients with low-PD-L1 expression in the groups, respectively; and 8.5 vs. 4.9 months in 88 and 75 PD-L1-negative patients in the groups, respectively, she reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
Interim analyses also showed a numerically superior improvement in median and 12-month overall survival in the atezolizumab vs. control group (median, 18.1 vs. 13.6 months; HR, 0.813; P = .0797; 12-month, 59.6% vs. 55.4%), she said, adding that overall survival will be looked at again at the final analysis of the data, which is anticipated some time in the first half of 2019.
Study participants were chemotherapy-naive patients with measurable stage IV nonsquamous NSCLC and Eastern Cooperative Oncology Group Performance Status 0-1. Those with tumors known to harbor epidermal growth factor receptor or anaplastic lymphoma kinase driver mutations were excluded, as were those with untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy.
All patients received four or six cycles of carboplatin at a dose of area under the curve 6 mg/mL/min or cisplatin at a dose of 75 mg/m2 plus 500 mg/m2 of pemetrexed every 3 weeks, and those in the experimental arm also received 1,200 mg of atezolizumab every 3 weeks. Maintenance therapy included pemetrexed alone in the control arm, and atezolizumab plus pemetrexed in the experimental arm.
Treatment was well tolerated, and no new safety signals emerged, Dr. Papadimitrakopoulou said, noting that adverse events were similar in the groups, but more common in the atezolizumab-treated patients. Grade 3-4 treatment-related adverse events occurred in 54% of patients receiving atezolizumab vs. 39% of those in the control group, and serious adverse events occurred in 33% vs. 16%.
“The findings from IMpower132 indicate that the addition of atezolizumab to a backbone of carboplatin and pemetrexed chemotherapy provides better clinical efficacy than carboplatin and pemetrexed alone,” Dr. Papadimitrakopoulou said in a press statement. “By inhibiting the interaction of PD-L1 with its receptors PD-1 and B7.1, atezolizumab restores tumor-specific T-cell immunity, offering a valuable treatment option that prolongs survival for patients with stage IV nonsquamous NSCLC.”
IMpower132 is sponsored by F. Hoffmann–La Roche Ltd. Dr. Papadimitrakopoulou has received research support from, and/or is an advisory board member for numerous companies including F. Hoffmann–La Roche.
SOURCE: Papadimitrakopoulou V et al. WCLC 2018 Abstract OA05.07.
TORONTO – Adding the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to standard first-line chemotherapy and maintenance therapy in patients with advanced nonsquamous non–small-cell lung cancer significantly improved progression-free survival (PFS), in the randomized, open-label IMpower132 trial.
At a minimum follow-up of 11.7 months (median, 14.8 months), investigator-assessed median PFS in 292 patients enrolled in the atezolizumab arm of the global study was 7.6 months, compared with 5.2 months – a 40% reduction in risk of disease progression – in 286 patients who received only first-line carboplatin plus pemetrexed and pemetrexed maintenance therapy (hazard ratio, 0.60), Vassiliki A Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.
“The landmark PFS at 12-months showed almost a doubling for the investigational arm [at] 33.7% vs. 17%,” said Dr. Papadimitrakopoulou, professor of medicine and chief of the section of thoracic medical oncology at MD Anderson Cancer Center in Houston. “PFS benefit was seen across all key subgroups, [and was] especially pronounced for female patients (HR, 0.51), Asian patients (HR, 0.42), never-smokers (HR, 0.49), and patients who didn’t have liver metastases (HR, 0.56).”
PFS was also looked at – as an exploratory endpoint – by PD-L1 status in biomarker-evaluable patients, and “again, benefit was seen across all PD-L1-defined subgroups with a consistent trend for most benefit among the highest expressers,” she noted.
Median PFS was 10.8 months in 25 atezolizumab-treated patients with high PD-L1 expression, vs. 6.5 months in 20 control group patients with high PD-L1 expression; 6.2 vs. 5.7 months in 63 and 73 patients with low-PD-L1 expression in the groups, respectively; and 8.5 vs. 4.9 months in 88 and 75 PD-L1-negative patients in the groups, respectively, she reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
Interim analyses also showed a numerically superior improvement in median and 12-month overall survival in the atezolizumab vs. control group (median, 18.1 vs. 13.6 months; HR, 0.813; P = .0797; 12-month, 59.6% vs. 55.4%), she said, adding that overall survival will be looked at again at the final analysis of the data, which is anticipated some time in the first half of 2019.
Study participants were chemotherapy-naive patients with measurable stage IV nonsquamous NSCLC and Eastern Cooperative Oncology Group Performance Status 0-1. Those with tumors known to harbor epidermal growth factor receptor or anaplastic lymphoma kinase driver mutations were excluded, as were those with untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy.
All patients received four or six cycles of carboplatin at a dose of area under the curve 6 mg/mL/min or cisplatin at a dose of 75 mg/m2 plus 500 mg/m2 of pemetrexed every 3 weeks, and those in the experimental arm also received 1,200 mg of atezolizumab every 3 weeks. Maintenance therapy included pemetrexed alone in the control arm, and atezolizumab plus pemetrexed in the experimental arm.
Treatment was well tolerated, and no new safety signals emerged, Dr. Papadimitrakopoulou said, noting that adverse events were similar in the groups, but more common in the atezolizumab-treated patients. Grade 3-4 treatment-related adverse events occurred in 54% of patients receiving atezolizumab vs. 39% of those in the control group, and serious adverse events occurred in 33% vs. 16%.
“The findings from IMpower132 indicate that the addition of atezolizumab to a backbone of carboplatin and pemetrexed chemotherapy provides better clinical efficacy than carboplatin and pemetrexed alone,” Dr. Papadimitrakopoulou said in a press statement. “By inhibiting the interaction of PD-L1 with its receptors PD-1 and B7.1, atezolizumab restores tumor-specific T-cell immunity, offering a valuable treatment option that prolongs survival for patients with stage IV nonsquamous NSCLC.”
IMpower132 is sponsored by F. Hoffmann–La Roche Ltd. Dr. Papadimitrakopoulou has received research support from, and/or is an advisory board member for numerous companies including F. Hoffmann–La Roche.
SOURCE: Papadimitrakopoulou V et al. WCLC 2018 Abstract OA05.07.
TORONTO – Adding the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to standard first-line chemotherapy and maintenance therapy in patients with advanced nonsquamous non–small-cell lung cancer significantly improved progression-free survival (PFS), in the randomized, open-label IMpower132 trial.
At a minimum follow-up of 11.7 months (median, 14.8 months), investigator-assessed median PFS in 292 patients enrolled in the atezolizumab arm of the global study was 7.6 months, compared with 5.2 months – a 40% reduction in risk of disease progression – in 286 patients who received only first-line carboplatin plus pemetrexed and pemetrexed maintenance therapy (hazard ratio, 0.60), Vassiliki A Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.
“The landmark PFS at 12-months showed almost a doubling for the investigational arm [at] 33.7% vs. 17%,” said Dr. Papadimitrakopoulou, professor of medicine and chief of the section of thoracic medical oncology at MD Anderson Cancer Center in Houston. “PFS benefit was seen across all key subgroups, [and was] especially pronounced for female patients (HR, 0.51), Asian patients (HR, 0.42), never-smokers (HR, 0.49), and patients who didn’t have liver metastases (HR, 0.56).”
PFS was also looked at – as an exploratory endpoint – by PD-L1 status in biomarker-evaluable patients, and “again, benefit was seen across all PD-L1-defined subgroups with a consistent trend for most benefit among the highest expressers,” she noted.
Median PFS was 10.8 months in 25 atezolizumab-treated patients with high PD-L1 expression, vs. 6.5 months in 20 control group patients with high PD-L1 expression; 6.2 vs. 5.7 months in 63 and 73 patients with low-PD-L1 expression in the groups, respectively; and 8.5 vs. 4.9 months in 88 and 75 PD-L1-negative patients in the groups, respectively, she reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
Interim analyses also showed a numerically superior improvement in median and 12-month overall survival in the atezolizumab vs. control group (median, 18.1 vs. 13.6 months; HR, 0.813; P = .0797; 12-month, 59.6% vs. 55.4%), she said, adding that overall survival will be looked at again at the final analysis of the data, which is anticipated some time in the first half of 2019.
Study participants were chemotherapy-naive patients with measurable stage IV nonsquamous NSCLC and Eastern Cooperative Oncology Group Performance Status 0-1. Those with tumors known to harbor epidermal growth factor receptor or anaplastic lymphoma kinase driver mutations were excluded, as were those with untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy.
All patients received four or six cycles of carboplatin at a dose of area under the curve 6 mg/mL/min or cisplatin at a dose of 75 mg/m2 plus 500 mg/m2 of pemetrexed every 3 weeks, and those in the experimental arm also received 1,200 mg of atezolizumab every 3 weeks. Maintenance therapy included pemetrexed alone in the control arm, and atezolizumab plus pemetrexed in the experimental arm.
Treatment was well tolerated, and no new safety signals emerged, Dr. Papadimitrakopoulou said, noting that adverse events were similar in the groups, but more common in the atezolizumab-treated patients. Grade 3-4 treatment-related adverse events occurred in 54% of patients receiving atezolizumab vs. 39% of those in the control group, and serious adverse events occurred in 33% vs. 16%.
“The findings from IMpower132 indicate that the addition of atezolizumab to a backbone of carboplatin and pemetrexed chemotherapy provides better clinical efficacy than carboplatin and pemetrexed alone,” Dr. Papadimitrakopoulou said in a press statement. “By inhibiting the interaction of PD-L1 with its receptors PD-1 and B7.1, atezolizumab restores tumor-specific T-cell immunity, offering a valuable treatment option that prolongs survival for patients with stage IV nonsquamous NSCLC.”
IMpower132 is sponsored by F. Hoffmann–La Roche Ltd. Dr. Papadimitrakopoulou has received research support from, and/or is an advisory board member for numerous companies including F. Hoffmann–La Roche.
SOURCE: Papadimitrakopoulou V et al. WCLC 2018 Abstract OA05.07.
REPORTING FROM WCLC 2018
Key clinical point: Atezolizumab added to first-line chemotherapy and maintenance improved PFS in advanced nonsquamous NSCLC
Major finding: Median PFS was 7.6 months vs. 5.2 months (HR, 0.60).
Study details: A global, randomized, open-label trial of 578 patients.
Disclosures: IMpower132 is sponsored by F. Hoffmann–La Roche Ltd. Dr. Papadimitrakopoulou has received research support from, and/or is an advisory board member for numerous companies including F. Hoffmann–La Roche.
Source: Papadimitrakopoulou V et al. WCLC 2018 Abstract OA05.07.
IMpower133: Atezolizumab plus standard chemotherapy boosted survival in ES-SCLC
TORONTO – Adding the humanized monoclonal programmed death-ligand 1 (PD-L1) antibody atezolizumab to standard first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall and progression-free survival in the phase 1/3 IMpower133 trial.
The combination may represent a new standard-of-care regimen for patients with untreated ES-SCLC, which is highly lethal – with 5-year survival of about 1%-3% – and represents about 13% of all lung cancers, Stephen V. Liu, MD, reported at the World Conference on Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The median overall survival in 201 patients randomized to receive atezolizumab in addition to carboplatin and etoposide was 12.3 months, compared with 10.3 months in 202 patients who received placebo plus carboplatin and etoposide (hazard ratio, 0.7), Dr. Liu of Georgetown University, Washington, and a member of the trial steering committee said at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“That translates to a 30% reduction in the risk of patient death,” he said at a press briefing during the conference. “Patients receiving atezolizumab had a much greater likelihood of being alive at 1 year, with a 1-year survival rate of 51.7% versus 38.2%.”
Median progression-free survival(PFS) also improved with atezolizumab (5.2 months vs. 4.3 months with placebo; HR, 0.77), as did 6-month PFS. At 12 months there was more than a doubling of PFS in the atezolizumab group (5.0% vs. 12.6%), he said.
Participants in the double-blind trial were treatment-naive all-comers with measurable ES-SCLC and good performance status. They received four 21-day cycles of intravenous carboplatin (area under the curve, 5 mg/mL per minute) on day 1 plus intravenous etoposide (100 mg/m2) on days 1-3 with either concurrent 1,200 mg of atezolizumab on day 1 or placebo, followed by maintenance therapy with atezolizumab or placebo until intolerable toxicity or disease progression.
The treatment benefits were seen across many patient subgroups and regardless of tumor mutational burden.
The atezolizumab safety profile was as expected with no new safety signals and did not compromise patients’ ability to complete four treatment cycles, Dr. Liu noted.
The findings are exciting in that they represent the first in decades to show a significant improvement in survival in patients with ES-SCLC, he said. Although most patients have an initial response to standard-of-care chemotherapy, that response isn’t durable. “As much as we expect a response, we also know that it’s transient; we expect a response, we expect relapse. There hasn’t been a change really in the past 20 years, at least, with this regimen that we’ve been using since the 1980s.”
That’s not for lack of trying, he added, noting that more than 40 phase 3 studies have looked at more than 60 different drugs since the 1970s and have “failed to move the needle.”
Immunotherapy, however, has dramatically improved the therapeutic landscape in non–small cell lung cancer, and preclinical data and clinical experience suggest “a possible synergy between checkpoint inhibition and chemotherapy,” which led to this global study, he explained.
“This is the first study in over 20 years to show a significant improvement in survival and progression-free survival in initial treatment of small cell lung cancer. The concurrent administration of atezolizumab with chemotherapy helped people live longer, compared to chemotherapy alone,” Dr. Liu concluded, adding in a press statement that “this is an exciting time in oncology, and we are thrilled to finally see real progress in the SCLC space.”
When questioned about the role of PD-L1 in this population and the possibility of identifying a subgroup in which this treatment may be more cost effective, he noted that tissue samples weren’t required at enrollment in this study, but were collected from some patients, and future analyses will assess those samples to try to determine if there are subsets of patients who derive particular benefit from immunotherapy in this setting.
“But today, in an all-comer population, this combination has improved survival,” he said.
IMpower133 was sponsored by F. Hoffman–La Roche. Dr. Liu is a speaker or advisory board member for Genentech, Pfizer, Takeda, Celgene, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, and Ignyta, and has received research or grant support from Genentech, Pfizer, Threshold Pharmaceuticals, Clovis Oncology, Corvus Pharmaceuticals, Esanex, Bayer, OncoMed Pharmaceuticals, Ignyta, Merck, Lycera, AstraZeneca, and Molecular Partners.
SOURCE: Liu SV et al. WCLC 2018, Abstract PL02.07.
Invited discussant Natasha B. Leighl, MD, said that, while many questions remain, the IMpower133 findings do present a new standard of care for extensive-stage small cell lung cancer given the hazard ratio of 0.70 for survival, the unmet need in this population, and the 4 decades without progress.
“We have a long way to go to catch up with non–small cell lung cancer, and it starts today,” she said, noting, however, that uptake will vary depending on regulatory and economic thresholds in different areas. “I think that really highlights the urgent need for progress in patient selection, biomarker research, and the need to change our culture to one of tissue collection at trial.
“Finally, small cell lung cancer ... is a preventable disease and we need urgent steps in tobacco control to help us eradicate this killer,” she concluded.
Dr. Leighl is a medical oncologist at Princess Margaret Cancer Centre in Toronto. She has received research, grant, or other support from Novartis, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, and the Canadian Agency for Drugs and Technologies in Health.
Invited discussant Natasha B. Leighl, MD, said that, while many questions remain, the IMpower133 findings do present a new standard of care for extensive-stage small cell lung cancer given the hazard ratio of 0.70 for survival, the unmet need in this population, and the 4 decades without progress.
“We have a long way to go to catch up with non–small cell lung cancer, and it starts today,” she said, noting, however, that uptake will vary depending on regulatory and economic thresholds in different areas. “I think that really highlights the urgent need for progress in patient selection, biomarker research, and the need to change our culture to one of tissue collection at trial.
“Finally, small cell lung cancer ... is a preventable disease and we need urgent steps in tobacco control to help us eradicate this killer,” she concluded.
Dr. Leighl is a medical oncologist at Princess Margaret Cancer Centre in Toronto. She has received research, grant, or other support from Novartis, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, and the Canadian Agency for Drugs and Technologies in Health.
Invited discussant Natasha B. Leighl, MD, said that, while many questions remain, the IMpower133 findings do present a new standard of care for extensive-stage small cell lung cancer given the hazard ratio of 0.70 for survival, the unmet need in this population, and the 4 decades without progress.
“We have a long way to go to catch up with non–small cell lung cancer, and it starts today,” she said, noting, however, that uptake will vary depending on regulatory and economic thresholds in different areas. “I think that really highlights the urgent need for progress in patient selection, biomarker research, and the need to change our culture to one of tissue collection at trial.
“Finally, small cell lung cancer ... is a preventable disease and we need urgent steps in tobacco control to help us eradicate this killer,” she concluded.
Dr. Leighl is a medical oncologist at Princess Margaret Cancer Centre in Toronto. She has received research, grant, or other support from Novartis, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, and the Canadian Agency for Drugs and Technologies in Health.
TORONTO – Adding the humanized monoclonal programmed death-ligand 1 (PD-L1) antibody atezolizumab to standard first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall and progression-free survival in the phase 1/3 IMpower133 trial.
The combination may represent a new standard-of-care regimen for patients with untreated ES-SCLC, which is highly lethal – with 5-year survival of about 1%-3% – and represents about 13% of all lung cancers, Stephen V. Liu, MD, reported at the World Conference on Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The median overall survival in 201 patients randomized to receive atezolizumab in addition to carboplatin and etoposide was 12.3 months, compared with 10.3 months in 202 patients who received placebo plus carboplatin and etoposide (hazard ratio, 0.7), Dr. Liu of Georgetown University, Washington, and a member of the trial steering committee said at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“That translates to a 30% reduction in the risk of patient death,” he said at a press briefing during the conference. “Patients receiving atezolizumab had a much greater likelihood of being alive at 1 year, with a 1-year survival rate of 51.7% versus 38.2%.”
Median progression-free survival(PFS) also improved with atezolizumab (5.2 months vs. 4.3 months with placebo; HR, 0.77), as did 6-month PFS. At 12 months there was more than a doubling of PFS in the atezolizumab group (5.0% vs. 12.6%), he said.
Participants in the double-blind trial were treatment-naive all-comers with measurable ES-SCLC and good performance status. They received four 21-day cycles of intravenous carboplatin (area under the curve, 5 mg/mL per minute) on day 1 plus intravenous etoposide (100 mg/m2) on days 1-3 with either concurrent 1,200 mg of atezolizumab on day 1 or placebo, followed by maintenance therapy with atezolizumab or placebo until intolerable toxicity or disease progression.
The treatment benefits were seen across many patient subgroups and regardless of tumor mutational burden.
The atezolizumab safety profile was as expected with no new safety signals and did not compromise patients’ ability to complete four treatment cycles, Dr. Liu noted.
The findings are exciting in that they represent the first in decades to show a significant improvement in survival in patients with ES-SCLC, he said. Although most patients have an initial response to standard-of-care chemotherapy, that response isn’t durable. “As much as we expect a response, we also know that it’s transient; we expect a response, we expect relapse. There hasn’t been a change really in the past 20 years, at least, with this regimen that we’ve been using since the 1980s.”
That’s not for lack of trying, he added, noting that more than 40 phase 3 studies have looked at more than 60 different drugs since the 1970s and have “failed to move the needle.”
Immunotherapy, however, has dramatically improved the therapeutic landscape in non–small cell lung cancer, and preclinical data and clinical experience suggest “a possible synergy between checkpoint inhibition and chemotherapy,” which led to this global study, he explained.
“This is the first study in over 20 years to show a significant improvement in survival and progression-free survival in initial treatment of small cell lung cancer. The concurrent administration of atezolizumab with chemotherapy helped people live longer, compared to chemotherapy alone,” Dr. Liu concluded, adding in a press statement that “this is an exciting time in oncology, and we are thrilled to finally see real progress in the SCLC space.”
When questioned about the role of PD-L1 in this population and the possibility of identifying a subgroup in which this treatment may be more cost effective, he noted that tissue samples weren’t required at enrollment in this study, but were collected from some patients, and future analyses will assess those samples to try to determine if there are subsets of patients who derive particular benefit from immunotherapy in this setting.
“But today, in an all-comer population, this combination has improved survival,” he said.
IMpower133 was sponsored by F. Hoffman–La Roche. Dr. Liu is a speaker or advisory board member for Genentech, Pfizer, Takeda, Celgene, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, and Ignyta, and has received research or grant support from Genentech, Pfizer, Threshold Pharmaceuticals, Clovis Oncology, Corvus Pharmaceuticals, Esanex, Bayer, OncoMed Pharmaceuticals, Ignyta, Merck, Lycera, AstraZeneca, and Molecular Partners.
SOURCE: Liu SV et al. WCLC 2018, Abstract PL02.07.
TORONTO – Adding the humanized monoclonal programmed death-ligand 1 (PD-L1) antibody atezolizumab to standard first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall and progression-free survival in the phase 1/3 IMpower133 trial.
The combination may represent a new standard-of-care regimen for patients with untreated ES-SCLC, which is highly lethal – with 5-year survival of about 1%-3% – and represents about 13% of all lung cancers, Stephen V. Liu, MD, reported at the World Conference on Lung Cancer.
The findings were published simultaneously in the New England Journal of Medicine.
The median overall survival in 201 patients randomized to receive atezolizumab in addition to carboplatin and etoposide was 12.3 months, compared with 10.3 months in 202 patients who received placebo plus carboplatin and etoposide (hazard ratio, 0.7), Dr. Liu of Georgetown University, Washington, and a member of the trial steering committee said at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“That translates to a 30% reduction in the risk of patient death,” he said at a press briefing during the conference. “Patients receiving atezolizumab had a much greater likelihood of being alive at 1 year, with a 1-year survival rate of 51.7% versus 38.2%.”
Median progression-free survival(PFS) also improved with atezolizumab (5.2 months vs. 4.3 months with placebo; HR, 0.77), as did 6-month PFS. At 12 months there was more than a doubling of PFS in the atezolizumab group (5.0% vs. 12.6%), he said.
Participants in the double-blind trial were treatment-naive all-comers with measurable ES-SCLC and good performance status. They received four 21-day cycles of intravenous carboplatin (area under the curve, 5 mg/mL per minute) on day 1 plus intravenous etoposide (100 mg/m2) on days 1-3 with either concurrent 1,200 mg of atezolizumab on day 1 or placebo, followed by maintenance therapy with atezolizumab or placebo until intolerable toxicity or disease progression.
The treatment benefits were seen across many patient subgroups and regardless of tumor mutational burden.
The atezolizumab safety profile was as expected with no new safety signals and did not compromise patients’ ability to complete four treatment cycles, Dr. Liu noted.
The findings are exciting in that they represent the first in decades to show a significant improvement in survival in patients with ES-SCLC, he said. Although most patients have an initial response to standard-of-care chemotherapy, that response isn’t durable. “As much as we expect a response, we also know that it’s transient; we expect a response, we expect relapse. There hasn’t been a change really in the past 20 years, at least, with this regimen that we’ve been using since the 1980s.”
That’s not for lack of trying, he added, noting that more than 40 phase 3 studies have looked at more than 60 different drugs since the 1970s and have “failed to move the needle.”
Immunotherapy, however, has dramatically improved the therapeutic landscape in non–small cell lung cancer, and preclinical data and clinical experience suggest “a possible synergy between checkpoint inhibition and chemotherapy,” which led to this global study, he explained.
“This is the first study in over 20 years to show a significant improvement in survival and progression-free survival in initial treatment of small cell lung cancer. The concurrent administration of atezolizumab with chemotherapy helped people live longer, compared to chemotherapy alone,” Dr. Liu concluded, adding in a press statement that “this is an exciting time in oncology, and we are thrilled to finally see real progress in the SCLC space.”
When questioned about the role of PD-L1 in this population and the possibility of identifying a subgroup in which this treatment may be more cost effective, he noted that tissue samples weren’t required at enrollment in this study, but were collected from some patients, and future analyses will assess those samples to try to determine if there are subsets of patients who derive particular benefit from immunotherapy in this setting.
“But today, in an all-comer population, this combination has improved survival,” he said.
IMpower133 was sponsored by F. Hoffman–La Roche. Dr. Liu is a speaker or advisory board member for Genentech, Pfizer, Takeda, Celgene, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, and Ignyta, and has received research or grant support from Genentech, Pfizer, Threshold Pharmaceuticals, Clovis Oncology, Corvus Pharmaceuticals, Esanex, Bayer, OncoMed Pharmaceuticals, Ignyta, Merck, Lycera, AstraZeneca, and Molecular Partners.
SOURCE: Liu SV et al. WCLC 2018, Abstract PL02.07.
REPORTING FROM WCLC 2018
Key clinical point: Immunotherapy added to standard chemotherapy improves survival outcomes in extensive-stage small cell lung cancer.
Major finding: Median overall survival was 12.3 months with atezolizumab versus 10.3 months with placebo (HR, 0.7).
Study details: A global phase 1/3 study of 403 extensive-stage small cell lung cancer patients.
Disclosures: IMpower 133 was sponsored by F. Hoffman–La Roche. Dr. Liu is a speaker or advisory board member for Genentech, Pfizer, Takeda, Celgene, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, and Ignyta, and has received research or grant support from Genentech, Pfizer, Threshold Pharmaceuticals, Clovis Oncology, Corvus Pharmaceuticals, Esanex, Bayer, OncoMed Pharmaceuticals, Ignyta, Merck, Lycera, AstraZeneca, and Molecular Partners.
Source: Liu SV et al. WCLC 2018, Abstract PL02.07.