Immuno-oncology

For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.

In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).

“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”

The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.

All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.

The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).

Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).

The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.

A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.

The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.

One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.

[email protected]

For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.

In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).

“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”

The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.

All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.

The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).

Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).

The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.

A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.

The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.

One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.

[email protected]

For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.

In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).

“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”

The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.

All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.

The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).

Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).

The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.

A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.

The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.

One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.

[email protected]

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

[email protected]

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

[email protected]

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

[email protected]

ORLANDO – In patients with advanced cervical cancer, combining chemotherapy with a vaccine against human papillomavirus (HPV) type 16 resulted in a robust, T-cell–mediated immune response and long duration survival for a large proportion of patients, reported investigators from the Netherlands.

Patients with advanced, HPV16-positive cervical cancer who were treated with standard chemotherapy and vaccinated with HPV16 synthetic long peptides (HPV16-SLP) had substantially increased T-cell responses, and these responses correlated with survival, said Marij Welters, PhD, from Leiden (the Netherlands) University Medical Center.

Neil Osterweil/Frontline Medical News

Combination required

Although therapeutic vaccination with HPV16-SLP has been shown to evoke T-cell–mediated shrinkage of HPV16-induced cervical neoplasia, the investigators found in a previous study that vaccination did not result in either tumor regression or prolonged progression-free survival of patients with advanced or recurrent HPV16-induced cervical cancer.

In the phase I trial reported here, the investigators explored whether combination HPV16-SLP with chemotherapy could potentiate T-cell responses.

In a second study, Welters et al. also showed that vaccination with HPV16-SLP after the second round of chemotherapy, when myeloid cells were at their nadir, resulted in robust T-cell responses in both mice and humans.

In the phase I trial reported here, the authors reported on the feasibility and efficacy of the technique in a larger cohort of patients with late-stage, HPV16-positive cervical cancer.

The investigators enrolled cohorts of 12 patients each and delivered one HPV16-SLP vaccine dose 2 weeks after the second, third, and fourth cycles of a total of six chemotherapy cycles with carboplatin and paclitaxel. The vaccine was test dosed at levels of 20, 40, 100, and 300 mcg/peptide, with or without 1 mcg/kg of pegylated interferon-alpha at each peptide dose level. The peptides covered the length of the HPV16 E6 and E7 proteins.

“Upon vaccination, we see a very strong T-cell response induced by the vaccine,” Dr. Welters said.

They also tested general immune responses to various microbial antigens and saw no significant differences in responses among the various dose cohorts.

Early response data was available for a total of 59 patients, 35 of whom received the vaccine/chemotherapy combination as first-line therapy and 24 of whom received it in the second line.

Two of the first-line patients had a complete response, as did one patient who received the combination as second-line therapy. Respective rates of partial responses were 22 and 5, stable disease was seen in 9 and 13 patients, and disease progression in 2 and 5 patients.

The overall response rate for patients treated in the first line was 69%, and the combined overall response and stable-disease rates were 94%. Among patients treated in the second line, the respective rates were 25% and 79%.

Median overall survival (OS) from the time of the first chemotherapy dose was 16.8 months among the first-line patients vs. 7.9 months among second-line patients (P = .0110)

At the data cutoff, median OS had not been reached for the two highest peptide dose levels (100 and 300 mcg).

The investigators also found that OS was independent of general immune status among the patients, suggesting that the benefit was derived specifically from induced T-cell responses.

‘Provocative and promising’

Invited discussant Heather McArthur, MD, MPH, from Cedars-Sinai Medical Center, Los Angeles, called the finding “provocative and promising.”

Neil Osterweil/Frontline Medical News

ORLANDO – In patients with advanced cervical cancer, combining chemotherapy with a vaccine against human papillomavirus (HPV) type 16 resulted in a robust, T-cell–mediated immune response and long duration survival for a large proportion of patients, reported investigators from the Netherlands.

Patients with advanced, HPV16-positive cervical cancer who were treated with standard chemotherapy and vaccinated with HPV16 synthetic long peptides (HPV16-SLP) had substantially increased T-cell responses, and these responses correlated with survival, said Marij Welters, PhD, from Leiden (the Netherlands) University Medical Center.

Neil Osterweil/Frontline Medical News

Combination required

Although therapeutic vaccination with HPV16-SLP has been shown to evoke T-cell–mediated shrinkage of HPV16-induced cervical neoplasia, the investigators found in a previous study that vaccination did not result in either tumor regression or prolonged progression-free survival of patients with advanced or recurrent HPV16-induced cervical cancer.

In the phase I trial reported here, the investigators explored whether combination HPV16-SLP with chemotherapy could potentiate T-cell responses.

In a second study, Welters et al. also showed that vaccination with HPV16-SLP after the second round of chemotherapy, when myeloid cells were at their nadir, resulted in robust T-cell responses in both mice and humans.

In the phase I trial reported here, the authors reported on the feasibility and efficacy of the technique in a larger cohort of patients with late-stage, HPV16-positive cervical cancer.

The investigators enrolled cohorts of 12 patients each and delivered one HPV16-SLP vaccine dose 2 weeks after the second, third, and fourth cycles of a total of six chemotherapy cycles with carboplatin and paclitaxel. The vaccine was test dosed at levels of 20, 40, 100, and 300 mcg/peptide, with or without 1 mcg/kg of pegylated interferon-alpha at each peptide dose level. The peptides covered the length of the HPV16 E6 and E7 proteins.

“Upon vaccination, we see a very strong T-cell response induced by the vaccine,” Dr. Welters said.

They also tested general immune responses to various microbial antigens and saw no significant differences in responses among the various dose cohorts.

Early response data was available for a total of 59 patients, 35 of whom received the vaccine/chemotherapy combination as first-line therapy and 24 of whom received it in the second line.

Two of the first-line patients had a complete response, as did one patient who received the combination as second-line therapy. Respective rates of partial responses were 22 and 5, stable disease was seen in 9 and 13 patients, and disease progression in 2 and 5 patients.

The overall response rate for patients treated in the first line was 69%, and the combined overall response and stable-disease rates were 94%. Among patients treated in the second line, the respective rates were 25% and 79%.

Median overall survival (OS) from the time of the first chemotherapy dose was 16.8 months among the first-line patients vs. 7.9 months among second-line patients (P = .0110)

At the data cutoff, median OS had not been reached for the two highest peptide dose levels (100 and 300 mcg).

The investigators also found that OS was independent of general immune status among the patients, suggesting that the benefit was derived specifically from induced T-cell responses.

‘Provocative and promising’

Invited discussant Heather McArthur, MD, MPH, from Cedars-Sinai Medical Center, Los Angeles, called the finding “provocative and promising.”

Neil Osterweil/Frontline Medical News

ORLANDO – In patients with advanced cervical cancer, combining chemotherapy with a vaccine against human papillomavirus (HPV) type 16 resulted in a robust, T-cell–mediated immune response and long duration survival for a large proportion of patients, reported investigators from the Netherlands.

Patients with advanced, HPV16-positive cervical cancer who were treated with standard chemotherapy and vaccinated with HPV16 synthetic long peptides (HPV16-SLP) had substantially increased T-cell responses, and these responses correlated with survival, said Marij Welters, PhD, from Leiden (the Netherlands) University Medical Center.

Neil Osterweil/Frontline Medical News

Combination required

Although therapeutic vaccination with HPV16-SLP has been shown to evoke T-cell–mediated shrinkage of HPV16-induced cervical neoplasia, the investigators found in a previous study that vaccination did not result in either tumor regression or prolonged progression-free survival of patients with advanced or recurrent HPV16-induced cervical cancer.

In the phase I trial reported here, the investigators explored whether combination HPV16-SLP with chemotherapy could potentiate T-cell responses.

In a second study, Welters et al. also showed that vaccination with HPV16-SLP after the second round of chemotherapy, when myeloid cells were at their nadir, resulted in robust T-cell responses in both mice and humans.

In the phase I trial reported here, the authors reported on the feasibility and efficacy of the technique in a larger cohort of patients with late-stage, HPV16-positive cervical cancer.

The investigators enrolled cohorts of 12 patients each and delivered one HPV16-SLP vaccine dose 2 weeks after the second, third, and fourth cycles of a total of six chemotherapy cycles with carboplatin and paclitaxel. The vaccine was test dosed at levels of 20, 40, 100, and 300 mcg/peptide, with or without 1 mcg/kg of pegylated interferon-alpha at each peptide dose level. The peptides covered the length of the HPV16 E6 and E7 proteins.

“Upon vaccination, we see a very strong T-cell response induced by the vaccine,” Dr. Welters said.

They also tested general immune responses to various microbial antigens and saw no significant differences in responses among the various dose cohorts.

Early response data was available for a total of 59 patients, 35 of whom received the vaccine/chemotherapy combination as first-line therapy and 24 of whom received it in the second line.

Two of the first-line patients had a complete response, as did one patient who received the combination as second-line therapy. Respective rates of partial responses were 22 and 5, stable disease was seen in 9 and 13 patients, and disease progression in 2 and 5 patients.

The overall response rate for patients treated in the first line was 69%, and the combined overall response and stable-disease rates were 94%. Among patients treated in the second line, the respective rates were 25% and 79%.

Median overall survival (OS) from the time of the first chemotherapy dose was 16.8 months among the first-line patients vs. 7.9 months among second-line patients (P = .0110)

At the data cutoff, median OS had not been reached for the two highest peptide dose levels (100 and 300 mcg).

The investigators also found that OS was independent of general immune status among the patients, suggesting that the benefit was derived specifically from induced T-cell responses.

‘Provocative and promising’

Invited discussant Heather McArthur, MD, MPH, from Cedars-Sinai Medical Center, Los Angeles, called the finding “provocative and promising.”

Neil Osterweil/Frontline Medical News

ORLANDO – In the largest assessment to date of circulating tumor DNA (ctDNA) in patients with metastatic renal cell carcinoma (mRCC), the majority of patients were found to have clinically relevant genomic alterations.

The most frequently occurring alterations for the entire cohort were TP53, VHL, NF1, EGFR, and ARID1A, but, importantly, the genetic profiles differed between patients receiving first-line therapy and those receiving second-line treatments.

“Compared to patients receiving first-line therapy, patients receiving post–first-line agents had increased genomic alterations in TP53, NF1, EGFR, and PIK3CA,” said lead study author Sumanta K. Pal, MD, a urologic oncologist at City of Hope, Duarte, Calif.

“These alterations underscore potential mechanisms of resistance,” said Dr. Pal, who presented the findings of his study in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology..

Several targeted therapies have been approved for mRCC, including vascular endothelial growth factor–targeted therapies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors. However, treatment of mRCC is generally distinctly different for the first- and second-line settings.

Dr. Pal noted that, while “efforts such as the TCGA [The Cancer Genome Atlas] have shed some light on the tumor biology, it is important to keep in mind that these datasets reflect earlier stages of disease. Certainly, there may be an evolution of tumor biology as patients progress toward metastasis.”

Circulating tumor markers represent a practical means of serially assessing tumor biology, and ctDNA can account for tumor heterogeneity. In this study, the authors sought to determine the mutational landscape of mRCC as well as to assess changes across patients receiving first-line and subsequent therapies by using ctDNA.

Data were obtained from 224 patients who received ctDNA profiling at progression as part of routine clinical care using Guardant360, a CLIA-certified comprehensive plasma assay that evaluated 70 genes. Of this group, 64 and 56 patients were coded as receiving frontline and post–first-line agents, respectively.

Genomic alterations were pooled for the entire group, and first and second (subsequent) therapies were compared, based on conventional practice patterns (first-line regimens included sunitinib, pazopanib and bevacizumab, and second line included everolimus, axitinib, cabozantinib, and nivolumab).

Genomic alterations were found in 78.6% of patients, with an average of 3.3 genomic alterations per patient. For patients receiving first-line therapy, the average number of ctDNA alterations was 2.9, compared with 3.7 for those in the cohort who were receiving second-line therapy. The median (range) ctDNA variant allele fractions were 0.23 (0.05-9.92) in the first-line group and 0.24 (0.04-47.14) in second line.

The authors observed that there were disparities in genomic alterations between both patient cohorts, with the highest disparity seen in (second vs. first line) TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%).

“These alterations underscore potential mechanisms of resistance,” said Dr. Pal.

He also pointed out that there were significant differences between the current dataset and other published reports, which may reflect the advanced state of the disease of the patients in this study.

Efforts are also ongoing to add detailed data on demographics and clinical outcomes to the current dataset, Dr. Pal added.

Acting as the paper’s discussant, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center pointed out that as there are no validated biomarkers of drug resistance or tumor evolution and that liquid biopsy offers a potential platform.

The use of ctDNA is a “convenient technology that offers new means to assess RCC biology,” said Dr. Lara, but the caveat is that it is “still in its infancy and has no immediate clinical application.”

The current study is “hypothesis generating only.” ctDNA changes need to be related to outcome following treatment, and the functional role of genomic alterations in RCC biology must be validated, he said.

ORLANDO – In the largest assessment to date of circulating tumor DNA (ctDNA) in patients with metastatic renal cell carcinoma (mRCC), the majority of patients were found to have clinically relevant genomic alterations.

The most frequently occurring alterations for the entire cohort were TP53, VHL, NF1, EGFR, and ARID1A, but, importantly, the genetic profiles differed between patients receiving first-line therapy and those receiving second-line treatments.

“Compared to patients receiving first-line therapy, patients receiving post–first-line agents had increased genomic alterations in TP53, NF1, EGFR, and PIK3CA,” said lead study author Sumanta K. Pal, MD, a urologic oncologist at City of Hope, Duarte, Calif.

“These alterations underscore potential mechanisms of resistance,” said Dr. Pal, who presented the findings of his study in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology..

Several targeted therapies have been approved for mRCC, including vascular endothelial growth factor–targeted therapies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors. However, treatment of mRCC is generally distinctly different for the first- and second-line settings.

Dr. Pal noted that, while “efforts such as the TCGA [The Cancer Genome Atlas] have shed some light on the tumor biology, it is important to keep in mind that these datasets reflect earlier stages of disease. Certainly, there may be an evolution of tumor biology as patients progress toward metastasis.”

Circulating tumor markers represent a practical means of serially assessing tumor biology, and ctDNA can account for tumor heterogeneity. In this study, the authors sought to determine the mutational landscape of mRCC as well as to assess changes across patients receiving first-line and subsequent therapies by using ctDNA.

Data were obtained from 224 patients who received ctDNA profiling at progression as part of routine clinical care using Guardant360, a CLIA-certified comprehensive plasma assay that evaluated 70 genes. Of this group, 64 and 56 patients were coded as receiving frontline and post–first-line agents, respectively.

Genomic alterations were pooled for the entire group, and first and second (subsequent) therapies were compared, based on conventional practice patterns (first-line regimens included sunitinib, pazopanib and bevacizumab, and second line included everolimus, axitinib, cabozantinib, and nivolumab).

Genomic alterations were found in 78.6% of patients, with an average of 3.3 genomic alterations per patient. For patients receiving first-line therapy, the average number of ctDNA alterations was 2.9, compared with 3.7 for those in the cohort who were receiving second-line therapy. The median (range) ctDNA variant allele fractions were 0.23 (0.05-9.92) in the first-line group and 0.24 (0.04-47.14) in second line.

The authors observed that there were disparities in genomic alterations between both patient cohorts, with the highest disparity seen in (second vs. first line) TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%).

“These alterations underscore potential mechanisms of resistance,” said Dr. Pal.

He also pointed out that there were significant differences between the current dataset and other published reports, which may reflect the advanced state of the disease of the patients in this study.

Efforts are also ongoing to add detailed data on demographics and clinical outcomes to the current dataset, Dr. Pal added.

Acting as the paper’s discussant, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center pointed out that as there are no validated biomarkers of drug resistance or tumor evolution and that liquid biopsy offers a potential platform.

The use of ctDNA is a “convenient technology that offers new means to assess RCC biology,” said Dr. Lara, but the caveat is that it is “still in its infancy and has no immediate clinical application.”

The current study is “hypothesis generating only.” ctDNA changes need to be related to outcome following treatment, and the functional role of genomic alterations in RCC biology must be validated, he said.

ORLANDO – In the largest assessment to date of circulating tumor DNA (ctDNA) in patients with metastatic renal cell carcinoma (mRCC), the majority of patients were found to have clinically relevant genomic alterations.

The most frequently occurring alterations for the entire cohort were TP53, VHL, NF1, EGFR, and ARID1A, but, importantly, the genetic profiles differed between patients receiving first-line therapy and those receiving second-line treatments.

“Compared to patients receiving first-line therapy, patients receiving post–first-line agents had increased genomic alterations in TP53, NF1, EGFR, and PIK3CA,” said lead study author Sumanta K. Pal, MD, a urologic oncologist at City of Hope, Duarte, Calif.

“These alterations underscore potential mechanisms of resistance,” said Dr. Pal, who presented the findings of his study in a press briefing held at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology..

Several targeted therapies have been approved for mRCC, including vascular endothelial growth factor–targeted therapies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors. However, treatment of mRCC is generally distinctly different for the first- and second-line settings.

Dr. Pal noted that, while “efforts such as the TCGA [The Cancer Genome Atlas] have shed some light on the tumor biology, it is important to keep in mind that these datasets reflect earlier stages of disease. Certainly, there may be an evolution of tumor biology as patients progress toward metastasis.”

Circulating tumor markers represent a practical means of serially assessing tumor biology, and ctDNA can account for tumor heterogeneity. In this study, the authors sought to determine the mutational landscape of mRCC as well as to assess changes across patients receiving first-line and subsequent therapies by using ctDNA.

Data were obtained from 224 patients who received ctDNA profiling at progression as part of routine clinical care using Guardant360, a CLIA-certified comprehensive plasma assay that evaluated 70 genes. Of this group, 64 and 56 patients were coded as receiving frontline and post–first-line agents, respectively.

Genomic alterations were pooled for the entire group, and first and second (subsequent) therapies were compared, based on conventional practice patterns (first-line regimens included sunitinib, pazopanib and bevacizumab, and second line included everolimus, axitinib, cabozantinib, and nivolumab).

Genomic alterations were found in 78.6% of patients, with an average of 3.3 genomic alterations per patient. For patients receiving first-line therapy, the average number of ctDNA alterations was 2.9, compared with 3.7 for those in the cohort who were receiving second-line therapy. The median (range) ctDNA variant allele fractions were 0.23 (0.05-9.92) in the first-line group and 0.24 (0.04-47.14) in second line.

The authors observed that there were disparities in genomic alterations between both patient cohorts, with the highest disparity seen in (second vs. first line) TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%).

“These alterations underscore potential mechanisms of resistance,” said Dr. Pal.

He also pointed out that there were significant differences between the current dataset and other published reports, which may reflect the advanced state of the disease of the patients in this study.

Efforts are also ongoing to add detailed data on demographics and clinical outcomes to the current dataset, Dr. Pal added.

Acting as the paper’s discussant, Primo N. Lara Jr., MD, of the University of California, Davis, Comprehensive Cancer Center pointed out that as there are no validated biomarkers of drug resistance or tumor evolution and that liquid biopsy offers a potential platform.

The use of ctDNA is a “convenient technology that offers new means to assess RCC biology,” said Dr. Lara, but the caveat is that it is “still in its infancy and has no immediate clinical application.”

The current study is “hypothesis generating only.” ctDNA changes need to be related to outcome following treatment, and the functional role of genomic alterations in RCC biology must be validated, he said.

Using the immune system to help fight cancer is one of newest and most promising directions in cancer research. While many of the findings so far remain preliminary, a number of new studies are being developed or are already underway. Not surprisingly, federal oncologists and hematologists are leading the way with ground-breaking research. Importantly, a number of trials are recruiting patients at VA facilities. Here are a few of the studies already underway:

Study: Vaccine Therapy in Treating Patients With Newly Diagnosed Advanced Colon Polyps

Sponsor: National Cancer Institute

This randomized phase II clinical trial studies how well MUC1 peptide-poly-ICLC adjuvant vaccine works in treating patients with newly diagnosed advanced colon polyps (adenomatous polyps). Adenomatous polyps are growths in the colon that may develop into colorectal cancer over time. Vaccines made from peptides may help the body build an effective immune response to kill polyp cells. MUC1 peptide-poly-ICLC adjuvant vaccine may also prevent the recurrence of adenomatous polyps and may prevent the development of colorectal cancer.

Federal Study Locations (7 total): Kansas City VAMC

Study: Nivolumab and Ipilimumab With or Without Sargramostim in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

Sponsor: National Cancer Institute

This randomized phase II/III trial studies the side effects and best dose of nivolumab and ipilimumab when given together with or without sargramostim and to see how well these drugs work in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may kill tumor cells by blocking blood flow to the tumor, by stimulating white blood cells to kill the tumor cells, or by attacking specific tumor cells and stop them from growing or kill them. Colony-stimulating factors, such as sargramostim, may increase the production of white blood cells. It is not yet known whether nivolumab and ipilimumab are more effective with or without sargramostim in treating patients with melanoma.

Federal Study Locations (311 total): Little Rock (Arkansas) VAMC

Study: Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma (NCT01169337)

Sponsor: National Cancer Institute

This randomized phase II/III trial studies how well lenalidomide works in treating patients with asymptomatic high-risk asymptomatic (smoldering) multiple myeloma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether lenalidomide is effective in treating patients with high-risk smoldering multiple myeloma than observation alone.

Federal Study Locations (600 total): Kansas City VAMC, VA New Jersey Health Care System, East Orange

Study: Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia (NCT02143414)

Sponsor: National Cancer Institute

This phase II trial studies the side effects and how well blinatumomab and combination chemotherapy or dasatinib, prednisone, and blinatumomab work in treating older patients with acute lymphoblastic leukemia. Monoclonal antibodies, such as blinatumomab, find cancer cells and help kill them. Drugs used in chemotherapy, such as prednisone, vincristine sulfate, methotrexate, and mercaptopurine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or halting the cells’ ability to spread. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving blinatumomab with combination chemotherapy or dasatinib and prednisone may kill more cancer cells.

Federal Study Locations (180 total): Little Rock (Arkansas) VAMC

Study: Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma (NCT01415752)

Sponsor: Eastern Cooperative Oncology Group

Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as bendamustine hydrochloride, also work in different ways to kill cancer cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab together with bendamustine and bortezomib is more effective than rituximab and bendamustine, followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma.

Federal Study Locations (426 total): Kansas City VAMC, VA New Jersey Health Care System, East Orange

Study: Rituximab and Combination Chemotherapy With or Without Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Diffuse Large B Cell Lymphoma (NCT01856192)

This randomized phase II trial studies how well rituximab and combination chemotherapy with or without lenalidomide work in treating patients with newly diagnosed stage II-IV diffuse large B cell lymphoma. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether rituximab and combination chemotherapy are more effective when given with or without lenalidomide in treating patients with diffuse large B cell lymphoma.

Federal Study Locations (511 total): Little Rock (Arkansas) VAMC

Using the immune system to help fight cancer is one of newest and most promising directions in cancer research. While many of the findings so far remain preliminary, a number of new studies are being developed or are already underway. Not surprisingly, federal oncologists and hematologists are leading the way with ground-breaking research. Importantly, a number of trials are recruiting patients at VA facilities. Here are a few of the studies already underway:

Study: Vaccine Therapy in Treating Patients With Newly Diagnosed Advanced Colon Polyps

Sponsor: National Cancer Institute

This randomized phase II clinical trial studies how well MUC1 peptide-poly-ICLC adjuvant vaccine works in treating patients with newly diagnosed advanced colon polyps (adenomatous polyps). Adenomatous polyps are growths in the colon that may develop into colorectal cancer over time. Vaccines made from peptides may help the body build an effective immune response to kill polyp cells. MUC1 peptide-poly-ICLC adjuvant vaccine may also prevent the recurrence of adenomatous polyps and may prevent the development of colorectal cancer.

Federal Study Locations (7 total): Kansas City VAMC

Study: Nivolumab and Ipilimumab With or Without Sargramostim in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

Sponsor: National Cancer Institute

This randomized phase II/III trial studies the side effects and best dose of nivolumab and ipilimumab when given together with or without sargramostim and to see how well these drugs work in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may kill tumor cells by blocking blood flow to the tumor, by stimulating white blood cells to kill the tumor cells, or by attacking specific tumor cells and stop them from growing or kill them. Colony-stimulating factors, such as sargramostim, may increase the production of white blood cells. It is not yet known whether nivolumab and ipilimumab are more effective with or without sargramostim in treating patients with melanoma.

Federal Study Locations (311 total): Little Rock (Arkansas) VAMC

Study: Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma (NCT01169337)

Sponsor: National Cancer Institute

This randomized phase II/III trial studies how well lenalidomide works in treating patients with asymptomatic high-risk asymptomatic (smoldering) multiple myeloma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether lenalidomide is effective in treating patients with high-risk smoldering multiple myeloma than observation alone.

Federal Study Locations (600 total): Kansas City VAMC, VA New Jersey Health Care System, East Orange

Study: Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia (NCT02143414)

Sponsor: National Cancer Institute

This phase II trial studies the side effects and how well blinatumomab and combination chemotherapy or dasatinib, prednisone, and blinatumomab work in treating older patients with acute lymphoblastic leukemia. Monoclonal antibodies, such as blinatumomab, find cancer cells and help kill them. Drugs used in chemotherapy, such as prednisone, vincristine sulfate, methotrexate, and mercaptopurine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or halting the cells’ ability to spread. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving blinatumomab with combination chemotherapy or dasatinib and prednisone may kill more cancer cells.

Federal Study Locations (180 total): Little Rock (Arkansas) VAMC

Study: Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma (NCT01415752)

Sponsor: Eastern Cooperative Oncology Group

Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as bendamustine hydrochloride, also work in different ways to kill cancer cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab together with bendamustine and bortezomib is more effective than rituximab and bendamustine, followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma.

Federal Study Locations (426 total): Kansas City VAMC, VA New Jersey Health Care System, East Orange

Study: Rituximab and Combination Chemotherapy With or Without Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Diffuse Large B Cell Lymphoma (NCT01856192)

This randomized phase II trial studies how well rituximab and combination chemotherapy with or without lenalidomide work in treating patients with newly diagnosed stage II-IV diffuse large B cell lymphoma. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether rituximab and combination chemotherapy are more effective when given with or without lenalidomide in treating patients with diffuse large B cell lymphoma.

Federal Study Locations (511 total): Little Rock (Arkansas) VAMC

Using the immune system to help fight cancer is one of newest and most promising directions in cancer research. While many of the findings so far remain preliminary, a number of new studies are being developed or are already underway. Not surprisingly, federal oncologists and hematologists are leading the way with ground-breaking research. Importantly, a number of trials are recruiting patients at VA facilities. Here are a few of the studies already underway:

Study: Vaccine Therapy in Treating Patients With Newly Diagnosed Advanced Colon Polyps

Sponsor: National Cancer Institute

This randomized phase II clinical trial studies how well MUC1 peptide-poly-ICLC adjuvant vaccine works in treating patients with newly diagnosed advanced colon polyps (adenomatous polyps). Adenomatous polyps are growths in the colon that may develop into colorectal cancer over time. Vaccines made from peptides may help the body build an effective immune response to kill polyp cells. MUC1 peptide-poly-ICLC adjuvant vaccine may also prevent the recurrence of adenomatous polyps and may prevent the development of colorectal cancer.

Federal Study Locations (7 total): Kansas City VAMC

Study: Nivolumab and Ipilimumab With or Without Sargramostim in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

Sponsor: National Cancer Institute

This randomized phase II/III trial studies the side effects and best dose of nivolumab and ipilimumab when given together with or without sargramostim and to see how well these drugs work in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may kill tumor cells by blocking blood flow to the tumor, by stimulating white blood cells to kill the tumor cells, or by attacking specific tumor cells and stop them from growing or kill them. Colony-stimulating factors, such as sargramostim, may increase the production of white blood cells. It is not yet known whether nivolumab and ipilimumab are more effective with or without sargramostim in treating patients with melanoma.

Federal Study Locations (311 total): Little Rock (Arkansas) VAMC

Study: Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma (NCT01169337)

Sponsor: National Cancer Institute

This randomized phase II/III trial studies how well lenalidomide works in treating patients with asymptomatic high-risk asymptomatic (smoldering) multiple myeloma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether lenalidomide is effective in treating patients with high-risk smoldering multiple myeloma than observation alone.

Federal Study Locations (600 total): Kansas City VAMC, VA New Jersey Health Care System, East Orange

Study: Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia (NCT02143414)

Sponsor: National Cancer Institute

This phase II trial studies the side effects and how well blinatumomab and combination chemotherapy or dasatinib, prednisone, and blinatumomab work in treating older patients with acute lymphoblastic leukemia. Monoclonal antibodies, such as blinatumomab, find cancer cells and help kill them. Drugs used in chemotherapy, such as prednisone, vincristine sulfate, methotrexate, and mercaptopurine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or halting the cells’ ability to spread. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving blinatumomab with combination chemotherapy or dasatinib and prednisone may kill more cancer cells.

Federal Study Locations (180 total): Little Rock (Arkansas) VAMC

Study: Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma (NCT01415752)

Sponsor: Eastern Cooperative Oncology Group

Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as bendamustine hydrochloride, also work in different ways to kill cancer cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab together with bendamustine and bortezomib is more effective than rituximab and bendamustine, followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma.

Federal Study Locations (426 total): Kansas City VAMC, VA New Jersey Health Care System, East Orange

Study: Rituximab and Combination Chemotherapy With or Without Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Diffuse Large B Cell Lymphoma (NCT01856192)

This randomized phase II trial studies how well rituximab and combination chemotherapy with or without lenalidomide work in treating patients with newly diagnosed stage II-IV diffuse large B cell lymphoma. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether rituximab and combination chemotherapy are more effective when given with or without lenalidomide in treating patients with diffuse large B cell lymphoma.

Federal Study Locations (511 total): Little Rock (Arkansas) VAMC

Two patients taking the immune checkpoint inhibitors nivolumab and ipilimumab for metastatic melanoma developed fulminant, fatal myocarditis, investigators reported in the New England Journal of Medicine.

Even though this adverse effect is rare, “clinicians should be vigilant for immune-mediated myocarditis, particularly because of its early onset, nonspecific symptomatology, and fulminant progression,” said Douglas B. Johnson, MD, of Vanderbilt University Medical Center, Nashville, and his associates.

The first case involved a 65-year-old woman with no cardiac risk factors who was admitted to the hospital with chest pain, dyspnea, and fatigue 12 days after she received her first dose of the combination therapy. She was found to have myocarditis and myositis with rhabdomylysis. Despite treatment with high-dose glucocorticoids, she developed intraventricular conduction delay within 24 hours, followed by complete heart block. She died from multisystem organ failure and refractory ventricular tachycardia.

The second case involved a 63-year-old man with no cardiac risk factors who was admitted with fatigue and myalgias 15 days after he received his first dose of the combination therapy. He showed profound ST-segment depression, an intraventricular conduction delay, myocarditis, and myositis. He also was treated with high-dose glucocorticoids but developed complete heart block and died from cardiac arrest.

Both patients had “strikingly elevated troponin levels and refractory conduction-system abnormalities with preserved cardiac function,” the investigators noted. Postmortem assessments showed intense lymphocytic infiltrates only in striated cardiac and skeletal muscle and in metastases; adjacent smooth muscle and other tissues were unaffected. Pathology results “were reminiscent of those observed in patients with acute allograft rejection after cardiac transplantation,” Dr. Johnson and his associates said (N Engl J Med. 2016 Nov 3. doi: 10.1056/NEJMoa1609214).

To assess the frequency of myocarditis and myositis in patients receiving immune checkpoint inhibitors for many different cancers, the investigators searched Bristol-Myers Squibb safety databases. They found 18 drug-related cases of severe myocarditis among 20,594 patients, for a frequency of 0.09%. Patients who received combined nivolumab and ipilimumab had more frequent and more severe myocarditis than those who took either agent alone.

“There are no known data regarding what monitoring strategy may be of value; in our practice, we are performing baseline ECG and weekly testing of troponin levels during weeks 1-3 for patients receiving combination immunotherapy,” the researchers noted.

This work was supported by the Bready Family Foundation, the National Cancer Institute, Vanderbilt-Ingram Cancer Center Ambassadors, the Breast Cancer Specialized Program of Research Excellence, the National Comprehensive Cancer Network, the National Institutes of Health, the Howard Hughes Medical Institute, and Gilead Life Sciences. Dr. Johnson reported receiving personal fees from Genoptix and Bristol-Myers Squibb, and his associates reported ties to numerous industry sources.

Two patients taking the immune checkpoint inhibitors nivolumab and ipilimumab for metastatic melanoma developed fulminant, fatal myocarditis, investigators reported in the New England Journal of Medicine.

Even though this adverse effect is rare, “clinicians should be vigilant for immune-mediated myocarditis, particularly because of its early onset, nonspecific symptomatology, and fulminant progression,” said Douglas B. Johnson, MD, of Vanderbilt University Medical Center, Nashville, and his associates.

The first case involved a 65-year-old woman with no cardiac risk factors who was admitted to the hospital with chest pain, dyspnea, and fatigue 12 days after she received her first dose of the combination therapy. She was found to have myocarditis and myositis with rhabdomylysis. Despite treatment with high-dose glucocorticoids, she developed intraventricular conduction delay within 24 hours, followed by complete heart block. She died from multisystem organ failure and refractory ventricular tachycardia.

The second case involved a 63-year-old man with no cardiac risk factors who was admitted with fatigue and myalgias 15 days after he received his first dose of the combination therapy. He showed profound ST-segment depression, an intraventricular conduction delay, myocarditis, and myositis. He also was treated with high-dose glucocorticoids but developed complete heart block and died from cardiac arrest.

Both patients had “strikingly elevated troponin levels and refractory conduction-system abnormalities with preserved cardiac function,” the investigators noted. Postmortem assessments showed intense lymphocytic infiltrates only in striated cardiac and skeletal muscle and in metastases; adjacent smooth muscle and other tissues were unaffected. Pathology results “were reminiscent of those observed in patients with acute allograft rejection after cardiac transplantation,” Dr. Johnson and his associates said (N Engl J Med. 2016 Nov 3. doi: 10.1056/NEJMoa1609214).

To assess the frequency of myocarditis and myositis in patients receiving immune checkpoint inhibitors for many different cancers, the investigators searched Bristol-Myers Squibb safety databases. They found 18 drug-related cases of severe myocarditis among 20,594 patients, for a frequency of 0.09%. Patients who received combined nivolumab and ipilimumab had more frequent and more severe myocarditis than those who took either agent alone.

“There are no known data regarding what monitoring strategy may be of value; in our practice, we are performing baseline ECG and weekly testing of troponin levels during weeks 1-3 for patients receiving combination immunotherapy,” the researchers noted.

This work was supported by the Bready Family Foundation, the National Cancer Institute, Vanderbilt-Ingram Cancer Center Ambassadors, the Breast Cancer Specialized Program of Research Excellence, the National Comprehensive Cancer Network, the National Institutes of Health, the Howard Hughes Medical Institute, and Gilead Life Sciences. Dr. Johnson reported receiving personal fees from Genoptix and Bristol-Myers Squibb, and his associates reported ties to numerous industry sources.

Two patients taking the immune checkpoint inhibitors nivolumab and ipilimumab for metastatic melanoma developed fulminant, fatal myocarditis, investigators reported in the New England Journal of Medicine.

Even though this adverse effect is rare, “clinicians should be vigilant for immune-mediated myocarditis, particularly because of its early onset, nonspecific symptomatology, and fulminant progression,” said Douglas B. Johnson, MD, of Vanderbilt University Medical Center, Nashville, and his associates.

The first case involved a 65-year-old woman with no cardiac risk factors who was admitted to the hospital with chest pain, dyspnea, and fatigue 12 days after she received her first dose of the combination therapy. She was found to have myocarditis and myositis with rhabdomylysis. Despite treatment with high-dose glucocorticoids, she developed intraventricular conduction delay within 24 hours, followed by complete heart block. She died from multisystem organ failure and refractory ventricular tachycardia.

The second case involved a 63-year-old man with no cardiac risk factors who was admitted with fatigue and myalgias 15 days after he received his first dose of the combination therapy. He showed profound ST-segment depression, an intraventricular conduction delay, myocarditis, and myositis. He also was treated with high-dose glucocorticoids but developed complete heart block and died from cardiac arrest.

Both patients had “strikingly elevated troponin levels and refractory conduction-system abnormalities with preserved cardiac function,” the investigators noted. Postmortem assessments showed intense lymphocytic infiltrates only in striated cardiac and skeletal muscle and in metastases; adjacent smooth muscle and other tissues were unaffected. Pathology results “were reminiscent of those observed in patients with acute allograft rejection after cardiac transplantation,” Dr. Johnson and his associates said (N Engl J Med. 2016 Nov 3. doi: 10.1056/NEJMoa1609214).

To assess the frequency of myocarditis and myositis in patients receiving immune checkpoint inhibitors for many different cancers, the investigators searched Bristol-Myers Squibb safety databases. They found 18 drug-related cases of severe myocarditis among 20,594 patients, for a frequency of 0.09%. Patients who received combined nivolumab and ipilimumab had more frequent and more severe myocarditis than those who took either agent alone.

“There are no known data regarding what monitoring strategy may be of value; in our practice, we are performing baseline ECG and weekly testing of troponin levels during weeks 1-3 for patients receiving combination immunotherapy,” the researchers noted.

This work was supported by the Bready Family Foundation, the National Cancer Institute, Vanderbilt-Ingram Cancer Center Ambassadors, the Breast Cancer Specialized Program of Research Excellence, the National Comprehensive Cancer Network, the National Institutes of Health, the Howard Hughes Medical Institute, and Gilead Life Sciences. Dr. Johnson reported receiving personal fees from Genoptix and Bristol-Myers Squibb, and his associates reported ties to numerous industry sources.

COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.

Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.

COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.

Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.

COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.

Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.

With the passage of the Medicare Access and CHIP Reauthorization Act, changes to how cancer care is delivered are fast approaching. This legislation aims to reward value-based care and incentivize alternative payment models that prize quality. The shift from quantity-based to value-based reimbursement is motivated in part by the rising cost of health care as well as the growing demand from patients, employers, and payers to better understand the quality of care being delivered. In cancer care, one area of high-cost and questionable value being examined is aggressive care at the end of life.

Dr. Bobby Daly, Dr. Andrew Hantel, and Dr. Blase Polite are with the University of Chicago.

With the passage of the Medicare Access and CHIP Reauthorization Act, changes to how cancer care is delivered are fast approaching. This legislation aims to reward value-based care and incentivize alternative payment models that prize quality. The shift from quantity-based to value-based reimbursement is motivated in part by the rising cost of health care as well as the growing demand from patients, employers, and payers to better understand the quality of care being delivered. In cancer care, one area of high-cost and questionable value being examined is aggressive care at the end of life.

Dr. Bobby Daly, Dr. Andrew Hantel, and Dr. Blase Polite are with the University of Chicago.

With the passage of the Medicare Access and CHIP Reauthorization Act, changes to how cancer care is delivered are fast approaching. This legislation aims to reward value-based care and incentivize alternative payment models that prize quality. The shift from quantity-based to value-based reimbursement is motivated in part by the rising cost of health care as well as the growing demand from patients, employers, and payers to better understand the quality of care being delivered. In cancer care, one area of high-cost and questionable value being examined is aggressive care at the end of life.

Dr. Bobby Daly, Dr. Andrew Hantel, and Dr. Blase Polite are with the University of Chicago.

COPENHAGEN – Adding the PD-1 checkpoint inhibitor pembrolizumab (Keytruda) to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous non–small cell lung cancer, but did not result in an overall survival advantage, results of a phase II trial show.

After a median follow-up of 10.6 months, the objective response rate among patients randomized to receive carboplatin and pemetrexed plus pembrolizumab was 55%, compared with 29% for patients treated with the platinum doublet alone, reported Corey J. Langer, MD, from the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

COPENHAGEN – Adding the PD-1 checkpoint inhibitor pembrolizumab (Keytruda) to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous non–small cell lung cancer, but did not result in an overall survival advantage, results of a phase II trial show.

After a median follow-up of 10.6 months, the objective response rate among patients randomized to receive carboplatin and pemetrexed plus pembrolizumab was 55%, compared with 29% for patients treated with the platinum doublet alone, reported Corey J. Langer, MD, from the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

COPENHAGEN – Adding the PD-1 checkpoint inhibitor pembrolizumab (Keytruda) to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous non–small cell lung cancer, but did not result in an overall survival advantage, results of a phase II trial show.

After a median follow-up of 10.6 months, the objective response rate among patients randomized to receive carboplatin and pemetrexed plus pembrolizumab was 55%, compared with 29% for patients treated with the platinum doublet alone, reported Corey J. Langer, MD, from the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.

Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

[email protected]

COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.

Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

[email protected]

COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.

Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

[email protected]