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Durvalumab could offer option for difficult-to-treat NSCLC
VIENNA – In a heavily pretreated population of patients with non–small-cell lung cancer (NSCLC), the investigational checkpoint inhibitor durvalumab was associated with good objective response rates (ORR) and ‘impressive’ overall survival (OS) in a phase II study, Marina Garassino, MD, reported at the World Conference on Lung Cancer.
The primary endpoint of ORR in the open-label, single-arm ATLANTIC trial was achieved by 7% of patients with low (less than 25% of tumor cells) expression of the programmed death ligand 1 (PD-L1) that durvalumab targets (n = 93), by 16.4% of patients with PD-L1 expression of 25% or higher (n = 146), and by 30.9% in patients with PD-L1 expression of 90% or more (n = 68).
Yet the results of ATLANTIC show not only that durvalumab is active, but also that it can produce long-lasting responses in patients who have been treated with a mean of three prior regimens, she reported.
The median duration of response to date was not reached in patients with PD-L1 expression of 25% or less, was 12.3 months in patients with greater than 25% PD-L1 expression, and had again not yet been reached in those with greater than 90% PD-L1 expression. At the time the data were pulled for analysis, June 2016, 18 of 21 patients in the latter group were progression free.
The disease control rate at 6 months was 20.4%, 28.8%, 38.2% for patients with PD-L1 expression of less than 25%, 25%-90%, and greater than 90%, respectively.
“One-year overall survival was about 48% in patients with PD-L1 greater than 25% and about 51% in those with PD-L1 greater than 90%,” Dr. Garassino said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
The respective median OS times for patients with 25% and greater and less than 25% PD-L1 expression were 10.9 (95% CI 8.6-13.6) and 9.3 (95% CI 5.9-10.8) months, and not yet reached for patients with 90% or greater PD-L1 expression.
“Most adverse events were low grade and immune mediated adverse events were easily manageable,” Dr. Garassino said. Overall, 10.2% of patients had grade 3 or 4 treatment-related adverse events and 2.7% had treatment-related adverse events that led to discontinuation.
Any immune-mediated adverse event occurred in 12.3% of patients, of which 6.3% were due to an underactive and 2.4% to a hyperactive thyroid.
“Results are consistent with other anti-PD-1/PD-L1 compounds in metastatic, relapsed NSCLC and we are awaiting the final results of phase III trials to clarify the role of durvalumab [treatment] alone or in combination in NSCLC,” Dr. Garassino said.
Overall, 1,990 patients were screened for inclusion in the ATLANTIC study, which recruited 444 patients with stage IIIB-IV NSCLC who had received at least two prior systemic treatments, one of which had to be platinum based and had a recent (within 3 months) tumor biopsy and archived tissue available for PD-L1 assessment. Dr. Garassino reported results for two of the three cohorts.
Durvalumab was given at an intravenous dose of 10 mg/kg every 2 weeks for up to 1 year. The mean number of prior regimens was 3.2 for patients with less than 25% and greater than or equal to 25% PD-L1 expression combined and 2.6 for those with greater than 90% PD-L1 expression.
“This drug clearly does have activity and we can see that in the response rates, which range from 7% all the way up to 31%,” said Michael Boyer, MBBS, chief clinical officer of Chris O’Brien Lifehouse in Melbourne, who was the invited discussant for the trial. “The higher the PD-L1 expression, the higher the response rate,” he observed.
“There was quite impressive survival, if you bear in mind that this is a third-line, or more than third-line cohort of patients, with a median overall survival in the strongest PD-L1 expressing patients that is clearly going to exceed 1 year” he added.
The big question for the future is what will be the relevance of having an immunotherapy that works well in such a heavily pretreated population when these drugs are more likely to be used second- or even first-line, especially in those who have high PD-L1 expression where the drug seems to be at its most effective, Dr. Boyer said.
AstraZeneca funded the study. Dr. Garassino disclosed relationships with AstraZeneca, Bristol Myers Squibb, Roche, Merck, Sharp & Dohme, Boehringer Ingelheim, and Eli Lilly. Dr. Boyer disclosed that he had received research funding, honoraria, or both that were paid to his institution from Pfizer, Roche, Eli Lilly, Merck, Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, and Clovis.
VIENNA – In a heavily pretreated population of patients with non–small-cell lung cancer (NSCLC), the investigational checkpoint inhibitor durvalumab was associated with good objective response rates (ORR) and ‘impressive’ overall survival (OS) in a phase II study, Marina Garassino, MD, reported at the World Conference on Lung Cancer.
The primary endpoint of ORR in the open-label, single-arm ATLANTIC trial was achieved by 7% of patients with low (less than 25% of tumor cells) expression of the programmed death ligand 1 (PD-L1) that durvalumab targets (n = 93), by 16.4% of patients with PD-L1 expression of 25% or higher (n = 146), and by 30.9% in patients with PD-L1 expression of 90% or more (n = 68).
Yet the results of ATLANTIC show not only that durvalumab is active, but also that it can produce long-lasting responses in patients who have been treated with a mean of three prior regimens, she reported.
The median duration of response to date was not reached in patients with PD-L1 expression of 25% or less, was 12.3 months in patients with greater than 25% PD-L1 expression, and had again not yet been reached in those with greater than 90% PD-L1 expression. At the time the data were pulled for analysis, June 2016, 18 of 21 patients in the latter group were progression free.
The disease control rate at 6 months was 20.4%, 28.8%, 38.2% for patients with PD-L1 expression of less than 25%, 25%-90%, and greater than 90%, respectively.
“One-year overall survival was about 48% in patients with PD-L1 greater than 25% and about 51% in those with PD-L1 greater than 90%,” Dr. Garassino said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
The respective median OS times for patients with 25% and greater and less than 25% PD-L1 expression were 10.9 (95% CI 8.6-13.6) and 9.3 (95% CI 5.9-10.8) months, and not yet reached for patients with 90% or greater PD-L1 expression.
“Most adverse events were low grade and immune mediated adverse events were easily manageable,” Dr. Garassino said. Overall, 10.2% of patients had grade 3 or 4 treatment-related adverse events and 2.7% had treatment-related adverse events that led to discontinuation.
Any immune-mediated adverse event occurred in 12.3% of patients, of which 6.3% were due to an underactive and 2.4% to a hyperactive thyroid.
“Results are consistent with other anti-PD-1/PD-L1 compounds in metastatic, relapsed NSCLC and we are awaiting the final results of phase III trials to clarify the role of durvalumab [treatment] alone or in combination in NSCLC,” Dr. Garassino said.
Overall, 1,990 patients were screened for inclusion in the ATLANTIC study, which recruited 444 patients with stage IIIB-IV NSCLC who had received at least two prior systemic treatments, one of which had to be platinum based and had a recent (within 3 months) tumor biopsy and archived tissue available for PD-L1 assessment. Dr. Garassino reported results for two of the three cohorts.
Durvalumab was given at an intravenous dose of 10 mg/kg every 2 weeks for up to 1 year. The mean number of prior regimens was 3.2 for patients with less than 25% and greater than or equal to 25% PD-L1 expression combined and 2.6 for those with greater than 90% PD-L1 expression.
“This drug clearly does have activity and we can see that in the response rates, which range from 7% all the way up to 31%,” said Michael Boyer, MBBS, chief clinical officer of Chris O’Brien Lifehouse in Melbourne, who was the invited discussant for the trial. “The higher the PD-L1 expression, the higher the response rate,” he observed.
“There was quite impressive survival, if you bear in mind that this is a third-line, or more than third-line cohort of patients, with a median overall survival in the strongest PD-L1 expressing patients that is clearly going to exceed 1 year” he added.
The big question for the future is what will be the relevance of having an immunotherapy that works well in such a heavily pretreated population when these drugs are more likely to be used second- or even first-line, especially in those who have high PD-L1 expression where the drug seems to be at its most effective, Dr. Boyer said.
AstraZeneca funded the study. Dr. Garassino disclosed relationships with AstraZeneca, Bristol Myers Squibb, Roche, Merck, Sharp & Dohme, Boehringer Ingelheim, and Eli Lilly. Dr. Boyer disclosed that he had received research funding, honoraria, or both that were paid to his institution from Pfizer, Roche, Eli Lilly, Merck, Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, and Clovis.
VIENNA – In a heavily pretreated population of patients with non–small-cell lung cancer (NSCLC), the investigational checkpoint inhibitor durvalumab was associated with good objective response rates (ORR) and ‘impressive’ overall survival (OS) in a phase II study, Marina Garassino, MD, reported at the World Conference on Lung Cancer.
The primary endpoint of ORR in the open-label, single-arm ATLANTIC trial was achieved by 7% of patients with low (less than 25% of tumor cells) expression of the programmed death ligand 1 (PD-L1) that durvalumab targets (n = 93), by 16.4% of patients with PD-L1 expression of 25% or higher (n = 146), and by 30.9% in patients with PD-L1 expression of 90% or more (n = 68).
Yet the results of ATLANTIC show not only that durvalumab is active, but also that it can produce long-lasting responses in patients who have been treated with a mean of three prior regimens, she reported.
The median duration of response to date was not reached in patients with PD-L1 expression of 25% or less, was 12.3 months in patients with greater than 25% PD-L1 expression, and had again not yet been reached in those with greater than 90% PD-L1 expression. At the time the data were pulled for analysis, June 2016, 18 of 21 patients in the latter group were progression free.
The disease control rate at 6 months was 20.4%, 28.8%, 38.2% for patients with PD-L1 expression of less than 25%, 25%-90%, and greater than 90%, respectively.
“One-year overall survival was about 48% in patients with PD-L1 greater than 25% and about 51% in those with PD-L1 greater than 90%,” Dr. Garassino said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
The respective median OS times for patients with 25% and greater and less than 25% PD-L1 expression were 10.9 (95% CI 8.6-13.6) and 9.3 (95% CI 5.9-10.8) months, and not yet reached for patients with 90% or greater PD-L1 expression.
“Most adverse events were low grade and immune mediated adverse events were easily manageable,” Dr. Garassino said. Overall, 10.2% of patients had grade 3 or 4 treatment-related adverse events and 2.7% had treatment-related adverse events that led to discontinuation.
Any immune-mediated adverse event occurred in 12.3% of patients, of which 6.3% were due to an underactive and 2.4% to a hyperactive thyroid.
“Results are consistent with other anti-PD-1/PD-L1 compounds in metastatic, relapsed NSCLC and we are awaiting the final results of phase III trials to clarify the role of durvalumab [treatment] alone or in combination in NSCLC,” Dr. Garassino said.
Overall, 1,990 patients were screened for inclusion in the ATLANTIC study, which recruited 444 patients with stage IIIB-IV NSCLC who had received at least two prior systemic treatments, one of which had to be platinum based and had a recent (within 3 months) tumor biopsy and archived tissue available for PD-L1 assessment. Dr. Garassino reported results for two of the three cohorts.
Durvalumab was given at an intravenous dose of 10 mg/kg every 2 weeks for up to 1 year. The mean number of prior regimens was 3.2 for patients with less than 25% and greater than or equal to 25% PD-L1 expression combined and 2.6 for those with greater than 90% PD-L1 expression.
“This drug clearly does have activity and we can see that in the response rates, which range from 7% all the way up to 31%,” said Michael Boyer, MBBS, chief clinical officer of Chris O’Brien Lifehouse in Melbourne, who was the invited discussant for the trial. “The higher the PD-L1 expression, the higher the response rate,” he observed.
“There was quite impressive survival, if you bear in mind that this is a third-line, or more than third-line cohort of patients, with a median overall survival in the strongest PD-L1 expressing patients that is clearly going to exceed 1 year” he added.
The big question for the future is what will be the relevance of having an immunotherapy that works well in such a heavily pretreated population when these drugs are more likely to be used second- or even first-line, especially in those who have high PD-L1 expression where the drug seems to be at its most effective, Dr. Boyer said.
AstraZeneca funded the study. Dr. Garassino disclosed relationships with AstraZeneca, Bristol Myers Squibb, Roche, Merck, Sharp & Dohme, Boehringer Ingelheim, and Eli Lilly. Dr. Boyer disclosed that he had received research funding, honoraria, or both that were paid to his institution from Pfizer, Roche, Eli Lilly, Merck, Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, and Clovis.
Key clinical point: Durvalumab had substantial antitumor activity and produced long-lasting responses in patients with previously treated advanced non–small-cell lung cancer (NSCLC).
Major finding: Objective response rates of 16.4% and 30.1% were achieved in patients with the highest PD-L1 expression profiles.
Data source: Phase II, open-label, single-arm ATLANTIC trial of 444 patients with relapsed, locally advanced or metastatic NSCLC treated with two or more prior systemic regimens.
Disclosures: AstraZeneca funded the study. Dr. Garassino disclosed relationships with AstraZeneca, Bristol Myers Squibb, Roche, Merck, Sharp & Dohme, Boehringer Ingelheim, and Eli Lilly. Dr. Boyer disclosed that he had received research funding, honoraria, or both that were paid to his institution from Pfizer, Roche, Eli Lilly, Merck, Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, and Clovis.
Pembrolizumab proves promising for treating advanced SCLC
VIENNA – One third of patients with extensive-stage small-cell lung cancer (SCLC) treated with the checkpoint inhibitor pembrolizumab achieved an objective response, according to updated data from the KEYNOTE-28 trial.
Of the 24 patients with advanced SCLC who received pembrolizumab in the multicohort phase Ib study, one had a complete response, seven had a partial response, and one further patient had stable disease for 6 or more months, giving a clinical benefit rate of 33.3% (95% CI, 15.6-53.3%).
“Pembrolizumab demonstrated meaningful antitumor activity in previously treated patients with PD-L1-positive small-cell lung cancer,” said presenting study author Patrick A. Ott, MD, PhD, of the Dana-Faber Cancer Institute in Boston.
“Responses were durable, with a median duration of response of 19.4 months,” Dr. Ott said at the World Conference on Cancer, which is sponsored by the International Association for the Study of Lung Cancer. About 40% of patients exhibited a decrease in tumor size, he added.
Treatment with pembrolizumab was associated with a progression-free survival (PFS) of 1.2 months, with a range of 1.7-5.9 months. The 6- and 12-month PFS rates were 28.6% and 23.8%, respectively.
The median overall survival (OS) was 9.7 months, ranging from 4.1 months to an upper limit that has not yet been reached. The respective 6- and 12-month OS rates were 66.0% and 37.7%.
“The safety experience was consistent with previous experience for pembrolizumab in other tumor types, and was identical with longer follow-up” Dr. Ott said.
Over a median follow-up duration of 9.8 months, treatment-related adverse events occurred in two-thirds of patients, with arthralgia, asthenia, and rash reported by four (16.7%) patients each, and diarrhea and fatigue by three (12.5%) patients each. There were no cases of pneumonitis.
The mean age of patients recruited into the KEYNOTE-28 trial was 60.5 years; more than half of the patients (58%) were male. Five (20.8%) had stable brain metastases, and 95.8% had small cell histology.
All recruited patients had received prior standard-of-care chemotherapy with cisplatin or carboplatin plus etoposide, 45.8% had received irinotecan or topotecan, and 29.2% had been treated with a taxane. In addition, one patient had received prior radiotherapy, one had been given an investigational tyrosine kinase inhibitor therapy, and another had received another, unspecified, investigational treatment.
After enrollment, all patients were treated with pembrolizumab at an intravenous dose of 10 mg/kg every 2 weeks. Response was assessed every 8 weeks for the first 6 months and then annually, with patients continuing to respond continuing to be treated for up to 2 years or until progression or unacceptable toxicity.
There are two ongoing, phase II trials with pembrolizumab in patients with advanced SCLC. One is looking at maintenance therapy with pembrolizumab after combination chemotherapy and is sponsored by the Barbara Ann Karmanos Cancer Institute in collaboration with the National Cancer Institute (NCT02359019). The other, the REACTION trial sponsored by the European Organisation for Research and Treatment of Cancer, is looking at the use of pembrolizumab together with etoposide and platinum chemotherapy in previously untreated patients (NCT02580994).
Merck funded the KEYNOTE-28 study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
VIENNA – One third of patients with extensive-stage small-cell lung cancer (SCLC) treated with the checkpoint inhibitor pembrolizumab achieved an objective response, according to updated data from the KEYNOTE-28 trial.
Of the 24 patients with advanced SCLC who received pembrolizumab in the multicohort phase Ib study, one had a complete response, seven had a partial response, and one further patient had stable disease for 6 or more months, giving a clinical benefit rate of 33.3% (95% CI, 15.6-53.3%).
“Pembrolizumab demonstrated meaningful antitumor activity in previously treated patients with PD-L1-positive small-cell lung cancer,” said presenting study author Patrick A. Ott, MD, PhD, of the Dana-Faber Cancer Institute in Boston.
“Responses were durable, with a median duration of response of 19.4 months,” Dr. Ott said at the World Conference on Cancer, which is sponsored by the International Association for the Study of Lung Cancer. About 40% of patients exhibited a decrease in tumor size, he added.
Treatment with pembrolizumab was associated with a progression-free survival (PFS) of 1.2 months, with a range of 1.7-5.9 months. The 6- and 12-month PFS rates were 28.6% and 23.8%, respectively.
The median overall survival (OS) was 9.7 months, ranging from 4.1 months to an upper limit that has not yet been reached. The respective 6- and 12-month OS rates were 66.0% and 37.7%.
“The safety experience was consistent with previous experience for pembrolizumab in other tumor types, and was identical with longer follow-up” Dr. Ott said.
Over a median follow-up duration of 9.8 months, treatment-related adverse events occurred in two-thirds of patients, with arthralgia, asthenia, and rash reported by four (16.7%) patients each, and diarrhea and fatigue by three (12.5%) patients each. There were no cases of pneumonitis.
The mean age of patients recruited into the KEYNOTE-28 trial was 60.5 years; more than half of the patients (58%) were male. Five (20.8%) had stable brain metastases, and 95.8% had small cell histology.
All recruited patients had received prior standard-of-care chemotherapy with cisplatin or carboplatin plus etoposide, 45.8% had received irinotecan or topotecan, and 29.2% had been treated with a taxane. In addition, one patient had received prior radiotherapy, one had been given an investigational tyrosine kinase inhibitor therapy, and another had received another, unspecified, investigational treatment.
After enrollment, all patients were treated with pembrolizumab at an intravenous dose of 10 mg/kg every 2 weeks. Response was assessed every 8 weeks for the first 6 months and then annually, with patients continuing to respond continuing to be treated for up to 2 years or until progression or unacceptable toxicity.
There are two ongoing, phase II trials with pembrolizumab in patients with advanced SCLC. One is looking at maintenance therapy with pembrolizumab after combination chemotherapy and is sponsored by the Barbara Ann Karmanos Cancer Institute in collaboration with the National Cancer Institute (NCT02359019). The other, the REACTION trial sponsored by the European Organisation for Research and Treatment of Cancer, is looking at the use of pembrolizumab together with etoposide and platinum chemotherapy in previously untreated patients (NCT02580994).
Merck funded the KEYNOTE-28 study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
VIENNA – One third of patients with extensive-stage small-cell lung cancer (SCLC) treated with the checkpoint inhibitor pembrolizumab achieved an objective response, according to updated data from the KEYNOTE-28 trial.
Of the 24 patients with advanced SCLC who received pembrolizumab in the multicohort phase Ib study, one had a complete response, seven had a partial response, and one further patient had stable disease for 6 or more months, giving a clinical benefit rate of 33.3% (95% CI, 15.6-53.3%).
“Pembrolizumab demonstrated meaningful antitumor activity in previously treated patients with PD-L1-positive small-cell lung cancer,” said presenting study author Patrick A. Ott, MD, PhD, of the Dana-Faber Cancer Institute in Boston.
“Responses were durable, with a median duration of response of 19.4 months,” Dr. Ott said at the World Conference on Cancer, which is sponsored by the International Association for the Study of Lung Cancer. About 40% of patients exhibited a decrease in tumor size, he added.
Treatment with pembrolizumab was associated with a progression-free survival (PFS) of 1.2 months, with a range of 1.7-5.9 months. The 6- and 12-month PFS rates were 28.6% and 23.8%, respectively.
The median overall survival (OS) was 9.7 months, ranging from 4.1 months to an upper limit that has not yet been reached. The respective 6- and 12-month OS rates were 66.0% and 37.7%.
“The safety experience was consistent with previous experience for pembrolizumab in other tumor types, and was identical with longer follow-up” Dr. Ott said.
Over a median follow-up duration of 9.8 months, treatment-related adverse events occurred in two-thirds of patients, with arthralgia, asthenia, and rash reported by four (16.7%) patients each, and diarrhea and fatigue by three (12.5%) patients each. There were no cases of pneumonitis.
The mean age of patients recruited into the KEYNOTE-28 trial was 60.5 years; more than half of the patients (58%) were male. Five (20.8%) had stable brain metastases, and 95.8% had small cell histology.
All recruited patients had received prior standard-of-care chemotherapy with cisplatin or carboplatin plus etoposide, 45.8% had received irinotecan or topotecan, and 29.2% had been treated with a taxane. In addition, one patient had received prior radiotherapy, one had been given an investigational tyrosine kinase inhibitor therapy, and another had received another, unspecified, investigational treatment.
After enrollment, all patients were treated with pembrolizumab at an intravenous dose of 10 mg/kg every 2 weeks. Response was assessed every 8 weeks for the first 6 months and then annually, with patients continuing to respond continuing to be treated for up to 2 years or until progression or unacceptable toxicity.
There are two ongoing, phase II trials with pembrolizumab in patients with advanced SCLC. One is looking at maintenance therapy with pembrolizumab after combination chemotherapy and is sponsored by the Barbara Ann Karmanos Cancer Institute in collaboration with the National Cancer Institute (NCT02359019). The other, the REACTION trial sponsored by the European Organisation for Research and Treatment of Cancer, is looking at the use of pembrolizumab together with etoposide and platinum chemotherapy in previously untreated patients (NCT02580994).
Merck funded the KEYNOTE-28 study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
AT WCLC 2016
Key clinical point: Pembrolizumab has antitumor activity in patients with advanced small-cell lung cancer.
Major finding: The objective response rate was 33.3% (95% CI 15.6-55.3%), including one complete and seven partial responses.
Data source: Phase Ib, nonrandomized, multicohort trial of 24 heavily pretreated patients with extensive-disease small-cell lung cancer.
Disclosures: Merck funded the study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
Ganetespib fails to hit mark in phase III NSCLC trial
VIENNA – The addition of ganetespib to docetaxel for the treatment of advanced non–small cell lung cancer (NSCLC) did not live up to its earlier promise of improved efficacy over docetaxel alone in a phase III study.
Interim results of the GALAXY-2 study, which led to the trial’s termination for futility, showed that there was no difference in the primary endpoint of overall survival (OS). The median OS was a respective 10.9 months and 10.5 months for the combination of ganetespib plus docetaxel versus docetaxel alone (hazard ratio, 1.111, 95% confidence interval, 0.899-1.372, P = .03293).
The combination had looked promising in the phase II GALAXY-1 study (Ann Oncol. 2015;26:1741-8), with a trend towards improved PFS and OS, with patients diagnosed with advanced disease perhaps gaining the most benefit.
“The addition of ganetespib to docetaxel did not result in improved efficacy for the salvage therapy of patients with advanced-stage lung adenocarcinoma,” Rathi Pillai, MD, said at the World Conference on Lung Cancer.
“Based on these findings, further development of Hsp [heat shock protein] 90 inhibitors in lung cancer should be limited to patients with driver mutations with relevant client proteins,” added Dr. Pillai of the Winship Cancer Institute at Emory University in Atlanta.
In GALAXY-2, 672 patients were randomized, 1:1, to receive docetaxel (75 mg/m2 on day 1) with ganetespib (150 mg/m2 on days 1 and 15) or a placebo every 3 weeks. The median number of cycles received was five in the combination arm and four in the docetaxel-only arm. All patients had advanced non–small cell lung adenocarcinoma diagnosed at least 6 months prior to enrollment and had received only one prior treatment regimen.
Response rates were similar between the two groups, with 13.7% and 16% of ganetespib/docetaxel– and docetaxel/placebo–treated patients achieving a partial response (P = .448) and 56.1% and 50.1%, respectively, having stable disease (P = .123).
Almost two-thirds (65%) of patients given ganetespib/docetaxel reported any grade 3-4 adverse event versus 54% of patients given docetaxel/placebo. The most frequent treatment-emergent grade 3-4 adverse event was neutropenia, occurring in 34.6% ad 29.5% of patients in each arm (P = .1807), with only diarrhea (46.2% vs. 14.6%; P less than .0001) and weight loss (11.3% vs. 5.2%; P = .0044) occurring more frequently in the combination than the docetaxel-only arm.
Ganetespib is a second-generation Hsp90 inhibitor and the rationale for using Hsp90 inhibitors as cancer therapy remains sound, Dr. Gandara maintained. One of the issues is finding a biomarker to predict the benefit for these drugs in a clinical setting, he said. In the phase II GALAXY-1 trial it was noted that patients diagnosed with advanced disease more than 6 months prior to study entry fared better than those with more recent diagnosis if they were treated with ganetespib/docetaxel than docetaxel alone. Patients with elevated levels of lactate dehydrogenase (eLDH) also seemed to do better than those with normal LDH levels if they were treated with the combination.
These two subpopulations were specifically looked at the in the phase III study, but again no differences in OS or PFS were observed, nor were differences observed in any of the other subgroups analyzed, which included EGFR- and ALK-negative patients, by response rate or progression because of new metastatic lesions.
“Were these the right surrogates to use as predictive biomarkers for heat shock protein inhibition? Of course, in retrospect, it is easy to say that they were not,” Dr. Gandara said.
“Is there still an opportunity for this class of drugs to make a meaningful impact in NSCLC? In my own opinion I think the answer is yes, but not in this broad page approach and not with these potential surrogates as were used in GALAXY-2,” he said at the meeting sponsored by the International Association for the Study of Lung Cancer.
The study was sponsored by Synta Pharmaceuticals, which became part of Madrigal Pharmaceuticals in June 2016. Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
VIENNA – The addition of ganetespib to docetaxel for the treatment of advanced non–small cell lung cancer (NSCLC) did not live up to its earlier promise of improved efficacy over docetaxel alone in a phase III study.
Interim results of the GALAXY-2 study, which led to the trial’s termination for futility, showed that there was no difference in the primary endpoint of overall survival (OS). The median OS was a respective 10.9 months and 10.5 months for the combination of ganetespib plus docetaxel versus docetaxel alone (hazard ratio, 1.111, 95% confidence interval, 0.899-1.372, P = .03293).
The combination had looked promising in the phase II GALAXY-1 study (Ann Oncol. 2015;26:1741-8), with a trend towards improved PFS and OS, with patients diagnosed with advanced disease perhaps gaining the most benefit.
“The addition of ganetespib to docetaxel did not result in improved efficacy for the salvage therapy of patients with advanced-stage lung adenocarcinoma,” Rathi Pillai, MD, said at the World Conference on Lung Cancer.
“Based on these findings, further development of Hsp [heat shock protein] 90 inhibitors in lung cancer should be limited to patients with driver mutations with relevant client proteins,” added Dr. Pillai of the Winship Cancer Institute at Emory University in Atlanta.
In GALAXY-2, 672 patients were randomized, 1:1, to receive docetaxel (75 mg/m2 on day 1) with ganetespib (150 mg/m2 on days 1 and 15) or a placebo every 3 weeks. The median number of cycles received was five in the combination arm and four in the docetaxel-only arm. All patients had advanced non–small cell lung adenocarcinoma diagnosed at least 6 months prior to enrollment and had received only one prior treatment regimen.
Response rates were similar between the two groups, with 13.7% and 16% of ganetespib/docetaxel– and docetaxel/placebo–treated patients achieving a partial response (P = .448) and 56.1% and 50.1%, respectively, having stable disease (P = .123).
Almost two-thirds (65%) of patients given ganetespib/docetaxel reported any grade 3-4 adverse event versus 54% of patients given docetaxel/placebo. The most frequent treatment-emergent grade 3-4 adverse event was neutropenia, occurring in 34.6% ad 29.5% of patients in each arm (P = .1807), with only diarrhea (46.2% vs. 14.6%; P less than .0001) and weight loss (11.3% vs. 5.2%; P = .0044) occurring more frequently in the combination than the docetaxel-only arm.
Ganetespib is a second-generation Hsp90 inhibitor and the rationale for using Hsp90 inhibitors as cancer therapy remains sound, Dr. Gandara maintained. One of the issues is finding a biomarker to predict the benefit for these drugs in a clinical setting, he said. In the phase II GALAXY-1 trial it was noted that patients diagnosed with advanced disease more than 6 months prior to study entry fared better than those with more recent diagnosis if they were treated with ganetespib/docetaxel than docetaxel alone. Patients with elevated levels of lactate dehydrogenase (eLDH) also seemed to do better than those with normal LDH levels if they were treated with the combination.
These two subpopulations were specifically looked at the in the phase III study, but again no differences in OS or PFS were observed, nor were differences observed in any of the other subgroups analyzed, which included EGFR- and ALK-negative patients, by response rate or progression because of new metastatic lesions.
“Were these the right surrogates to use as predictive biomarkers for heat shock protein inhibition? Of course, in retrospect, it is easy to say that they were not,” Dr. Gandara said.
“Is there still an opportunity for this class of drugs to make a meaningful impact in NSCLC? In my own opinion I think the answer is yes, but not in this broad page approach and not with these potential surrogates as were used in GALAXY-2,” he said at the meeting sponsored by the International Association for the Study of Lung Cancer.
The study was sponsored by Synta Pharmaceuticals, which became part of Madrigal Pharmaceuticals in June 2016. Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
VIENNA – The addition of ganetespib to docetaxel for the treatment of advanced non–small cell lung cancer (NSCLC) did not live up to its earlier promise of improved efficacy over docetaxel alone in a phase III study.
Interim results of the GALAXY-2 study, which led to the trial’s termination for futility, showed that there was no difference in the primary endpoint of overall survival (OS). The median OS was a respective 10.9 months and 10.5 months for the combination of ganetespib plus docetaxel versus docetaxel alone (hazard ratio, 1.111, 95% confidence interval, 0.899-1.372, P = .03293).
The combination had looked promising in the phase II GALAXY-1 study (Ann Oncol. 2015;26:1741-8), with a trend towards improved PFS and OS, with patients diagnosed with advanced disease perhaps gaining the most benefit.
“The addition of ganetespib to docetaxel did not result in improved efficacy for the salvage therapy of patients with advanced-stage lung adenocarcinoma,” Rathi Pillai, MD, said at the World Conference on Lung Cancer.
“Based on these findings, further development of Hsp [heat shock protein] 90 inhibitors in lung cancer should be limited to patients with driver mutations with relevant client proteins,” added Dr. Pillai of the Winship Cancer Institute at Emory University in Atlanta.
In GALAXY-2, 672 patients were randomized, 1:1, to receive docetaxel (75 mg/m2 on day 1) with ganetespib (150 mg/m2 on days 1 and 15) or a placebo every 3 weeks. The median number of cycles received was five in the combination arm and four in the docetaxel-only arm. All patients had advanced non–small cell lung adenocarcinoma diagnosed at least 6 months prior to enrollment and had received only one prior treatment regimen.
Response rates were similar between the two groups, with 13.7% and 16% of ganetespib/docetaxel– and docetaxel/placebo–treated patients achieving a partial response (P = .448) and 56.1% and 50.1%, respectively, having stable disease (P = .123).
Almost two-thirds (65%) of patients given ganetespib/docetaxel reported any grade 3-4 adverse event versus 54% of patients given docetaxel/placebo. The most frequent treatment-emergent grade 3-4 adverse event was neutropenia, occurring in 34.6% ad 29.5% of patients in each arm (P = .1807), with only diarrhea (46.2% vs. 14.6%; P less than .0001) and weight loss (11.3% vs. 5.2%; P = .0044) occurring more frequently in the combination than the docetaxel-only arm.
Ganetespib is a second-generation Hsp90 inhibitor and the rationale for using Hsp90 inhibitors as cancer therapy remains sound, Dr. Gandara maintained. One of the issues is finding a biomarker to predict the benefit for these drugs in a clinical setting, he said. In the phase II GALAXY-1 trial it was noted that patients diagnosed with advanced disease more than 6 months prior to study entry fared better than those with more recent diagnosis if they were treated with ganetespib/docetaxel than docetaxel alone. Patients with elevated levels of lactate dehydrogenase (eLDH) also seemed to do better than those with normal LDH levels if they were treated with the combination.
These two subpopulations were specifically looked at the in the phase III study, but again no differences in OS or PFS were observed, nor were differences observed in any of the other subgroups analyzed, which included EGFR- and ALK-negative patients, by response rate or progression because of new metastatic lesions.
“Were these the right surrogates to use as predictive biomarkers for heat shock protein inhibition? Of course, in retrospect, it is easy to say that they were not,” Dr. Gandara said.
“Is there still an opportunity for this class of drugs to make a meaningful impact in NSCLC? In my own opinion I think the answer is yes, but not in this broad page approach and not with these potential surrogates as were used in GALAXY-2,” he said at the meeting sponsored by the International Association for the Study of Lung Cancer.
The study was sponsored by Synta Pharmaceuticals, which became part of Madrigal Pharmaceuticals in June 2016. Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
AT WCLC 2016
Key clinical point: Adding ganetespib to docetaxel did not improve the survival of the patients studied versus docetaxel alone.
Major finding: Median overall survival was 10.9 months for ganetespib/docetaxel and 10.5 months for docetaxel alone (HR, 1.111; 95% CI, 0.899-1.372; P = .03293).
Data source: International, randomized, phase III, open-label GALAXY-2 study of docetaxel with or without ganetespib in 672 patients with advanced non–small cell lung adenocarcinoma.
Disclosures: The study was sponsored by Synta Pharmaceuticals (Madrigal Pharmaceuticals since June 2016). Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
Periostin level may indicate upper-airway disease in asthmatics
LONDON – Measuring serum levels of the extracellular protein periostin could help identify patients with asthma who have comorbid upper-airway disease, according to research from a late-breaking oral abstract presented at the annual congress of the European Respiratory Society.
Periostin is known to be involved in the pathophysiology of upper-airway disease, linked to both airway remodeling and inflammation. Levels of periostin have been shown to be higher in patients with asthma, allergic rhinitis, and chronic rhinosinusitis than in healthy individuals, and there are data suggesting that it could be linked to severity. However, little is known about whether serum periostin can be used to detect and perhaps monitor upper-airway disease in patients with asthma.
Serum periostin levels were found to be higher in asthma patients with comorbid chronic rhinosinusitis, compared with those with no comorbid upper-airway disease (119.8 vs. 86.3 ng/mL; P = .04).
Levels of periostin in the serum were also significantly higher in asthma patients with chronic rhinosinusitis who also had nasal polyps than in those who did not have nasal polyps (143.3 vs. 94.0 ng/mL; P = .01).
“Serum periostin is a sensitive biomarker for detecting comorbid chronic rhinosinusitis, especially in patients with chronic rhinosinusitis with nasal polyps,” said Dr. Takamitsu Asano, who reported the findings at the meeting. Dr. Asano of Nagoya (Japan) City University Graduate School of Medical Sciences noted that the serum periostin could also reflect the severity of chronic rhinosinusitis in patients with asthma.
“Upper-airway diseases are considered risk factors for the exacerbation and poor control of asthma,” Dr. Asano explained. It is thought, he said, that 40%-50% of patients with asthma have comorbid chronic rhinosinusitis, and 57%-70% have comorbid allergic rhinitis.
Dr. Asano and colleagues at Nagoya City University and Saga (Japan) Medical School recruited 65 patients with stable asthma, with or without comorbid upper-airway disease, between July 2014 and December 2015. Of these patients, 20 had no comorbid upper-airway disease, 22 had rhinitis, 21 had chronic rhinosinusitis, and two had confirmed nasal polyps. Of the 21 patients with chronic rhinosinusitis, 10 had and 11 did not have nasal polyps. Patients’ diagnoses were checked by otorhinolaryngology specialists.
The recruited patients, who were a mean age of 56 years, with an asthma disease duration of 9 years, underwent the following tests: fractional exhaled nitric oxide testing, spirometry, sputum induction, and sinus computed tomography scanning. They also had their blood tested for serum periostin, eosinophils, eotaxin, and immunoglobulin E levels.
Serum periostin levels were found to correlate with the results of fractional exhaled nitric oxide testing, and with blood and sputum eosinophil counts, with respective correlation coefficients of 0.36 (P = .003), 0.35 (P = .005), and 0.44 (P = .004).
In a separate study presented by Dr. Cecile Holweg of Genentech, several patient factors were found to influence the level of serum periostin. Using data from trials of the experimental asthma therapy lebrikizumab and the asthma therapy omalizumab (Xolair), the biologic variability in serum periostin and blood eosinophils was characterized according to patient demographics, asthma severity, concomitant medication use, and comorbidities, including upper-airway diseases.
Multivariate analysis showed that serum periostin levels were higher in patients with nasal polyps and in patients from South America and Asia. Conversely, serum periostin levels were lower in patients with high body mass index and in patients who were current smokers.
Raised eosinophil counts were also seen in patients with nasal polyps and lower eosinophil counts were observed in current smokers.
“These factors should be taken into account when making treatment decisions based on these biomarkers,” Dr. Holweg concluded.
Dr. Asano has received financial support from Novartis, AstraZeneca, Merck Sharp & Dohme, and Eisai Co. Dr. Holweg is an employee of Genentech.
LONDON – Measuring serum levels of the extracellular protein periostin could help identify patients with asthma who have comorbid upper-airway disease, according to research from a late-breaking oral abstract presented at the annual congress of the European Respiratory Society.
Periostin is known to be involved in the pathophysiology of upper-airway disease, linked to both airway remodeling and inflammation. Levels of periostin have been shown to be higher in patients with asthma, allergic rhinitis, and chronic rhinosinusitis than in healthy individuals, and there are data suggesting that it could be linked to severity. However, little is known about whether serum periostin can be used to detect and perhaps monitor upper-airway disease in patients with asthma.
Serum periostin levels were found to be higher in asthma patients with comorbid chronic rhinosinusitis, compared with those with no comorbid upper-airway disease (119.8 vs. 86.3 ng/mL; P = .04).
Levels of periostin in the serum were also significantly higher in asthma patients with chronic rhinosinusitis who also had nasal polyps than in those who did not have nasal polyps (143.3 vs. 94.0 ng/mL; P = .01).
“Serum periostin is a sensitive biomarker for detecting comorbid chronic rhinosinusitis, especially in patients with chronic rhinosinusitis with nasal polyps,” said Dr. Takamitsu Asano, who reported the findings at the meeting. Dr. Asano of Nagoya (Japan) City University Graduate School of Medical Sciences noted that the serum periostin could also reflect the severity of chronic rhinosinusitis in patients with asthma.
“Upper-airway diseases are considered risk factors for the exacerbation and poor control of asthma,” Dr. Asano explained. It is thought, he said, that 40%-50% of patients with asthma have comorbid chronic rhinosinusitis, and 57%-70% have comorbid allergic rhinitis.
Dr. Asano and colleagues at Nagoya City University and Saga (Japan) Medical School recruited 65 patients with stable asthma, with or without comorbid upper-airway disease, between July 2014 and December 2015. Of these patients, 20 had no comorbid upper-airway disease, 22 had rhinitis, 21 had chronic rhinosinusitis, and two had confirmed nasal polyps. Of the 21 patients with chronic rhinosinusitis, 10 had and 11 did not have nasal polyps. Patients’ diagnoses were checked by otorhinolaryngology specialists.
The recruited patients, who were a mean age of 56 years, with an asthma disease duration of 9 years, underwent the following tests: fractional exhaled nitric oxide testing, spirometry, sputum induction, and sinus computed tomography scanning. They also had their blood tested for serum periostin, eosinophils, eotaxin, and immunoglobulin E levels.
Serum periostin levels were found to correlate with the results of fractional exhaled nitric oxide testing, and with blood and sputum eosinophil counts, with respective correlation coefficients of 0.36 (P = .003), 0.35 (P = .005), and 0.44 (P = .004).
In a separate study presented by Dr. Cecile Holweg of Genentech, several patient factors were found to influence the level of serum periostin. Using data from trials of the experimental asthma therapy lebrikizumab and the asthma therapy omalizumab (Xolair), the biologic variability in serum periostin and blood eosinophils was characterized according to patient demographics, asthma severity, concomitant medication use, and comorbidities, including upper-airway diseases.
Multivariate analysis showed that serum periostin levels were higher in patients with nasal polyps and in patients from South America and Asia. Conversely, serum periostin levels were lower in patients with high body mass index and in patients who were current smokers.
Raised eosinophil counts were also seen in patients with nasal polyps and lower eosinophil counts were observed in current smokers.
“These factors should be taken into account when making treatment decisions based on these biomarkers,” Dr. Holweg concluded.
Dr. Asano has received financial support from Novartis, AstraZeneca, Merck Sharp & Dohme, and Eisai Co. Dr. Holweg is an employee of Genentech.
LONDON – Measuring serum levels of the extracellular protein periostin could help identify patients with asthma who have comorbid upper-airway disease, according to research from a late-breaking oral abstract presented at the annual congress of the European Respiratory Society.
Periostin is known to be involved in the pathophysiology of upper-airway disease, linked to both airway remodeling and inflammation. Levels of periostin have been shown to be higher in patients with asthma, allergic rhinitis, and chronic rhinosinusitis than in healthy individuals, and there are data suggesting that it could be linked to severity. However, little is known about whether serum periostin can be used to detect and perhaps monitor upper-airway disease in patients with asthma.
Serum periostin levels were found to be higher in asthma patients with comorbid chronic rhinosinusitis, compared with those with no comorbid upper-airway disease (119.8 vs. 86.3 ng/mL; P = .04).
Levels of periostin in the serum were also significantly higher in asthma patients with chronic rhinosinusitis who also had nasal polyps than in those who did not have nasal polyps (143.3 vs. 94.0 ng/mL; P = .01).
“Serum periostin is a sensitive biomarker for detecting comorbid chronic rhinosinusitis, especially in patients with chronic rhinosinusitis with nasal polyps,” said Dr. Takamitsu Asano, who reported the findings at the meeting. Dr. Asano of Nagoya (Japan) City University Graduate School of Medical Sciences noted that the serum periostin could also reflect the severity of chronic rhinosinusitis in patients with asthma.
“Upper-airway diseases are considered risk factors for the exacerbation and poor control of asthma,” Dr. Asano explained. It is thought, he said, that 40%-50% of patients with asthma have comorbid chronic rhinosinusitis, and 57%-70% have comorbid allergic rhinitis.
Dr. Asano and colleagues at Nagoya City University and Saga (Japan) Medical School recruited 65 patients with stable asthma, with or without comorbid upper-airway disease, between July 2014 and December 2015. Of these patients, 20 had no comorbid upper-airway disease, 22 had rhinitis, 21 had chronic rhinosinusitis, and two had confirmed nasal polyps. Of the 21 patients with chronic rhinosinusitis, 10 had and 11 did not have nasal polyps. Patients’ diagnoses were checked by otorhinolaryngology specialists.
The recruited patients, who were a mean age of 56 years, with an asthma disease duration of 9 years, underwent the following tests: fractional exhaled nitric oxide testing, spirometry, sputum induction, and sinus computed tomography scanning. They also had their blood tested for serum periostin, eosinophils, eotaxin, and immunoglobulin E levels.
Serum periostin levels were found to correlate with the results of fractional exhaled nitric oxide testing, and with blood and sputum eosinophil counts, with respective correlation coefficients of 0.36 (P = .003), 0.35 (P = .005), and 0.44 (P = .004).
In a separate study presented by Dr. Cecile Holweg of Genentech, several patient factors were found to influence the level of serum periostin. Using data from trials of the experimental asthma therapy lebrikizumab and the asthma therapy omalizumab (Xolair), the biologic variability in serum periostin and blood eosinophils was characterized according to patient demographics, asthma severity, concomitant medication use, and comorbidities, including upper-airway diseases.
Multivariate analysis showed that serum periostin levels were higher in patients with nasal polyps and in patients from South America and Asia. Conversely, serum periostin levels were lower in patients with high body mass index and in patients who were current smokers.
Raised eosinophil counts were also seen in patients with nasal polyps and lower eosinophil counts were observed in current smokers.
“These factors should be taken into account when making treatment decisions based on these biomarkers,” Dr. Holweg concluded.
Dr. Asano has received financial support from Novartis, AstraZeneca, Merck Sharp & Dohme, and Eisai Co. Dr. Holweg is an employee of Genentech.
AT THE ERS CONGRESS 2016
Key clinical point: Measuring serum periostin could be useful for chronic rhinosinusitis detection in asthma patients.
Major finding: Serum periostin levels were higher in patients with comorbid chronic rhinosinusitis, compared with those with no comorbid upper-airway disease (119.8 vs. 86.3 ng/mL, P = .04).
Data source: Prospective study of comorbid upper-airway disease, rhinitis, and chronic rhinosinusitis in 65 patients with asthma.
Disclosures: Dr. Asano has received financial support from Novartis, AstraZeneca, Merck Sharp & Dohme, and Eisai Co.
Lung cryobiopsies could reduce need for surgical biopsy
LONDON – The vast majority of surgical lung biopsies currently used to diagnose interstitial lung diseases (ILDs) could be avoided, suggests research presented at the annual congress of the European Respiratory Society.
During an oral presentation, Benjamin Bondue, MD, of Hopital Erasme, Brussels, presented the preliminary results of a Belgian prospective study evaluating the role of transbronchial lung cryobiopsies in 24 patients with undefined ILD treated at three participating centers.
Cryobiopsies were found to have a diagnostic yield of 79%, meaning that patients might be able to avoid undergoing a more invasive surgical removal of tissue in many cases. Compared with surgical biopsy, cryobiopsies offered the potential advantage of lower morbidity and shorter hospitalization time, Dr. Bondue said. He reported that patients needed to stay in hospital just 1.2 days after the procedure in the study.
“Our data also show that there is some benefit of surgical lung biopsy after cryobiopsy if we identify an NSIP [nonspecific interstitial pneumonia] pattern or idiopathic conditions, or if we cannot obtain a clear pathological diagnosis,” he reported. Acknowledging the study was small and conducted in a single center, he said the use of cryobiopsies following surgical biopsy might be worth further study.
Transbronchial lung cryobiopsy is a relatively new technique that uses a cryoprobe inserted down through a bronchoscope about 1-2 cm from the thoracic wall. Once in place, the probe is cooled for between 3 and 6 seconds, lung tissue freezes to the probe, and the probe and bronchoscope are removed together. This method allows for larger samples of tissue to be taken than does traditional transbronchial biopsy, which involves using large forceps to obtain tissue samples (Respirology. 2014;19:645-54).
In the Belgian study, Dr. Bondue noted that a Fogarty balloon was used to control any bleeding and that four transbronchial lung cryobiopsies were obtained from two different segments of the same lobe of a patient’s lungs. All biopsies were then analyzed by an expert pathologist in ILDs, and reviewed by two other expert pathologists when needed. The mean sample size obtained was 16 mm2.
The patients included in the study had undergone chest X-ray and had inconclusive findings in the majority (84%) of cases. They then had the option to undergo cryobiopsy or surgical lung biopsy, with the latter performed following discussion among a multidisciplinary team’s members.
Following cryobiopsy, 16 of the 24 patients – who were a mean age of 62 years, and over half of whom were past (56%) or current (12%) smokers – were diagnosed with a specific pattern of ILD not due to NSIP. Of the 16 cases, 6 were due to hypersensitive pneumonitis, 4 were due to interstitial pulmonary fibrosis, and 2 were due to sarcoidosis. The other four cases included patients with one of the following conditions: adenocarcinoma, desquamative interstitial pneumonia, eosinophilic pneumonia, and amyloidosis.
Six of the 24 cases were defined as NSIP, with 2 reclassified as definite and 1 as probable hypersensitive pneumonitis, after discussion within the multidisciplinary team.
Five patients – three who had been diagnosed with NSIP and two who had been given no pathological diagnosis after cryobiopsy – underwent surgical lung biopsy. Of these, following the surgical biopsies, only one patient was considered to have NSIP and the other four were eventually diagnosed with interstitial pulmonary fibrosis.
In terms of safety, five patients experienced pneumothorax, two patients required chest drainage, two needed simple aspiration and one underwent observation. In the majority of cases, patients experienced mild bleeding, with only one patient having experienced severe bleeding. During this study, none of the participants experienced significant chest pain, acute exacerbations, or infections, and none of them died.
Dr. Bondue has received research grants and fees for consulting from Boehringer Ingelheim and Roche.
LONDON – The vast majority of surgical lung biopsies currently used to diagnose interstitial lung diseases (ILDs) could be avoided, suggests research presented at the annual congress of the European Respiratory Society.
During an oral presentation, Benjamin Bondue, MD, of Hopital Erasme, Brussels, presented the preliminary results of a Belgian prospective study evaluating the role of transbronchial lung cryobiopsies in 24 patients with undefined ILD treated at three participating centers.
Cryobiopsies were found to have a diagnostic yield of 79%, meaning that patients might be able to avoid undergoing a more invasive surgical removal of tissue in many cases. Compared with surgical biopsy, cryobiopsies offered the potential advantage of lower morbidity and shorter hospitalization time, Dr. Bondue said. He reported that patients needed to stay in hospital just 1.2 days after the procedure in the study.
“Our data also show that there is some benefit of surgical lung biopsy after cryobiopsy if we identify an NSIP [nonspecific interstitial pneumonia] pattern or idiopathic conditions, or if we cannot obtain a clear pathological diagnosis,” he reported. Acknowledging the study was small and conducted in a single center, he said the use of cryobiopsies following surgical biopsy might be worth further study.
Transbronchial lung cryobiopsy is a relatively new technique that uses a cryoprobe inserted down through a bronchoscope about 1-2 cm from the thoracic wall. Once in place, the probe is cooled for between 3 and 6 seconds, lung tissue freezes to the probe, and the probe and bronchoscope are removed together. This method allows for larger samples of tissue to be taken than does traditional transbronchial biopsy, which involves using large forceps to obtain tissue samples (Respirology. 2014;19:645-54).
In the Belgian study, Dr. Bondue noted that a Fogarty balloon was used to control any bleeding and that four transbronchial lung cryobiopsies were obtained from two different segments of the same lobe of a patient’s lungs. All biopsies were then analyzed by an expert pathologist in ILDs, and reviewed by two other expert pathologists when needed. The mean sample size obtained was 16 mm2.
The patients included in the study had undergone chest X-ray and had inconclusive findings in the majority (84%) of cases. They then had the option to undergo cryobiopsy or surgical lung biopsy, with the latter performed following discussion among a multidisciplinary team’s members.
Following cryobiopsy, 16 of the 24 patients – who were a mean age of 62 years, and over half of whom were past (56%) or current (12%) smokers – were diagnosed with a specific pattern of ILD not due to NSIP. Of the 16 cases, 6 were due to hypersensitive pneumonitis, 4 were due to interstitial pulmonary fibrosis, and 2 were due to sarcoidosis. The other four cases included patients with one of the following conditions: adenocarcinoma, desquamative interstitial pneumonia, eosinophilic pneumonia, and amyloidosis.
Six of the 24 cases were defined as NSIP, with 2 reclassified as definite and 1 as probable hypersensitive pneumonitis, after discussion within the multidisciplinary team.
Five patients – three who had been diagnosed with NSIP and two who had been given no pathological diagnosis after cryobiopsy – underwent surgical lung biopsy. Of these, following the surgical biopsies, only one patient was considered to have NSIP and the other four were eventually diagnosed with interstitial pulmonary fibrosis.
In terms of safety, five patients experienced pneumothorax, two patients required chest drainage, two needed simple aspiration and one underwent observation. In the majority of cases, patients experienced mild bleeding, with only one patient having experienced severe bleeding. During this study, none of the participants experienced significant chest pain, acute exacerbations, or infections, and none of them died.
Dr. Bondue has received research grants and fees for consulting from Boehringer Ingelheim and Roche.
LONDON – The vast majority of surgical lung biopsies currently used to diagnose interstitial lung diseases (ILDs) could be avoided, suggests research presented at the annual congress of the European Respiratory Society.
During an oral presentation, Benjamin Bondue, MD, of Hopital Erasme, Brussels, presented the preliminary results of a Belgian prospective study evaluating the role of transbronchial lung cryobiopsies in 24 patients with undefined ILD treated at three participating centers.
Cryobiopsies were found to have a diagnostic yield of 79%, meaning that patients might be able to avoid undergoing a more invasive surgical removal of tissue in many cases. Compared with surgical biopsy, cryobiopsies offered the potential advantage of lower morbidity and shorter hospitalization time, Dr. Bondue said. He reported that patients needed to stay in hospital just 1.2 days after the procedure in the study.
“Our data also show that there is some benefit of surgical lung biopsy after cryobiopsy if we identify an NSIP [nonspecific interstitial pneumonia] pattern or idiopathic conditions, or if we cannot obtain a clear pathological diagnosis,” he reported. Acknowledging the study was small and conducted in a single center, he said the use of cryobiopsies following surgical biopsy might be worth further study.
Transbronchial lung cryobiopsy is a relatively new technique that uses a cryoprobe inserted down through a bronchoscope about 1-2 cm from the thoracic wall. Once in place, the probe is cooled for between 3 and 6 seconds, lung tissue freezes to the probe, and the probe and bronchoscope are removed together. This method allows for larger samples of tissue to be taken than does traditional transbronchial biopsy, which involves using large forceps to obtain tissue samples (Respirology. 2014;19:645-54).
In the Belgian study, Dr. Bondue noted that a Fogarty balloon was used to control any bleeding and that four transbronchial lung cryobiopsies were obtained from two different segments of the same lobe of a patient’s lungs. All biopsies were then analyzed by an expert pathologist in ILDs, and reviewed by two other expert pathologists when needed. The mean sample size obtained was 16 mm2.
The patients included in the study had undergone chest X-ray and had inconclusive findings in the majority (84%) of cases. They then had the option to undergo cryobiopsy or surgical lung biopsy, with the latter performed following discussion among a multidisciplinary team’s members.
Following cryobiopsy, 16 of the 24 patients – who were a mean age of 62 years, and over half of whom were past (56%) or current (12%) smokers – were diagnosed with a specific pattern of ILD not due to NSIP. Of the 16 cases, 6 were due to hypersensitive pneumonitis, 4 were due to interstitial pulmonary fibrosis, and 2 were due to sarcoidosis. The other four cases included patients with one of the following conditions: adenocarcinoma, desquamative interstitial pneumonia, eosinophilic pneumonia, and amyloidosis.
Six of the 24 cases were defined as NSIP, with 2 reclassified as definite and 1 as probable hypersensitive pneumonitis, after discussion within the multidisciplinary team.
Five patients – three who had been diagnosed with NSIP and two who had been given no pathological diagnosis after cryobiopsy – underwent surgical lung biopsy. Of these, following the surgical biopsies, only one patient was considered to have NSIP and the other four were eventually diagnosed with interstitial pulmonary fibrosis.
In terms of safety, five patients experienced pneumothorax, two patients required chest drainage, two needed simple aspiration and one underwent observation. In the majority of cases, patients experienced mild bleeding, with only one patient having experienced severe bleeding. During this study, none of the participants experienced significant chest pain, acute exacerbations, or infections, and none of them died.
Dr. Bondue has received research grants and fees for consulting from Boehringer Ingelheim and Roche.
AT THE ERS CONGRESS 2016 LONDON
Key clinical point: Transbronchial lung cryobiopsies are useful for the diagnosis of interstitial lung diseases and could help avoid surgical lung biopsies.
Major finding: Transbronchial lung cryobiopsy had a diagnostic yield of 79%.
Data source: Single-center study of 24 patients with interstitial lung diseases who underwent transbronchial lung cryobiopsies, surgical lung biopsies, or both.
Disclosures: Dr. Bondue has received research grants and fees for consulting from Boehringer Ingelheim and Roche.
Smoking, vitamin D deficiency linked to early MS disability
LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.
Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.
However, neither vitamin D deficiency nor current smoking predicted the conversion of CIS to clinically definite multiple sclerosis (CDMS), said María Zuluaga, MD, of the Centre d’Esclerosi Múltiple de Catalunya at Vall d’Hebron University Hospital in Barcelona.
Environmental factors such as vitamin D levels and smoking have been purported to play a role in the development of CIS to CDMS, Dr. Zuluaga explained at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood samples collected within 6 months of a diagnosis of CIS were examined and vitamin D deficiency defined as normal, mild, moderate, or severe based on serum 25-hydroxy vitamin D of greater than 20, 16-20, 8-15, and less that 8 ng/mL.
Levels of the nicotine metabolite cotinine in the blood were used as a proxy for current smoking. Cotinine has a half-life of around 20 hours and smokers – active or passive – have a level of 14 ng/mL or more while nonsmokers have a level of less than 14 ng/mL.
The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.
Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.
However, neither vitamin D deficiency nor current smoking predicted the conversion of CIS to clinically definite multiple sclerosis (CDMS), said María Zuluaga, MD, of the Centre d’Esclerosi Múltiple de Catalunya at Vall d’Hebron University Hospital in Barcelona.
Environmental factors such as vitamin D levels and smoking have been purported to play a role in the development of CIS to CDMS, Dr. Zuluaga explained at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood samples collected within 6 months of a diagnosis of CIS were examined and vitamin D deficiency defined as normal, mild, moderate, or severe based on serum 25-hydroxy vitamin D of greater than 20, 16-20, 8-15, and less that 8 ng/mL.
Levels of the nicotine metabolite cotinine in the blood were used as a proxy for current smoking. Cotinine has a half-life of around 20 hours and smokers – active or passive – have a level of 14 ng/mL or more while nonsmokers have a level of less than 14 ng/mL.
The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.
Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.
However, neither vitamin D deficiency nor current smoking predicted the conversion of CIS to clinically definite multiple sclerosis (CDMS), said María Zuluaga, MD, of the Centre d’Esclerosi Múltiple de Catalunya at Vall d’Hebron University Hospital in Barcelona.
Environmental factors such as vitamin D levels and smoking have been purported to play a role in the development of CIS to CDMS, Dr. Zuluaga explained at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood samples collected within 6 months of a diagnosis of CIS were examined and vitamin D deficiency defined as normal, mild, moderate, or severe based on serum 25-hydroxy vitamin D of greater than 20, 16-20, 8-15, and less that 8 ng/mL.
Levels of the nicotine metabolite cotinine in the blood were used as a proxy for current smoking. Cotinine has a half-life of around 20 hours and smokers – active or passive – have a level of 14 ng/mL or more while nonsmokers have a level of less than 14 ng/mL.
The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
Key clinical point:
Major finding: Patients with a serum 25-hydroxy vitamin D level of less than 8.0 ng/mL showed an increased risk for disability in a multivariate analysis (HR, 2.3; P = .049). Nonsmokers were significantly less likely to have disability progression (HR, 0.4; P = .002).
Data source: Barcelona CIS cohort of 1,127 individuals
Disclosures: The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
Fluoxetine fails to slow progressive multiple sclerosis
LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.
The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.
“The progressive phase of MS remains an ill-understood part of the disease and it is a holy grail to find a drug that can stop this progression,” Dr. Cambron said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The rationale for looking at whether fluoxetine, a well-studied antidepressant drug, could be such a drug, was that it had several neuroprotective features – it has been shown to stimulate the release of brain-derived neurotrophic factor, stimulate metabolism in astrocytes, and lower glutamatergic toxicity, she said. All of these could potentially help prevent axonal degeneration.
The FLUOX-PMS (Fluoxetine in Progressive Multiple Sclerosis) trial (Trials. 2014;15:37) ran from 2012 to June 2016 and enrolled patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS), as defined by the 2010 McDonald criteria. A total of 137 patients were enrolled, and 69 were randomized to treatment with fluoxetine 40 mg/day and 68 were randomized to placebo. Fluoxetine treatment was started at a dose of 20 mg and titrated to the full 40-mg dose by 12 weeks.
Patient demographics were mostly similar between the groups. Around 44% of patients in the fluoxetine and placebo groups were female; roughly 40% had PPMS and 60% had SPMS in both groups; the mean Expanded Disability Status Scale score was 5.2 in both groups; the mean age was 54 and 51 years, respectively; and the disease duration was between 18 and 20 years.
Dr. Cambron also reported that the trials’ secondary endpoints showed no advantage of using fluoxetine over placebo. The proportion of patients without sustained progression during the trial was similar among the fluoxetine- and placebo-treated patients, at a respective 69.6% and 61.8% (P = .434). The proportion of patients with a stable Hauser Ambulation Index was also similar (P = .371).
The primary and secondary endpoints were assessed every 3 months in the trial. Patients also underwent cognitive testing, completed the Beck Depression Inventory-II, and Modified Fatigue Impact Scale before treatment and at 48 and 108 weeks after treatment with fluoxetine or placebo. Brain MRI was also performed at baseline and at week 108. The results of these measurements have yet to be analyzed.
Although patients in the fluoxetine group versus the placebo arm experienced more side effects, there was no evidence of an excess of severe adverse events.
“Unfortunately, our study was inconclusive because we failed to show a statistical significant difference between the placebo arm and the fluoxetine group, although I’m convinced that there’s a trend that can certainly not be ignored,” Dr. Cambron maintained. “Probably there was not enough progression in the study and possibly the study duration was too short, she suggested, “but it remains challenging to study these patients for a long period of time, especially with a placebo-controlled design.”
The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.
The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.
“The progressive phase of MS remains an ill-understood part of the disease and it is a holy grail to find a drug that can stop this progression,” Dr. Cambron said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The rationale for looking at whether fluoxetine, a well-studied antidepressant drug, could be such a drug, was that it had several neuroprotective features – it has been shown to stimulate the release of brain-derived neurotrophic factor, stimulate metabolism in astrocytes, and lower glutamatergic toxicity, she said. All of these could potentially help prevent axonal degeneration.
The FLUOX-PMS (Fluoxetine in Progressive Multiple Sclerosis) trial (Trials. 2014;15:37) ran from 2012 to June 2016 and enrolled patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS), as defined by the 2010 McDonald criteria. A total of 137 patients were enrolled, and 69 were randomized to treatment with fluoxetine 40 mg/day and 68 were randomized to placebo. Fluoxetine treatment was started at a dose of 20 mg and titrated to the full 40-mg dose by 12 weeks.
Patient demographics were mostly similar between the groups. Around 44% of patients in the fluoxetine and placebo groups were female; roughly 40% had PPMS and 60% had SPMS in both groups; the mean Expanded Disability Status Scale score was 5.2 in both groups; the mean age was 54 and 51 years, respectively; and the disease duration was between 18 and 20 years.
Dr. Cambron also reported that the trials’ secondary endpoints showed no advantage of using fluoxetine over placebo. The proportion of patients without sustained progression during the trial was similar among the fluoxetine- and placebo-treated patients, at a respective 69.6% and 61.8% (P = .434). The proportion of patients with a stable Hauser Ambulation Index was also similar (P = .371).
The primary and secondary endpoints were assessed every 3 months in the trial. Patients also underwent cognitive testing, completed the Beck Depression Inventory-II, and Modified Fatigue Impact Scale before treatment and at 48 and 108 weeks after treatment with fluoxetine or placebo. Brain MRI was also performed at baseline and at week 108. The results of these measurements have yet to be analyzed.
Although patients in the fluoxetine group versus the placebo arm experienced more side effects, there was no evidence of an excess of severe adverse events.
“Unfortunately, our study was inconclusive because we failed to show a statistical significant difference between the placebo arm and the fluoxetine group, although I’m convinced that there’s a trend that can certainly not be ignored,” Dr. Cambron maintained. “Probably there was not enough progression in the study and possibly the study duration was too short, she suggested, “but it remains challenging to study these patients for a long period of time, especially with a placebo-controlled design.”
The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.
The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.
“The progressive phase of MS remains an ill-understood part of the disease and it is a holy grail to find a drug that can stop this progression,” Dr. Cambron said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The rationale for looking at whether fluoxetine, a well-studied antidepressant drug, could be such a drug, was that it had several neuroprotective features – it has been shown to stimulate the release of brain-derived neurotrophic factor, stimulate metabolism in astrocytes, and lower glutamatergic toxicity, she said. All of these could potentially help prevent axonal degeneration.
The FLUOX-PMS (Fluoxetine in Progressive Multiple Sclerosis) trial (Trials. 2014;15:37) ran from 2012 to June 2016 and enrolled patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS), as defined by the 2010 McDonald criteria. A total of 137 patients were enrolled, and 69 were randomized to treatment with fluoxetine 40 mg/day and 68 were randomized to placebo. Fluoxetine treatment was started at a dose of 20 mg and titrated to the full 40-mg dose by 12 weeks.
Patient demographics were mostly similar between the groups. Around 44% of patients in the fluoxetine and placebo groups were female; roughly 40% had PPMS and 60% had SPMS in both groups; the mean Expanded Disability Status Scale score was 5.2 in both groups; the mean age was 54 and 51 years, respectively; and the disease duration was between 18 and 20 years.
Dr. Cambron also reported that the trials’ secondary endpoints showed no advantage of using fluoxetine over placebo. The proportion of patients without sustained progression during the trial was similar among the fluoxetine- and placebo-treated patients, at a respective 69.6% and 61.8% (P = .434). The proportion of patients with a stable Hauser Ambulation Index was also similar (P = .371).
The primary and secondary endpoints were assessed every 3 months in the trial. Patients also underwent cognitive testing, completed the Beck Depression Inventory-II, and Modified Fatigue Impact Scale before treatment and at 48 and 108 weeks after treatment with fluoxetine or placebo. Brain MRI was also performed at baseline and at week 108. The results of these measurements have yet to be analyzed.
Although patients in the fluoxetine group versus the placebo arm experienced more side effects, there was no evidence of an excess of severe adverse events.
“Unfortunately, our study was inconclusive because we failed to show a statistical significant difference between the placebo arm and the fluoxetine group, although I’m convinced that there’s a trend that can certainly not be ignored,” Dr. Cambron maintained. “Probably there was not enough progression in the study and possibly the study duration was too short, she suggested, “but it remains challenging to study these patients for a long period of time, especially with a placebo-controlled design.”
The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
Key clinical point:
Major finding: There was no difference in the time to confirmed disease progression between fluoxetine- and placebo-treated patients (P = .07).
Data source: FLUOX-PMS, a multicenter, randomized, double-blind, placebo-controlled clinical study of 137 patients with primary or secondary progressive multiple sclerosis treated with fluoxetine or placebo.
Disclosures: The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
Neuronal protein could be multiple sclerosis blood biomarker
LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.
“These findings support a role for neurofilament light chain (NfL) as a peripheral biomarker for MS,” said the reporting investigator Jens Kuhle, MD, of University Hospital Basel (Switzerland).
“There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials,” Dr. Kuhle said.
He added: “NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF [cerebral spinal fluid], and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.
Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that using an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623365).
In the current study, a Single Molecule Array Immunoassay (Quanterix) was used. This is based on an enzyme-linked immunoassay with more than 280,000 wells and developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood” when compared with conventional ELISA or electrochemiluminescence (Clin Chem Lab Med. 2016;54[10]:1655-61).
Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and these were compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.
Patients with two or more relapses in the past 24 months had significantly higher NfL levels than did those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.
Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at 6 months being highly predictive of brain volume changes at 24 months (P less than .0001).
And, in this preliminary dataset, patients who had been treated with fingolimod (Gilenya) versus placebo in the FREEDOMS trial had lower NfL levels at 6, 12, and 24 months.
Dr. Kuhle observed that the findings of this study were corroborated by other study data presented during the poster sessions at the ECTRIMS 2016 meeting.
The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.
“These findings support a role for neurofilament light chain (NfL) as a peripheral biomarker for MS,” said the reporting investigator Jens Kuhle, MD, of University Hospital Basel (Switzerland).
“There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials,” Dr. Kuhle said.
He added: “NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF [cerebral spinal fluid], and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.
Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that using an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623365).
In the current study, a Single Molecule Array Immunoassay (Quanterix) was used. This is based on an enzyme-linked immunoassay with more than 280,000 wells and developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood” when compared with conventional ELISA or electrochemiluminescence (Clin Chem Lab Med. 2016;54[10]:1655-61).
Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and these were compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.
Patients with two or more relapses in the past 24 months had significantly higher NfL levels than did those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.
Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at 6 months being highly predictive of brain volume changes at 24 months (P less than .0001).
And, in this preliminary dataset, patients who had been treated with fingolimod (Gilenya) versus placebo in the FREEDOMS trial had lower NfL levels at 6, 12, and 24 months.
Dr. Kuhle observed that the findings of this study were corroborated by other study data presented during the poster sessions at the ECTRIMS 2016 meeting.
The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.
“These findings support a role for neurofilament light chain (NfL) as a peripheral biomarker for MS,” said the reporting investigator Jens Kuhle, MD, of University Hospital Basel (Switzerland).
“There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials,” Dr. Kuhle said.
He added: “NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF [cerebral spinal fluid], and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.
Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that using an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623365).
In the current study, a Single Molecule Array Immunoassay (Quanterix) was used. This is based on an enzyme-linked immunoassay with more than 280,000 wells and developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood” when compared with conventional ELISA or electrochemiluminescence (Clin Chem Lab Med. 2016;54[10]:1655-61).
Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and these were compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.
Patients with two or more relapses in the past 24 months had significantly higher NfL levels than did those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.
Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at 6 months being highly predictive of brain volume changes at 24 months (P less than .0001).
And, in this preliminary dataset, patients who had been treated with fingolimod (Gilenya) versus placebo in the FREEDOMS trial had lower NfL levels at 6, 12, and 24 months.
Dr. Kuhle observed that the findings of this study were corroborated by other study data presented during the poster sessions at the ECTRIMS 2016 meeting.
The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
Key clinical point:
Major finding: Blood NfL levels were significantly higher in MS patients than in healthy individuals (28.1 vs. 12.5 pg/mL; P less than .0001); NfL levels were also increased in patients with greater disease activity seen on MRI.
Data source: Proof-of-concept study involving blood samples taken from 149 patients with relapsing-remitting MS (RRMS) participating in the phase III FREEDOMS trial and 29 healthy individuals without MS from a separate biobank.
Disclosures: The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
Mobility benefits of MS drug dalfampridine confirmed by patient-reported outcomes
LONDON – Patients with relapsing-remitting multiple sclerosis reported that their ability to walk was significantly improved following 6 months of treatment with extended-release dalfampridine – compared with patients on placebo – in a double-blind, randomized trial.
In the ENHANCE study, 43.2% of the 315 patients treated with extended-release dalfampridine (dalfampridine-ER; Ampyra) and 33.6% of the 318 who were given placebo achieved a clinically meaningful improvement of 8 or more points on the 12-item MS Walking Scale (MSWS-12) measured at week 24.
The odds ratio (OR) was 1.61, highlighting a significant difference between the two study arms (P = .006).
“This is one of the only studies to use a PRO [patient-reported outcome] as the primary outcome and to use an a priori threshold of clinical meaningfulness,” said Jeremy Hobart, MD, of Plymouth Hospitals NHS Trust (England), who reported the study’s findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. This is an important, and challenging, development in MS trials, he added.
“We are all aware that walking impairments are one of the hallmarks of multiple sclerosis,” Dr. Hobart said, adding that it affects the “vast majority” of patients.
Dalfampridine-ER, which is known as prolonged-release fampridine in Europe, is the only therapy licensed to improve walking in MS, he observed. The pivotal studies that led to the drug’s approval, however, were of relatively short duration and the ENHANCE study was conducted to answer questions that have been raised about the durability of its effect on patients’ mobility.
Patients in ENHANCE received either dalfampridine-ER at a twice-daily dose of 10 mg or placebo for 24 weeks. The mean age of patients in each group was 49 and 48 years, respectively, and 59% and 57% of recruited patients in each arm were female. Patients were stratified according to their baseline Expanded Disability Status Scale (EDSS) score, with 78% and 77% in the dalfampridine-ER and placebo groups having a score of 6 or less.
Dr. Hobart noted that the mean change in MSWS-12 scores over time and an analysis of the cumulative proportion of responders at any particular threshold score on the MWSW-12 showed a clear benefit of dalfampridine-ER treatment over placebo.
The study investigators also assessed patients’ balance via the Timed Up and Go (TUG) test, with a benefit threshold set at obtaining at least a 15% or more improvement at 24 weeks. Significantly more dalfampridine-ER–treated than placebo-treated patients achieved this threshold (43.4% vs. 34.7%; OR, 1.46; P = .03).
There was a significant improvement between the two study arms on the 29-item physical scale of the Multiple Sclerosis Impact Scale (P less than .001).
However, there was no change seen in upper extremity function, with similar mean changes in the Berg Balance Scale score and the ABILHAND score at 24 weeks. The mean baseline scores for both of these measures were high, Dr. Hobart observed, which probably affected the findings. That said, patients with a baseline EDSS of 6 or higher had greater improvement in ABILHAND scores if they had received dalfampridine-ER, compared with placebo, but the difference was not statistically significant.
The safety profile was consistent with what has been seen in other trials, Dr. Hobart said, and there were no new safety concerns raised.
“The findings from ENHANCE expand and tend to ... confirm the favorable risk-benefit profile established in prior pivotal trials,” he said.
Biogen sponsored the study. Dr. Hobart disclosed receiving fees, honoraria, and research support from Biogen, Acorda, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita.
LONDON – Patients with relapsing-remitting multiple sclerosis reported that their ability to walk was significantly improved following 6 months of treatment with extended-release dalfampridine – compared with patients on placebo – in a double-blind, randomized trial.
In the ENHANCE study, 43.2% of the 315 patients treated with extended-release dalfampridine (dalfampridine-ER; Ampyra) and 33.6% of the 318 who were given placebo achieved a clinically meaningful improvement of 8 or more points on the 12-item MS Walking Scale (MSWS-12) measured at week 24.
The odds ratio (OR) was 1.61, highlighting a significant difference between the two study arms (P = .006).
“This is one of the only studies to use a PRO [patient-reported outcome] as the primary outcome and to use an a priori threshold of clinical meaningfulness,” said Jeremy Hobart, MD, of Plymouth Hospitals NHS Trust (England), who reported the study’s findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. This is an important, and challenging, development in MS trials, he added.
“We are all aware that walking impairments are one of the hallmarks of multiple sclerosis,” Dr. Hobart said, adding that it affects the “vast majority” of patients.
Dalfampridine-ER, which is known as prolonged-release fampridine in Europe, is the only therapy licensed to improve walking in MS, he observed. The pivotal studies that led to the drug’s approval, however, were of relatively short duration and the ENHANCE study was conducted to answer questions that have been raised about the durability of its effect on patients’ mobility.
Patients in ENHANCE received either dalfampridine-ER at a twice-daily dose of 10 mg or placebo for 24 weeks. The mean age of patients in each group was 49 and 48 years, respectively, and 59% and 57% of recruited patients in each arm were female. Patients were stratified according to their baseline Expanded Disability Status Scale (EDSS) score, with 78% and 77% in the dalfampridine-ER and placebo groups having a score of 6 or less.
Dr. Hobart noted that the mean change in MSWS-12 scores over time and an analysis of the cumulative proportion of responders at any particular threshold score on the MWSW-12 showed a clear benefit of dalfampridine-ER treatment over placebo.
The study investigators also assessed patients’ balance via the Timed Up and Go (TUG) test, with a benefit threshold set at obtaining at least a 15% or more improvement at 24 weeks. Significantly more dalfampridine-ER–treated than placebo-treated patients achieved this threshold (43.4% vs. 34.7%; OR, 1.46; P = .03).
There was a significant improvement between the two study arms on the 29-item physical scale of the Multiple Sclerosis Impact Scale (P less than .001).
However, there was no change seen in upper extremity function, with similar mean changes in the Berg Balance Scale score and the ABILHAND score at 24 weeks. The mean baseline scores for both of these measures were high, Dr. Hobart observed, which probably affected the findings. That said, patients with a baseline EDSS of 6 or higher had greater improvement in ABILHAND scores if they had received dalfampridine-ER, compared with placebo, but the difference was not statistically significant.
The safety profile was consistent with what has been seen in other trials, Dr. Hobart said, and there were no new safety concerns raised.
“The findings from ENHANCE expand and tend to ... confirm the favorable risk-benefit profile established in prior pivotal trials,” he said.
Biogen sponsored the study. Dr. Hobart disclosed receiving fees, honoraria, and research support from Biogen, Acorda, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita.
LONDON – Patients with relapsing-remitting multiple sclerosis reported that their ability to walk was significantly improved following 6 months of treatment with extended-release dalfampridine – compared with patients on placebo – in a double-blind, randomized trial.
In the ENHANCE study, 43.2% of the 315 patients treated with extended-release dalfampridine (dalfampridine-ER; Ampyra) and 33.6% of the 318 who were given placebo achieved a clinically meaningful improvement of 8 or more points on the 12-item MS Walking Scale (MSWS-12) measured at week 24.
The odds ratio (OR) was 1.61, highlighting a significant difference between the two study arms (P = .006).
“This is one of the only studies to use a PRO [patient-reported outcome] as the primary outcome and to use an a priori threshold of clinical meaningfulness,” said Jeremy Hobart, MD, of Plymouth Hospitals NHS Trust (England), who reported the study’s findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. This is an important, and challenging, development in MS trials, he added.
“We are all aware that walking impairments are one of the hallmarks of multiple sclerosis,” Dr. Hobart said, adding that it affects the “vast majority” of patients.
Dalfampridine-ER, which is known as prolonged-release fampridine in Europe, is the only therapy licensed to improve walking in MS, he observed. The pivotal studies that led to the drug’s approval, however, were of relatively short duration and the ENHANCE study was conducted to answer questions that have been raised about the durability of its effect on patients’ mobility.
Patients in ENHANCE received either dalfampridine-ER at a twice-daily dose of 10 mg or placebo for 24 weeks. The mean age of patients in each group was 49 and 48 years, respectively, and 59% and 57% of recruited patients in each arm were female. Patients were stratified according to their baseline Expanded Disability Status Scale (EDSS) score, with 78% and 77% in the dalfampridine-ER and placebo groups having a score of 6 or less.
Dr. Hobart noted that the mean change in MSWS-12 scores over time and an analysis of the cumulative proportion of responders at any particular threshold score on the MWSW-12 showed a clear benefit of dalfampridine-ER treatment over placebo.
The study investigators also assessed patients’ balance via the Timed Up and Go (TUG) test, with a benefit threshold set at obtaining at least a 15% or more improvement at 24 weeks. Significantly more dalfampridine-ER–treated than placebo-treated patients achieved this threshold (43.4% vs. 34.7%; OR, 1.46; P = .03).
There was a significant improvement between the two study arms on the 29-item physical scale of the Multiple Sclerosis Impact Scale (P less than .001).
However, there was no change seen in upper extremity function, with similar mean changes in the Berg Balance Scale score and the ABILHAND score at 24 weeks. The mean baseline scores for both of these measures were high, Dr. Hobart observed, which probably affected the findings. That said, patients with a baseline EDSS of 6 or higher had greater improvement in ABILHAND scores if they had received dalfampridine-ER, compared with placebo, but the difference was not statistically significant.
The safety profile was consistent with what has been seen in other trials, Dr. Hobart said, and there were no new safety concerns raised.
“The findings from ENHANCE expand and tend to ... confirm the favorable risk-benefit profile established in prior pivotal trials,” he said.
Biogen sponsored the study. Dr. Hobart disclosed receiving fees, honoraria, and research support from Biogen, Acorda, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita.
AT ECTRIMS 2016
Key clinical point:The findings support the continued use of extended-release dalfampridine to improve multiple sclerosis patients’ mobility.
Major finding: Twelve-item Multiple Sclerosis Walking Scale scores at 24 weeks were significantly improved in more patients treated with dalfampridine, compared with those on placebo (43.2% vs. 33.6%; OR 1.61, P = .006).
Data source: Double-blind, randomized, placebo-controlled study of 636 patients with relapsing-remitting multiple sclerosis (RRMS) treated with extended-release dalfampridine or placebo for 24 weeks.
Disclosures: Biogen sponsored the study. Dr. Hobart disclosed receiving fees, honoraria, and research support from Biogen, Acorda, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita.
Alemtuzumab, natalizumab found equally effective for relapsing-remitting MS
LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.
“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.
Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.
Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.
Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.
Versus interferon beta-1a
The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.
In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.
Versus fingolimod
The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.
“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.
Versus natalizumab
The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.
Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.
A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.
Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.
Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.
“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.
Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.
Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.
Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.
Versus interferon beta-1a
The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.
In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.
Versus fingolimod
The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.
“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.
Versus natalizumab
The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.
Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.
A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.
Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.
Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.
“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.
Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.
Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.
Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.
Versus interferon beta-1a
The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.
In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.
Versus fingolimod
The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.
“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.
Versus natalizumab
The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.
Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.
A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.
Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.
Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
AT ECTRIMS 2016
Key clinical point:Alemtuzumab and natalizumab are similarly effective at preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Major finding: The annualized relapse rates comparing alemtuzumab with natalizumab, interferon beta-1a, and fingolimod were 0.2 and 0.2 (P = .8), 0.2 and 0.5 (P less than .001), and 0.15 and 0.30 (P less than .001).
Data source: Retrospective, propensity-matched analysis of prospectively collected observational data of more than 4,000 patients with RRMS treated with alemtuzumab (n = 189), natalizumab (n = 1,160), interferon beta-1a (n = 2,155), or fingolimod (n = 828).
Disclosures: Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
