Patrice Wendling

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, a retrospective chart review was performed in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the present study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, a retrospective chart review was performed in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the present study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, a retrospective chart review was performed in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the present study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.

In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.

There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).

Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).

Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).

“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.

The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).

At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.

An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.

Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.

Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.

Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.

In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.

There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).

Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).

Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).

“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.

The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).

At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.

An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.

Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.

Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.

Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.

In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.

There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).

Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).

Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).

“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.

The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).

At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.

An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.

Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.

Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.

Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Researchers have identified a new histologic subset of metastatic castration-resistant prostate cancer called intermediate atypical carcinoma.

“Despite being cytologically bland, this is an aggressive cancer with shortened survival similar to that seen with small-cell neuroendocrine cancer,” study author Dr. Eric J. Small said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Therapies targeting the androgen receptor (AR) like abiraterone and enzalutamide have revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC), but resistance to these agents is near-universal and leads to progressive disease and death. At the same time, clinicians are seeing an increasing number of patients with small cell neuroendocrine prostate cancer (SCNC), Dr. Small, professor of medicine at the University of California, San Francisco, said.

As part of a larger project designed to understand the mechanisms of resistance to abiraterone (Zytiga) and enzalutamide (Xtandi) undertaken by the West Coast Prostate Cancer Dream Team, biopsies were performed of a metastatic site in about 160 eligible men with mCRPC.Most (58%) had a Gleason score of 8 or more at diagnosis; 40% had been treated with abiraterone, 10% with enzalutamide, and 17% with both.

Formalin-fixed paraffin-embedded tissue was collected for histologic evaluation by three independent pathologists. Fresh frozen tissue, which underwent laser capture microdissection, was used for genomic analysis.

As of May 1, 173 of 300 planned biopsies have been conducted. In the 160 samples evaluated to date, there was adequate tissue for analysis in 124, for a 78% biopsy success rate, he said.

Among the 124 evaluable biopsies, 35% were classified as pure adenocarcinoma and 13% as pure SCNC.

A novel subtype was identified in another 26% that “consisted of a pure population of cells that was distinct from adenocarcinoma and distinct from small cell neuroendocrine cancer. We have termed this group intermediate atypical carcinoma (IAC),” Dr. Small said.

The remaining quarter of biopsies was composed of mixed populations.

In addition to the independent review, a consensus meeting with two additional pathologists confirmed that this was a new, highly reproducible pathologic subclass, he said.

The researchers next sought to determine whether IAC is phenotypically distinct. A survival analysis was performed based on biopsy pathology and revealed that men who develop IAC have poor survival.

Indeed, survival with IAC (median 11.9 months) tracks with that of SCNC (median 6.6 months) and is distinct from adenocarcinoma, with a log-rank P value of .041, Dr. Small said. Further, when IAC and SCNC were grouped together, there was a dramatically different survival curve (median 8.9 months) than that seen with adenocarcinoma (P = .006).

An analysis using microresected samples indicated that IAC is also genomically distinct, he said. Small cell nuclear clusters showed enrichment of neuronal and cell cycle elements and downregulation of androgen-receptor elements and the immune system.

Based on these findings, machine learning was used to develop a 50-gene signature, with 88.3% accuracy to distinguish small cell from non–small cell histology and 78.5% accuracy to distinguish small cell or IAC histology from adenocarcinoma. The test is not clinically available at this time, but is being used to identify new therapeutic targets.

“We are actively identifying the unique features of this subtype that can be targeted with therapy,” Dr. Small said in an interview. “There is a huge unmet need, since no one knows how to treat these patients, who comprise a significant portion of patients.”

Indeed, in the analysis, IAC represented a fourth of all metastatic castration-resistant biopsies and when combined with small cell neuroendocrine cancer accounted for 40% of all samples.

“This comprises the single largest group of abiraterone- and enzalutamide-refractory patients,” he concluded. “The increasing use of highly potent AR-targeted therapy may contribute to the increasing frequency of this entity, although that is conjecture at this point and certainly ascertainment bias may play a role.”

Discussant Dr. Scott Tomlins, a pathologist from the University of Michigan in Ann Arbor, said one of the study’s major findings is that collecting tissue for comprehensive molecular analysis is feasible in the context of a well-funded, team-based infrastructure, adding that this will likely have to be the way going forward. Despite limited sample numbers, there also appears to be a “strong signal” that gene expression signatures can discriminate various subtypes.

The study was funded by StandUpToCancer, the Prostate Cancer Foundation, and American Association for Cancer Research. Dr. Small reported having no disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Researchers have identified a new histologic subset of metastatic castration-resistant prostate cancer called intermediate atypical carcinoma.

“Despite being cytologically bland, this is an aggressive cancer with shortened survival similar to that seen with small-cell neuroendocrine cancer,” study author Dr. Eric J. Small said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Therapies targeting the androgen receptor (AR) like abiraterone and enzalutamide have revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC), but resistance to these agents is near-universal and leads to progressive disease and death. At the same time, clinicians are seeing an increasing number of patients with small cell neuroendocrine prostate cancer (SCNC), Dr. Small, professor of medicine at the University of California, San Francisco, said.

As part of a larger project designed to understand the mechanisms of resistance to abiraterone (Zytiga) and enzalutamide (Xtandi) undertaken by the West Coast Prostate Cancer Dream Team, biopsies were performed of a metastatic site in about 160 eligible men with mCRPC.Most (58%) had a Gleason score of 8 or more at diagnosis; 40% had been treated with abiraterone, 10% with enzalutamide, and 17% with both.

Formalin-fixed paraffin-embedded tissue was collected for histologic evaluation by three independent pathologists. Fresh frozen tissue, which underwent laser capture microdissection, was used for genomic analysis.

As of May 1, 173 of 300 planned biopsies have been conducted. In the 160 samples evaluated to date, there was adequate tissue for analysis in 124, for a 78% biopsy success rate, he said.

Among the 124 evaluable biopsies, 35% were classified as pure adenocarcinoma and 13% as pure SCNC.

A novel subtype was identified in another 26% that “consisted of a pure population of cells that was distinct from adenocarcinoma and distinct from small cell neuroendocrine cancer. We have termed this group intermediate atypical carcinoma (IAC),” Dr. Small said.

The remaining quarter of biopsies was composed of mixed populations.

In addition to the independent review, a consensus meeting with two additional pathologists confirmed that this was a new, highly reproducible pathologic subclass, he said.

The researchers next sought to determine whether IAC is phenotypically distinct. A survival analysis was performed based on biopsy pathology and revealed that men who develop IAC have poor survival.

Indeed, survival with IAC (median 11.9 months) tracks with that of SCNC (median 6.6 months) and is distinct from adenocarcinoma, with a log-rank P value of .041, Dr. Small said. Further, when IAC and SCNC were grouped together, there was a dramatically different survival curve (median 8.9 months) than that seen with adenocarcinoma (P = .006).

An analysis using microresected samples indicated that IAC is also genomically distinct, he said. Small cell nuclear clusters showed enrichment of neuronal and cell cycle elements and downregulation of androgen-receptor elements and the immune system.

Based on these findings, machine learning was used to develop a 50-gene signature, with 88.3% accuracy to distinguish small cell from non–small cell histology and 78.5% accuracy to distinguish small cell or IAC histology from adenocarcinoma. The test is not clinically available at this time, but is being used to identify new therapeutic targets.

“We are actively identifying the unique features of this subtype that can be targeted with therapy,” Dr. Small said in an interview. “There is a huge unmet need, since no one knows how to treat these patients, who comprise a significant portion of patients.”

Indeed, in the analysis, IAC represented a fourth of all metastatic castration-resistant biopsies and when combined with small cell neuroendocrine cancer accounted for 40% of all samples.

“This comprises the single largest group of abiraterone- and enzalutamide-refractory patients,” he concluded. “The increasing use of highly potent AR-targeted therapy may contribute to the increasing frequency of this entity, although that is conjecture at this point and certainly ascertainment bias may play a role.”

Discussant Dr. Scott Tomlins, a pathologist from the University of Michigan in Ann Arbor, said one of the study’s major findings is that collecting tissue for comprehensive molecular analysis is feasible in the context of a well-funded, team-based infrastructure, adding that this will likely have to be the way going forward. Despite limited sample numbers, there also appears to be a “strong signal” that gene expression signatures can discriminate various subtypes.

The study was funded by StandUpToCancer, the Prostate Cancer Foundation, and American Association for Cancer Research. Dr. Small reported having no disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Researchers have identified a new histologic subset of metastatic castration-resistant prostate cancer called intermediate atypical carcinoma.

“Despite being cytologically bland, this is an aggressive cancer with shortened survival similar to that seen with small-cell neuroendocrine cancer,” study author Dr. Eric J. Small said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Therapies targeting the androgen receptor (AR) like abiraterone and enzalutamide have revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC), but resistance to these agents is near-universal and leads to progressive disease and death. At the same time, clinicians are seeing an increasing number of patients with small cell neuroendocrine prostate cancer (SCNC), Dr. Small, professor of medicine at the University of California, San Francisco, said.

As part of a larger project designed to understand the mechanisms of resistance to abiraterone (Zytiga) and enzalutamide (Xtandi) undertaken by the West Coast Prostate Cancer Dream Team, biopsies were performed of a metastatic site in about 160 eligible men with mCRPC.Most (58%) had a Gleason score of 8 or more at diagnosis; 40% had been treated with abiraterone, 10% with enzalutamide, and 17% with both.

Formalin-fixed paraffin-embedded tissue was collected for histologic evaluation by three independent pathologists. Fresh frozen tissue, which underwent laser capture microdissection, was used for genomic analysis.

As of May 1, 173 of 300 planned biopsies have been conducted. In the 160 samples evaluated to date, there was adequate tissue for analysis in 124, for a 78% biopsy success rate, he said.

Among the 124 evaluable biopsies, 35% were classified as pure adenocarcinoma and 13% as pure SCNC.

A novel subtype was identified in another 26% that “consisted of a pure population of cells that was distinct from adenocarcinoma and distinct from small cell neuroendocrine cancer. We have termed this group intermediate atypical carcinoma (IAC),” Dr. Small said.

The remaining quarter of biopsies was composed of mixed populations.

In addition to the independent review, a consensus meeting with two additional pathologists confirmed that this was a new, highly reproducible pathologic subclass, he said.

The researchers next sought to determine whether IAC is phenotypically distinct. A survival analysis was performed based on biopsy pathology and revealed that men who develop IAC have poor survival.

Indeed, survival with IAC (median 11.9 months) tracks with that of SCNC (median 6.6 months) and is distinct from adenocarcinoma, with a log-rank P value of .041, Dr. Small said. Further, when IAC and SCNC were grouped together, there was a dramatically different survival curve (median 8.9 months) than that seen with adenocarcinoma (P = .006).

An analysis using microresected samples indicated that IAC is also genomically distinct, he said. Small cell nuclear clusters showed enrichment of neuronal and cell cycle elements and downregulation of androgen-receptor elements and the immune system.

Based on these findings, machine learning was used to develop a 50-gene signature, with 88.3% accuracy to distinguish small cell from non–small cell histology and 78.5% accuracy to distinguish small cell or IAC histology from adenocarcinoma. The test is not clinically available at this time, but is being used to identify new therapeutic targets.

“We are actively identifying the unique features of this subtype that can be targeted with therapy,” Dr. Small said in an interview. “There is a huge unmet need, since no one knows how to treat these patients, who comprise a significant portion of patients.”

Indeed, in the analysis, IAC represented a fourth of all metastatic castration-resistant biopsies and when combined with small cell neuroendocrine cancer accounted for 40% of all samples.

“This comprises the single largest group of abiraterone- and enzalutamide-refractory patients,” he concluded. “The increasing use of highly potent AR-targeted therapy may contribute to the increasing frequency of this entity, although that is conjecture at this point and certainly ascertainment bias may play a role.”

Discussant Dr. Scott Tomlins, a pathologist from the University of Michigan in Ann Arbor, said one of the study’s major findings is that collecting tissue for comprehensive molecular analysis is feasible in the context of a well-funded, team-based infrastructure, adding that this will likely have to be the way going forward. Despite limited sample numbers, there also appears to be a “strong signal” that gene expression signatures can discriminate various subtypes.

The study was funded by StandUpToCancer, the Prostate Cancer Foundation, and American Association for Cancer Research. Dr. Small reported having no disclosures.

[email protected]

On Twitter @pwendl

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that she and her colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real-world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

Dr. Backus had no conflicts of interest.

[email protected]


On Twitter @pwendl

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that she and her colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real-world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

Dr. Backus had no conflicts of interest.

[email protected]


On Twitter @pwendl

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that she and her colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real-world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

Dr. Backus had no conflicts of interest.

[email protected]


On Twitter @pwendl

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.

Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that he and his colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.

Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that he and his colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.

Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that he and his colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.

Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that she and her* colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

[email protected]


On Twitter @pwendl

*This story was updated July 1, 2015

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.

Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that she and her* colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

[email protected]


On Twitter @pwendl

*This story was updated July 1, 2015

WASHINGTON – Sustained virologic response rates for genotype 1 and 2 patients are lower with sofosbuvir-based hepatitis C virus regimens in routine clinical practice than clinical trials, results from a large observational cohort analysis showed.

Patients with advanced liver disease and those with detectable HCV RNA at 4 weeks were significantly less likely to achieve a sustained virologic response (SVR), study author Dr. Lisa Backus reported at the annual Digestive Disease Week.

SVR rates with sofosbuvir (Sovaldi), which was approved in late 2013 for the treatment of HCV, have been reported in clinical trials generally in the 90%-plus range in genotype 1 (GT1) and 2 (GT2) patients.

“Often, however, it’s apparent that there are differences between the outcomes in clinical trials and routine medical practice,” said Dr. Backus of the VA Palo Alto (Calif.) Health Care System.

As a result, the investigators assessed clinical data from electronic medical records for 4,026 patients with GT1 or GT2 HCV who started sofosbuvir-based therapy for the recommended 12-week duration through the U.S. Department of Veterans Affairs, the largest integrated national provider of HCV care. Roughly a third of the patients were treatment experienced, and their average age was 61 years.

Among 3,203 GT1 patients, 1,302 started sofosbuvir, peginterferon, and ribavirin (SOF+PEG+RBV); 1,559, sofosbuvir plus simeprevir (SOF+SIM; Olysio); and 342, SOF+SIM+RBV. All 823 GT2 patients started SOF+RBV. About 10%-14% of patients did not receive 84 days of drug.

Patients were considered to have no SVR if HCV RNA was detectable on any test after the end of treatment, if they had no test after the end of treatment and HCV RNA was detectable on their last on-treatment test, or if they died before 12 weeks after the end of treatment. In all, 2,417 GT1 patients and 619 GT2 patients had SVR results.

Overall SVR rates were 66.8% with SOF+PEG+RBV, 75.3% with SOF+SIM, and 74.1% with SOF+SIM+RBV in GT1 patients and 79% with SOF+RBV in GT2 patients, Dr. Backus said.

For GT1 patients, SVR rates for treatment-naive vs. treatment-experienced patients were significantly different with SOF+PEG+RBV (73.7% vs. 55.6%; P <.001), but not with SOF+SIM (77.8% vs. 71.2%) or SOF+SIM+RBV (74.7% vs. 73.3%).

SVR rates were also different with SOF+RBV for GT2 treatment-naive vs. treatment-experienced patients (81.6% vs. 70.9%; P <.01), she reported.

Baseline factors associated with significantly lower SVR rates varied in GT1 treatment-naive and treatment-experienced patients by regimen, although an aspartate aminotransferase-to-platelet ratio index (APRI) score >2 was a significant predictor in treatment-naive patients for all three regimens and in treatment-experienced patients on SOF+PEG+RBV or SOF+SIM.

In a multivariate analysis adjusted for age, sex, race, body mass index (BMI), decompensated liver disease, diabetes, treatment experience, APRI score, HCV subtype, and regimen, GT1 patients with a BMI of at least 30 kg/m² had significantly lower odds of achieving a sustained virologic response (odds ratio, 0.64), as did those with decompensated liver disease (OR, 0.51), prior treatment experience (OR, 0.58), or an APRI score >2 (OR, 0.44), or those receiving SOF+PEG+RBV, compared with SOF-SIM (OR, 0.50; P values for all <.001), Dr. Backus said. The odds of achieving a sustained virologic response with SOF+SIM+RBV did not differ from the odds of doing so with SOF+SIM (OR, 1.03; P = .86).

Adding 4-week HCV RNA levels to the model did not change most baseline predictors, but showed that the odds of an SVR were reduced 41% for patients with 4-week HCV RNA <43 IU/mL (OR, 0.59; P <.001) and 58% for those with 4-week HCV RNA ≥43 IU/mL (OR, 0.42; P <.001), compared with patients with undetectable levels.

In GT2 patients, significant baseline predictors of lower SVR rates were an APRI >2 and a fibrosis-4 (FIB-4) index >3.25 in treatment-naive patients and a FIB-4 >3.25 in treatment-experienced patients.

Using the first multivariate model, treatment experience (OR, 0.55; P <.01) and an APRI >2 (OR, 0.39; P <.001) predicted markedly lower odds of a sustained virologic response. Both factors remained significant in the second multivariate model, along with 4-week HCV RNA <43 IU/mL (OR, 0.29; P <.001) and ≥43 IU/mL (OR, 0.21; P <.001), Dr. Backus reported.

Study limitations were the lack of treatment randomization, testing and follow-up at the discretion of the provider, the use of surrogate laboratory markers (APRI or FIB-4) since few patients had biopsy or fibroscan results, and the lack of data on Q80K polymorphism status, she said.

Attendees questioned whether compliance could have caused such vastly lower SVR rates than reported in other trial settings. Dr. Backus acknowledged that she and her* colleagues did not do chart reviews of actual discontinuation rates, but argued that adherence rates of 70%-80% in regular clinical practice in other fields of medicine, such as infectious diseases, are considered incredibly high.

“I think some of it is people have just gotten really spoiled, and we now think that 95% treatment completion is the real world,” she said. “We just don’t see it. I think one may argue that some of the other supposed real world trials, the TARGET or TRIO trials, those generally are people getting seen at academic medical centers. … Those kinds of centers, although they’re a version of the real world, it’s not quite the same as my nurse practitioner in some of the VA clinics.”

[email protected]


On Twitter @pwendl

*This story was updated July 1, 2015

CHICAGO – Adding bevacizumab to standard carboplatin and paclitaxel chemotherapy reduced the risk of progression by 41%, compared with chemotherapy alone for patients with advanced or recurrent endometrial cancer in the MITO END-2 study.

Median investigator-assessed progression-free survival was 8.7 months for chemotherapy alone and 13 months for bevacizumab plus chemotherapy (hazard ratio, 0.59; P = .036).

A subgroup analysis of the primary end point showed a significant benefit favoring the bevacizumab (Avastin) arm for patients who were older than 65 years, had an EGOG performance status of 1-2, had recurrent disease, and serous or clear cell histology.

Patrice Wendling/Frontline Medical News

“MITO END-2 is the first randomized trial suggesting efficacy of bevacizumab in advanced or recurrent endometrial cancer. These results merit, in our opinion, further exploration in a randomized phase III trial,” study author Dr. Domenica Lorusso said at the annual meeting of the American Society of Clinical Oncology.

Discussant Dr. Rebecca Kristeleit of University College London said, “I think most promising is that benefits appear greatest in the groups with the greatest need – those older patients, patients with poor prognosis, poor histological subtypes, and recurrence.”

MITO END-2 evenly randomized 108 women with stage III-IV or recurrent type 1 or type 2 endometrial cancer treated with 0-1 previous lines of chemotherapy to receive standard carboplatin and paclitaxel (Taxol) chemotherapy (AUC5) for 6-8 cycles with or without bevacizumab 15 mg/kg. Bevacizumab maintenance was continued until progression or unacceptable toxicity. In all, 5% of patients had prior chemotherapy, about 25% had serous or clear cell histology, and 65% had recurrent disease.

Among 92 evaluable patients, the objective response rate was 54.3% vs. 71.7% (P = .065) and 6-month disease control rate 69% vs. 83% (P = .09), both favoring the experimental arm, Dr. Lorusso of Fondazione IRCCS National Cancer Institute, Milan, said.

Overall survival data are immature with only 34% of required events, but show a similar trend, she said. Median OS was 18 months in patients receiving chemotherapy and 23.5 months in those receiving bevacizumab plus chemotherapy (HR, 0.65; P = .24).

Patrice Wendling/Frontline Medical News

No new safety signals appeared, but particular attention should be paid to cardiovascular toxicity when using bevacizumab in this population, which is typically older and has several comorbidities that are risk factors for cardiovascular disorders, Dr. Lorusso said. In the bevacizumab arm, one myocardial infarction, three arterial thromboses, and three venous thromboses occurred.

Dr. Kristeleit said there has been limited development of new treatments for endometrial cancer and that this must be a time for “catching up.” Advanced endometrial cancer is among the most common gynecologic cancers in the Western world and yet there are no approved molecular targeted agents, no validated predictive biomarkers, and there is a limited understanding of histopathologic selection, despite prognoses known to vary with the different subtypes.

“There’s a lot we need to do to focus our efforts in development of novel treatments for this group of patients,” she said.

[email protected]

On Twitter @pwendl

CHICAGO – Adding bevacizumab to standard carboplatin and paclitaxel chemotherapy reduced the risk of progression by 41%, compared with chemotherapy alone for patients with advanced or recurrent endometrial cancer in the MITO END-2 study.

Median investigator-assessed progression-free survival was 8.7 months for chemotherapy alone and 13 months for bevacizumab plus chemotherapy (hazard ratio, 0.59; P = .036).

A subgroup analysis of the primary end point showed a significant benefit favoring the bevacizumab (Avastin) arm for patients who were older than 65 years, had an EGOG performance status of 1-2, had recurrent disease, and serous or clear cell histology.

Patrice Wendling/Frontline Medical News

“MITO END-2 is the first randomized trial suggesting efficacy of bevacizumab in advanced or recurrent endometrial cancer. These results merit, in our opinion, further exploration in a randomized phase III trial,” study author Dr. Domenica Lorusso said at the annual meeting of the American Society of Clinical Oncology.

Discussant Dr. Rebecca Kristeleit of University College London said, “I think most promising is that benefits appear greatest in the groups with the greatest need – those older patients, patients with poor prognosis, poor histological subtypes, and recurrence.”

MITO END-2 evenly randomized 108 women with stage III-IV or recurrent type 1 or type 2 endometrial cancer treated with 0-1 previous lines of chemotherapy to receive standard carboplatin and paclitaxel (Taxol) chemotherapy (AUC5) for 6-8 cycles with or without bevacizumab 15 mg/kg. Bevacizumab maintenance was continued until progression or unacceptable toxicity. In all, 5% of patients had prior chemotherapy, about 25% had serous or clear cell histology, and 65% had recurrent disease.

Among 92 evaluable patients, the objective response rate was 54.3% vs. 71.7% (P = .065) and 6-month disease control rate 69% vs. 83% (P = .09), both favoring the experimental arm, Dr. Lorusso of Fondazione IRCCS National Cancer Institute, Milan, said.

Overall survival data are immature with only 34% of required events, but show a similar trend, she said. Median OS was 18 months in patients receiving chemotherapy and 23.5 months in those receiving bevacizumab plus chemotherapy (HR, 0.65; P = .24).

Patrice Wendling/Frontline Medical News

No new safety signals appeared, but particular attention should be paid to cardiovascular toxicity when using bevacizumab in this population, which is typically older and has several comorbidities that are risk factors for cardiovascular disorders, Dr. Lorusso said. In the bevacizumab arm, one myocardial infarction, three arterial thromboses, and three venous thromboses occurred.

Dr. Kristeleit said there has been limited development of new treatments for endometrial cancer and that this must be a time for “catching up.” Advanced endometrial cancer is among the most common gynecologic cancers in the Western world and yet there are no approved molecular targeted agents, no validated predictive biomarkers, and there is a limited understanding of histopathologic selection, despite prognoses known to vary with the different subtypes.

“There’s a lot we need to do to focus our efforts in development of novel treatments for this group of patients,” she said.

[email protected]

On Twitter @pwendl

CHICAGO – Adding bevacizumab to standard carboplatin and paclitaxel chemotherapy reduced the risk of progression by 41%, compared with chemotherapy alone for patients with advanced or recurrent endometrial cancer in the MITO END-2 study.

Median investigator-assessed progression-free survival was 8.7 months for chemotherapy alone and 13 months for bevacizumab plus chemotherapy (hazard ratio, 0.59; P = .036).

A subgroup analysis of the primary end point showed a significant benefit favoring the bevacizumab (Avastin) arm for patients who were older than 65 years, had an EGOG performance status of 1-2, had recurrent disease, and serous or clear cell histology.

Patrice Wendling/Frontline Medical News

“MITO END-2 is the first randomized trial suggesting efficacy of bevacizumab in advanced or recurrent endometrial cancer. These results merit, in our opinion, further exploration in a randomized phase III trial,” study author Dr. Domenica Lorusso said at the annual meeting of the American Society of Clinical Oncology.

Discussant Dr. Rebecca Kristeleit of University College London said, “I think most promising is that benefits appear greatest in the groups with the greatest need – those older patients, patients with poor prognosis, poor histological subtypes, and recurrence.”

MITO END-2 evenly randomized 108 women with stage III-IV or recurrent type 1 or type 2 endometrial cancer treated with 0-1 previous lines of chemotherapy to receive standard carboplatin and paclitaxel (Taxol) chemotherapy (AUC5) for 6-8 cycles with or without bevacizumab 15 mg/kg. Bevacizumab maintenance was continued until progression or unacceptable toxicity. In all, 5% of patients had prior chemotherapy, about 25% had serous or clear cell histology, and 65% had recurrent disease.

Among 92 evaluable patients, the objective response rate was 54.3% vs. 71.7% (P = .065) and 6-month disease control rate 69% vs. 83% (P = .09), both favoring the experimental arm, Dr. Lorusso of Fondazione IRCCS National Cancer Institute, Milan, said.

Overall survival data are immature with only 34% of required events, but show a similar trend, she said. Median OS was 18 months in patients receiving chemotherapy and 23.5 months in those receiving bevacizumab plus chemotherapy (HR, 0.65; P = .24).

Patrice Wendling/Frontline Medical News

No new safety signals appeared, but particular attention should be paid to cardiovascular toxicity when using bevacizumab in this population, which is typically older and has several comorbidities that are risk factors for cardiovascular disorders, Dr. Lorusso said. In the bevacizumab arm, one myocardial infarction, three arterial thromboses, and three venous thromboses occurred.

Dr. Kristeleit said there has been limited development of new treatments for endometrial cancer and that this must be a time for “catching up.” Advanced endometrial cancer is among the most common gynecologic cancers in the Western world and yet there are no approved molecular targeted agents, no validated predictive biomarkers, and there is a limited understanding of histopathologic selection, despite prognoses known to vary with the different subtypes.

“There’s a lot we need to do to focus our efforts in development of novel treatments for this group of patients,” she said.

[email protected]

On Twitter @pwendl

CHICAGO – Nivolumab reduced the risk of death by nearly a third over docetaxel for patients with advanced, refractory nonsquamous non–small cell lung cancer, results of CheckMate 057 showed.

The primary endpoint of median overall survival was 12.2 months for those receiving the PD-1 immune checkpoint inhibitor nivolumab and 9.4 months for those given docetaxel (hazard ratio, 0.73; P = .0015), study author Dr. Luis Paz-Ares reported at the annual meeting of the American Society of Clinical Oncology.

At 1 year, 51% of the nivolumab (Opdivo) group were alive vs. 39% of the docetaxel (Taxotere) group.

The survival advantage was seen across most subgroups, except never smokers and those whose tumors were positive for epidermal growth factor receptor (EGFR) mutations.

The magnitude of the overall survival benefit in patients with PD-L1–positive tumors, however, was “unprecedented in this setting” and ranged from 17.2 months to 19.4 months, Dr. Paz-Ares of the Hospital Universitario Virgen Del Rocio, Seville, Spain, said.

Treatment options for patients with nonsquamous histology who progress following platinum-based doublet chemotherapy are limited. Typical response rates in this context are about 10%, and median overall survival is about 8-10 months, he said.

Discussant Dr. Roy Herbst, chief of medical oncology at Yale Comprehensive Cancer Center in New Haven, Conn., said, “This is a positive randomized phase III trial with a primary endpoint for all comers. The trial sets a new standard for the treatment of previously treated disease … and nivolumab is significantly less toxic than docetaxel.”

Check Mate 057 randomly assigned 292 patients to nivolumab 3 mg/kg every 2 weeks and 290 patients to docetaxel 75 mg/kg every 3 weeks until disease progression or unacceptable toxicity occurred. Patients were stratified by prior maintenance therapy and line of therapy. PD-L1 expression was measured in pretreatment (archival or recent) tumor biopsies.

The objective response rate was significantly higher for patients receiving nivolumab than docetaxel (19% vs. 12%; P = .0246; odds ratio, 1.72), Dr. Paz-Ares said.

Most responses were partial (18% vs. 12%), with only one complete response to nivolumab. The median duration of response was 17.2 months with nivolumab vs. 5.6 months with docetaxel.

Progression-free survival (PFS) was similar between the nivolumab and docetaxel groups (2.3 months vs. 4.2 months; HR, 0.92; P = .39), he said, explaining that progression was more rapid with nivolumab during the first 6 months before slowing to a 1-year PFS rate of 19% vs. 8% for docetaxel.

PD-L1 expression emerged as a significant predictor of objective response rate, PFS, and overall survival, with objective response rates as much as three times higher with nivolumab than docetaxel for patients with high PD-L1 expression, Dr. Paz-Ares said.

Using three predefined cut points of ≥1%, ≥5%, and ≥10% PD-L1 expression, overall survival was 17.2 months, 18.2 months, and 19.4 months with nivolumab vs. 9.0 months, 8.1 months, and 8 months with docetaxel, respectively.

Dr. Herbst described the PD-L1 biomarker as intriguing, but said for now it is only hypothesis generating and should not be used for patient selection. PD-L1 expression was not prospectively stratified in the study, and was not available for 22% of patients, and while it does improve objective response rate, PFS, and overall survival, even patients with less than 1% expression appear to have at least equal activity to that of docetaxel with less toxicity, he noted.

Adverse events of any grade were reported in 69% of patients receiving nivolumab and 88% receiving docetaxel. More importantly, grade 3-4 events occurred in 10% vs. 54%, Dr. Paz-Ares said. The most common events with nivolumab were fatigue, nausea, and decreased appetite.

Notably, the dose intensity delivered was higher for nivolumab than for docetaxel (83% vs. 66%), and 42% of nivolumab patients vs. 50% of docetaxel patients received subsequent systemic therapy, suggesting little influence of further treatment on survival.

In a separate presentation at ASCO, nivolumab reduced the risk of death by 41%, compared with docetaxel, in previously treated advanced squamous NSCLC (HR, 0.59; P = .00025) in the phase III Check Mate 017 study.

Nivolumab received a second indication in March 2015 for use in metastatic squamous NSCLC following failure with platinum-based chemotherapy

Bristol-Myers Squibb sponsored the study. Dr. Paz-Ares reported honoraria from Bristol-Myers Squibb, Roche/Genentech, Lilly, Pfizer, Boehringer, and Clovis. Dr. Herbst reported honoraria from Boehringer Ingelheim, Celgene, Lilly, Merck, NovaRx, and Pfizer; a consulting or advisory role with Biothera, DiaTech Oncology, Koltan Pharmaceuticals, N-of-One, and Quintiles; and research funding from Genentech/Roche and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Nivolumab reduced the risk of death by nearly a third over docetaxel for patients with advanced, refractory nonsquamous non–small cell lung cancer, results of CheckMate 057 showed.

The primary endpoint of median overall survival was 12.2 months for those receiving the PD-1 immune checkpoint inhibitor nivolumab and 9.4 months for those given docetaxel (hazard ratio, 0.73; P = .0015), study author Dr. Luis Paz-Ares reported at the annual meeting of the American Society of Clinical Oncology.

At 1 year, 51% of the nivolumab (Opdivo) group were alive vs. 39% of the docetaxel (Taxotere) group.

The survival advantage was seen across most subgroups, except never smokers and those whose tumors were positive for epidermal growth factor receptor (EGFR) mutations.

The magnitude of the overall survival benefit in patients with PD-L1–positive tumors, however, was “unprecedented in this setting” and ranged from 17.2 months to 19.4 months, Dr. Paz-Ares of the Hospital Universitario Virgen Del Rocio, Seville, Spain, said.

Treatment options for patients with nonsquamous histology who progress following platinum-based doublet chemotherapy are limited. Typical response rates in this context are about 10%, and median overall survival is about 8-10 months, he said.

Discussant Dr. Roy Herbst, chief of medical oncology at Yale Comprehensive Cancer Center in New Haven, Conn., said, “This is a positive randomized phase III trial with a primary endpoint for all comers. The trial sets a new standard for the treatment of previously treated disease … and nivolumab is significantly less toxic than docetaxel.”

Check Mate 057 randomly assigned 292 patients to nivolumab 3 mg/kg every 2 weeks and 290 patients to docetaxel 75 mg/kg every 3 weeks until disease progression or unacceptable toxicity occurred. Patients were stratified by prior maintenance therapy and line of therapy. PD-L1 expression was measured in pretreatment (archival or recent) tumor biopsies.

The objective response rate was significantly higher for patients receiving nivolumab than docetaxel (19% vs. 12%; P = .0246; odds ratio, 1.72), Dr. Paz-Ares said.

Most responses were partial (18% vs. 12%), with only one complete response to nivolumab. The median duration of response was 17.2 months with nivolumab vs. 5.6 months with docetaxel.

Progression-free survival (PFS) was similar between the nivolumab and docetaxel groups (2.3 months vs. 4.2 months; HR, 0.92; P = .39), he said, explaining that progression was more rapid with nivolumab during the first 6 months before slowing to a 1-year PFS rate of 19% vs. 8% for docetaxel.

PD-L1 expression emerged as a significant predictor of objective response rate, PFS, and overall survival, with objective response rates as much as three times higher with nivolumab than docetaxel for patients with high PD-L1 expression, Dr. Paz-Ares said.

Using three predefined cut points of ≥1%, ≥5%, and ≥10% PD-L1 expression, overall survival was 17.2 months, 18.2 months, and 19.4 months with nivolumab vs. 9.0 months, 8.1 months, and 8 months with docetaxel, respectively.

Dr. Herbst described the PD-L1 biomarker as intriguing, but said for now it is only hypothesis generating and should not be used for patient selection. PD-L1 expression was not prospectively stratified in the study, and was not available for 22% of patients, and while it does improve objective response rate, PFS, and overall survival, even patients with less than 1% expression appear to have at least equal activity to that of docetaxel with less toxicity, he noted.

Adverse events of any grade were reported in 69% of patients receiving nivolumab and 88% receiving docetaxel. More importantly, grade 3-4 events occurred in 10% vs. 54%, Dr. Paz-Ares said. The most common events with nivolumab were fatigue, nausea, and decreased appetite.

Notably, the dose intensity delivered was higher for nivolumab than for docetaxel (83% vs. 66%), and 42% of nivolumab patients vs. 50% of docetaxel patients received subsequent systemic therapy, suggesting little influence of further treatment on survival.

In a separate presentation at ASCO, nivolumab reduced the risk of death by 41%, compared with docetaxel, in previously treated advanced squamous NSCLC (HR, 0.59; P = .00025) in the phase III Check Mate 017 study.

Nivolumab received a second indication in March 2015 for use in metastatic squamous NSCLC following failure with platinum-based chemotherapy

Bristol-Myers Squibb sponsored the study. Dr. Paz-Ares reported honoraria from Bristol-Myers Squibb, Roche/Genentech, Lilly, Pfizer, Boehringer, and Clovis. Dr. Herbst reported honoraria from Boehringer Ingelheim, Celgene, Lilly, Merck, NovaRx, and Pfizer; a consulting or advisory role with Biothera, DiaTech Oncology, Koltan Pharmaceuticals, N-of-One, and Quintiles; and research funding from Genentech/Roche and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Nivolumab reduced the risk of death by nearly a third over docetaxel for patients with advanced, refractory nonsquamous non–small cell lung cancer, results of CheckMate 057 showed.

The primary endpoint of median overall survival was 12.2 months for those receiving the PD-1 immune checkpoint inhibitor nivolumab and 9.4 months for those given docetaxel (hazard ratio, 0.73; P = .0015), study author Dr. Luis Paz-Ares reported at the annual meeting of the American Society of Clinical Oncology.

At 1 year, 51% of the nivolumab (Opdivo) group were alive vs. 39% of the docetaxel (Taxotere) group.

The survival advantage was seen across most subgroups, except never smokers and those whose tumors were positive for epidermal growth factor receptor (EGFR) mutations.

The magnitude of the overall survival benefit in patients with PD-L1–positive tumors, however, was “unprecedented in this setting” and ranged from 17.2 months to 19.4 months, Dr. Paz-Ares of the Hospital Universitario Virgen Del Rocio, Seville, Spain, said.

Treatment options for patients with nonsquamous histology who progress following platinum-based doublet chemotherapy are limited. Typical response rates in this context are about 10%, and median overall survival is about 8-10 months, he said.

Discussant Dr. Roy Herbst, chief of medical oncology at Yale Comprehensive Cancer Center in New Haven, Conn., said, “This is a positive randomized phase III trial with a primary endpoint for all comers. The trial sets a new standard for the treatment of previously treated disease … and nivolumab is significantly less toxic than docetaxel.”

Check Mate 057 randomly assigned 292 patients to nivolumab 3 mg/kg every 2 weeks and 290 patients to docetaxel 75 mg/kg every 3 weeks until disease progression or unacceptable toxicity occurred. Patients were stratified by prior maintenance therapy and line of therapy. PD-L1 expression was measured in pretreatment (archival or recent) tumor biopsies.

The objective response rate was significantly higher for patients receiving nivolumab than docetaxel (19% vs. 12%; P = .0246; odds ratio, 1.72), Dr. Paz-Ares said.

Most responses were partial (18% vs. 12%), with only one complete response to nivolumab. The median duration of response was 17.2 months with nivolumab vs. 5.6 months with docetaxel.

Progression-free survival (PFS) was similar between the nivolumab and docetaxel groups (2.3 months vs. 4.2 months; HR, 0.92; P = .39), he said, explaining that progression was more rapid with nivolumab during the first 6 months before slowing to a 1-year PFS rate of 19% vs. 8% for docetaxel.

PD-L1 expression emerged as a significant predictor of objective response rate, PFS, and overall survival, with objective response rates as much as three times higher with nivolumab than docetaxel for patients with high PD-L1 expression, Dr. Paz-Ares said.

Using three predefined cut points of ≥1%, ≥5%, and ≥10% PD-L1 expression, overall survival was 17.2 months, 18.2 months, and 19.4 months with nivolumab vs. 9.0 months, 8.1 months, and 8 months with docetaxel, respectively.

Dr. Herbst described the PD-L1 biomarker as intriguing, but said for now it is only hypothesis generating and should not be used for patient selection. PD-L1 expression was not prospectively stratified in the study, and was not available for 22% of patients, and while it does improve objective response rate, PFS, and overall survival, even patients with less than 1% expression appear to have at least equal activity to that of docetaxel with less toxicity, he noted.

Adverse events of any grade were reported in 69% of patients receiving nivolumab and 88% receiving docetaxel. More importantly, grade 3-4 events occurred in 10% vs. 54%, Dr. Paz-Ares said. The most common events with nivolumab were fatigue, nausea, and decreased appetite.

Notably, the dose intensity delivered was higher for nivolumab than for docetaxel (83% vs. 66%), and 42% of nivolumab patients vs. 50% of docetaxel patients received subsequent systemic therapy, suggesting little influence of further treatment on survival.

In a separate presentation at ASCO, nivolumab reduced the risk of death by 41%, compared with docetaxel, in previously treated advanced squamous NSCLC (HR, 0.59; P = .00025) in the phase III Check Mate 017 study.

Nivolumab received a second indication in March 2015 for use in metastatic squamous NSCLC following failure with platinum-based chemotherapy

Bristol-Myers Squibb sponsored the study. Dr. Paz-Ares reported honoraria from Bristol-Myers Squibb, Roche/Genentech, Lilly, Pfizer, Boehringer, and Clovis. Dr. Herbst reported honoraria from Boehringer Ingelheim, Celgene, Lilly, Merck, NovaRx, and Pfizer; a consulting or advisory role with Biothera, DiaTech Oncology, Koltan Pharmaceuticals, N-of-One, and Quintiles; and research funding from Genentech/Roche and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab alone in first-line metastatic melanoma, results from the phase III CheckMate 067 study suggest.

After a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P value < .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P < .001).

The study was not powered to compare nivolumab (Opdivo) plus ipilimumab (Yervoy) with nivolumab.

Patrice Wendling/Frontline Medical News

Median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 6.9 months with nivolumab, and 2.9 months with ipilimumab alone, Dr. Jedd Wolchok said at the annual meeting of the American Society of Clinical Oncology.

Overall, 43.7% of patients in the nivolumab arm, 57.6% in the combination arm, and 19% in the ipilimumab arm had objective responses assessed by RECIST version 1.1. Complete responses were more common in the combination arm (11.5%) than in the nivolumab (9%) or ipilimumab (2.2%) arms, as were partial responses (46.2% vs. 34.8% vs. 16.8%).

The median duration of response has not been reached in any group, Dr. Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan-Kettering Cancer Center, New York, reported in the plenary session. The results were also simultaneously published in the New England Journal of Medicine (doi:10.1056/NEJMoa1504030).

Dr. Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, who was invited to discuss CheckMate 067, said the principal take-home message is that, “Ipilimumab can no longer be considered as standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”

Combination nivolumab and ipilimumab, however, is “expensive treatment” and raises legitimate concerns about cost and value, he added. Judgment about whether the combination is worth it will need to be withheld until it’s determined if it “can produce more long-term responses or cures, which may reduce the need for other therapies. Further, because of its early toxicity, in contrast to the long duration of monotherapy, the combination may actually involve less treatment and expense.”

Ipilimumab, an anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, revolutionized the treatment of advanced melanoma just 5 years ago. But the landscape has changed with the 2014 approval of nivolumab and pembrolizumab (Keytruda), two anti–programmed death (PD-1) antibodies, and with recent phase III results reporting that pembrolizumab is superior to ipilimumab in advanced melanoma.

There are no clear-cut distinctions in efficacy or toxicity between nivolumab and pembrolizumab, so therefore, treatment decisions will be largely based on other factors such as dosing schedule, marketing cost, and experience, Dr. Atkins said. Pembrolizumab is FDA approved at 2 mg/kg every 3 weeks, while nivolumab is approved at 3 mg/kg every 2 weeks.

CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-ligand 1 expression, BRAF status, and American Joint Commission on Cancer M stage.

The impact of PD-L1 expression

As seen in other studies, PD-L1 expression enriched response. Objective response rates in patients with tumors showing less than 5% PD-L1 expression were 41.3% with nivolumab, 54.% with nivolumab plus ipilimumab, and 17.8% with ipilimumab. This increased to 57.5%, 72.1%, and 21.3% in patients with at least 5% PD-L1 expression in their tumors, Dr. Wolchok said.

In patients with PD-L1–negative tumors, median progression-free survival was 5.3 months with nivolumab, 11.2 months with nivolumab plus ipilimumab, and 2.8 months with ipilimumab. In patients with PD-L1–positive tumors, the median PFS was 14 months in both nivolumab groups and 3.9 months in the ipilimumab group.

The results suggest that nivolumab alone may have comparable efficacy to nivolumab plus ipilimumab in PD-L1–positive patients, Dr. Atkins said, but added several caveats. Notably, that median PFS is not the optimal way to evaluate immunotherapy because it can be compounded by pseudo progression. Better measures include overall survival and response duration, but those data are immature. Further, only 25%-28% of patients in the study were PD-L1 positive and two-thirds of responders to nivolumab alone were PD-L1 negative.

“PD-L1 expression is a weak biomarker,” he said.

Greater efficacy, greater toxicity

Both Dr. Wolchok and Dr. Atkins agreed that combining the two immunotherapies increased treatment-related adverse events, but that most events were manageable. Moreover, treatment interruption did not prevent tumor response, with 67.5% of patients who discontinued the nivolumab-ipilimumab combination because of a treatment-related adverse event developing a response.

Grade 3-4 events were reported in 55% of the combination group, 16.3% of the nivolumab-alone group, and 27.3% of the ipilimumab-alone group. The most common of these events were diarrhea in 2.2% of patients in the nivolumab group, 9.3% of the combination group and 6.1% of the ipilimumab group, colitis (0.6%, 7.7%, 8.7%) and increased alanine aminotransferase levels (1.3%, 8.3%, 1.6%).

“There is no signature adverse event for the combination,” Dr. Wolchok said. “With the use of immune-modulating agents, the majority of grade 3 and 4 select adverse events resolved in all of the groups with the use of established algorithms. However, as we observed in prior studies, most endocrine events did not.”

There was one treatment-related death due to neutropenia in the nivolumab group, one due to cardiac arrest in the ipilimumab group, and none in the combination group.

An expanded access program is available for the combination of nivolumab and ipilimumab through the study sponsor, Bristol-Myers Squibb, Dr. Wolchok noted.

[email protected]

On Twitter@pwendl

CHICAGO – Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab alone in first-line metastatic melanoma, results from the phase III CheckMate 067 study suggest.

After a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P value < .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P < .001).

The study was not powered to compare nivolumab (Opdivo) plus ipilimumab (Yervoy) with nivolumab.

Patrice Wendling/Frontline Medical News

Median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 6.9 months with nivolumab, and 2.9 months with ipilimumab alone, Dr. Jedd Wolchok said at the annual meeting of the American Society of Clinical Oncology.

Overall, 43.7% of patients in the nivolumab arm, 57.6% in the combination arm, and 19% in the ipilimumab arm had objective responses assessed by RECIST version 1.1. Complete responses were more common in the combination arm (11.5%) than in the nivolumab (9%) or ipilimumab (2.2%) arms, as were partial responses (46.2% vs. 34.8% vs. 16.8%).

The median duration of response has not been reached in any group, Dr. Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan-Kettering Cancer Center, New York, reported in the plenary session. The results were also simultaneously published in the New England Journal of Medicine (doi:10.1056/NEJMoa1504030).

Dr. Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, who was invited to discuss CheckMate 067, said the principal take-home message is that, “Ipilimumab can no longer be considered as standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”

Combination nivolumab and ipilimumab, however, is “expensive treatment” and raises legitimate concerns about cost and value, he added. Judgment about whether the combination is worth it will need to be withheld until it’s determined if it “can produce more long-term responses or cures, which may reduce the need for other therapies. Further, because of its early toxicity, in contrast to the long duration of monotherapy, the combination may actually involve less treatment and expense.”

Ipilimumab, an anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, revolutionized the treatment of advanced melanoma just 5 years ago. But the landscape has changed with the 2014 approval of nivolumab and pembrolizumab (Keytruda), two anti–programmed death (PD-1) antibodies, and with recent phase III results reporting that pembrolizumab is superior to ipilimumab in advanced melanoma.

There are no clear-cut distinctions in efficacy or toxicity between nivolumab and pembrolizumab, so therefore, treatment decisions will be largely based on other factors such as dosing schedule, marketing cost, and experience, Dr. Atkins said. Pembrolizumab is FDA approved at 2 mg/kg every 3 weeks, while nivolumab is approved at 3 mg/kg every 2 weeks.

CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-ligand 1 expression, BRAF status, and American Joint Commission on Cancer M stage.

The impact of PD-L1 expression

As seen in other studies, PD-L1 expression enriched response. Objective response rates in patients with tumors showing less than 5% PD-L1 expression were 41.3% with nivolumab, 54.% with nivolumab plus ipilimumab, and 17.8% with ipilimumab. This increased to 57.5%, 72.1%, and 21.3% in patients with at least 5% PD-L1 expression in their tumors, Dr. Wolchok said.

In patients with PD-L1–negative tumors, median progression-free survival was 5.3 months with nivolumab, 11.2 months with nivolumab plus ipilimumab, and 2.8 months with ipilimumab. In patients with PD-L1–positive tumors, the median PFS was 14 months in both nivolumab groups and 3.9 months in the ipilimumab group.

The results suggest that nivolumab alone may have comparable efficacy to nivolumab plus ipilimumab in PD-L1–positive patients, Dr. Atkins said, but added several caveats. Notably, that median PFS is not the optimal way to evaluate immunotherapy because it can be compounded by pseudo progression. Better measures include overall survival and response duration, but those data are immature. Further, only 25%-28% of patients in the study were PD-L1 positive and two-thirds of responders to nivolumab alone were PD-L1 negative.

“PD-L1 expression is a weak biomarker,” he said.

Greater efficacy, greater toxicity

Both Dr. Wolchok and Dr. Atkins agreed that combining the two immunotherapies increased treatment-related adverse events, but that most events were manageable. Moreover, treatment interruption did not prevent tumor response, with 67.5% of patients who discontinued the nivolumab-ipilimumab combination because of a treatment-related adverse event developing a response.

Grade 3-4 events were reported in 55% of the combination group, 16.3% of the nivolumab-alone group, and 27.3% of the ipilimumab-alone group. The most common of these events were diarrhea in 2.2% of patients in the nivolumab group, 9.3% of the combination group and 6.1% of the ipilimumab group, colitis (0.6%, 7.7%, 8.7%) and increased alanine aminotransferase levels (1.3%, 8.3%, 1.6%).

“There is no signature adverse event for the combination,” Dr. Wolchok said. “With the use of immune-modulating agents, the majority of grade 3 and 4 select adverse events resolved in all of the groups with the use of established algorithms. However, as we observed in prior studies, most endocrine events did not.”

There was one treatment-related death due to neutropenia in the nivolumab group, one due to cardiac arrest in the ipilimumab group, and none in the combination group.

An expanded access program is available for the combination of nivolumab and ipilimumab through the study sponsor, Bristol-Myers Squibb, Dr. Wolchok noted.

[email protected]

On Twitter@pwendl

CHICAGO – Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab alone in first-line metastatic melanoma, results from the phase III CheckMate 067 study suggest.

After a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P value < .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P < .001).

The study was not powered to compare nivolumab (Opdivo) plus ipilimumab (Yervoy) with nivolumab.

Patrice Wendling/Frontline Medical News

Median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 6.9 months with nivolumab, and 2.9 months with ipilimumab alone, Dr. Jedd Wolchok said at the annual meeting of the American Society of Clinical Oncology.

Overall, 43.7% of patients in the nivolumab arm, 57.6% in the combination arm, and 19% in the ipilimumab arm had objective responses assessed by RECIST version 1.1. Complete responses were more common in the combination arm (11.5%) than in the nivolumab (9%) or ipilimumab (2.2%) arms, as were partial responses (46.2% vs. 34.8% vs. 16.8%).

The median duration of response has not been reached in any group, Dr. Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan-Kettering Cancer Center, New York, reported in the plenary session. The results were also simultaneously published in the New England Journal of Medicine (doi:10.1056/NEJMoa1504030).

Dr. Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, who was invited to discuss CheckMate 067, said the principal take-home message is that, “Ipilimumab can no longer be considered as standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”

Combination nivolumab and ipilimumab, however, is “expensive treatment” and raises legitimate concerns about cost and value, he added. Judgment about whether the combination is worth it will need to be withheld until it’s determined if it “can produce more long-term responses or cures, which may reduce the need for other therapies. Further, because of its early toxicity, in contrast to the long duration of monotherapy, the combination may actually involve less treatment and expense.”

Ipilimumab, an anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, revolutionized the treatment of advanced melanoma just 5 years ago. But the landscape has changed with the 2014 approval of nivolumab and pembrolizumab (Keytruda), two anti–programmed death (PD-1) antibodies, and with recent phase III results reporting that pembrolizumab is superior to ipilimumab in advanced melanoma.

There are no clear-cut distinctions in efficacy or toxicity between nivolumab and pembrolizumab, so therefore, treatment decisions will be largely based on other factors such as dosing schedule, marketing cost, and experience, Dr. Atkins said. Pembrolizumab is FDA approved at 2 mg/kg every 3 weeks, while nivolumab is approved at 3 mg/kg every 2 weeks.

CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-ligand 1 expression, BRAF status, and American Joint Commission on Cancer M stage.

The impact of PD-L1 expression

As seen in other studies, PD-L1 expression enriched response. Objective response rates in patients with tumors showing less than 5% PD-L1 expression were 41.3% with nivolumab, 54.% with nivolumab plus ipilimumab, and 17.8% with ipilimumab. This increased to 57.5%, 72.1%, and 21.3% in patients with at least 5% PD-L1 expression in their tumors, Dr. Wolchok said.

In patients with PD-L1–negative tumors, median progression-free survival was 5.3 months with nivolumab, 11.2 months with nivolumab plus ipilimumab, and 2.8 months with ipilimumab. In patients with PD-L1–positive tumors, the median PFS was 14 months in both nivolumab groups and 3.9 months in the ipilimumab group.

The results suggest that nivolumab alone may have comparable efficacy to nivolumab plus ipilimumab in PD-L1–positive patients, Dr. Atkins said, but added several caveats. Notably, that median PFS is not the optimal way to evaluate immunotherapy because it can be compounded by pseudo progression. Better measures include overall survival and response duration, but those data are immature. Further, only 25%-28% of patients in the study were PD-L1 positive and two-thirds of responders to nivolumab alone were PD-L1 negative.

“PD-L1 expression is a weak biomarker,” he said.

Greater efficacy, greater toxicity

Both Dr. Wolchok and Dr. Atkins agreed that combining the two immunotherapies increased treatment-related adverse events, but that most events were manageable. Moreover, treatment interruption did not prevent tumor response, with 67.5% of patients who discontinued the nivolumab-ipilimumab combination because of a treatment-related adverse event developing a response.

Grade 3-4 events were reported in 55% of the combination group, 16.3% of the nivolumab-alone group, and 27.3% of the ipilimumab-alone group. The most common of these events were diarrhea in 2.2% of patients in the nivolumab group, 9.3% of the combination group and 6.1% of the ipilimumab group, colitis (0.6%, 7.7%, 8.7%) and increased alanine aminotransferase levels (1.3%, 8.3%, 1.6%).

“There is no signature adverse event for the combination,” Dr. Wolchok said. “With the use of immune-modulating agents, the majority of grade 3 and 4 select adverse events resolved in all of the groups with the use of established algorithms. However, as we observed in prior studies, most endocrine events did not.”

There was one treatment-related death due to neutropenia in the nivolumab group, one due to cardiac arrest in the ipilimumab group, and none in the combination group.

An expanded access program is available for the combination of nivolumab and ipilimumab through the study sponsor, Bristol-Myers Squibb, Dr. Wolchok noted.

[email protected]

On Twitter@pwendl