Neil Osterweil

SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.

In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.

Fry_Terry_J_MD_web.jpg

“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.

Tough target

As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.

In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.

However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.

CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen

In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.

The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.

The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 10⁵ transduced T-cells per recipient weight in kilograms (DL-1), 1 x 10⁶/kg (DL-2), and 3 x 10⁶/kg (DL-3).

The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.

As noted before, three of the remissions were comparatively durable, with one lasting more than a year.

There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.

In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.

“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.

The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.

SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.

In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.

Fry_Terry_J_MD_web.jpg

“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.

Tough target

As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.

In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.

However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.

CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen

In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.

The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.

The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 10⁵ transduced T-cells per recipient weight in kilograms (DL-1), 1 x 10⁶/kg (DL-2), and 3 x 10⁶/kg (DL-3).

The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.

As noted before, three of the remissions were comparatively durable, with one lasting more than a year.

There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.

In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.

“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.

The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.

SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.

In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.

Fry_Terry_J_MD_web.jpg

“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.

Tough target

As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.

In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.

However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.

CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen

In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.

The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.

The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 10⁵ transduced T-cells per recipient weight in kilograms (DL-1), 1 x 10⁶/kg (DL-2), and 3 x 10⁶/kg (DL-3).

The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.

As noted before, three of the remissions were comparatively durable, with one lasting more than a year.

There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.

In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.

“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.

The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.

SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.

In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.

SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.

In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.

SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.

In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

122154_Annels_Nicola_UK_web.jpg

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

122154_Annels_Nicola_UK_web.jpg

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

122154_Annels_Nicola_UK_web.jpg

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

122142_McNeel_Douglas_web.jpg

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

122142_McNeel_Douglas_web.jpg

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

122142_McNeel_Douglas_web.jpg

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

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Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

121966_Tsai_Katy_SanDiego_web.jpg

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

121966_Tsai_Katy_SanDiego_web.jpg

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Density in tumors of two key immune cells may be a biomarker for response to an inhibitor of programmed death–ligand 1 (PD-L1) among patients with non–small cell lung cancer (NSCLC).

Patients with NSCLC whose tumors bore high densities of both CD8-positive cytotoxic T lymphocytes and PD-L1 had significantly better outcomes when treated with the investigational PD-L1 inhibitor durvalumab than patients with high densities of either cell type alone, reported Sonja Althammer, PhD, a scientist at Definiens AG, maker of the anti–PD-L1 compound.

Althammer_Sonja_web.jpg

NATIONAL HARBOR, MD. – Density in tumors of two key immune cells may be a biomarker for response to an inhibitor of programmed death–ligand 1 (PD-L1) among patients with non–small cell lung cancer (NSCLC).

Patients with NSCLC whose tumors bore high densities of both CD8-positive cytotoxic T lymphocytes and PD-L1 had significantly better outcomes when treated with the investigational PD-L1 inhibitor durvalumab than patients with high densities of either cell type alone, reported Sonja Althammer, PhD, a scientist at Definiens AG, maker of the anti–PD-L1 compound.

Althammer_Sonja_web.jpg

NATIONAL HARBOR, MD. – Density in tumors of two key immune cells may be a biomarker for response to an inhibitor of programmed death–ligand 1 (PD-L1) among patients with non–small cell lung cancer (NSCLC).

Patients with NSCLC whose tumors bore high densities of both CD8-positive cytotoxic T lymphocytes and PD-L1 had significantly better outcomes when treated with the investigational PD-L1 inhibitor durvalumab than patients with high densities of either cell type alone, reported Sonja Althammer, PhD, a scientist at Definiens AG, maker of the anti–PD-L1 compound.

Althammer_Sonja_web.jpg

BOSTON – Biosimilar versions of disease-modifying antirheumatic drugs have arrived in the United States, but even the best, most efficacious drugs are worthless if patients don’t want to take them.

“The science is important, the medicine is important, but at the end of the day, acceptance and use is what’s going to measure success,” said Seth D. Ginsberg, at a biosimilars symposium sponsored by Corrona, a business that provides registry data and consulting services to biopharmaceutical companies.

wheelchair hospital_web.jpg

Biosimilar confidence

His group has launched “Operation: Biosimilar Confidence” which is designed to educate patients and physicians about the clinical value and scientific underpinnings of biosimilars, as well as the thorough development, review, and regulatory processes involved.

The goal of the project is to instill confidence in patients by helping them to understand the manufacturer’s safety track record, reliability of the biosimilar supply chain, and the availability to them of support services, if they make the switch to a biosimilar.

“Generics don’t have equivalent patient-support programs, and the projection is theoretically that [biosimilar] manufacturers won’t either. We will not accept that. We are going to do everything we can for those patients, to advocate for the continuation of the support programs that we rely on as patients,” he said.

Patient concerns

Surveys of patient concerns about biosimilars have highlighted four key areas:

• What is the manufacturer’s overall safety record in both biologic agents and small-molecule therapies?
• Supply-chain logistic – Will the manufacturer commit to consistent production and supply?
• Will biosimilar manufacturers provide patient support at levels equal to those offered by innovator biologic makers, and what kind of support will be available – phone, websites, social media, copays, etc.?
• Payer ethics – Will payers offer lower copays, deductibles, or premiums, and are payers as concerned as patients about product safety, supply chain, and support?

The implementation strategy for the campaign will focus on speaking directly to patients through CreakyJoints.org, partner Global Healthy Living Foundation, patient and physician organizations, social and conventional media, advertising, and one-on-one encounters.

“We have to talk directly and indirectly to employers and employee-advocacy groups. We have to let these big self-insured employers understand what the perspective of the patient is and what life is like thanks to these medicine, and why biosimilars are a critical component to the success of living with these conditions,” he said.

Advocates also have to work with the media to create “a surround-sound message that reaches all audiences with additional frequency.”

“We cannot allow Wall Street Journal business analysts to dictate the conversations about biosimilars. Why? They’re looking at one thing, and only one thing, and they’re ignoring the patient perspective,” Ginsberg said.

Lastly, patient groups need to work closely with payers, physician groups, and manufacturers to ensure that biosimilars can be smoothly integrated into the healthcare system, he emphasized.

“I want to be crystal clear here: We can’t wait for biosimilars. Bring it on! We want them,” he said.

BOSTON – Biosimilar versions of disease-modifying antirheumatic drugs have arrived in the United States, but even the best, most efficacious drugs are worthless if patients don’t want to take them.

“The science is important, the medicine is important, but at the end of the day, acceptance and use is what’s going to measure success,” said Seth D. Ginsberg, at a biosimilars symposium sponsored by Corrona, a business that provides registry data and consulting services to biopharmaceutical companies.

wheelchair hospital_web.jpg

Biosimilar confidence

His group has launched “Operation: Biosimilar Confidence” which is designed to educate patients and physicians about the clinical value and scientific underpinnings of biosimilars, as well as the thorough development, review, and regulatory processes involved.

The goal of the project is to instill confidence in patients by helping them to understand the manufacturer’s safety track record, reliability of the biosimilar supply chain, and the availability to them of support services, if they make the switch to a biosimilar.

“Generics don’t have equivalent patient-support programs, and the projection is theoretically that [biosimilar] manufacturers won’t either. We will not accept that. We are going to do everything we can for those patients, to advocate for the continuation of the support programs that we rely on as patients,” he said.

Patient concerns

Surveys of patient concerns about biosimilars have highlighted four key areas:

• What is the manufacturer’s overall safety record in both biologic agents and small-molecule therapies?
• Supply-chain logistic – Will the manufacturer commit to consistent production and supply?
• Will biosimilar manufacturers provide patient support at levels equal to those offered by innovator biologic makers, and what kind of support will be available – phone, websites, social media, copays, etc.?
• Payer ethics – Will payers offer lower copays, deductibles, or premiums, and are payers as concerned as patients about product safety, supply chain, and support?

The implementation strategy for the campaign will focus on speaking directly to patients through CreakyJoints.org, partner Global Healthy Living Foundation, patient and physician organizations, social and conventional media, advertising, and one-on-one encounters.

“We have to talk directly and indirectly to employers and employee-advocacy groups. We have to let these big self-insured employers understand what the perspective of the patient is and what life is like thanks to these medicine, and why biosimilars are a critical component to the success of living with these conditions,” he said.

Advocates also have to work with the media to create “a surround-sound message that reaches all audiences with additional frequency.”

“We cannot allow Wall Street Journal business analysts to dictate the conversations about biosimilars. Why? They’re looking at one thing, and only one thing, and they’re ignoring the patient perspective,” Ginsberg said.

Lastly, patient groups need to work closely with payers, physician groups, and manufacturers to ensure that biosimilars can be smoothly integrated into the healthcare system, he emphasized.

“I want to be crystal clear here: We can’t wait for biosimilars. Bring it on! We want them,” he said.

BOSTON – Biosimilar versions of disease-modifying antirheumatic drugs have arrived in the United States, but even the best, most efficacious drugs are worthless if patients don’t want to take them.

“The science is important, the medicine is important, but at the end of the day, acceptance and use is what’s going to measure success,” said Seth D. Ginsberg, at a biosimilars symposium sponsored by Corrona, a business that provides registry data and consulting services to biopharmaceutical companies.

wheelchair hospital_web.jpg

Biosimilar confidence

His group has launched “Operation: Biosimilar Confidence” which is designed to educate patients and physicians about the clinical value and scientific underpinnings of biosimilars, as well as the thorough development, review, and regulatory processes involved.

The goal of the project is to instill confidence in patients by helping them to understand the manufacturer’s safety track record, reliability of the biosimilar supply chain, and the availability to them of support services, if they make the switch to a biosimilar.

“Generics don’t have equivalent patient-support programs, and the projection is theoretically that [biosimilar] manufacturers won’t either. We will not accept that. We are going to do everything we can for those patients, to advocate for the continuation of the support programs that we rely on as patients,” he said.

Patient concerns

Surveys of patient concerns about biosimilars have highlighted four key areas:

• What is the manufacturer’s overall safety record in both biologic agents and small-molecule therapies?
• Supply-chain logistic – Will the manufacturer commit to consistent production and supply?
• Will biosimilar manufacturers provide patient support at levels equal to those offered by innovator biologic makers, and what kind of support will be available – phone, websites, social media, copays, etc.?
• Payer ethics – Will payers offer lower copays, deductibles, or premiums, and are payers as concerned as patients about product safety, supply chain, and support?

The implementation strategy for the campaign will focus on speaking directly to patients through CreakyJoints.org, partner Global Healthy Living Foundation, patient and physician organizations, social and conventional media, advertising, and one-on-one encounters.

“We have to talk directly and indirectly to employers and employee-advocacy groups. We have to let these big self-insured employers understand what the perspective of the patient is and what life is like thanks to these medicine, and why biosimilars are a critical component to the success of living with these conditions,” he said.

Advocates also have to work with the media to create “a surround-sound message that reaches all audiences with additional frequency.”

“We cannot allow Wall Street Journal business analysts to dictate the conversations about biosimilars. Why? They’re looking at one thing, and only one thing, and they’re ignoring the patient perspective,” Ginsberg said.

Lastly, patient groups need to work closely with payers, physician groups, and manufacturers to ensure that biosimilars can be smoothly integrated into the healthcare system, he emphasized.

“I want to be crystal clear here: We can’t wait for biosimilars. Bring it on! We want them,” he said.

BOSTON – Biosimilar drugs are not identical twins of original biologic agents, but there are very strong family ties, and the newcomer is expected to look and behave very much like its older relative, said Janet Woodcock, MD, director of the Center for Drug Evaluation and Research at the Food and Drug Administration.

Although biosimilars differ from generic, small-molecule drugs, concerns about the development of biosimilars mirrors the kerfuffle over generic drugs surrounding the passage of the Hatch-Waxman (Drug Price Competition and Patent Term Restoration) Act in 1984.

Woodcock_Janet_FDA_1_web.jpg

• Are biosimilars as effective and as safe as the originally licensed biopharmaceuticals?
• If pharmacists substitute biosimilars for prescribed biologics, will patients be adversely affected?
• Can biosimilars reduce the high cost of biologic therapy?

“In certain specialties, this skepticism has persisted to this very day,” she said.

ACA mandate

Biosimilars owe their existence in large measure to the Biologics Price Competition and Innovation Act of 2009 (BPCI), passed as a part of the Affordable Care Act and signed into law by President Obama in 2010.

The act created an abbreviated licensure pathway for biologic products that can be shown to be either biosimilar to or interchangeable with an FDA-licensed reference drug.

A biosimilar is defined as a biological product that is highly similar to the reference product “notwithstanding minor differences in clinically inactive components,” and with no clinically meaningful differences between it and the reference product in terms of purity, safety, and potency.

To be interchangeable, a biosimilar must be expected to produce the same clinical results as the reference drug in any given patient, and “for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.”

The definition of interchangeability includes the understanding that the prescriber’s approval is not necessary for substitution of a biosimilar for its reference product.

“If we’re going to have that kind of switching, if they are going to be interchangeable, then we have to have a very high bar,” Dr. Woodcock said.

She added that “any pressure people are feeling to push their patients to biosimilars is from the reimbursement system. There is no non-prescriber switching allowed currently; however, that doesn’t say there isn’t pressure on prescribers to write a different prescription.”

Faster track and bridge to approval

The biosimilar development and approval requires only convincing demonstration of biosimilarity to an existing agent, rather than an independent finding of safety or effectiveness, and the purpose of clinical studies in this case is to address “residual uncertainties,” Dr. Woodcock said.

Drug developers and regulatory authorities alike “are having trouble getting their mind around this concept,” she said.

The FDA requires manufacturers to provide data in their biosimilar drug license applications demonstrating biosimilarity based on analytical studies, animal studies that include toxicity assessments, and one or more clinical studies that include information on immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD) that is sufficient to demonstrate the safety, purity, and potency of the candidate biosimilar.

The FDA is also allowing manufacturers to submit data from animal studies and specified clinical studies comparing a proposed biosimilar product with a product not licensed in the United States, “as long as we are convinced that the reference product is equivalent to the U.S. product,” Dr. Woodcock said.

This “analytical bridge” process was requested by manufacturers who began development of biosimilars in Europe. The European Medicines Agency approved a biosimilar process in 2005, and gave the nod to the first biosimilar agents to existing erythropoietin products in 2007.

Current and pending

As of early October 2016, 66 programs were enrolled in FDA’s Biosimilar Product Development Program, and CDER has received requests for meetings with manufacturers to discuss what tests and documents are required for the development of biosimilars to 20 different reference products.

The FDA is prohibited from publicly discussing the existence of a pending application unless it has been previously disclosed or acknowledged publicly with the manufacturer’s permission, Dr. Woodcock noted, but as of Oct. 10, 2016, seven companies have announced a total of 10 biologic license applications for biosimilars to etanercept (Enbrel), adalimumab (Humira), pegfilgrastim (Neulasta), epoetin alfa (Epogen/Procrit), filgrastim (Neupogen), and infliximab (Remicade).

The FDA has granted licenses to four biosimilars to date (the four-letter suffix is intended to differentiate biosimilars agents from other biosimilars to the same reference product):

• Zarxio (filgrastim-sndz).
• Inflectra (infliximab-dyyb).
• Erelzi (etanercept-szzs).
• Amjevita (adalimumab-atto).

Physician perspective

“Everything I have heard suggests that biosimilars will be useful, but the scientist in me is a skeptic,” commented Donald Massenburg, MD, PhD, a rheumatologist at Wheaton Franciscan Healthcare in Franklin, Wisc., in an interview.

“I feel better now after learning that current biosimilars are not considered interchangeable, meaning that there can’t be substitutions made without the treating physician’s consent,” he said.

He acknowledged that “I wouldn’t be that excited” if a specific biosimilar was approved for interchangeability and was given to his patients without his knowledge.

Dr. Massenburg pointed to data from the NOR-SWITCH trial comparing the biosimilar Remsima to the reference product Remicade for treatment of rheumatic diseases, psoriasis, and inflammatory bowel disease. The trial showed that Remsima was noninferior to the reference product.

Tebbey_PaulW_ABBVIE_web.jpg

BOSTON – Biosimilar drugs are not identical twins of original biologic agents, but there are very strong family ties, and the newcomer is expected to look and behave very much like its older relative, said Janet Woodcock, MD, director of the Center for Drug Evaluation and Research at the Food and Drug Administration.

Although biosimilars differ from generic, small-molecule drugs, concerns about the development of biosimilars mirrors the kerfuffle over generic drugs surrounding the passage of the Hatch-Waxman (Drug Price Competition and Patent Term Restoration) Act in 1984.

Woodcock_Janet_FDA_1_web.jpg

• Are biosimilars as effective and as safe as the originally licensed biopharmaceuticals?
• If pharmacists substitute biosimilars for prescribed biologics, will patients be adversely affected?
• Can biosimilars reduce the high cost of biologic therapy?

“In certain specialties, this skepticism has persisted to this very day,” she said.

ACA mandate

Biosimilars owe their existence in large measure to the Biologics Price Competition and Innovation Act of 2009 (BPCI), passed as a part of the Affordable Care Act and signed into law by President Obama in 2010.

The act created an abbreviated licensure pathway for biologic products that can be shown to be either biosimilar to or interchangeable with an FDA-licensed reference drug.

A biosimilar is defined as a biological product that is highly similar to the reference product “notwithstanding minor differences in clinically inactive components,” and with no clinically meaningful differences between it and the reference product in terms of purity, safety, and potency.

To be interchangeable, a biosimilar must be expected to produce the same clinical results as the reference drug in any given patient, and “for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.”

The definition of interchangeability includes the understanding that the prescriber’s approval is not necessary for substitution of a biosimilar for its reference product.

“If we’re going to have that kind of switching, if they are going to be interchangeable, then we have to have a very high bar,” Dr. Woodcock said.

She added that “any pressure people are feeling to push their patients to biosimilars is from the reimbursement system. There is no non-prescriber switching allowed currently; however, that doesn’t say there isn’t pressure on prescribers to write a different prescription.”

Faster track and bridge to approval

The biosimilar development and approval requires only convincing demonstration of biosimilarity to an existing agent, rather than an independent finding of safety or effectiveness, and the purpose of clinical studies in this case is to address “residual uncertainties,” Dr. Woodcock said.

Drug developers and regulatory authorities alike “are having trouble getting their mind around this concept,” she said.

The FDA requires manufacturers to provide data in their biosimilar drug license applications demonstrating biosimilarity based on analytical studies, animal studies that include toxicity assessments, and one or more clinical studies that include information on immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD) that is sufficient to demonstrate the safety, purity, and potency of the candidate biosimilar.

The FDA is also allowing manufacturers to submit data from animal studies and specified clinical studies comparing a proposed biosimilar product with a product not licensed in the United States, “as long as we are convinced that the reference product is equivalent to the U.S. product,” Dr. Woodcock said.

This “analytical bridge” process was requested by manufacturers who began development of biosimilars in Europe. The European Medicines Agency approved a biosimilar process in 2005, and gave the nod to the first biosimilar agents to existing erythropoietin products in 2007.

Current and pending

As of early October 2016, 66 programs were enrolled in FDA’s Biosimilar Product Development Program, and CDER has received requests for meetings with manufacturers to discuss what tests and documents are required for the development of biosimilars to 20 different reference products.

The FDA is prohibited from publicly discussing the existence of a pending application unless it has been previously disclosed or acknowledged publicly with the manufacturer’s permission, Dr. Woodcock noted, but as of Oct. 10, 2016, seven companies have announced a total of 10 biologic license applications for biosimilars to etanercept (Enbrel), adalimumab (Humira), pegfilgrastim (Neulasta), epoetin alfa (Epogen/Procrit), filgrastim (Neupogen), and infliximab (Remicade).

The FDA has granted licenses to four biosimilars to date (the four-letter suffix is intended to differentiate biosimilars agents from other biosimilars to the same reference product):

• Zarxio (filgrastim-sndz).
• Inflectra (infliximab-dyyb).
• Erelzi (etanercept-szzs).
• Amjevita (adalimumab-atto).

Physician perspective

“Everything I have heard suggests that biosimilars will be useful, but the scientist in me is a skeptic,” commented Donald Massenburg, MD, PhD, a rheumatologist at Wheaton Franciscan Healthcare in Franklin, Wisc., in an interview.

“I feel better now after learning that current biosimilars are not considered interchangeable, meaning that there can’t be substitutions made without the treating physician’s consent,” he said.

He acknowledged that “I wouldn’t be that excited” if a specific biosimilar was approved for interchangeability and was given to his patients without his knowledge.

Dr. Massenburg pointed to data from the NOR-SWITCH trial comparing the biosimilar Remsima to the reference product Remicade for treatment of rheumatic diseases, psoriasis, and inflammatory bowel disease. The trial showed that Remsima was noninferior to the reference product.

Tebbey_PaulW_ABBVIE_web.jpg

BOSTON – Biosimilar drugs are not identical twins of original biologic agents, but there are very strong family ties, and the newcomer is expected to look and behave very much like its older relative, said Janet Woodcock, MD, director of the Center for Drug Evaluation and Research at the Food and Drug Administration.

Although biosimilars differ from generic, small-molecule drugs, concerns about the development of biosimilars mirrors the kerfuffle over generic drugs surrounding the passage of the Hatch-Waxman (Drug Price Competition and Patent Term Restoration) Act in 1984.

Woodcock_Janet_FDA_1_web.jpg

• Are biosimilars as effective and as safe as the originally licensed biopharmaceuticals?
• If pharmacists substitute biosimilars for prescribed biologics, will patients be adversely affected?
• Can biosimilars reduce the high cost of biologic therapy?

“In certain specialties, this skepticism has persisted to this very day,” she said.

ACA mandate

Biosimilars owe their existence in large measure to the Biologics Price Competition and Innovation Act of 2009 (BPCI), passed as a part of the Affordable Care Act and signed into law by President Obama in 2010.

The act created an abbreviated licensure pathway for biologic products that can be shown to be either biosimilar to or interchangeable with an FDA-licensed reference drug.

A biosimilar is defined as a biological product that is highly similar to the reference product “notwithstanding minor differences in clinically inactive components,” and with no clinically meaningful differences between it and the reference product in terms of purity, safety, and potency.

To be interchangeable, a biosimilar must be expected to produce the same clinical results as the reference drug in any given patient, and “for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.”

The definition of interchangeability includes the understanding that the prescriber’s approval is not necessary for substitution of a biosimilar for its reference product.

“If we’re going to have that kind of switching, if they are going to be interchangeable, then we have to have a very high bar,” Dr. Woodcock said.

She added that “any pressure people are feeling to push their patients to biosimilars is from the reimbursement system. There is no non-prescriber switching allowed currently; however, that doesn’t say there isn’t pressure on prescribers to write a different prescription.”

Faster track and bridge to approval

The biosimilar development and approval requires only convincing demonstration of biosimilarity to an existing agent, rather than an independent finding of safety or effectiveness, and the purpose of clinical studies in this case is to address “residual uncertainties,” Dr. Woodcock said.

Drug developers and regulatory authorities alike “are having trouble getting their mind around this concept,” she said.

The FDA requires manufacturers to provide data in their biosimilar drug license applications demonstrating biosimilarity based on analytical studies, animal studies that include toxicity assessments, and one or more clinical studies that include information on immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD) that is sufficient to demonstrate the safety, purity, and potency of the candidate biosimilar.

The FDA is also allowing manufacturers to submit data from animal studies and specified clinical studies comparing a proposed biosimilar product with a product not licensed in the United States, “as long as we are convinced that the reference product is equivalent to the U.S. product,” Dr. Woodcock said.

This “analytical bridge” process was requested by manufacturers who began development of biosimilars in Europe. The European Medicines Agency approved a biosimilar process in 2005, and gave the nod to the first biosimilar agents to existing erythropoietin products in 2007.

Current and pending

As of early October 2016, 66 programs were enrolled in FDA’s Biosimilar Product Development Program, and CDER has received requests for meetings with manufacturers to discuss what tests and documents are required for the development of biosimilars to 20 different reference products.

The FDA is prohibited from publicly discussing the existence of a pending application unless it has been previously disclosed or acknowledged publicly with the manufacturer’s permission, Dr. Woodcock noted, but as of Oct. 10, 2016, seven companies have announced a total of 10 biologic license applications for biosimilars to etanercept (Enbrel), adalimumab (Humira), pegfilgrastim (Neulasta), epoetin alfa (Epogen/Procrit), filgrastim (Neupogen), and infliximab (Remicade).

The FDA has granted licenses to four biosimilars to date (the four-letter suffix is intended to differentiate biosimilars agents from other biosimilars to the same reference product):

• Zarxio (filgrastim-sndz).
• Inflectra (infliximab-dyyb).
• Erelzi (etanercept-szzs).
• Amjevita (adalimumab-atto).

Physician perspective

“Everything I have heard suggests that biosimilars will be useful, but the scientist in me is a skeptic,” commented Donald Massenburg, MD, PhD, a rheumatologist at Wheaton Franciscan Healthcare in Franklin, Wisc., in an interview.

“I feel better now after learning that current biosimilars are not considered interchangeable, meaning that there can’t be substitutions made without the treating physician’s consent,” he said.

He acknowledged that “I wouldn’t be that excited” if a specific biosimilar was approved for interchangeability and was given to his patients without his knowledge.

Dr. Massenburg pointed to data from the NOR-SWITCH trial comparing the biosimilar Remsima to the reference product Remicade for treatment of rheumatic diseases, psoriasis, and inflammatory bowel disease. The trial showed that Remsima was noninferior to the reference product.

Tebbey_PaulW_ABBVIE_web.jpg

BOSTON – For rheumatologists, the primary selling points of biosimilar agents are their presumed efficacy and safety, and their promised cost savings, compared with the reference product, an original biologic agent.

But market forces, patient worries, and provider concerns threaten to file off at least some of biosimilars’ presumed competitive edge, says a rheumatologist involved in the development of biosimilars to treat rheumatic diseases.

“The availability of lower-priced biosimilars, if they’re truly lower priced, should decrease the cost of treating patients; if they’re not lower cost, then this advantage is not holding true,” said Jonathan Kay, MD, professor of medicine at UMass Memorial Medical Center in Worcester.

Kay_Jonathan_MASS_web.jpg

Misperceptions

A common concern among patients and uninformed providers is that biosimilars are the same as biomimics – cheap, usually foreign-made knockoffs of existing drugs that have not undergone regulatory scrutiny and may be neither effective nor safe.

“Biomimics scare patients and scare physicians,” he said, “and misunderstanding of the regulatory approval process, or lack of understanding of the regulatory review or approval process, also intimidates individuals about biosimilars.”

Acceptance of biosimilars is also hampered by a lack of long-term, real-world efficacy and safety data. This is due, in part, to the “inverted pyramid” nature of the biosimilar development and approval process, which starts with myriad analytical, chemical, and functional characterization studies; nonclinical studies; and pharmacokinetic and pharmacodynamic analyses, but only one or two clinical trials. In contrast, the development process for innovator biologics starts with molecular characterization, then moves through the traditional drug development stages of laboratory and preclinical studies, phase I and II trials, and finally phase III registration trials and post-marketing studies.

Because most of the drug development for biosimilars happens behind the scenes, patients and their physicians are often leery about the finished product, no matter how rigorously it was developed. Similarly, there is a paucity of data on long-term immunogenicity of biosimilars, Dr. Kay noted.

Extrapolating about extrapolation

The idea of extrapolation of indications for biosimilars is also an alien concept to many. Simply put, if a reference product is approved for rheumatoid arthritis and has additional indications for treatment of psoriatic arthritis, the approved biosimilar to the original can be extrapolated to be effective against the same indications, even if it has only been tested against one of the indications.

“We have a tremendous amount of clinical experience not only in randomized, controlled clinical trials but also years of marketing experience showing that the reference product is effective and safe for each of the indications for which it’s been approved, and knowing that the biosimilar is essentially like another [manufacturing] run of the reference product allows us to extrapolate indications. But until you become comfortable with accepting that concept, it is certainly a barrier to biosimilars,” he said.

Patients are also scared by the issue of interchangeability, which would allow pharmacists to substitute one product for another without approval of either the patient or the prescribing physician. However, there are currently no biosimilar agents approved as interchangeable by the Food and Drug Administration.

What cost savings?

In the United States, the price of marketed biosimilars has been only 15% lower than that of the reference product, Dr. Kay noted, and multiple discount programs and rebates offered by marketers of the reference product make it difficult to figure out the actual costs of the drugs to payers and whether biosimilars are actually any cheaper.

Additionally, clinicians may be reluctant to adopt biosimilars because of a Centers for Medicare & Medicaid Services billing quirk that currently offers only a single “J” code with a blended reimbursement for all biosimilar agents of a reference product, regardless of cost differences.

Nordic competition model

Dr. Kay pointed to the Norwegian Tender System as a model for using biosimilars to drive down drug costs.

The Norwegian Drug Procurement Cooperation (LIS) annually procures drugs for all publicly funded hospitals, which ensures that prices offered to hospitals for patent-protected medicines are lower than those offered for distribution to wholesalers or pharmacies. Under this system, cost is the driving factor, assuming that drugs in a similar class have similar efficacy and safety, he said.

In 2015, when Norway was purchasing infliximab, it chose Remsima, the biosimilar, over the reference product Remicade, resulting in a 69% cost saving.

The potential interchangeability of Remsima and Remicade in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, and chronic plaque psoriasis is currently being explored in the NOR-SWITCH trial.

Dr. Kay disclosed receiving institutional grants from AbbVie, Genentech, Roche Laboratories, and UCB, and serving as a consultant for those companies.

BOSTON – For rheumatologists, the primary selling points of biosimilar agents are their presumed efficacy and safety, and their promised cost savings, compared with the reference product, an original biologic agent.

But market forces, patient worries, and provider concerns threaten to file off at least some of biosimilars’ presumed competitive edge, says a rheumatologist involved in the development of biosimilars to treat rheumatic diseases.

“The availability of lower-priced biosimilars, if they’re truly lower priced, should decrease the cost of treating patients; if they’re not lower cost, then this advantage is not holding true,” said Jonathan Kay, MD, professor of medicine at UMass Memorial Medical Center in Worcester.

Kay_Jonathan_MASS_web.jpg

Misperceptions

A common concern among patients and uninformed providers is that biosimilars are the same as biomimics – cheap, usually foreign-made knockoffs of existing drugs that have not undergone regulatory scrutiny and may be neither effective nor safe.

“Biomimics scare patients and scare physicians,” he said, “and misunderstanding of the regulatory approval process, or lack of understanding of the regulatory review or approval process, also intimidates individuals about biosimilars.”

Acceptance of biosimilars is also hampered by a lack of long-term, real-world efficacy and safety data. This is due, in part, to the “inverted pyramid” nature of the biosimilar development and approval process, which starts with myriad analytical, chemical, and functional characterization studies; nonclinical studies; and pharmacokinetic and pharmacodynamic analyses, but only one or two clinical trials. In contrast, the development process for innovator biologics starts with molecular characterization, then moves through the traditional drug development stages of laboratory and preclinical studies, phase I and II trials, and finally phase III registration trials and post-marketing studies.

Because most of the drug development for biosimilars happens behind the scenes, patients and their physicians are often leery about the finished product, no matter how rigorously it was developed. Similarly, there is a paucity of data on long-term immunogenicity of biosimilars, Dr. Kay noted.

Extrapolating about extrapolation

The idea of extrapolation of indications for biosimilars is also an alien concept to many. Simply put, if a reference product is approved for rheumatoid arthritis and has additional indications for treatment of psoriatic arthritis, the approved biosimilar to the original can be extrapolated to be effective against the same indications, even if it has only been tested against one of the indications.

“We have a tremendous amount of clinical experience not only in randomized, controlled clinical trials but also years of marketing experience showing that the reference product is effective and safe for each of the indications for which it’s been approved, and knowing that the biosimilar is essentially like another [manufacturing] run of the reference product allows us to extrapolate indications. But until you become comfortable with accepting that concept, it is certainly a barrier to biosimilars,” he said.

Patients are also scared by the issue of interchangeability, which would allow pharmacists to substitute one product for another without approval of either the patient or the prescribing physician. However, there are currently no biosimilar agents approved as interchangeable by the Food and Drug Administration.

What cost savings?

In the United States, the price of marketed biosimilars has been only 15% lower than that of the reference product, Dr. Kay noted, and multiple discount programs and rebates offered by marketers of the reference product make it difficult to figure out the actual costs of the drugs to payers and whether biosimilars are actually any cheaper.

Additionally, clinicians may be reluctant to adopt biosimilars because of a Centers for Medicare & Medicaid Services billing quirk that currently offers only a single “J” code with a blended reimbursement for all biosimilar agents of a reference product, regardless of cost differences.

Nordic competition model

Dr. Kay pointed to the Norwegian Tender System as a model for using biosimilars to drive down drug costs.

The Norwegian Drug Procurement Cooperation (LIS) annually procures drugs for all publicly funded hospitals, which ensures that prices offered to hospitals for patent-protected medicines are lower than those offered for distribution to wholesalers or pharmacies. Under this system, cost is the driving factor, assuming that drugs in a similar class have similar efficacy and safety, he said.

In 2015, when Norway was purchasing infliximab, it chose Remsima, the biosimilar, over the reference product Remicade, resulting in a 69% cost saving.

The potential interchangeability of Remsima and Remicade in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, and chronic plaque psoriasis is currently being explored in the NOR-SWITCH trial.

Dr. Kay disclosed receiving institutional grants from AbbVie, Genentech, Roche Laboratories, and UCB, and serving as a consultant for those companies.

BOSTON – For rheumatologists, the primary selling points of biosimilar agents are their presumed efficacy and safety, and their promised cost savings, compared with the reference product, an original biologic agent.

But market forces, patient worries, and provider concerns threaten to file off at least some of biosimilars’ presumed competitive edge, says a rheumatologist involved in the development of biosimilars to treat rheumatic diseases.

“The availability of lower-priced biosimilars, if they’re truly lower priced, should decrease the cost of treating patients; if they’re not lower cost, then this advantage is not holding true,” said Jonathan Kay, MD, professor of medicine at UMass Memorial Medical Center in Worcester.

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Misperceptions

A common concern among patients and uninformed providers is that biosimilars are the same as biomimics – cheap, usually foreign-made knockoffs of existing drugs that have not undergone regulatory scrutiny and may be neither effective nor safe.

“Biomimics scare patients and scare physicians,” he said, “and misunderstanding of the regulatory approval process, or lack of understanding of the regulatory review or approval process, also intimidates individuals about biosimilars.”

Acceptance of biosimilars is also hampered by a lack of long-term, real-world efficacy and safety data. This is due, in part, to the “inverted pyramid” nature of the biosimilar development and approval process, which starts with myriad analytical, chemical, and functional characterization studies; nonclinical studies; and pharmacokinetic and pharmacodynamic analyses, but only one or two clinical trials. In contrast, the development process for innovator biologics starts with molecular characterization, then moves through the traditional drug development stages of laboratory and preclinical studies, phase I and II trials, and finally phase III registration trials and post-marketing studies.

Because most of the drug development for biosimilars happens behind the scenes, patients and their physicians are often leery about the finished product, no matter how rigorously it was developed. Similarly, there is a paucity of data on long-term immunogenicity of biosimilars, Dr. Kay noted.

Extrapolating about extrapolation

The idea of extrapolation of indications for biosimilars is also an alien concept to many. Simply put, if a reference product is approved for rheumatoid arthritis and has additional indications for treatment of psoriatic arthritis, the approved biosimilar to the original can be extrapolated to be effective against the same indications, even if it has only been tested against one of the indications.

“We have a tremendous amount of clinical experience not only in randomized, controlled clinical trials but also years of marketing experience showing that the reference product is effective and safe for each of the indications for which it’s been approved, and knowing that the biosimilar is essentially like another [manufacturing] run of the reference product allows us to extrapolate indications. But until you become comfortable with accepting that concept, it is certainly a barrier to biosimilars,” he said.

Patients are also scared by the issue of interchangeability, which would allow pharmacists to substitute one product for another without approval of either the patient or the prescribing physician. However, there are currently no biosimilar agents approved as interchangeable by the Food and Drug Administration.

What cost savings?

In the United States, the price of marketed biosimilars has been only 15% lower than that of the reference product, Dr. Kay noted, and multiple discount programs and rebates offered by marketers of the reference product make it difficult to figure out the actual costs of the drugs to payers and whether biosimilars are actually any cheaper.

Additionally, clinicians may be reluctant to adopt biosimilars because of a Centers for Medicare & Medicaid Services billing quirk that currently offers only a single “J” code with a blended reimbursement for all biosimilar agents of a reference product, regardless of cost differences.

Nordic competition model

Dr. Kay pointed to the Norwegian Tender System as a model for using biosimilars to drive down drug costs.

The Norwegian Drug Procurement Cooperation (LIS) annually procures drugs for all publicly funded hospitals, which ensures that prices offered to hospitals for patent-protected medicines are lower than those offered for distribution to wholesalers or pharmacies. Under this system, cost is the driving factor, assuming that drugs in a similar class have similar efficacy and safety, he said.

In 2015, when Norway was purchasing infliximab, it chose Remsima, the biosimilar, over the reference product Remicade, resulting in a 69% cost saving.

The potential interchangeability of Remsima and Remicade in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, and chronic plaque psoriasis is currently being explored in the NOR-SWITCH trial.

Dr. Kay disclosed receiving institutional grants from AbbVie, Genentech, Roche Laboratories, and UCB, and serving as a consultant for those companies.

COPENHAGEN – Fulvestrant continues to show superiority over anastrozole in treatment of hormone receptor-positive breast cancer, particularly in women with lower-volume disease, reported investigators in the phase III FALCON trial.

At a median follow-up of 25 months, median progression-free survival (PFS) for women assigned to receive the selective estrogen-receptor degrader fulvestrant (Faslodex) was 16.6 months, compared with 13.8 months for women assigned to receive the aromatase inhibitor anastrozole (Arimidex), reported Matthew J. Ellis, PhD, of the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston.

“These results are consistent with data from the FIRST study and confirm that fulvestrant is more efficacious than anastrozole in postmenopausal women with hormone receptor–positive locally advanced or metastatic breast cancer who have not received prior endocrine therapy,” he said at the European Society for Medical Oncology Congress.

The benefit of fulvestrant appeared to be only among patients who did not have visceral metastases, however.

In the FIRST study, results of which were reported at the San Antonio Breast Cancer Symposium in 2014, median overall survival at a median follow-up of 48.8 months was 54.1 months in patients on fulvestrant, vs. 48.4 months with anastrozole (hazard ratio [HR] 0.70, P = .04). The median PFS durations were 23.4 months vs. 13.1 months, respectively (HR 0.66, P = .01).

The FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy-Naive Advanced Breast Cancer) trial was a phase III study designed to confirm the PFS benefit seen with fulvestrant in the earlier trial.

Postmenopausal women with locally advanced or metastatic breast cancer positive for the estrogen and/or progesterone receptor and negative for HER2 who had not previously received endocrine therapy were enrolled. They were randomly assigned to receive fulvestrant 500 mg intramuscularly on days 0, 14, and 28 then every 28 days plus an anastrozole placebo (232 patients), or oral anastrozole 1 mg daily plus fulvestrant placebo (230 patients).

Women with life-threatening visceral metastases, systemic estrogen-containing hormone replacement therapy within 6 months of randomization, or prior systemic treatment for breast cancer other than one line of chemotherapy or radiotherapy within 28 days of randomization (except radiation for control of bone pain) were excluded.

As noted, the primary endpoint of PFS was 16.6 months in the fulvestrant arm vs. 13.8 months in the anastrozole arm, translating into an HR for progression on fulvestrant of 0.797 (P = .0486).

Among the 208 patients with no visceral disease, median PFS with fulvestrant was 22.3 months, vs. 13.8 months (HR 0.59, P less than .01). In contrast, among the 254 patients with visceral disease, the respective median PFS durations were 13.8 and 15.9 months (nonsignificant).

For the secondary endpoint of overall survival, at 31% maturity (longest follow-up out to 39 months), there was no significant difference between the study arms.

There were also no significant differences in the secondary endpoints of overall response rate (among patients with measurable disease at baseline), clinical benefit rate, median duration of response, median duration of clinical benefit, or median time to deterioration of total score on the Functional Assessment of Cancer Therapy–Breast (FACT-B) patient-reported outcomes instrument.

Only estimated duration of response (11.4 vs. 7.5 months) and estimated duration of clinical benefit (21.9 vs. 17.5 months) were significantly better with fulvestrant (P less than .001 for each).

Schmid_Peter_LONDON_web.jpg

COPENHAGEN – Fulvestrant continues to show superiority over anastrozole in treatment of hormone receptor-positive breast cancer, particularly in women with lower-volume disease, reported investigators in the phase III FALCON trial.

At a median follow-up of 25 months, median progression-free survival (PFS) for women assigned to receive the selective estrogen-receptor degrader fulvestrant (Faslodex) was 16.6 months, compared with 13.8 months for women assigned to receive the aromatase inhibitor anastrozole (Arimidex), reported Matthew J. Ellis, PhD, of the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston.

“These results are consistent with data from the FIRST study and confirm that fulvestrant is more efficacious than anastrozole in postmenopausal women with hormone receptor–positive locally advanced or metastatic breast cancer who have not received prior endocrine therapy,” he said at the European Society for Medical Oncology Congress.

The benefit of fulvestrant appeared to be only among patients who did not have visceral metastases, however.

In the FIRST study, results of which were reported at the San Antonio Breast Cancer Symposium in 2014, median overall survival at a median follow-up of 48.8 months was 54.1 months in patients on fulvestrant, vs. 48.4 months with anastrozole (hazard ratio [HR] 0.70, P = .04). The median PFS durations were 23.4 months vs. 13.1 months, respectively (HR 0.66, P = .01).

The FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy-Naive Advanced Breast Cancer) trial was a phase III study designed to confirm the PFS benefit seen with fulvestrant in the earlier trial.

Postmenopausal women with locally advanced or metastatic breast cancer positive for the estrogen and/or progesterone receptor and negative for HER2 who had not previously received endocrine therapy were enrolled. They were randomly assigned to receive fulvestrant 500 mg intramuscularly on days 0, 14, and 28 then every 28 days plus an anastrozole placebo (232 patients), or oral anastrozole 1 mg daily plus fulvestrant placebo (230 patients).

Women with life-threatening visceral metastases, systemic estrogen-containing hormone replacement therapy within 6 months of randomization, or prior systemic treatment for breast cancer other than one line of chemotherapy or radiotherapy within 28 days of randomization (except radiation for control of bone pain) were excluded.

As noted, the primary endpoint of PFS was 16.6 months in the fulvestrant arm vs. 13.8 months in the anastrozole arm, translating into an HR for progression on fulvestrant of 0.797 (P = .0486).

Among the 208 patients with no visceral disease, median PFS with fulvestrant was 22.3 months, vs. 13.8 months (HR 0.59, P less than .01). In contrast, among the 254 patients with visceral disease, the respective median PFS durations were 13.8 and 15.9 months (nonsignificant).

For the secondary endpoint of overall survival, at 31% maturity (longest follow-up out to 39 months), there was no significant difference between the study arms.

There were also no significant differences in the secondary endpoints of overall response rate (among patients with measurable disease at baseline), clinical benefit rate, median duration of response, median duration of clinical benefit, or median time to deterioration of total score on the Functional Assessment of Cancer Therapy–Breast (FACT-B) patient-reported outcomes instrument.

Only estimated duration of response (11.4 vs. 7.5 months) and estimated duration of clinical benefit (21.9 vs. 17.5 months) were significantly better with fulvestrant (P less than .001 for each).

Schmid_Peter_LONDON_web.jpg

COPENHAGEN – Fulvestrant continues to show superiority over anastrozole in treatment of hormone receptor-positive breast cancer, particularly in women with lower-volume disease, reported investigators in the phase III FALCON trial.

At a median follow-up of 25 months, median progression-free survival (PFS) for women assigned to receive the selective estrogen-receptor degrader fulvestrant (Faslodex) was 16.6 months, compared with 13.8 months for women assigned to receive the aromatase inhibitor anastrozole (Arimidex), reported Matthew J. Ellis, PhD, of the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston.

“These results are consistent with data from the FIRST study and confirm that fulvestrant is more efficacious than anastrozole in postmenopausal women with hormone receptor–positive locally advanced or metastatic breast cancer who have not received prior endocrine therapy,” he said at the European Society for Medical Oncology Congress.

The benefit of fulvestrant appeared to be only among patients who did not have visceral metastases, however.

In the FIRST study, results of which were reported at the San Antonio Breast Cancer Symposium in 2014, median overall survival at a median follow-up of 48.8 months was 54.1 months in patients on fulvestrant, vs. 48.4 months with anastrozole (hazard ratio [HR] 0.70, P = .04). The median PFS durations were 23.4 months vs. 13.1 months, respectively (HR 0.66, P = .01).

The FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy-Naive Advanced Breast Cancer) trial was a phase III study designed to confirm the PFS benefit seen with fulvestrant in the earlier trial.

Postmenopausal women with locally advanced or metastatic breast cancer positive for the estrogen and/or progesterone receptor and negative for HER2 who had not previously received endocrine therapy were enrolled. They were randomly assigned to receive fulvestrant 500 mg intramuscularly on days 0, 14, and 28 then every 28 days plus an anastrozole placebo (232 patients), or oral anastrozole 1 mg daily plus fulvestrant placebo (230 patients).

Women with life-threatening visceral metastases, systemic estrogen-containing hormone replacement therapy within 6 months of randomization, or prior systemic treatment for breast cancer other than one line of chemotherapy or radiotherapy within 28 days of randomization (except radiation for control of bone pain) were excluded.

As noted, the primary endpoint of PFS was 16.6 months in the fulvestrant arm vs. 13.8 months in the anastrozole arm, translating into an HR for progression on fulvestrant of 0.797 (P = .0486).

Among the 208 patients with no visceral disease, median PFS with fulvestrant was 22.3 months, vs. 13.8 months (HR 0.59, P less than .01). In contrast, among the 254 patients with visceral disease, the respective median PFS durations were 13.8 and 15.9 months (nonsignificant).

For the secondary endpoint of overall survival, at 31% maturity (longest follow-up out to 39 months), there was no significant difference between the study arms.

There were also no significant differences in the secondary endpoints of overall response rate (among patients with measurable disease at baseline), clinical benefit rate, median duration of response, median duration of clinical benefit, or median time to deterioration of total score on the Functional Assessment of Cancer Therapy–Breast (FACT-B) patient-reported outcomes instrument.

Only estimated duration of response (11.4 vs. 7.5 months) and estimated duration of clinical benefit (21.9 vs. 17.5 months) were significantly better with fulvestrant (P less than .001 for each).

Schmid_Peter_LONDON_web.jpg