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Cabozantinib boosts dual immunotherapy in advanced RCC
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
First drug for desmoid tumors: ‘Impressive’ data for nirogacestat
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
FROM ESMO 2022
Blood test for multiple cancers: Many false positives
PARIS –
“As this technology develops, people must continue with their standard cancer screening, but this is a glimpse of what the future may hold,” commented study investigator Deborah Schrag, MD, MPH, chair, department of medicine, Memorial Sloan Kettering Cancer Center, New York.
For the PATHFINDER study, the Galleri blood test (developed by Grail) was used in 6,621 healthy individuals aged over 50, with or without additional cancer risk factors (such as history of smoking or genetic risk).
It found a positive cancer signal in 92 individuals (1.4%).
None of the individuals who tested positive was known to have cancer at the time of testing. Subsequent workup, which could include scans and/or biopsy, found cancer in 38% of those with a positive test.
“When the test was positive, the workups were typically done in less than 3 months,” Dr. Schrag commented, adding that “the blood test typically predicted the origin of the cancer.”
Dr. Schrag presented the findings at the annual meeting of the European Society for Medical Oncology (ESMO).
Approached for comment, Anthony J. Olszanski, MD, RPh, vice chair of research at the Fox Chase Cancer Center, Philadelphia, noted that the use of a blood test to “find” cancer has long been on the minds of patients. “It is not uncommon to hear oncology patients ask: ‘Why didn’t my doctor find my cancer earlier, on blood tests?’ ”
As this study suggests, finding a malignancy before it becomes apparent on imaging or because of symptoms is one step closer to becoming a reality. “But although this is an important study, it must be noted that only about 40% of patients with a positive test result were actually found to have cancer,” Dr. Olszanski said. “Conversely, about 60% of patients with a positive test result likely suffered from a considerable amount of anxiety that may persist even after further testing did not reveal a malignancy.”
Another important issue is that such testing may incur substantial health care cost. “Less than 2 participants per 100 had a positive test result, and those patients underwent further testing to interrogate the result,” he added. “It also remains unclear if detecting cancer early will lead to better outcomes.”
Whether or not the test will be cost-effective remains unknown, as Dr. Schrag emphasized they do not have a formal cost analysis at this time. “This technology is not ready for population-wide screening, but as the technology improves, costs will go down,” she said.
Dr. Schrag also added that this is a new concept and the trial shows it is feasible to detect cancer using a blood test. “It was not designed to determine if the test can decrease cancer mortality, which is obviously the purpose of screening, but it’s premature for that,” she said.
Details of the results
The Galleri test uses cell-free DNA and machine learning to detect a common cancer signal across more than 50 cancer types as well as to predict cancer signal origin.
Overall, the test detected a cancer signal in 1.4% (n = 92) of participants with analyzable samples.
A total of 90 participants underwent diagnostic testing (33 true positives and 57 false positives). Of the true positives, 81.8% underwent more than one invasive diagnostic test, as did 29.8% of false positives.
Specificity was 99.1%, positive predictive value (PPV) was approximately 40%, and 73% of those who were true positives had diagnostic resolution in less than 3 months.
Of the cancers that were diagnosed, 19 were solid tumors and 17 were hematologic cancers; 7 were diagnosed in a person with a history of cancer, 26 were cancer types without standard screening, and 14 were diagnosed at an early stage.
“What is exciting about this new paradigm is that many of these were cancers for which we don’t have standard screening,” said Dr. Schrag.
Dr. Schrag noted that given the immense interest in this study, the manufacturer is working toward refining the assay and improving the test. A reanalysis was conducted on all specimens using a refined version of the test.
“Importantly, the new analysis identified fewer patients with having positive signals, from 1.4% to 0.9%,” she said. “Specificity improved to 99.5% as did PPV – from 38% to 43.1% – and more people need to be screened to find a cancer – up to 263 from 189.”
False positives concerning
Previous, and very similar, results from the PATHFINDER trial were presented last year at the annual meeting of the American Society of Clinical Oncology.
Max Diehn, MD, PhD, associate professor of radiation oncology at Stanford (Calif.) University, was an invited discussant for the study.
He pointed out that there were more false positives than true positives and noted that “there were a significant number of invasive procedures in false positives, which could cause harm to these patients who don’t have cancer.”
Dr. Diehn also explained that most true positives were for lymphoid malignancies, not solid tumors, and it is not known whether early detection of lymphoid malignancy has clinical utility.
The Galleri test is already available in the United States and is being offered by a number of U.S. health networks. However, it is not approved by the U.S. Food and Drug Administration and is not covered by medical insurance, so individuals have to pay around $950 for it out of pocket.
Although some experts are excited by its potential, describing it as a “game-changer,” others are concerned that there are no clinical pathways in place yet to deal with the results of such a blood test, and say it is not ready for prime time.
The study was funded by Grail, a subsidiary of Illumina. Dr. Shrag has reported relationships with Grail, the Journal of the American Medical Association, and Pfizer. Several coauthors also have disclosed relationships with industry. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and Instil Bio, and running trials for them.
A version of this article first appeared on Medscape.com.
PARIS –
“As this technology develops, people must continue with their standard cancer screening, but this is a glimpse of what the future may hold,” commented study investigator Deborah Schrag, MD, MPH, chair, department of medicine, Memorial Sloan Kettering Cancer Center, New York.
For the PATHFINDER study, the Galleri blood test (developed by Grail) was used in 6,621 healthy individuals aged over 50, with or without additional cancer risk factors (such as history of smoking or genetic risk).
It found a positive cancer signal in 92 individuals (1.4%).
None of the individuals who tested positive was known to have cancer at the time of testing. Subsequent workup, which could include scans and/or biopsy, found cancer in 38% of those with a positive test.
“When the test was positive, the workups were typically done in less than 3 months,” Dr. Schrag commented, adding that “the blood test typically predicted the origin of the cancer.”
Dr. Schrag presented the findings at the annual meeting of the European Society for Medical Oncology (ESMO).
Approached for comment, Anthony J. Olszanski, MD, RPh, vice chair of research at the Fox Chase Cancer Center, Philadelphia, noted that the use of a blood test to “find” cancer has long been on the minds of patients. “It is not uncommon to hear oncology patients ask: ‘Why didn’t my doctor find my cancer earlier, on blood tests?’ ”
As this study suggests, finding a malignancy before it becomes apparent on imaging or because of symptoms is one step closer to becoming a reality. “But although this is an important study, it must be noted that only about 40% of patients with a positive test result were actually found to have cancer,” Dr. Olszanski said. “Conversely, about 60% of patients with a positive test result likely suffered from a considerable amount of anxiety that may persist even after further testing did not reveal a malignancy.”
Another important issue is that such testing may incur substantial health care cost. “Less than 2 participants per 100 had a positive test result, and those patients underwent further testing to interrogate the result,” he added. “It also remains unclear if detecting cancer early will lead to better outcomes.”
Whether or not the test will be cost-effective remains unknown, as Dr. Schrag emphasized they do not have a formal cost analysis at this time. “This technology is not ready for population-wide screening, but as the technology improves, costs will go down,” she said.
Dr. Schrag also added that this is a new concept and the trial shows it is feasible to detect cancer using a blood test. “It was not designed to determine if the test can decrease cancer mortality, which is obviously the purpose of screening, but it’s premature for that,” she said.
Details of the results
The Galleri test uses cell-free DNA and machine learning to detect a common cancer signal across more than 50 cancer types as well as to predict cancer signal origin.
Overall, the test detected a cancer signal in 1.4% (n = 92) of participants with analyzable samples.
A total of 90 participants underwent diagnostic testing (33 true positives and 57 false positives). Of the true positives, 81.8% underwent more than one invasive diagnostic test, as did 29.8% of false positives.
Specificity was 99.1%, positive predictive value (PPV) was approximately 40%, and 73% of those who were true positives had diagnostic resolution in less than 3 months.
Of the cancers that were diagnosed, 19 were solid tumors and 17 were hematologic cancers; 7 were diagnosed in a person with a history of cancer, 26 were cancer types without standard screening, and 14 were diagnosed at an early stage.
“What is exciting about this new paradigm is that many of these were cancers for which we don’t have standard screening,” said Dr. Schrag.
Dr. Schrag noted that given the immense interest in this study, the manufacturer is working toward refining the assay and improving the test. A reanalysis was conducted on all specimens using a refined version of the test.
“Importantly, the new analysis identified fewer patients with having positive signals, from 1.4% to 0.9%,” she said. “Specificity improved to 99.5% as did PPV – from 38% to 43.1% – and more people need to be screened to find a cancer – up to 263 from 189.”
False positives concerning
Previous, and very similar, results from the PATHFINDER trial were presented last year at the annual meeting of the American Society of Clinical Oncology.
Max Diehn, MD, PhD, associate professor of radiation oncology at Stanford (Calif.) University, was an invited discussant for the study.
He pointed out that there were more false positives than true positives and noted that “there were a significant number of invasive procedures in false positives, which could cause harm to these patients who don’t have cancer.”
Dr. Diehn also explained that most true positives were for lymphoid malignancies, not solid tumors, and it is not known whether early detection of lymphoid malignancy has clinical utility.
The Galleri test is already available in the United States and is being offered by a number of U.S. health networks. However, it is not approved by the U.S. Food and Drug Administration and is not covered by medical insurance, so individuals have to pay around $950 for it out of pocket.
Although some experts are excited by its potential, describing it as a “game-changer,” others are concerned that there are no clinical pathways in place yet to deal with the results of such a blood test, and say it is not ready for prime time.
The study was funded by Grail, a subsidiary of Illumina. Dr. Shrag has reported relationships with Grail, the Journal of the American Medical Association, and Pfizer. Several coauthors also have disclosed relationships with industry. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and Instil Bio, and running trials for them.
A version of this article first appeared on Medscape.com.
PARIS –
“As this technology develops, people must continue with their standard cancer screening, but this is a glimpse of what the future may hold,” commented study investigator Deborah Schrag, MD, MPH, chair, department of medicine, Memorial Sloan Kettering Cancer Center, New York.
For the PATHFINDER study, the Galleri blood test (developed by Grail) was used in 6,621 healthy individuals aged over 50, with or without additional cancer risk factors (such as history of smoking or genetic risk).
It found a positive cancer signal in 92 individuals (1.4%).
None of the individuals who tested positive was known to have cancer at the time of testing. Subsequent workup, which could include scans and/or biopsy, found cancer in 38% of those with a positive test.
“When the test was positive, the workups were typically done in less than 3 months,” Dr. Schrag commented, adding that “the blood test typically predicted the origin of the cancer.”
Dr. Schrag presented the findings at the annual meeting of the European Society for Medical Oncology (ESMO).
Approached for comment, Anthony J. Olszanski, MD, RPh, vice chair of research at the Fox Chase Cancer Center, Philadelphia, noted that the use of a blood test to “find” cancer has long been on the minds of patients. “It is not uncommon to hear oncology patients ask: ‘Why didn’t my doctor find my cancer earlier, on blood tests?’ ”
As this study suggests, finding a malignancy before it becomes apparent on imaging or because of symptoms is one step closer to becoming a reality. “But although this is an important study, it must be noted that only about 40% of patients with a positive test result were actually found to have cancer,” Dr. Olszanski said. “Conversely, about 60% of patients with a positive test result likely suffered from a considerable amount of anxiety that may persist even after further testing did not reveal a malignancy.”
Another important issue is that such testing may incur substantial health care cost. “Less than 2 participants per 100 had a positive test result, and those patients underwent further testing to interrogate the result,” he added. “It also remains unclear if detecting cancer early will lead to better outcomes.”
Whether or not the test will be cost-effective remains unknown, as Dr. Schrag emphasized they do not have a formal cost analysis at this time. “This technology is not ready for population-wide screening, but as the technology improves, costs will go down,” she said.
Dr. Schrag also added that this is a new concept and the trial shows it is feasible to detect cancer using a blood test. “It was not designed to determine if the test can decrease cancer mortality, which is obviously the purpose of screening, but it’s premature for that,” she said.
Details of the results
The Galleri test uses cell-free DNA and machine learning to detect a common cancer signal across more than 50 cancer types as well as to predict cancer signal origin.
Overall, the test detected a cancer signal in 1.4% (n = 92) of participants with analyzable samples.
A total of 90 participants underwent diagnostic testing (33 true positives and 57 false positives). Of the true positives, 81.8% underwent more than one invasive diagnostic test, as did 29.8% of false positives.
Specificity was 99.1%, positive predictive value (PPV) was approximately 40%, and 73% of those who were true positives had diagnostic resolution in less than 3 months.
Of the cancers that were diagnosed, 19 were solid tumors and 17 were hematologic cancers; 7 were diagnosed in a person with a history of cancer, 26 were cancer types without standard screening, and 14 were diagnosed at an early stage.
“What is exciting about this new paradigm is that many of these were cancers for which we don’t have standard screening,” said Dr. Schrag.
Dr. Schrag noted that given the immense interest in this study, the manufacturer is working toward refining the assay and improving the test. A reanalysis was conducted on all specimens using a refined version of the test.
“Importantly, the new analysis identified fewer patients with having positive signals, from 1.4% to 0.9%,” she said. “Specificity improved to 99.5% as did PPV – from 38% to 43.1% – and more people need to be screened to find a cancer – up to 263 from 189.”
False positives concerning
Previous, and very similar, results from the PATHFINDER trial were presented last year at the annual meeting of the American Society of Clinical Oncology.
Max Diehn, MD, PhD, associate professor of radiation oncology at Stanford (Calif.) University, was an invited discussant for the study.
He pointed out that there were more false positives than true positives and noted that “there were a significant number of invasive procedures in false positives, which could cause harm to these patients who don’t have cancer.”
Dr. Diehn also explained that most true positives were for lymphoid malignancies, not solid tumors, and it is not known whether early detection of lymphoid malignancy has clinical utility.
The Galleri test is already available in the United States and is being offered by a number of U.S. health networks. However, it is not approved by the U.S. Food and Drug Administration and is not covered by medical insurance, so individuals have to pay around $950 for it out of pocket.
Although some experts are excited by its potential, describing it as a “game-changer,” others are concerned that there are no clinical pathways in place yet to deal with the results of such a blood test, and say it is not ready for prime time.
The study was funded by Grail, a subsidiary of Illumina. Dr. Shrag has reported relationships with Grail, the Journal of the American Medical Association, and Pfizer. Several coauthors also have disclosed relationships with industry. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and Instil Bio, and running trials for them.
A version of this article first appeared on Medscape.com.
AT ESMO 2022