TBD Meeting (5014-17)

CHICAGO – Compared with docetaxel in matched external controls, combination therapy with dabrafenib and trametinib was associated with significantly prolonged progression-free and overall survival in previously treated patients with metastatic non–small cell lung cancer in a phase 2 trial.

Median progression-free survival (PFS) was 9.7 months in 57 patients in an open-label, multicenter phase 2 trial that investigated dabrafenib/trametinib treatment for metastatic BRAF V600E–mutated NSCLC, compared with 4.2 months in 290 patients treated with docetaxel in the randomized phase 3 CheckMate057 trial, which compared nivolumab and docetaxel in similar patients (hazard ratio, 0.32). Overall survival in the groups was 19.2 vs. 9.3 months, respectively (HR, 0.41), Junlong Li, MD, of Analysis Group, Boston, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Patients treated with the combination of dabrafenib and trametinib also had a significantly higher overall response rate (61% vs. 12%) and disease control rate (77% vs. 55%), Dr. Li said.

Patient-level data for the combination therapy patients and summary data for the docetaxel-treated patients were used for the current analysis. Patients and controls were matched based on age, sex, race, smoking history, performance score, tumor histology, prior regimens, prior radiotherapy, and prior maintenance therapy. The two trials used for the analysis (NCT01336634 and CheckMate 057) were comparable in design and inclusion/exclusion criteria, and both used RECIST v1.1 to evaluate response to therapy.

“In the absence of head-to-head trials ... this study contributes some comparative efficacy evidence in this area,” Dr. Li concluded.

Invited discussant, Thomas Eldridge Stinchcombe, MD, of Duke University, Durham, N.C., said that the findings are unsurprising but important in that they are confirmatory.

Dr. Li is a consultant for Novartis, which sponsored the analysis.

[email protected]

CHICAGO – Compared with docetaxel in matched external controls, combination therapy with dabrafenib and trametinib was associated with significantly prolonged progression-free and overall survival in previously treated patients with metastatic non–small cell lung cancer in a phase 2 trial.

Median progression-free survival (PFS) was 9.7 months in 57 patients in an open-label, multicenter phase 2 trial that investigated dabrafenib/trametinib treatment for metastatic BRAF V600E–mutated NSCLC, compared with 4.2 months in 290 patients treated with docetaxel in the randomized phase 3 CheckMate057 trial, which compared nivolumab and docetaxel in similar patients (hazard ratio, 0.32). Overall survival in the groups was 19.2 vs. 9.3 months, respectively (HR, 0.41), Junlong Li, MD, of Analysis Group, Boston, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Patients treated with the combination of dabrafenib and trametinib also had a significantly higher overall response rate (61% vs. 12%) and disease control rate (77% vs. 55%), Dr. Li said.

Patient-level data for the combination therapy patients and summary data for the docetaxel-treated patients were used for the current analysis. Patients and controls were matched based on age, sex, race, smoking history, performance score, tumor histology, prior regimens, prior radiotherapy, and prior maintenance therapy. The two trials used for the analysis (NCT01336634 and CheckMate 057) were comparable in design and inclusion/exclusion criteria, and both used RECIST v1.1 to evaluate response to therapy.

“In the absence of head-to-head trials ... this study contributes some comparative efficacy evidence in this area,” Dr. Li concluded.

Invited discussant, Thomas Eldridge Stinchcombe, MD, of Duke University, Durham, N.C., said that the findings are unsurprising but important in that they are confirmatory.

Dr. Li is a consultant for Novartis, which sponsored the analysis.

[email protected]

CHICAGO – Compared with docetaxel in matched external controls, combination therapy with dabrafenib and trametinib was associated with significantly prolonged progression-free and overall survival in previously treated patients with metastatic non–small cell lung cancer in a phase 2 trial.

Median progression-free survival (PFS) was 9.7 months in 57 patients in an open-label, multicenter phase 2 trial that investigated dabrafenib/trametinib treatment for metastatic BRAF V600E–mutated NSCLC, compared with 4.2 months in 290 patients treated with docetaxel in the randomized phase 3 CheckMate057 trial, which compared nivolumab and docetaxel in similar patients (hazard ratio, 0.32). Overall survival in the groups was 19.2 vs. 9.3 months, respectively (HR, 0.41), Junlong Li, MD, of Analysis Group, Boston, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Patients treated with the combination of dabrafenib and trametinib also had a significantly higher overall response rate (61% vs. 12%) and disease control rate (77% vs. 55%), Dr. Li said.

Patient-level data for the combination therapy patients and summary data for the docetaxel-treated patients were used for the current analysis. Patients and controls were matched based on age, sex, race, smoking history, performance score, tumor histology, prior regimens, prior radiotherapy, and prior maintenance therapy. The two trials used for the analysis (NCT01336634 and CheckMate 057) were comparable in design and inclusion/exclusion criteria, and both used RECIST v1.1 to evaluate response to therapy.

“In the absence of head-to-head trials ... this study contributes some comparative efficacy evidence in this area,” Dr. Li concluded.

Invited discussant, Thomas Eldridge Stinchcombe, MD, of Duke University, Durham, N.C., said that the findings are unsurprising but important in that they are confirmatory.

Dr. Li is a consultant for Novartis, which sponsored the analysis.

[email protected]

CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.

The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.

In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).

There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).

Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).

“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.

Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m² and cisplatin at a dose of 75 mg/m² on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.

“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.

[email protected]

CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.

The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.

In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).

There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).

Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).

“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.

Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m² and cisplatin at a dose of 75 mg/m² on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.

“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.

[email protected]

CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.

The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.

In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).

There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).

Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).

“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.

Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m² and cisplatin at a dose of 75 mg/m² on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.

“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.

[email protected]

CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.

The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.

The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.

“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”

However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.

The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.

Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.

Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.

“It appears safe; there will be more coming,” she said.

Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]

CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.

The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.

The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.

“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”

However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.

The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.

Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.

Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.

“It appears safe; there will be more coming,” she said.

Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]

CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.

The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.

The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.

“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”

However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.

The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.

Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.

Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.

“It appears safe; there will be more coming,” she said.

Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]

CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.

In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.

The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.

Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.

The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.

However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.

Dr. Naqash reported having no disclosures.

[email protected]
 

CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.

In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.

The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.

Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.

The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.

However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.

Dr. Naqash reported having no disclosures.

[email protected]
 

CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.

In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.

The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.

Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.

The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.

However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.

Dr. Naqash reported having no disclosures.

[email protected]
 

CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.

Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.

There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.

“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.

At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.

Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.

“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.

The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.

Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.

C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.

Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.

“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.

Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”

Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.

“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.

However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”

Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]

CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.

Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.

There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.

“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.

At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.

Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.

“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.

The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.

Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.

C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.

Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.

“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.

Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”

Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.

“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.

However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”

Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]

CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.

Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.

There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.

“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.

At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.

Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.

“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.

The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.

Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.

C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.

Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.

“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.

Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”

Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.

“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.

However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”

Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]