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Prodige 7: No survival benefit with HIPEC for advanced colorectal cancer
CHICAGO – , according to findings from the randomized phase 3 UNICANCER Prodige 7 trial.
At a median follow up of 63.8 months, median overall survival – the primary endpoint of the study – was “completely comparable” at 41.7 and 41.2 months, respectively, in 133 patients randomized to receive HIPEC with oxaliplatin after cytoreductive surgery and 132 randomized to the cytoreductive surgery–only arm, François Quenet, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.
The postoperative mortality rate was 1.5% at 30 days in both groups, he said, noting that no difference was seen between the groups in the rate of side effects during the first 30 days after surgery.
“However, we did find a difference between the two arms concerning late, severe complications within 60 days,” said, explaining that the 60-day complication rate was nearly double in the HIPEC group vs. the no-HIPEC group (24.1% vs. 13.6%).
Patients in the trial had stage IV colorectal cancer with isolated peritoneal carcinomatosis and a median age of 60 years. They were enrolled and randomized at 17 centers in France between February 2008 and January 2014.
The survival rate of the surgery-alone group was unexpectedly high, Dr. Quenet said, adding that all colorectal cancer patients with an isolated peritoneal carcinomatosis should therefore be considered for surgery.
The use of HIPEC with cytoreductive surgery was introduced about 15 years ago and has become an accepted treatment option – and in some centers, a standard of care; the combination has been considered an effective treatment for peritoneal carcinomatosis, a metastatic tumor of the peritoneum that occurs in about 20% of colorectal cancer patients. The role of HIPEC in the success of the approach, however, has been unclear.
The current findings suggest that cytoreductive surgery alone is as effective as surgery with HIPEC, which “does not influence the survival result,” in most patients, Dr. Quenet said, noting that about 15% of patients were cured.
Additional study is needed to determine if there are certain subsets of patients who might benefit from HIPEC, he added, explaining that a subgroup analysis in the current study suggested that those with a midrange amount of disease in the abdominal cavity (peritoneal cancer index of 11-15) might experience some benefit with HIPEC, but the numbers were too small to be conclusive.
More research also is needed to determine if chemotherapy agents other than the oxaliplatin used with HIPEC in this study might be more effective, he said.
Prodige 7 was funded by UNICANCER. Dr. Quenet has received honoraria from Sanofi/Aventis, Ethicon, and Gamida Cell, as well as travel/accommodations/expenses from Sanofi, Novartis, and Ethicon.
SOURCE: Quenet F et al. ASCO 2018, Abstract LBA3503.
CHICAGO – , according to findings from the randomized phase 3 UNICANCER Prodige 7 trial.
At a median follow up of 63.8 months, median overall survival – the primary endpoint of the study – was “completely comparable” at 41.7 and 41.2 months, respectively, in 133 patients randomized to receive HIPEC with oxaliplatin after cytoreductive surgery and 132 randomized to the cytoreductive surgery–only arm, François Quenet, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.
The postoperative mortality rate was 1.5% at 30 days in both groups, he said, noting that no difference was seen between the groups in the rate of side effects during the first 30 days after surgery.
“However, we did find a difference between the two arms concerning late, severe complications within 60 days,” said, explaining that the 60-day complication rate was nearly double in the HIPEC group vs. the no-HIPEC group (24.1% vs. 13.6%).
Patients in the trial had stage IV colorectal cancer with isolated peritoneal carcinomatosis and a median age of 60 years. They were enrolled and randomized at 17 centers in France between February 2008 and January 2014.
The survival rate of the surgery-alone group was unexpectedly high, Dr. Quenet said, adding that all colorectal cancer patients with an isolated peritoneal carcinomatosis should therefore be considered for surgery.
The use of HIPEC with cytoreductive surgery was introduced about 15 years ago and has become an accepted treatment option – and in some centers, a standard of care; the combination has been considered an effective treatment for peritoneal carcinomatosis, a metastatic tumor of the peritoneum that occurs in about 20% of colorectal cancer patients. The role of HIPEC in the success of the approach, however, has been unclear.
The current findings suggest that cytoreductive surgery alone is as effective as surgery with HIPEC, which “does not influence the survival result,” in most patients, Dr. Quenet said, noting that about 15% of patients were cured.
Additional study is needed to determine if there are certain subsets of patients who might benefit from HIPEC, he added, explaining that a subgroup analysis in the current study suggested that those with a midrange amount of disease in the abdominal cavity (peritoneal cancer index of 11-15) might experience some benefit with HIPEC, but the numbers were too small to be conclusive.
More research also is needed to determine if chemotherapy agents other than the oxaliplatin used with HIPEC in this study might be more effective, he said.
Prodige 7 was funded by UNICANCER. Dr. Quenet has received honoraria from Sanofi/Aventis, Ethicon, and Gamida Cell, as well as travel/accommodations/expenses from Sanofi, Novartis, and Ethicon.
SOURCE: Quenet F et al. ASCO 2018, Abstract LBA3503.
CHICAGO – , according to findings from the randomized phase 3 UNICANCER Prodige 7 trial.
At a median follow up of 63.8 months, median overall survival – the primary endpoint of the study – was “completely comparable” at 41.7 and 41.2 months, respectively, in 133 patients randomized to receive HIPEC with oxaliplatin after cytoreductive surgery and 132 randomized to the cytoreductive surgery–only arm, François Quenet, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.
The postoperative mortality rate was 1.5% at 30 days in both groups, he said, noting that no difference was seen between the groups in the rate of side effects during the first 30 days after surgery.
“However, we did find a difference between the two arms concerning late, severe complications within 60 days,” said, explaining that the 60-day complication rate was nearly double in the HIPEC group vs. the no-HIPEC group (24.1% vs. 13.6%).
Patients in the trial had stage IV colorectal cancer with isolated peritoneal carcinomatosis and a median age of 60 years. They were enrolled and randomized at 17 centers in France between February 2008 and January 2014.
The survival rate of the surgery-alone group was unexpectedly high, Dr. Quenet said, adding that all colorectal cancer patients with an isolated peritoneal carcinomatosis should therefore be considered for surgery.
The use of HIPEC with cytoreductive surgery was introduced about 15 years ago and has become an accepted treatment option – and in some centers, a standard of care; the combination has been considered an effective treatment for peritoneal carcinomatosis, a metastatic tumor of the peritoneum that occurs in about 20% of colorectal cancer patients. The role of HIPEC in the success of the approach, however, has been unclear.
The current findings suggest that cytoreductive surgery alone is as effective as surgery with HIPEC, which “does not influence the survival result,” in most patients, Dr. Quenet said, noting that about 15% of patients were cured.
Additional study is needed to determine if there are certain subsets of patients who might benefit from HIPEC, he added, explaining that a subgroup analysis in the current study suggested that those with a midrange amount of disease in the abdominal cavity (peritoneal cancer index of 11-15) might experience some benefit with HIPEC, but the numbers were too small to be conclusive.
More research also is needed to determine if chemotherapy agents other than the oxaliplatin used with HIPEC in this study might be more effective, he said.
Prodige 7 was funded by UNICANCER. Dr. Quenet has received honoraria from Sanofi/Aventis, Ethicon, and Gamida Cell, as well as travel/accommodations/expenses from Sanofi, Novartis, and Ethicon.
SOURCE: Quenet F et al. ASCO 2018, Abstract LBA3503.
REPORTING FROM ASCO 2018
Key clinical point: HIPEC with oxaliplatin after surgery offers no survival benefit in patients with advanced colorectal cancer.
Major finding: Median overall survival was comparable at 41.7 and 41.2 months, respectively, in the HIPEC and no-HIPEC groups.
Study details: The randomized phase 3 Prodige 7 trial of 265 patients.
Disclosures: Prodige 7 was funded by UNICANCER. Dr. Quenet has received honoraria from Sanofi/Aventis, Ethicon, and Gamida Cell, as well as travel/accommodations/expenses from Sanofi, Novartis, and Ethicon.
Source: Quenet F et al. ASCO 2018, LBA3503.
Avelumab does not add punch to ALK inhibitors for ALK+/– NSCLC
CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.
In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.
In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.
“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
Synergism sought
The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.
Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.
Two groups, two TKIs, one PD-L1 inhibitor
Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.
Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.
In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.
There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.
Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.
In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.
Antitumor activity
In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.
In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.
“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.
But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.
“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.
She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.
“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.
The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”
In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.
“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.
She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.
SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.
CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.
In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.
In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.
“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
Synergism sought
The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.
Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.
Two groups, two TKIs, one PD-L1 inhibitor
Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.
Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.
In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.
There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.
Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.
In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.
Antitumor activity
In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.
In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.
“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.
But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.
“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.
She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.
“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.
The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”
In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.
“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.
She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.
SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.
CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.
In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.
In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.
“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
Synergism sought
The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.
Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.
Two groups, two TKIs, one PD-L1 inhibitor
Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.
Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.
In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.
There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.
Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.
In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.
Antitumor activity
In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.
In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.
“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.
But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.
“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.
She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.
“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.
The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”
In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.
“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.
She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.
SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.
REPORTING FROM ASCO 2018
Key clinical point: Adding an anti-PD-L1 checkpoint inhibitor to an ALK inhibitor did not add efficacy in patients with either ALK-negative or ALK-positive non–small-cell lung cancer.
Major finding: The ORR in patients treated with avelumab/lorlatinib was 46.4%, the same as ORR with lorlatinib alone.
Study details: Phase 1/2 trial of avelumab/crizotinib in 12 patients with ALK-negative NSCLC, and avelumab/lorlatinib in 28 patients with ALK-positive NSCLC.
Disclosures: Pfizer sponsored the trial. Dr. Shaw disclosed consultancy/advisory board membership, researching funding, and honoraria from Pfizer and other companies. Dr. Horn has previously disclosed serving as a consultant to AbbVie, BMS, Genentech, Merck, and AstraZeneca.
Source: Shaw AT et al. ASCO 2018, Abstract 9008.
Two agents could take AML therapy in new directions
CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.
“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.
Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.
Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).
Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).
“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.
Mivebresib (NCT02391480)
Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.
Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.
The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.
Bemcentinib (NCT02488408)
Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).
For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.
In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.
Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.
Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.
“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said.
*Data presented at the meeting differ from the abstracts.
CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.
“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.
Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.
Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).
Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).
“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.
Mivebresib (NCT02391480)
Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.
Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.
The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.
Bemcentinib (NCT02488408)
Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).
For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.
In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.
Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.
Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.
“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said.
*Data presented at the meeting differ from the abstracts.
CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.
“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.
Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.
Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).
Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).
“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.
Mivebresib (NCT02391480)
Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.
Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.
The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.
Bemcentinib (NCT02488408)
Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).
For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.
In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.
Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.
Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.
“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said.
*Data presented at the meeting differ from the abstracts.
H&N cancer may be undertreated in women
CHICAGO – Sex disparities in the treatment of head and neck cancer may be leading to poorer outcomes for women, according to a retrospective registry-based cohort study of 884 patients reported at annual meeting of the American Society of Clinical Oncology.
“The treatment of head and neck cancer often requires intensive treatment that can have lasting side effects,” senior study author Jed A. Katzel, MD, a medical oncologist at Kaiser Permanente in Santa Clara, Calif., said in a press briefing. “Our goal was to review data from a large group of patients in Northern California to determine which patients are most likely to benefit from aggressive therapy, while minimizing toxicity for those likely to die from competing events.”
The reasons for the observed sex disparities are not known, according to Dr. Katzel. However, they may include patient preferences, physician practices, and the higher proportion among men of oropharynx tumors, as those tumors are more commonly associated with human papillomavirus (HPV), which carries a more favorable prognosis.
“Further investigation is needed to determine if there is an actual difference in treatment and outcomes for women, compared with men,” he said. “To this end, we have planned a chart-by-chart review, as well as a prospective analysis that will be performed in the currently enrolling NRG HN004 clinical trial.”
“The outcome of this study was very surprising to us, the idea that there are disparities in both the treatment that women receive relative to men, but also in the rate of death from head and neck cancer for women compared to men,” commented ASCO Expert Joshua Jones, MD, MA, who is also a radiation oncologist at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia.
Dr. Katzel and his colleagues used the Kaiser Permanente Northern California registry to identify patients with stage II to IVB head and neck cancer diagnosed during 2000-2015.
Analyses were based on 223 women and 661 men, relative numbers that are not surprising given the known demographics of this cancer. Oropharyngeal tumors accounted for 38% of the cancers in the former, but 55% in the latter. (HPV status was not directly ascertained.)
The rate of receipt of intensive chemotherapy was 35% for women and 46% for men (adjusted odds ratio, 0.68; 95% CI, 0.48-0.98; P = .006). Similarly, the rate of receipt of radiation therapy was 60% for women and 70% for men (AOR, 0.79; 95% CI, 0.56-1.11; P = .008). Receipt of surgery was similar for the sexes.
The investigators analyzed deaths according to type using a GCE model that controlled for age, sex, tumor site, and Charlson Comorbidity Index. “The GCE model essentially describes the degree to which cancer is the patient’s problem,” Dr. Katzel explained.
Results showed that both women and men were more likely to die from cancer than from other causes; however, the ratio was 7 for women, compared with just 3.8 for men, a difference translating to a relative hazard ratio of 1.92 (95% CI, 1.07-3.43).
In terms of potential confounding, there were only 19 noncancer deaths among the women studied, suggesting that they may have been more healthy than the men, which could have influenced the calculations, according to Dr. Katzel.
“This GCE model has been validated in head and neck cancer, but also in breast cancer, prostate cancer, and endometrial cancer, so we are using a validated model to do this evaluation,” he noted. “So I would say we are confident in our findings.”
Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
SOURCE: Park A et al. ASCO 2018 Abstract LBA6002.
CHICAGO – Sex disparities in the treatment of head and neck cancer may be leading to poorer outcomes for women, according to a retrospective registry-based cohort study of 884 patients reported at annual meeting of the American Society of Clinical Oncology.
“The treatment of head and neck cancer often requires intensive treatment that can have lasting side effects,” senior study author Jed A. Katzel, MD, a medical oncologist at Kaiser Permanente in Santa Clara, Calif., said in a press briefing. “Our goal was to review data from a large group of patients in Northern California to determine which patients are most likely to benefit from aggressive therapy, while minimizing toxicity for those likely to die from competing events.”
The reasons for the observed sex disparities are not known, according to Dr. Katzel. However, they may include patient preferences, physician practices, and the higher proportion among men of oropharynx tumors, as those tumors are more commonly associated with human papillomavirus (HPV), which carries a more favorable prognosis.
“Further investigation is needed to determine if there is an actual difference in treatment and outcomes for women, compared with men,” he said. “To this end, we have planned a chart-by-chart review, as well as a prospective analysis that will be performed in the currently enrolling NRG HN004 clinical trial.”
“The outcome of this study was very surprising to us, the idea that there are disparities in both the treatment that women receive relative to men, but also in the rate of death from head and neck cancer for women compared to men,” commented ASCO Expert Joshua Jones, MD, MA, who is also a radiation oncologist at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia.
Dr. Katzel and his colleagues used the Kaiser Permanente Northern California registry to identify patients with stage II to IVB head and neck cancer diagnosed during 2000-2015.
Analyses were based on 223 women and 661 men, relative numbers that are not surprising given the known demographics of this cancer. Oropharyngeal tumors accounted for 38% of the cancers in the former, but 55% in the latter. (HPV status was not directly ascertained.)
The rate of receipt of intensive chemotherapy was 35% for women and 46% for men (adjusted odds ratio, 0.68; 95% CI, 0.48-0.98; P = .006). Similarly, the rate of receipt of radiation therapy was 60% for women and 70% for men (AOR, 0.79; 95% CI, 0.56-1.11; P = .008). Receipt of surgery was similar for the sexes.
The investigators analyzed deaths according to type using a GCE model that controlled for age, sex, tumor site, and Charlson Comorbidity Index. “The GCE model essentially describes the degree to which cancer is the patient’s problem,” Dr. Katzel explained.
Results showed that both women and men were more likely to die from cancer than from other causes; however, the ratio was 7 for women, compared with just 3.8 for men, a difference translating to a relative hazard ratio of 1.92 (95% CI, 1.07-3.43).
In terms of potential confounding, there were only 19 noncancer deaths among the women studied, suggesting that they may have been more healthy than the men, which could have influenced the calculations, according to Dr. Katzel.
“This GCE model has been validated in head and neck cancer, but also in breast cancer, prostate cancer, and endometrial cancer, so we are using a validated model to do this evaluation,” he noted. “So I would say we are confident in our findings.”
Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
SOURCE: Park A et al. ASCO 2018 Abstract LBA6002.
CHICAGO – Sex disparities in the treatment of head and neck cancer may be leading to poorer outcomes for women, according to a retrospective registry-based cohort study of 884 patients reported at annual meeting of the American Society of Clinical Oncology.
“The treatment of head and neck cancer often requires intensive treatment that can have lasting side effects,” senior study author Jed A. Katzel, MD, a medical oncologist at Kaiser Permanente in Santa Clara, Calif., said in a press briefing. “Our goal was to review data from a large group of patients in Northern California to determine which patients are most likely to benefit from aggressive therapy, while minimizing toxicity for those likely to die from competing events.”
The reasons for the observed sex disparities are not known, according to Dr. Katzel. However, they may include patient preferences, physician practices, and the higher proportion among men of oropharynx tumors, as those tumors are more commonly associated with human papillomavirus (HPV), which carries a more favorable prognosis.
“Further investigation is needed to determine if there is an actual difference in treatment and outcomes for women, compared with men,” he said. “To this end, we have planned a chart-by-chart review, as well as a prospective analysis that will be performed in the currently enrolling NRG HN004 clinical trial.”
“The outcome of this study was very surprising to us, the idea that there are disparities in both the treatment that women receive relative to men, but also in the rate of death from head and neck cancer for women compared to men,” commented ASCO Expert Joshua Jones, MD, MA, who is also a radiation oncologist at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia.
Dr. Katzel and his colleagues used the Kaiser Permanente Northern California registry to identify patients with stage II to IVB head and neck cancer diagnosed during 2000-2015.
Analyses were based on 223 women and 661 men, relative numbers that are not surprising given the known demographics of this cancer. Oropharyngeal tumors accounted for 38% of the cancers in the former, but 55% in the latter. (HPV status was not directly ascertained.)
The rate of receipt of intensive chemotherapy was 35% for women and 46% for men (adjusted odds ratio, 0.68; 95% CI, 0.48-0.98; P = .006). Similarly, the rate of receipt of radiation therapy was 60% for women and 70% for men (AOR, 0.79; 95% CI, 0.56-1.11; P = .008). Receipt of surgery was similar for the sexes.
The investigators analyzed deaths according to type using a GCE model that controlled for age, sex, tumor site, and Charlson Comorbidity Index. “The GCE model essentially describes the degree to which cancer is the patient’s problem,” Dr. Katzel explained.
Results showed that both women and men were more likely to die from cancer than from other causes; however, the ratio was 7 for women, compared with just 3.8 for men, a difference translating to a relative hazard ratio of 1.92 (95% CI, 1.07-3.43).
In terms of potential confounding, there were only 19 noncancer deaths among the women studied, suggesting that they may have been more healthy than the men, which could have influenced the calculations, according to Dr. Katzel.
“This GCE model has been validated in head and neck cancer, but also in breast cancer, prostate cancer, and endometrial cancer, so we are using a validated model to do this evaluation,” he noted. “So I would say we are confident in our findings.”
Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
SOURCE: Park A et al. ASCO 2018 Abstract LBA6002.
REPORTING FROM ASCO 2018
Key clinical point: Women with head and neck cancer may be relatively undertreated and therefore are more likely to die from the disease.
Major finding: Compared with male counterparts, female patients had lower rates of receiving intensive chemotherapy (35% vs. 46%) and radiation therapy (60% vs. 70%) and a higher ratio of cancer to noncancer mortality (adjusted relative hazard ratio, 1.92).
Study details: Retrospective, registry-based, cohort study of 884 patients with stage II to IVB H&N cancer diagnosed during 2000-2015.
Disclosures: Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
Source: Park A et al. ASCO 2018, Abstract LBA6002.
Novel antibody shifts ‘eat me/don’t eat me’ balance in refractory NHL
CHICAGO – A first-in-class antibody targeting the macrophage checkpoint CD47 is a promising novel immunotherapy in non-Hodgkin lymphoma, according to Ranjana H. Advani, MD, of Stanford (Calif.) Cancer Institute.
Treatment with Hu5F9-G4 (5F9), an antibody designed to overcome the “don’t eat me” signal associated with CD47, produced “encouraging” antitumor activity in a phase 1b study of 22 patients, Dr. Advani said in an oral abstract presentation at the annual meeting of the American Society of Clinical Oncology.
“5F9 was well tolerated in combination with rituximab, with no maximum tolerated dose achieved,” said Dr. Advani, noting that there were complete remissions in 43% of the refractory follicular lymphoma patients and 33% of refractory diffuse large B-cell lymphoma patients in the phase 1b/2 study.
The antibody has an on-target anemia effect that occurs upon administration, but that was mitigated considerably by a priming and maintenance dosing approach, she added.
The study has demonstrated “excellent” response rates in a highly refractory patient population, said Caron A. Jacobson, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston. “Targeting CD47 ... really helps to shift the balance from ‘don’t eat me’ to ‘eat me,’ ” Dr. Jacobson said at the meeting.
“Importantly, we saw very little toxicity in the study, with very few grade 4 adverse events and no immune-related adverse events,” she added.
Most adverse events were grade 1 or 2, with the most common being the expected on-target anemia associated with 5F9. Using an initial priming dose of 5F9 results in a “temporary and mild decline” in hemoglobin due to clearance of aged red blood cells, Dr. Advani said.
The objective response rate in the study was 50%, with efficacy observed in rituximab-refractory patients, Dr. Advani said. With a median follow-up of greater than 6 months, just 1 of 11 responders had progressed. The median duration of response was not reached, with the longest complete remission lasting more than 14 months.
5F9 is able to selectively eliminate cancer cells through blockade of CD47, while rituximab enhances 5F9’s activity via antibody-dependent cellular phagocytosis, according to Dr. Advani.
“CD47 blockade takes the foot off the brakes, while rituximab puts the foot on the accelerator, leading to maximal tumor phagocytosis,” she said.
The Food and Drug Administration recently granted 5F9 a fast track designation for both diffuse large B-cell lymphoma and follicular lymphoma. Phase 2 investigations of 5F9 in these lymphomas are ongoing, Dr. Advani said.
The trial is sponsored by Forty Seven. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
SOURCE: Advani RH et al. ASCO 2018, abstract 7504.
CHICAGO – A first-in-class antibody targeting the macrophage checkpoint CD47 is a promising novel immunotherapy in non-Hodgkin lymphoma, according to Ranjana H. Advani, MD, of Stanford (Calif.) Cancer Institute.
Treatment with Hu5F9-G4 (5F9), an antibody designed to overcome the “don’t eat me” signal associated with CD47, produced “encouraging” antitumor activity in a phase 1b study of 22 patients, Dr. Advani said in an oral abstract presentation at the annual meeting of the American Society of Clinical Oncology.
“5F9 was well tolerated in combination with rituximab, with no maximum tolerated dose achieved,” said Dr. Advani, noting that there were complete remissions in 43% of the refractory follicular lymphoma patients and 33% of refractory diffuse large B-cell lymphoma patients in the phase 1b/2 study.
The antibody has an on-target anemia effect that occurs upon administration, but that was mitigated considerably by a priming and maintenance dosing approach, she added.
The study has demonstrated “excellent” response rates in a highly refractory patient population, said Caron A. Jacobson, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston. “Targeting CD47 ... really helps to shift the balance from ‘don’t eat me’ to ‘eat me,’ ” Dr. Jacobson said at the meeting.
“Importantly, we saw very little toxicity in the study, with very few grade 4 adverse events and no immune-related adverse events,” she added.
Most adverse events were grade 1 or 2, with the most common being the expected on-target anemia associated with 5F9. Using an initial priming dose of 5F9 results in a “temporary and mild decline” in hemoglobin due to clearance of aged red blood cells, Dr. Advani said.
The objective response rate in the study was 50%, with efficacy observed in rituximab-refractory patients, Dr. Advani said. With a median follow-up of greater than 6 months, just 1 of 11 responders had progressed. The median duration of response was not reached, with the longest complete remission lasting more than 14 months.
5F9 is able to selectively eliminate cancer cells through blockade of CD47, while rituximab enhances 5F9’s activity via antibody-dependent cellular phagocytosis, according to Dr. Advani.
“CD47 blockade takes the foot off the brakes, while rituximab puts the foot on the accelerator, leading to maximal tumor phagocytosis,” she said.
The Food and Drug Administration recently granted 5F9 a fast track designation for both diffuse large B-cell lymphoma and follicular lymphoma. Phase 2 investigations of 5F9 in these lymphomas are ongoing, Dr. Advani said.
The trial is sponsored by Forty Seven. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
SOURCE: Advani RH et al. ASCO 2018, abstract 7504.
CHICAGO – A first-in-class antibody targeting the macrophage checkpoint CD47 is a promising novel immunotherapy in non-Hodgkin lymphoma, according to Ranjana H. Advani, MD, of Stanford (Calif.) Cancer Institute.
Treatment with Hu5F9-G4 (5F9), an antibody designed to overcome the “don’t eat me” signal associated with CD47, produced “encouraging” antitumor activity in a phase 1b study of 22 patients, Dr. Advani said in an oral abstract presentation at the annual meeting of the American Society of Clinical Oncology.
“5F9 was well tolerated in combination with rituximab, with no maximum tolerated dose achieved,” said Dr. Advani, noting that there were complete remissions in 43% of the refractory follicular lymphoma patients and 33% of refractory diffuse large B-cell lymphoma patients in the phase 1b/2 study.
The antibody has an on-target anemia effect that occurs upon administration, but that was mitigated considerably by a priming and maintenance dosing approach, she added.
The study has demonstrated “excellent” response rates in a highly refractory patient population, said Caron A. Jacobson, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston. “Targeting CD47 ... really helps to shift the balance from ‘don’t eat me’ to ‘eat me,’ ” Dr. Jacobson said at the meeting.
“Importantly, we saw very little toxicity in the study, with very few grade 4 adverse events and no immune-related adverse events,” she added.
Most adverse events were grade 1 or 2, with the most common being the expected on-target anemia associated with 5F9. Using an initial priming dose of 5F9 results in a “temporary and mild decline” in hemoglobin due to clearance of aged red blood cells, Dr. Advani said.
The objective response rate in the study was 50%, with efficacy observed in rituximab-refractory patients, Dr. Advani said. With a median follow-up of greater than 6 months, just 1 of 11 responders had progressed. The median duration of response was not reached, with the longest complete remission lasting more than 14 months.
5F9 is able to selectively eliminate cancer cells through blockade of CD47, while rituximab enhances 5F9’s activity via antibody-dependent cellular phagocytosis, according to Dr. Advani.
“CD47 blockade takes the foot off the brakes, while rituximab puts the foot on the accelerator, leading to maximal tumor phagocytosis,” she said.
The Food and Drug Administration recently granted 5F9 a fast track designation for both diffuse large B-cell lymphoma and follicular lymphoma. Phase 2 investigations of 5F9 in these lymphomas are ongoing, Dr. Advani said.
The trial is sponsored by Forty Seven. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
SOURCE: Advani RH et al. ASCO 2018, abstract 7504.
REPORTING FROM ASCO 2018
Key clinical point:
Major finding: Complete responses were seen in 43% of follicular lymphoma (FL) patients and 33% of diffuse large B-cell lymphoma (DLBCL) patients.
Study details: Initial reported results from a phase 1b/2 study of 7 patients with FL and 15 patients with DLBCL.
Disclosures: Forty Seven sponsored the trial. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
Source: Advani RH et al. ASCO 2018, abstract 7504.
TAILORx marks major advance for precision medicine in breast cancer
CHICAGO – , sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.
The recurrence score is known to be prognostic and to be predictive of benefit from adding chemotherapy to endocrine therapy, Dr. Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, about two-thirds of all patients who are treated.”
The phase 3 TAILORx trial registered 10,273 women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note, contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: The risk of invasive disease-free survival events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26), Dr. Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival.
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).
Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.
Tailoring treatment: ‘not too much and not too little’
“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
“This is not so much about de-escalation ... The goal of this study was not to just use less treatment, the goal was to tailor treatment – they chose the title very aptly, with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their tumor,” said Dr. Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”
Study details
All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.
Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”
Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.
The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
SOURCE: Sparano et al. ASCO 2018 Abstract LBA1
CHICAGO – , sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.
The recurrence score is known to be prognostic and to be predictive of benefit from adding chemotherapy to endocrine therapy, Dr. Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, about two-thirds of all patients who are treated.”
The phase 3 TAILORx trial registered 10,273 women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note, contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: The risk of invasive disease-free survival events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26), Dr. Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival.
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).
Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.
Tailoring treatment: ‘not too much and not too little’
“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
“This is not so much about de-escalation ... The goal of this study was not to just use less treatment, the goal was to tailor treatment – they chose the title very aptly, with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their tumor,” said Dr. Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”
Study details
All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.
Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”
Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.
The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
SOURCE: Sparano et al. ASCO 2018 Abstract LBA1
CHICAGO – , sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.
The recurrence score is known to be prognostic and to be predictive of benefit from adding chemotherapy to endocrine therapy, Dr. Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, about two-thirds of all patients who are treated.”
The phase 3 TAILORx trial registered 10,273 women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note, contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: The risk of invasive disease-free survival events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26), Dr. Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival.
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).
Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.
Tailoring treatment: ‘not too much and not too little’
“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
“This is not so much about de-escalation ... The goal of this study was not to just use less treatment, the goal was to tailor treatment – they chose the title very aptly, with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their tumor,” said Dr. Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”
Study details
All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.
Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”
Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.
The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
SOURCE: Sparano et al. ASCO 2018 Abstract LBA1
REPORTING FROM ASCO 2018
Key clinical point: The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy.
Major finding: Among women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive disease–free survival with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26).
Study details: A phase 3 trial among 10,273 women with HR-positive, HER2-negative, node-negative early-stage breast cancer, with a noninferiority randomized component among the 6,711 women with a midrange recurrence score (TAILORx trial).
Disclosures: Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
Source: Sparano et al. ASCO 2018 Abstract LBA1.
Single-agent acalabrutinib ‘impressive’ in patients with WM
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
Once-weekly carfilzomib combo improves PFS in R/R MM
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
Checkpoint inhibitor shows promise in advanced squamous-cell carcinoma
An immune checkpoint inhibitor that targets the PD-1 receptor has shown “robust” efficacy among patients with advanced cutaneous squamous-cell carcinoma, according to researchers.
A combined phase 1/phase 2 study, published in the New England Journal of Medicine and presented simultaneously at the annual meeting of the American Society of Clinical Oncology, looked at the effect of monoclonal antibody cemiplimab in an expansion cohort of 26 patients with locally-advanced or metastatic cutaneous squamous-cell carcinoma who were not eligible for surgery. The phase 2 component involved 59 patients with metastatic disease.
Patients were treated with intravenous cemiplimab every 2 weeks for 48 weeks in the phase 1 study, and up to 96 weeks – or until unacceptable toxicity or disease progression – in the phase 2 study.
In the phase 1 study, researchers saw a response rate of 50% and a 65% rate of durable disease control, after a median follow-up of 11 months (1.1-17). The median time to response was 2.3 months, and more than half the patients (54%) who showed a response maintained that response past 6 months.
In the phase 2 study in patients with metastatic disease, 47% responded to the treatment – 24 patients showed a partial response and 4 showed a complete response. Of those who responded, 61% showed durable disease control after a median follow-up of 7.9 months.
The median time to response in this group of patients was 1.9 months, and 57% of those who did respond still showed a response at 6 months. However neither median progression-free survival nor median overall survival had been reached at the point of data cut-off.
The treatment showed similar effects in patients with regional and distant metastatic disease.
Advanced cutaneous squamous-cell carcinoma was thought to be an ideal target for immunotherapy because the high mutation burden in the tumor meant it would be sensitive to effector T cell attack, wrote Michael R. Migden, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“In addition, the dramatically increased risk of cutaneous squamous-cell carcinoma among people with immunosuppression pointed to an important role for immune surveillance with this cancer,” the authors wrote.
In the phase 2 study, 29% of patients experienced a serious adverse event – including two cases of pneumonitis – and three patients (5%) discontinued treatment. There were three deaths due to adverse events: One patient died from pneumonia complications, one died in his sleep, and one patient died following hypercalcemia and deep vein thrombosis.
Aside from these, most adverse events were grade 1 or 2. Around one-quarter of patients experienced diarrhea (27%) or fatigue (24%), while the other most common adverse events were nausea (17%), constipation (15%) and rash (15%). The authors noted that these adverse events were similar to those seen in other PD-1 inhibitors.
“Our results are consistent with an emerging theme regarding the high efficacy of immune checkpoint blockade for the treatment of hypermutated cancers, since the mutation burden of cutaneous squamous-cell carcinoma is similar to that reported for advanced solid tumors with microsatellite instability,” the authors wrote.
Cemiplimab is now being tested in a phase 2 trial in patients with advanced basal cell carcinoma.
The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors also declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
SOURCE: Migden M et al. NEJM, 2018; June 4. doi: 10.1056/NEJMoa1805131.
An immune checkpoint inhibitor that targets the PD-1 receptor has shown “robust” efficacy among patients with advanced cutaneous squamous-cell carcinoma, according to researchers.
A combined phase 1/phase 2 study, published in the New England Journal of Medicine and presented simultaneously at the annual meeting of the American Society of Clinical Oncology, looked at the effect of monoclonal antibody cemiplimab in an expansion cohort of 26 patients with locally-advanced or metastatic cutaneous squamous-cell carcinoma who were not eligible for surgery. The phase 2 component involved 59 patients with metastatic disease.
Patients were treated with intravenous cemiplimab every 2 weeks for 48 weeks in the phase 1 study, and up to 96 weeks – or until unacceptable toxicity or disease progression – in the phase 2 study.
In the phase 1 study, researchers saw a response rate of 50% and a 65% rate of durable disease control, after a median follow-up of 11 months (1.1-17). The median time to response was 2.3 months, and more than half the patients (54%) who showed a response maintained that response past 6 months.
In the phase 2 study in patients with metastatic disease, 47% responded to the treatment – 24 patients showed a partial response and 4 showed a complete response. Of those who responded, 61% showed durable disease control after a median follow-up of 7.9 months.
The median time to response in this group of patients was 1.9 months, and 57% of those who did respond still showed a response at 6 months. However neither median progression-free survival nor median overall survival had been reached at the point of data cut-off.
The treatment showed similar effects in patients with regional and distant metastatic disease.
Advanced cutaneous squamous-cell carcinoma was thought to be an ideal target for immunotherapy because the high mutation burden in the tumor meant it would be sensitive to effector T cell attack, wrote Michael R. Migden, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“In addition, the dramatically increased risk of cutaneous squamous-cell carcinoma among people with immunosuppression pointed to an important role for immune surveillance with this cancer,” the authors wrote.
In the phase 2 study, 29% of patients experienced a serious adverse event – including two cases of pneumonitis – and three patients (5%) discontinued treatment. There were three deaths due to adverse events: One patient died from pneumonia complications, one died in his sleep, and one patient died following hypercalcemia and deep vein thrombosis.
Aside from these, most adverse events were grade 1 or 2. Around one-quarter of patients experienced diarrhea (27%) or fatigue (24%), while the other most common adverse events were nausea (17%), constipation (15%) and rash (15%). The authors noted that these adverse events were similar to those seen in other PD-1 inhibitors.
“Our results are consistent with an emerging theme regarding the high efficacy of immune checkpoint blockade for the treatment of hypermutated cancers, since the mutation burden of cutaneous squamous-cell carcinoma is similar to that reported for advanced solid tumors with microsatellite instability,” the authors wrote.
Cemiplimab is now being tested in a phase 2 trial in patients with advanced basal cell carcinoma.
The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors also declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
SOURCE: Migden M et al. NEJM, 2018; June 4. doi: 10.1056/NEJMoa1805131.
An immune checkpoint inhibitor that targets the PD-1 receptor has shown “robust” efficacy among patients with advanced cutaneous squamous-cell carcinoma, according to researchers.
A combined phase 1/phase 2 study, published in the New England Journal of Medicine and presented simultaneously at the annual meeting of the American Society of Clinical Oncology, looked at the effect of monoclonal antibody cemiplimab in an expansion cohort of 26 patients with locally-advanced or metastatic cutaneous squamous-cell carcinoma who were not eligible for surgery. The phase 2 component involved 59 patients with metastatic disease.
Patients were treated with intravenous cemiplimab every 2 weeks for 48 weeks in the phase 1 study, and up to 96 weeks – or until unacceptable toxicity or disease progression – in the phase 2 study.
In the phase 1 study, researchers saw a response rate of 50% and a 65% rate of durable disease control, after a median follow-up of 11 months (1.1-17). The median time to response was 2.3 months, and more than half the patients (54%) who showed a response maintained that response past 6 months.
In the phase 2 study in patients with metastatic disease, 47% responded to the treatment – 24 patients showed a partial response and 4 showed a complete response. Of those who responded, 61% showed durable disease control after a median follow-up of 7.9 months.
The median time to response in this group of patients was 1.9 months, and 57% of those who did respond still showed a response at 6 months. However neither median progression-free survival nor median overall survival had been reached at the point of data cut-off.
The treatment showed similar effects in patients with regional and distant metastatic disease.
Advanced cutaneous squamous-cell carcinoma was thought to be an ideal target for immunotherapy because the high mutation burden in the tumor meant it would be sensitive to effector T cell attack, wrote Michael R. Migden, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“In addition, the dramatically increased risk of cutaneous squamous-cell carcinoma among people with immunosuppression pointed to an important role for immune surveillance with this cancer,” the authors wrote.
In the phase 2 study, 29% of patients experienced a serious adverse event – including two cases of pneumonitis – and three patients (5%) discontinued treatment. There were three deaths due to adverse events: One patient died from pneumonia complications, one died in his sleep, and one patient died following hypercalcemia and deep vein thrombosis.
Aside from these, most adverse events were grade 1 or 2. Around one-quarter of patients experienced diarrhea (27%) or fatigue (24%), while the other most common adverse events were nausea (17%), constipation (15%) and rash (15%). The authors noted that these adverse events were similar to those seen in other PD-1 inhibitors.
“Our results are consistent with an emerging theme regarding the high efficacy of immune checkpoint blockade for the treatment of hypermutated cancers, since the mutation burden of cutaneous squamous-cell carcinoma is similar to that reported for advanced solid tumors with microsatellite instability,” the authors wrote.
Cemiplimab is now being tested in a phase 2 trial in patients with advanced basal cell carcinoma.
The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors also declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
SOURCE: Migden M et al. NEJM, 2018; June 4. doi: 10.1056/NEJMoa1805131.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: PD-1 inhibitor cemiplimab shows significant response in advanced squamous-cell carcinoma.
Major finding: Around half of patients with advanced squamous-cell carcinoma responded to checkpoint inhibitor cemiplimab.
Study details: Phase 1 expanded cohort study of 26 patients with advanced cutaneous squamous-cell carcinoma and phase 2 study of 59 patients with metastatic squamous-cell carcinoma.
Disclosures: The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
Source: Migden M et al. N Engl J Med. 2018 June 4. doi: 10.1056/NEJMoa1805131.
MRD-negative status signals better outcomes in CAR T–treated ALL
CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.
Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.
“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.
In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.
“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.
The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.
Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).
Most of the MRD-negative patients who relapsed did so within the first 6 months, an observation that led investigators to consider whether factors exist that could predict better outcomes.
In a multivariate analysis, they found three variables associated with disease free survival: higher LDH prior to lymphodepletion (hazard ratio, 1.39), along with higher platelet count prior to lymphodepletion and incorporation of fludarabine into the regimen, with hazard ratios of 0.65 and 0.34, respectively.
Using those three characteristics, investigators grouped patients as “good risk” if they had normal LDH, platelet count at or above 100 prior to lymphodepletion that included fludarabine. The 24-month disease-free survival for good-risk patients was 78%, and overall survival was 86%.
The role of allogeneic HSCT after ALL patients achieved MRD-negative complete remission with CAR T-cell therapy was one of the “major questions in the field,” Dr. Hay said.
In this analysis, Dr. Hay and colleagues found that patients who underwent transplant in MRD-negative complete remission had a 24-month disease free survival and overall survival of 61% and 72%, respectively, both of which were significantly higher than in patients with MRD-negative complete remission who had no transplant.
The disease-free survival benefit was not specific to the good-risk group, according to Dr. Hay, who said an interaction test demonstrated no significant interaction between risk group and allogeneic HSCT after CAR T-cell infusion (P = 0.53).
“This is a very important finding that should be further [studied] in an appropriately designed clinical trial,” Dr. Hay said during an oral presentation of the study results.
Dr. Hay and several coauthors reported financial disclosures related to Juno Therapeutics. Other disclosures reported by study coauthors included Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
SOURCE: Hay KA. ASCO 2018, Abstract 7005.
CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.
Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.
“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.
In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.
“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.
The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.
Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).
Most of the MRD-negative patients who relapsed did so within the first 6 months, an observation that led investigators to consider whether factors exist that could predict better outcomes.
In a multivariate analysis, they found three variables associated with disease free survival: higher LDH prior to lymphodepletion (hazard ratio, 1.39), along with higher platelet count prior to lymphodepletion and incorporation of fludarabine into the regimen, with hazard ratios of 0.65 and 0.34, respectively.
Using those three characteristics, investigators grouped patients as “good risk” if they had normal LDH, platelet count at or above 100 prior to lymphodepletion that included fludarabine. The 24-month disease-free survival for good-risk patients was 78%, and overall survival was 86%.
The role of allogeneic HSCT after ALL patients achieved MRD-negative complete remission with CAR T-cell therapy was one of the “major questions in the field,” Dr. Hay said.
In this analysis, Dr. Hay and colleagues found that patients who underwent transplant in MRD-negative complete remission had a 24-month disease free survival and overall survival of 61% and 72%, respectively, both of which were significantly higher than in patients with MRD-negative complete remission who had no transplant.
The disease-free survival benefit was not specific to the good-risk group, according to Dr. Hay, who said an interaction test demonstrated no significant interaction between risk group and allogeneic HSCT after CAR T-cell infusion (P = 0.53).
“This is a very important finding that should be further [studied] in an appropriately designed clinical trial,” Dr. Hay said during an oral presentation of the study results.
Dr. Hay and several coauthors reported financial disclosures related to Juno Therapeutics. Other disclosures reported by study coauthors included Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
SOURCE: Hay KA. ASCO 2018, Abstract 7005.
CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.
Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.
“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.
In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.
“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.
The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.
Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).
Most of the MRD-negative patients who relapsed did so within the first 6 months, an observation that led investigators to consider whether factors exist that could predict better outcomes.
In a multivariate analysis, they found three variables associated with disease free survival: higher LDH prior to lymphodepletion (hazard ratio, 1.39), along with higher platelet count prior to lymphodepletion and incorporation of fludarabine into the regimen, with hazard ratios of 0.65 and 0.34, respectively.
Using those three characteristics, investigators grouped patients as “good risk” if they had normal LDH, platelet count at or above 100 prior to lymphodepletion that included fludarabine. The 24-month disease-free survival for good-risk patients was 78%, and overall survival was 86%.
The role of allogeneic HSCT after ALL patients achieved MRD-negative complete remission with CAR T-cell therapy was one of the “major questions in the field,” Dr. Hay said.
In this analysis, Dr. Hay and colleagues found that patients who underwent transplant in MRD-negative complete remission had a 24-month disease free survival and overall survival of 61% and 72%, respectively, both of which were significantly higher than in patients with MRD-negative complete remission who had no transplant.
The disease-free survival benefit was not specific to the good-risk group, according to Dr. Hay, who said an interaction test demonstrated no significant interaction between risk group and allogeneic HSCT after CAR T-cell infusion (P = 0.53).
“This is a very important finding that should be further [studied] in an appropriately designed clinical trial,” Dr. Hay said during an oral presentation of the study results.
Dr. Hay and several coauthors reported financial disclosures related to Juno Therapeutics. Other disclosures reported by study coauthors included Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
SOURCE: Hay KA. ASCO 2018, Abstract 7005.
REPORTING FROM ASCO 2018
Key clinical point:
Major finding: Patients who achieved MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001)
Study details: A retrospective analysis including 53 patients with ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis.
Disclosures: Researchers reported financial ties to Juno Therapeutics, Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
Source: Hay KA. ASCO 2018, Abstract 7005.