User login
Huge trial casts doubt on bisphosphonates for breast cancer
say researchers reporting new results from a phase 3 trial with almost 3,000 women.
Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.
However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.
What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.
Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”
The study was published online on June 24 in JAMA Oncology.
An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.
With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.
“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
Risk for necrosis with 5 years of zoledronate
The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.
The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.
The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.
At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.
There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.
Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.
In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.
Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.
Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.
The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.
A version of this article first appeared on Medscape.com.
say researchers reporting new results from a phase 3 trial with almost 3,000 women.
Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.
However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.
What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.
Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”
The study was published online on June 24 in JAMA Oncology.
An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.
With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.
“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
Risk for necrosis with 5 years of zoledronate
The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.
The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.
The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.
At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.
There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.
Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.
In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.
Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.
Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.
The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.
A version of this article first appeared on Medscape.com.
say researchers reporting new results from a phase 3 trial with almost 3,000 women.
Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.
However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.
What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.
Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”
The study was published online on June 24 in JAMA Oncology.
An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.
With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.
“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
Risk for necrosis with 5 years of zoledronate
The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.
The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.
The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.
At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.
There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.
Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.
In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.
Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.
Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.
The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.
A version of this article first appeared on Medscape.com.
No increase in breast cancer risk with fertility treatments
No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.
This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.
With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.
This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.
There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.
More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.
The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study
The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”
In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.
There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).
There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).
The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.
Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.
Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.
A version of this article first appeared on Medscape.com.
No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.
This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.
With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.
This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.
There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.
More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.
The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study
The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”
In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.
There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).
There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).
The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.
Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.
Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.
A version of this article first appeared on Medscape.com.
No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.
This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.
With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.
This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.
There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.
More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.
The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study
The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”
In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.
There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).
There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).
The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.
Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.
Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.
A version of this article first appeared on Medscape.com.
New drug toripalimab improves survival in nasopharyngeal cancer
A new immunotherapy, toripalimab, has the potential to change practice in the treatment of nasopharyngeal carcinoma (NPC), say experts.
The drug is a monoclonal antibody that blocks programmed cell death protein 1 (PD-1), developed in China and recently approved there for the third-line treatment of NPC, among other indications. The U.S. Food and Drug Administration has granted it a breakthrough therapy designation for recurrent/metastatic NPC, as well as fast-track and orphan drug status for other tumor types.
New results show that when toripalimab was added onto chemotherapy with gemcitabine and cisplatin in the first line for recurrent or metastatic nasopharyngeal carcinoma, there was a significant improvement in both progression-free survival and overall survival.
The results come from the phase 3 trial dubbed JUPITER-02 and will be presented at the plenary session of the American Society of Clinical Oncology annual meeting this Sunday; some details were released earlier at a press briefing
The trial randomly assigned 146 patients to toripalimab and 143 to placebo on a background of gemcitabine and cisplatin, the current standard of care for recurrent/metastatic NPC.
Median progression-free survival (PFS) was 11.7 months with toripalimab vs. 8 months with placebo, a significant improvement (hazard ratio, 0.52; 95% confidence interval, 0.36-0.74. P = .0003). Overall survival was not mature at reporting but favored toripalimab with 25 deaths versus 39 in the placebo group, a 40% risk reduction (P = .0462).
The results “support the use of toripalimab in combination with [gemcitabine and cisplatin] as a new standard of care for first-line treatment of recurrent or metastatic nasopharyngeal carcinoma,” said lead investigator and medical oncologist Rui-Hua Xu, MD, PhD, of the Sun Yat-sen University Cancer Center in Guangzhou, China.
Potential to change practice
The significance of the study is that it used immunotherapy in the first-line setting for NPC instead of the second line where it’s frequently used today, commented Jared Weiss, MD, an associate professor of oncology and a head and neck cancer specialist at the University of North Carolina, Chapel Hill.
If FDA approves toripalimab for the indication, it “would change [first-line] standard of care to the triplet regimen,” he said in an interview.
The discussant for this presentation, Julie Gralow, MD, agreed. “This is one of the first studies in metastatic or recurrent NPC to show a benefit” for combining a PD-1 inhibitor with chemotherapy.
“With FDA approval, these findings should prove practice-changing,” said Dr. Gralow, a professor of breast medical oncology at the University of Washington, Seattle, and ASCO’s chief medical officer.
Toripalimab, dosed at 240 mg in the trial, or placebo were administered with gemcitabine and cisplatin every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance every 3 weeks until disease progression, intolerable toxicity, or completion of 2 years of treatment.
The overall response rate was 77.4% with toripalimab and 66.4% with placebo, and the median duration of response in the toripalimab group was 10 months vs. 5.7 months with placebo.
One-year PFS was 49.4% with toripalimab versus 27.9% with placebo; improved PFS was observed with toripalimab across PD-L1 subgroups.
Grade 3 or worse adverse events occurred in slightly less than 90% of both groups, with fatal adverse events occurring in slightly less than 3% in both.
Adverse events leading to discontinuation occurred in 7.5% of the study group and 4.9% on placebo. As expected with immunotherapy, immune-related adverse events such as hypothyroidism were more common with toripalimab (39.7% vs. 18.9%), as were grade 3 or worse immune-related adverse events (7.5% vs. 0.7%).
At interim analysis in May 2020, the median duration treatment was 39 weeks in the toripalimab group and 36 weeks in the placebo group.
The trial was conducted in China, Taiwan, and Singapore.
JUPITER-02 was funded by Shanghai Junshi Bioscience. Investigator disclosures weren’t reported. Dr. Weiss said he had no relevant disclosures. Dr. Gralow is an advisor for a number of companies, including Genentech, Novartis, and Roche.
A version of this article first appeared on Medscape.com.
A new immunotherapy, toripalimab, has the potential to change practice in the treatment of nasopharyngeal carcinoma (NPC), say experts.
The drug is a monoclonal antibody that blocks programmed cell death protein 1 (PD-1), developed in China and recently approved there for the third-line treatment of NPC, among other indications. The U.S. Food and Drug Administration has granted it a breakthrough therapy designation for recurrent/metastatic NPC, as well as fast-track and orphan drug status for other tumor types.
New results show that when toripalimab was added onto chemotherapy with gemcitabine and cisplatin in the first line for recurrent or metastatic nasopharyngeal carcinoma, there was a significant improvement in both progression-free survival and overall survival.
The results come from the phase 3 trial dubbed JUPITER-02 and will be presented at the plenary session of the American Society of Clinical Oncology annual meeting this Sunday; some details were released earlier at a press briefing
The trial randomly assigned 146 patients to toripalimab and 143 to placebo on a background of gemcitabine and cisplatin, the current standard of care for recurrent/metastatic NPC.
Median progression-free survival (PFS) was 11.7 months with toripalimab vs. 8 months with placebo, a significant improvement (hazard ratio, 0.52; 95% confidence interval, 0.36-0.74. P = .0003). Overall survival was not mature at reporting but favored toripalimab with 25 deaths versus 39 in the placebo group, a 40% risk reduction (P = .0462).
The results “support the use of toripalimab in combination with [gemcitabine and cisplatin] as a new standard of care for first-line treatment of recurrent or metastatic nasopharyngeal carcinoma,” said lead investigator and medical oncologist Rui-Hua Xu, MD, PhD, of the Sun Yat-sen University Cancer Center in Guangzhou, China.
Potential to change practice
The significance of the study is that it used immunotherapy in the first-line setting for NPC instead of the second line where it’s frequently used today, commented Jared Weiss, MD, an associate professor of oncology and a head and neck cancer specialist at the University of North Carolina, Chapel Hill.
If FDA approves toripalimab for the indication, it “would change [first-line] standard of care to the triplet regimen,” he said in an interview.
The discussant for this presentation, Julie Gralow, MD, agreed. “This is one of the first studies in metastatic or recurrent NPC to show a benefit” for combining a PD-1 inhibitor with chemotherapy.
“With FDA approval, these findings should prove practice-changing,” said Dr. Gralow, a professor of breast medical oncology at the University of Washington, Seattle, and ASCO’s chief medical officer.
Toripalimab, dosed at 240 mg in the trial, or placebo were administered with gemcitabine and cisplatin every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance every 3 weeks until disease progression, intolerable toxicity, or completion of 2 years of treatment.
The overall response rate was 77.4% with toripalimab and 66.4% with placebo, and the median duration of response in the toripalimab group was 10 months vs. 5.7 months with placebo.
One-year PFS was 49.4% with toripalimab versus 27.9% with placebo; improved PFS was observed with toripalimab across PD-L1 subgroups.
Grade 3 or worse adverse events occurred in slightly less than 90% of both groups, with fatal adverse events occurring in slightly less than 3% in both.
Adverse events leading to discontinuation occurred in 7.5% of the study group and 4.9% on placebo. As expected with immunotherapy, immune-related adverse events such as hypothyroidism were more common with toripalimab (39.7% vs. 18.9%), as were grade 3 or worse immune-related adverse events (7.5% vs. 0.7%).
At interim analysis in May 2020, the median duration treatment was 39 weeks in the toripalimab group and 36 weeks in the placebo group.
The trial was conducted in China, Taiwan, and Singapore.
JUPITER-02 was funded by Shanghai Junshi Bioscience. Investigator disclosures weren’t reported. Dr. Weiss said he had no relevant disclosures. Dr. Gralow is an advisor for a number of companies, including Genentech, Novartis, and Roche.
A version of this article first appeared on Medscape.com.
A new immunotherapy, toripalimab, has the potential to change practice in the treatment of nasopharyngeal carcinoma (NPC), say experts.
The drug is a monoclonal antibody that blocks programmed cell death protein 1 (PD-1), developed in China and recently approved there for the third-line treatment of NPC, among other indications. The U.S. Food and Drug Administration has granted it a breakthrough therapy designation for recurrent/metastatic NPC, as well as fast-track and orphan drug status for other tumor types.
New results show that when toripalimab was added onto chemotherapy with gemcitabine and cisplatin in the first line for recurrent or metastatic nasopharyngeal carcinoma, there was a significant improvement in both progression-free survival and overall survival.
The results come from the phase 3 trial dubbed JUPITER-02 and will be presented at the plenary session of the American Society of Clinical Oncology annual meeting this Sunday; some details were released earlier at a press briefing
The trial randomly assigned 146 patients to toripalimab and 143 to placebo on a background of gemcitabine and cisplatin, the current standard of care for recurrent/metastatic NPC.
Median progression-free survival (PFS) was 11.7 months with toripalimab vs. 8 months with placebo, a significant improvement (hazard ratio, 0.52; 95% confidence interval, 0.36-0.74. P = .0003). Overall survival was not mature at reporting but favored toripalimab with 25 deaths versus 39 in the placebo group, a 40% risk reduction (P = .0462).
The results “support the use of toripalimab in combination with [gemcitabine and cisplatin] as a new standard of care for first-line treatment of recurrent or metastatic nasopharyngeal carcinoma,” said lead investigator and medical oncologist Rui-Hua Xu, MD, PhD, of the Sun Yat-sen University Cancer Center in Guangzhou, China.
Potential to change practice
The significance of the study is that it used immunotherapy in the first-line setting for NPC instead of the second line where it’s frequently used today, commented Jared Weiss, MD, an associate professor of oncology and a head and neck cancer specialist at the University of North Carolina, Chapel Hill.
If FDA approves toripalimab for the indication, it “would change [first-line] standard of care to the triplet regimen,” he said in an interview.
The discussant for this presentation, Julie Gralow, MD, agreed. “This is one of the first studies in metastatic or recurrent NPC to show a benefit” for combining a PD-1 inhibitor with chemotherapy.
“With FDA approval, these findings should prove practice-changing,” said Dr. Gralow, a professor of breast medical oncology at the University of Washington, Seattle, and ASCO’s chief medical officer.
Toripalimab, dosed at 240 mg in the trial, or placebo were administered with gemcitabine and cisplatin every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance every 3 weeks until disease progression, intolerable toxicity, or completion of 2 years of treatment.
The overall response rate was 77.4% with toripalimab and 66.4% with placebo, and the median duration of response in the toripalimab group was 10 months vs. 5.7 months with placebo.
One-year PFS was 49.4% with toripalimab versus 27.9% with placebo; improved PFS was observed with toripalimab across PD-L1 subgroups.
Grade 3 or worse adverse events occurred in slightly less than 90% of both groups, with fatal adverse events occurring in slightly less than 3% in both.
Adverse events leading to discontinuation occurred in 7.5% of the study group and 4.9% on placebo. As expected with immunotherapy, immune-related adverse events such as hypothyroidism were more common with toripalimab (39.7% vs. 18.9%), as were grade 3 or worse immune-related adverse events (7.5% vs. 0.7%).
At interim analysis in May 2020, the median duration treatment was 39 weeks in the toripalimab group and 36 weeks in the placebo group.
The trial was conducted in China, Taiwan, and Singapore.
JUPITER-02 was funded by Shanghai Junshi Bioscience. Investigator disclosures weren’t reported. Dr. Weiss said he had no relevant disclosures. Dr. Gralow is an advisor for a number of companies, including Genentech, Novartis, and Roche.
A version of this article first appeared on Medscape.com.
Pregnancy outcomes ‘favorable’ after BRCA breast cancer treatment
said researchers reporting a review of more than 1,000 young women with breast cancer, mostly in Europe but also Israel and North and South America.
It’s been known that pregnancy after breast cancer treatment, even for hormone receptor–positive disease, is safe overall, the team commented. However, there have been concerns about women who have BRCA mutations because of a lack of data.
The new findings “provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility” and are of “paramount importance for health care providers involved in counseling young patients,” said the researchers, led by Matteo Lambertini, MD, PhD, a medical oncologist at the University of Genoa, Italy.
The review was published in September in the Journal of Clinical Oncology.
The team reviewed reproductive outcomes among 1,252 women who were no older than 40 years when diagnosed with stage I-III BRCA-mutated invasive breast cancer between January 2000 and December 2012.
More than half (65%; n = 811) had BRCA1 mutations, 430 women (34%) had BRCA2 mutations, and 11 women had both.
Overall, 195 women became pregnant, at a median of 4.5 years after the breast cancer diagnosis and at a median age of 36 years.
The miscarriage rate was 10.3%, lower than expected in the general population.
Among the 150 patients who gave birth to 170 infants, delivery complications occurred in 13 of the 112 pregnancies with available data (11.6%), and congenital anomalies were seen in just 2 pregnancies (1.8%). This is a lower rate of anomalies than expected in the general population, the team noted. The rate of preterm delivery was 9.2%, similar to the general population.
There was no difference between the women who became pregnant and those who did not in either disease-free survival (adjusted hazard ratio, 0.87; P = .41) or overall survival (aHR, 0.88; P = .66), over a median follow-up of 8.3 years from diagnosis. In addition to BRCA mutations, the analysis adjusted for age at diagnosis, tumor size, nodal status, hormone receptor status, type of endocrine therapy, and breast surgery.
Over 80% of the subjects had ductal carcinoma, and over 90% of women were HER2-negative. More women in the pregnancy cohort had tumor diameters of 2 cm or less (47.2% vs. 40.9%) and a higher percentage had breast conserving surgery (59% vs. 45.9%).
Chemotherapy was administered to 95.3% of the subjects, most commonly anthracycline and taxane based, and more than 90% received endocrine therapy, most often tamoxifen alone among women who did not become pregnant and tamoxifen plus a luteinizing hormone-releasing hormone agonist among those who did. Endocrine therapy was shorter among women who became pregnant (median, 50 vs. 60 months; P < .001).
The findings held when 176 pregnant cases were matched to 528 nonpregnant controls for year of diagnosis, nodal status, hormone receptor status, and type of BRCA mutation. However, disease-free survival was improved among pregnant women (HR, 0.71; P = .045) who were younger at diagnosis, with median ages of 31 years vs. 36 years (P < .001).
The study was funded by the Italian Association for Cancer Research, among others. Dr. Lambertini reports acting as a consultant for Roche and Novartis and as a speaker for Theramex, Takeda, Roche, Eli Lilly, Novartis. Several coauthors also report relationships with pharmaceutical companies, as detailed in the original article.
A version of this article originally appeared on Medscape.com.
said researchers reporting a review of more than 1,000 young women with breast cancer, mostly in Europe but also Israel and North and South America.
It’s been known that pregnancy after breast cancer treatment, even for hormone receptor–positive disease, is safe overall, the team commented. However, there have been concerns about women who have BRCA mutations because of a lack of data.
The new findings “provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility” and are of “paramount importance for health care providers involved in counseling young patients,” said the researchers, led by Matteo Lambertini, MD, PhD, a medical oncologist at the University of Genoa, Italy.
The review was published in September in the Journal of Clinical Oncology.
The team reviewed reproductive outcomes among 1,252 women who were no older than 40 years when diagnosed with stage I-III BRCA-mutated invasive breast cancer between January 2000 and December 2012.
More than half (65%; n = 811) had BRCA1 mutations, 430 women (34%) had BRCA2 mutations, and 11 women had both.
Overall, 195 women became pregnant, at a median of 4.5 years after the breast cancer diagnosis and at a median age of 36 years.
The miscarriage rate was 10.3%, lower than expected in the general population.
Among the 150 patients who gave birth to 170 infants, delivery complications occurred in 13 of the 112 pregnancies with available data (11.6%), and congenital anomalies were seen in just 2 pregnancies (1.8%). This is a lower rate of anomalies than expected in the general population, the team noted. The rate of preterm delivery was 9.2%, similar to the general population.
There was no difference between the women who became pregnant and those who did not in either disease-free survival (adjusted hazard ratio, 0.87; P = .41) or overall survival (aHR, 0.88; P = .66), over a median follow-up of 8.3 years from diagnosis. In addition to BRCA mutations, the analysis adjusted for age at diagnosis, tumor size, nodal status, hormone receptor status, type of endocrine therapy, and breast surgery.
Over 80% of the subjects had ductal carcinoma, and over 90% of women were HER2-negative. More women in the pregnancy cohort had tumor diameters of 2 cm or less (47.2% vs. 40.9%) and a higher percentage had breast conserving surgery (59% vs. 45.9%).
Chemotherapy was administered to 95.3% of the subjects, most commonly anthracycline and taxane based, and more than 90% received endocrine therapy, most often tamoxifen alone among women who did not become pregnant and tamoxifen plus a luteinizing hormone-releasing hormone agonist among those who did. Endocrine therapy was shorter among women who became pregnant (median, 50 vs. 60 months; P < .001).
The findings held when 176 pregnant cases were matched to 528 nonpregnant controls for year of diagnosis, nodal status, hormone receptor status, and type of BRCA mutation. However, disease-free survival was improved among pregnant women (HR, 0.71; P = .045) who were younger at diagnosis, with median ages of 31 years vs. 36 years (P < .001).
The study was funded by the Italian Association for Cancer Research, among others. Dr. Lambertini reports acting as a consultant for Roche and Novartis and as a speaker for Theramex, Takeda, Roche, Eli Lilly, Novartis. Several coauthors also report relationships with pharmaceutical companies, as detailed in the original article.
A version of this article originally appeared on Medscape.com.
said researchers reporting a review of more than 1,000 young women with breast cancer, mostly in Europe but also Israel and North and South America.
It’s been known that pregnancy after breast cancer treatment, even for hormone receptor–positive disease, is safe overall, the team commented. However, there have been concerns about women who have BRCA mutations because of a lack of data.
The new findings “provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility” and are of “paramount importance for health care providers involved in counseling young patients,” said the researchers, led by Matteo Lambertini, MD, PhD, a medical oncologist at the University of Genoa, Italy.
The review was published in September in the Journal of Clinical Oncology.
The team reviewed reproductive outcomes among 1,252 women who were no older than 40 years when diagnosed with stage I-III BRCA-mutated invasive breast cancer between January 2000 and December 2012.
More than half (65%; n = 811) had BRCA1 mutations, 430 women (34%) had BRCA2 mutations, and 11 women had both.
Overall, 195 women became pregnant, at a median of 4.5 years after the breast cancer diagnosis and at a median age of 36 years.
The miscarriage rate was 10.3%, lower than expected in the general population.
Among the 150 patients who gave birth to 170 infants, delivery complications occurred in 13 of the 112 pregnancies with available data (11.6%), and congenital anomalies were seen in just 2 pregnancies (1.8%). This is a lower rate of anomalies than expected in the general population, the team noted. The rate of preterm delivery was 9.2%, similar to the general population.
There was no difference between the women who became pregnant and those who did not in either disease-free survival (adjusted hazard ratio, 0.87; P = .41) or overall survival (aHR, 0.88; P = .66), over a median follow-up of 8.3 years from diagnosis. In addition to BRCA mutations, the analysis adjusted for age at diagnosis, tumor size, nodal status, hormone receptor status, type of endocrine therapy, and breast surgery.
Over 80% of the subjects had ductal carcinoma, and over 90% of women were HER2-negative. More women in the pregnancy cohort had tumor diameters of 2 cm or less (47.2% vs. 40.9%) and a higher percentage had breast conserving surgery (59% vs. 45.9%).
Chemotherapy was administered to 95.3% of the subjects, most commonly anthracycline and taxane based, and more than 90% received endocrine therapy, most often tamoxifen alone among women who did not become pregnant and tamoxifen plus a luteinizing hormone-releasing hormone agonist among those who did. Endocrine therapy was shorter among women who became pregnant (median, 50 vs. 60 months; P < .001).
The findings held when 176 pregnant cases were matched to 528 nonpregnant controls for year of diagnosis, nodal status, hormone receptor status, and type of BRCA mutation. However, disease-free survival was improved among pregnant women (HR, 0.71; P = .045) who were younger at diagnosis, with median ages of 31 years vs. 36 years (P < .001).
The study was funded by the Italian Association for Cancer Research, among others. Dr. Lambertini reports acting as a consultant for Roche and Novartis and as a speaker for Theramex, Takeda, Roche, Eli Lilly, Novartis. Several coauthors also report relationships with pharmaceutical companies, as detailed in the original article.
A version of this article originally appeared on Medscape.com.
Pembrolizumab approved for triple-negative breast cancer
The Food and Drug Administration has granted accelerated approval for pembrolizumab (Keytruda) in combination with chemotherapy to treat locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) that expresses PD-L1, as determined by a combined positive score of 10 or greater on an FDA-approved assay.
The FDA also approved a PD-L1 assay for selecting TNBC patients for pembrolizumab, the PD-L1 IHC 22C3 pharmDx.
Pembrolizumab is approved for numerous indications in the United States, but the new approval is its first breast cancer indication.
The accelerated approval for pembrolizumab in TNBC was based on progression-free survival (PFS) in the KEYNOTE-355 trial. The FDA noted that continued approval of pembrolizumab in TNBC “may be contingent upon verification and description of clinical benefit in the confirmatory trials.”
KEYNOTE-355 enrolled patients with locally recurrent unresectable or metastatic TNBC who had not received chemotherapy in the metastatic setting. Patients were randomized to chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) plus placebo (n = 281) or chemotherapy plus pembrolizumab at 200 mg on day 1 every 3 weeks (n = 562).
Among PD-L1-positive patients (n = 323), the median PFS was 5.6 months in the placebo arm and 9.7 months in the pembrolizumab arm (hazard ratio, 0.65; P = .0012).
The recommended pembrolizumab dose in TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months.
Pembrolizumab can cause immune-mediated adverse reactions that may be severe or fatal, according to Merck, the manufacturer of pembrolizumab. These adverse reactions include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplant.
“Based on the severity of the adverse reaction, [pembrolizumab] should be withheld or discontinued and corticosteroids administered if appropriate,” the company noted.
For more details on pembrolizumab, see the full prescribing information.
The Food and Drug Administration has granted accelerated approval for pembrolizumab (Keytruda) in combination with chemotherapy to treat locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) that expresses PD-L1, as determined by a combined positive score of 10 or greater on an FDA-approved assay.
The FDA also approved a PD-L1 assay for selecting TNBC patients for pembrolizumab, the PD-L1 IHC 22C3 pharmDx.
Pembrolizumab is approved for numerous indications in the United States, but the new approval is its first breast cancer indication.
The accelerated approval for pembrolizumab in TNBC was based on progression-free survival (PFS) in the KEYNOTE-355 trial. The FDA noted that continued approval of pembrolizumab in TNBC “may be contingent upon verification and description of clinical benefit in the confirmatory trials.”
KEYNOTE-355 enrolled patients with locally recurrent unresectable or metastatic TNBC who had not received chemotherapy in the metastatic setting. Patients were randomized to chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) plus placebo (n = 281) or chemotherapy plus pembrolizumab at 200 mg on day 1 every 3 weeks (n = 562).
Among PD-L1-positive patients (n = 323), the median PFS was 5.6 months in the placebo arm and 9.7 months in the pembrolizumab arm (hazard ratio, 0.65; P = .0012).
The recommended pembrolizumab dose in TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months.
Pembrolizumab can cause immune-mediated adverse reactions that may be severe or fatal, according to Merck, the manufacturer of pembrolizumab. These adverse reactions include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplant.
“Based on the severity of the adverse reaction, [pembrolizumab] should be withheld or discontinued and corticosteroids administered if appropriate,” the company noted.
For more details on pembrolizumab, see the full prescribing information.
The Food and Drug Administration has granted accelerated approval for pembrolizumab (Keytruda) in combination with chemotherapy to treat locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) that expresses PD-L1, as determined by a combined positive score of 10 or greater on an FDA-approved assay.
The FDA also approved a PD-L1 assay for selecting TNBC patients for pembrolizumab, the PD-L1 IHC 22C3 pharmDx.
Pembrolizumab is approved for numerous indications in the United States, but the new approval is its first breast cancer indication.
The accelerated approval for pembrolizumab in TNBC was based on progression-free survival (PFS) in the KEYNOTE-355 trial. The FDA noted that continued approval of pembrolizumab in TNBC “may be contingent upon verification and description of clinical benefit in the confirmatory trials.”
KEYNOTE-355 enrolled patients with locally recurrent unresectable or metastatic TNBC who had not received chemotherapy in the metastatic setting. Patients were randomized to chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) plus placebo (n = 281) or chemotherapy plus pembrolizumab at 200 mg on day 1 every 3 weeks (n = 562).
Among PD-L1-positive patients (n = 323), the median PFS was 5.6 months in the placebo arm and 9.7 months in the pembrolizumab arm (hazard ratio, 0.65; P = .0012).
The recommended pembrolizumab dose in TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months.
Pembrolizumab can cause immune-mediated adverse reactions that may be severe or fatal, according to Merck, the manufacturer of pembrolizumab. These adverse reactions include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplant.
“Based on the severity of the adverse reaction, [pembrolizumab] should be withheld or discontinued and corticosteroids administered if appropriate,” the company noted.
For more details on pembrolizumab, see the full prescribing information.
FROM THE FOOD AND DRUG ADMINISTRATION
Melanoma experts say ‘no’ to routine gene profile testing
“The currently published evidence is insufficient to establish that routine use of GEP testing provides additional clinical value for melanoma staging and prognostication beyond available clinicopathologic variables,” they argued.
Patients must be protected “from potentially inaccurate testing that may provide a false sense of security or perceived increased risk” that could lead to the wrong decisions, they said in a consensus statement from the United States’ national Melanoma Prevention Working Group. The statement was published on July 29 in JAMA Dermatology.
The GEP test for melanoma that is available in the United States – DecisionDx-Melanoma from Castle Biosciences – checks the expression levels of 31 genes reported to be associated with melanoma metastasis and recurrence. It uses quantitative reverse transcriptase and polymerase chain reaction on RNA from formalin-fixed, paraffin-embedded biopsy specimens.
The test stratifies patients as being at low, intermediate, or high risk. It is marketed as a guide to whether to perform sentinel lymph node biopsies (SLNB) on patients age 55 years or older with tumors less than 2 mm deep and to decide what levels of follow-up, imaging, and adjuvant treatment are appropriate for tumors at least 0.3 mm deep.
Medicare reimburses at $7,193 per test for SLNB-eligible patients.
However, this test is not endorsed by the American Academy of Dermatology or National Comprehensive Cancer Network outside of studies because the evidence of benefit is not strong enough, the consensus authors noted.
Even so, use of the test is growing, with up to 10% of cutaneous melanomas now being tested in the United States.
Company welcomes “further discussions”
“To date, thousands of clinicians – over 4,200 US clinicians in the last 12 months – have utilized our GEP test for cutaneous melanoma in their patients after reviewing our clinical data and determining that our test provides clinically actionable information that complements current melanoma staging,” said Castle Biosciences Vice President of Research and Development Bob Cook, PhD, when asked for comment.
Citing company-funded studies, he said that “the strength of the existing evidence in support of these claims has undergone rigorous evaluation to obtain Medicare reimbursement.”
“We believe that the application of the test to help guide [the] decision to pursue SLNB has the potential to realize significant cost savings by reducing unnecessary SLNB procedures, particularly in the T1 population.”
Asked for a reaction to the consensus statement, Dr. Cook said in an interview: “We recently launched two prospective studies with multiple centers nationwide that will involve thousands of patients and provide additional data relating our tests to patient outcomes. ... We welcome further discussions to promote collaborative efforts with centers that are part of the [Melanoma Prevention Working Group] to improve patient outcomes.”
Cart before the horse
Medicare, although it reimburses the test, has its doubts. Due to the “low strength of evidence,” the Centers for Medicare & Medicaid Services said in their local coverage determination that continued reimbursement depends on demonstration of 95% or greater distant-metastasis–free survival and melanoma-specific survival at 3 years “in patients directed to no SLNB by the test compared to standard of care, and ... evidence of higher SLNB positivity in patients selected for this procedure by the test compared to standard of care.”
The statement hints at the Achilles’ heel of GEP in melanoma – that is, the lack of evidence that test results improve outcomes. This was the main concern of the consensus statement; the cart is before the horse.
One of the consensus authors, David Polsky, MD, PhD, professor of dermatologic oncology at New York University, New York City, said that “most of the data for this test come from retrospectively collected patient groups.” The prospective studies have been generally small, with no comparator group. “While they have shown some promise in intermediate thickness melanoma, they have not yet demonstrated utility for thin, stage I melanomas.”
First, do no harm
A new meta-analysis of over 800 patients with cutaneous melanoma tested by DecisionDx-Melanoma, published in JAMA Dermatology alongside the consensus statement, shows how the tests perform.
Among patients with a recurrence, DecisionDx-Melanoma correctly classified 82% with stage II disease but only 29% with stage I disease as high risk. Among those without recurrence, the test correctly classified 90% of stage I patients but only 44% with stage II disease as low risk.
Similar results were seen with the melanoma GEP test available in Europe, MelaGenix (NeraCare GmbH). This test was developed from a panel that was narrowed to seven protective genes and one high-risk gene using a training cohort of 125 cutaneous melanomas.
“The prognostic ability of GEP tests ... appeared to be poor at correctly identifying recurrence in patients with stage I disease, suggesting limited potential for clinical utility in these patients,” commented the meta-analysis authors, led by Michael Marchetti, MD, an assistant professor of dermatology at Weill Cornell Medical College in New York City.
“Unknown are the harms associated with a false-positive result, which were 10-fold more frequent than true-positive results in patients with stage I disease,” they pointed out.
“Further research is needed to define the incremental improvement in risk predictions provided by the test beyond ... all other known clinicopathologic factors,” which include patient sex, age, tumor location and thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and other factors proven to be linked to outcomes, they said.
Studies so far suggesting benefit have incorporated a few of those factors, but not all of them. For now, “it is not clear which patients should be tested or how to act on the results,” Dr. Marchetti and colleagues concluded.
Breast cancer standard of proof
Larger, prospective studies are needed to address whether GEP testing can replace SLNB to predict relapse “and [can identify] patients who could be spared surveillance imaging and/or benefit from adjuvant therapy,” wrote the consensus authors. Follow-up also needs to be long enough to detect delayed recurrence of thin melanomas, they added.
With more research, there is reason to hope that gene expression profiling will help in melanoma; it’s already standard of care in breast cancer, they pointed out.
On the hope front, one cohort study evaluated whether DecisionDx-Melanoma could identify patients at low risk for positive lymph nodes in T1/T2 disease who were eligible for biopsy. Only 1.6% of subjects who were aged 65 years or older and identified by the test as low risk had a positive node.
“This is a promising direction of investigation ... in a narrow, defined population,” noted authors led by Carrie Kovarik, MD, associate professor of dermatology at the University of Pennsylvania, Philadelphia, in an opinion piece last spring.
But still, until there’s “clear evidence that [DecisionDx-Melanoma] results affect patient outcomes, we should not use it to influence care decisions in patients with thin” melanomas. Dermatology “should expect the same standards” of proof as breast cancer, they wrote.
What to do right now?
Despite the marketing, “think twice before ordering GEP tests for” T1a melanomas is the message in an editorial that accompanies the consensus statement. The 5- and 10-year melanoma-specific survival rates are 99% and 98%, respectively. GEP tests are unlikely to change these estimates significantly. In fact, the new meta-analysis indicates “that there may be an approximately 12% misassignment rate in this population,” wrote editorialists Warren Chan, of Baylor College of Medicine, Houston and Hensin Tsao, MD, PhD, director of the melanoma genetics program at Massachusetts General Hospital, Boston.
“Even if you use GEP testing and discover a low-risk class assignment for a 2 mm thick melanoma, avoid the urge to bypass the sentinel lymph node discussion. ... Nodal sampling, for good reasons, remains part of all major guidelines and determines eligibility for adjuvant treatments. ... Many of us engaged in genomics research believe that accurate [melanoma] GEP will be developed in time, but better tools and greater tenacity are needed,” they wrote.
There was no industry funding for the consensus statement and meta-analysis. Authors on the consensus statement reported numerous ties to pharmaceutical and other companies, as listed in the paper.
A version of this article originally appeared on Medscape.com.
“The currently published evidence is insufficient to establish that routine use of GEP testing provides additional clinical value for melanoma staging and prognostication beyond available clinicopathologic variables,” they argued.
Patients must be protected “from potentially inaccurate testing that may provide a false sense of security or perceived increased risk” that could lead to the wrong decisions, they said in a consensus statement from the United States’ national Melanoma Prevention Working Group. The statement was published on July 29 in JAMA Dermatology.
The GEP test for melanoma that is available in the United States – DecisionDx-Melanoma from Castle Biosciences – checks the expression levels of 31 genes reported to be associated with melanoma metastasis and recurrence. It uses quantitative reverse transcriptase and polymerase chain reaction on RNA from formalin-fixed, paraffin-embedded biopsy specimens.
The test stratifies patients as being at low, intermediate, or high risk. It is marketed as a guide to whether to perform sentinel lymph node biopsies (SLNB) on patients age 55 years or older with tumors less than 2 mm deep and to decide what levels of follow-up, imaging, and adjuvant treatment are appropriate for tumors at least 0.3 mm deep.
Medicare reimburses at $7,193 per test for SLNB-eligible patients.
However, this test is not endorsed by the American Academy of Dermatology or National Comprehensive Cancer Network outside of studies because the evidence of benefit is not strong enough, the consensus authors noted.
Even so, use of the test is growing, with up to 10% of cutaneous melanomas now being tested in the United States.
Company welcomes “further discussions”
“To date, thousands of clinicians – over 4,200 US clinicians in the last 12 months – have utilized our GEP test for cutaneous melanoma in their patients after reviewing our clinical data and determining that our test provides clinically actionable information that complements current melanoma staging,” said Castle Biosciences Vice President of Research and Development Bob Cook, PhD, when asked for comment.
Citing company-funded studies, he said that “the strength of the existing evidence in support of these claims has undergone rigorous evaluation to obtain Medicare reimbursement.”
“We believe that the application of the test to help guide [the] decision to pursue SLNB has the potential to realize significant cost savings by reducing unnecessary SLNB procedures, particularly in the T1 population.”
Asked for a reaction to the consensus statement, Dr. Cook said in an interview: “We recently launched two prospective studies with multiple centers nationwide that will involve thousands of patients and provide additional data relating our tests to patient outcomes. ... We welcome further discussions to promote collaborative efforts with centers that are part of the [Melanoma Prevention Working Group] to improve patient outcomes.”
Cart before the horse
Medicare, although it reimburses the test, has its doubts. Due to the “low strength of evidence,” the Centers for Medicare & Medicaid Services said in their local coverage determination that continued reimbursement depends on demonstration of 95% or greater distant-metastasis–free survival and melanoma-specific survival at 3 years “in patients directed to no SLNB by the test compared to standard of care, and ... evidence of higher SLNB positivity in patients selected for this procedure by the test compared to standard of care.”
The statement hints at the Achilles’ heel of GEP in melanoma – that is, the lack of evidence that test results improve outcomes. This was the main concern of the consensus statement; the cart is before the horse.
One of the consensus authors, David Polsky, MD, PhD, professor of dermatologic oncology at New York University, New York City, said that “most of the data for this test come from retrospectively collected patient groups.” The prospective studies have been generally small, with no comparator group. “While they have shown some promise in intermediate thickness melanoma, they have not yet demonstrated utility for thin, stage I melanomas.”
First, do no harm
A new meta-analysis of over 800 patients with cutaneous melanoma tested by DecisionDx-Melanoma, published in JAMA Dermatology alongside the consensus statement, shows how the tests perform.
Among patients with a recurrence, DecisionDx-Melanoma correctly classified 82% with stage II disease but only 29% with stage I disease as high risk. Among those without recurrence, the test correctly classified 90% of stage I patients but only 44% with stage II disease as low risk.
Similar results were seen with the melanoma GEP test available in Europe, MelaGenix (NeraCare GmbH). This test was developed from a panel that was narrowed to seven protective genes and one high-risk gene using a training cohort of 125 cutaneous melanomas.
“The prognostic ability of GEP tests ... appeared to be poor at correctly identifying recurrence in patients with stage I disease, suggesting limited potential for clinical utility in these patients,” commented the meta-analysis authors, led by Michael Marchetti, MD, an assistant professor of dermatology at Weill Cornell Medical College in New York City.
“Unknown are the harms associated with a false-positive result, which were 10-fold more frequent than true-positive results in patients with stage I disease,” they pointed out.
“Further research is needed to define the incremental improvement in risk predictions provided by the test beyond ... all other known clinicopathologic factors,” which include patient sex, age, tumor location and thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and other factors proven to be linked to outcomes, they said.
Studies so far suggesting benefit have incorporated a few of those factors, but not all of them. For now, “it is not clear which patients should be tested or how to act on the results,” Dr. Marchetti and colleagues concluded.
Breast cancer standard of proof
Larger, prospective studies are needed to address whether GEP testing can replace SLNB to predict relapse “and [can identify] patients who could be spared surveillance imaging and/or benefit from adjuvant therapy,” wrote the consensus authors. Follow-up also needs to be long enough to detect delayed recurrence of thin melanomas, they added.
With more research, there is reason to hope that gene expression profiling will help in melanoma; it’s already standard of care in breast cancer, they pointed out.
On the hope front, one cohort study evaluated whether DecisionDx-Melanoma could identify patients at low risk for positive lymph nodes in T1/T2 disease who were eligible for biopsy. Only 1.6% of subjects who were aged 65 years or older and identified by the test as low risk had a positive node.
“This is a promising direction of investigation ... in a narrow, defined population,” noted authors led by Carrie Kovarik, MD, associate professor of dermatology at the University of Pennsylvania, Philadelphia, in an opinion piece last spring.
But still, until there’s “clear evidence that [DecisionDx-Melanoma] results affect patient outcomes, we should not use it to influence care decisions in patients with thin” melanomas. Dermatology “should expect the same standards” of proof as breast cancer, they wrote.
What to do right now?
Despite the marketing, “think twice before ordering GEP tests for” T1a melanomas is the message in an editorial that accompanies the consensus statement. The 5- and 10-year melanoma-specific survival rates are 99% and 98%, respectively. GEP tests are unlikely to change these estimates significantly. In fact, the new meta-analysis indicates “that there may be an approximately 12% misassignment rate in this population,” wrote editorialists Warren Chan, of Baylor College of Medicine, Houston and Hensin Tsao, MD, PhD, director of the melanoma genetics program at Massachusetts General Hospital, Boston.
“Even if you use GEP testing and discover a low-risk class assignment for a 2 mm thick melanoma, avoid the urge to bypass the sentinel lymph node discussion. ... Nodal sampling, for good reasons, remains part of all major guidelines and determines eligibility for adjuvant treatments. ... Many of us engaged in genomics research believe that accurate [melanoma] GEP will be developed in time, but better tools and greater tenacity are needed,” they wrote.
There was no industry funding for the consensus statement and meta-analysis. Authors on the consensus statement reported numerous ties to pharmaceutical and other companies, as listed in the paper.
A version of this article originally appeared on Medscape.com.
“The currently published evidence is insufficient to establish that routine use of GEP testing provides additional clinical value for melanoma staging and prognostication beyond available clinicopathologic variables,” they argued.
Patients must be protected “from potentially inaccurate testing that may provide a false sense of security or perceived increased risk” that could lead to the wrong decisions, they said in a consensus statement from the United States’ national Melanoma Prevention Working Group. The statement was published on July 29 in JAMA Dermatology.
The GEP test for melanoma that is available in the United States – DecisionDx-Melanoma from Castle Biosciences – checks the expression levels of 31 genes reported to be associated with melanoma metastasis and recurrence. It uses quantitative reverse transcriptase and polymerase chain reaction on RNA from formalin-fixed, paraffin-embedded biopsy specimens.
The test stratifies patients as being at low, intermediate, or high risk. It is marketed as a guide to whether to perform sentinel lymph node biopsies (SLNB) on patients age 55 years or older with tumors less than 2 mm deep and to decide what levels of follow-up, imaging, and adjuvant treatment are appropriate for tumors at least 0.3 mm deep.
Medicare reimburses at $7,193 per test for SLNB-eligible patients.
However, this test is not endorsed by the American Academy of Dermatology or National Comprehensive Cancer Network outside of studies because the evidence of benefit is not strong enough, the consensus authors noted.
Even so, use of the test is growing, with up to 10% of cutaneous melanomas now being tested in the United States.
Company welcomes “further discussions”
“To date, thousands of clinicians – over 4,200 US clinicians in the last 12 months – have utilized our GEP test for cutaneous melanoma in their patients after reviewing our clinical data and determining that our test provides clinically actionable information that complements current melanoma staging,” said Castle Biosciences Vice President of Research and Development Bob Cook, PhD, when asked for comment.
Citing company-funded studies, he said that “the strength of the existing evidence in support of these claims has undergone rigorous evaluation to obtain Medicare reimbursement.”
“We believe that the application of the test to help guide [the] decision to pursue SLNB has the potential to realize significant cost savings by reducing unnecessary SLNB procedures, particularly in the T1 population.”
Asked for a reaction to the consensus statement, Dr. Cook said in an interview: “We recently launched two prospective studies with multiple centers nationwide that will involve thousands of patients and provide additional data relating our tests to patient outcomes. ... We welcome further discussions to promote collaborative efforts with centers that are part of the [Melanoma Prevention Working Group] to improve patient outcomes.”
Cart before the horse
Medicare, although it reimburses the test, has its doubts. Due to the “low strength of evidence,” the Centers for Medicare & Medicaid Services said in their local coverage determination that continued reimbursement depends on demonstration of 95% or greater distant-metastasis–free survival and melanoma-specific survival at 3 years “in patients directed to no SLNB by the test compared to standard of care, and ... evidence of higher SLNB positivity in patients selected for this procedure by the test compared to standard of care.”
The statement hints at the Achilles’ heel of GEP in melanoma – that is, the lack of evidence that test results improve outcomes. This was the main concern of the consensus statement; the cart is before the horse.
One of the consensus authors, David Polsky, MD, PhD, professor of dermatologic oncology at New York University, New York City, said that “most of the data for this test come from retrospectively collected patient groups.” The prospective studies have been generally small, with no comparator group. “While they have shown some promise in intermediate thickness melanoma, they have not yet demonstrated utility for thin, stage I melanomas.”
First, do no harm
A new meta-analysis of over 800 patients with cutaneous melanoma tested by DecisionDx-Melanoma, published in JAMA Dermatology alongside the consensus statement, shows how the tests perform.
Among patients with a recurrence, DecisionDx-Melanoma correctly classified 82% with stage II disease but only 29% with stage I disease as high risk. Among those without recurrence, the test correctly classified 90% of stage I patients but only 44% with stage II disease as low risk.
Similar results were seen with the melanoma GEP test available in Europe, MelaGenix (NeraCare GmbH). This test was developed from a panel that was narrowed to seven protective genes and one high-risk gene using a training cohort of 125 cutaneous melanomas.
“The prognostic ability of GEP tests ... appeared to be poor at correctly identifying recurrence in patients with stage I disease, suggesting limited potential for clinical utility in these patients,” commented the meta-analysis authors, led by Michael Marchetti, MD, an assistant professor of dermatology at Weill Cornell Medical College in New York City.
“Unknown are the harms associated with a false-positive result, which were 10-fold more frequent than true-positive results in patients with stage I disease,” they pointed out.
“Further research is needed to define the incremental improvement in risk predictions provided by the test beyond ... all other known clinicopathologic factors,” which include patient sex, age, tumor location and thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and other factors proven to be linked to outcomes, they said.
Studies so far suggesting benefit have incorporated a few of those factors, but not all of them. For now, “it is not clear which patients should be tested or how to act on the results,” Dr. Marchetti and colleagues concluded.
Breast cancer standard of proof
Larger, prospective studies are needed to address whether GEP testing can replace SLNB to predict relapse “and [can identify] patients who could be spared surveillance imaging and/or benefit from adjuvant therapy,” wrote the consensus authors. Follow-up also needs to be long enough to detect delayed recurrence of thin melanomas, they added.
With more research, there is reason to hope that gene expression profiling will help in melanoma; it’s already standard of care in breast cancer, they pointed out.
On the hope front, one cohort study evaluated whether DecisionDx-Melanoma could identify patients at low risk for positive lymph nodes in T1/T2 disease who were eligible for biopsy. Only 1.6% of subjects who were aged 65 years or older and identified by the test as low risk had a positive node.
“This is a promising direction of investigation ... in a narrow, defined population,” noted authors led by Carrie Kovarik, MD, associate professor of dermatology at the University of Pennsylvania, Philadelphia, in an opinion piece last spring.
But still, until there’s “clear evidence that [DecisionDx-Melanoma] results affect patient outcomes, we should not use it to influence care decisions in patients with thin” melanomas. Dermatology “should expect the same standards” of proof as breast cancer, they wrote.
What to do right now?
Despite the marketing, “think twice before ordering GEP tests for” T1a melanomas is the message in an editorial that accompanies the consensus statement. The 5- and 10-year melanoma-specific survival rates are 99% and 98%, respectively. GEP tests are unlikely to change these estimates significantly. In fact, the new meta-analysis indicates “that there may be an approximately 12% misassignment rate in this population,” wrote editorialists Warren Chan, of Baylor College of Medicine, Houston and Hensin Tsao, MD, PhD, director of the melanoma genetics program at Massachusetts General Hospital, Boston.
“Even if you use GEP testing and discover a low-risk class assignment for a 2 mm thick melanoma, avoid the urge to bypass the sentinel lymph node discussion. ... Nodal sampling, for good reasons, remains part of all major guidelines and determines eligibility for adjuvant treatments. ... Many of us engaged in genomics research believe that accurate [melanoma] GEP will be developed in time, but better tools and greater tenacity are needed,” they wrote.
There was no industry funding for the consensus statement and meta-analysis. Authors on the consensus statement reported numerous ties to pharmaceutical and other companies, as listed in the paper.
A version of this article originally appeared on Medscape.com.