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Novel gene therapy offers hope for some lymphomas
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
FROM ASCO 2022
Glofitamab prevails against r/r DLBCL
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
FROM ASCO 2022
Acetaminophen linked to diminished response to immunotherapy in cancer
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
‘Great optimism’ greets immunotherapy responses in dMMR rectal cancer
Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.
The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.
About 5%-10% of patients with rectal cancer have tumors with dMMR.
“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.
The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
Single-agent dostarlimab
For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.
Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.
All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.
For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.
As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.
“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”
To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.
In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.
Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.
The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
Editorial commentary
In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy.
For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”
Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.
“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.
“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.
In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.
The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.
The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.
In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”
The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others.
A version of this article first appeared on Medscape.com.
Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.
The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.
About 5%-10% of patients with rectal cancer have tumors with dMMR.
“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.
The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
Single-agent dostarlimab
For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.
Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.
All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.
For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.
As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.
“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”
To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.
In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.
Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.
The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
Editorial commentary
In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy.
For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”
Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.
“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.
“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.
In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.
The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.
The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.
In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”
The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others.
A version of this article first appeared on Medscape.com.
Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.
The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.
About 5%-10% of patients with rectal cancer have tumors with dMMR.
“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.
The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
Single-agent dostarlimab
For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.
Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.
All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.
For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.
As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.
“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”
To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.
In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.
Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.
The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
Editorial commentary
In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy.
For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”
Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.
“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.
“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.
In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.
The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.
The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.
In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”
The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
Pseudocirrhosis in breast cancer may signal liver metastases
CHICAGO – Pseudocirrhosis appears radiographically similar to cirrhosis, but lacks its classic pathologic features.
The study is the largest cohort of patients with pseudocirrhosis studied to date. “It provides important clinical information about the natural history of this condition to help oncologists better understand which patients develop this condition and what complications are most common. Interestingly, we found that patients who developed ascites had a worse overall survival than patients who did not develop ascites, which was not previously reported,” said Laura Huppert, MD, who presented the findings during a poster session at the annual meeting of the American Society of Clinical Oncology.
Pseudocirrhosis is commonly found in patients with metastatic breast cancer and can lead to ascites and varices, among other complications. “These problems can be quite debilitating and even life-threatening for our patients. In order to better diagnose and treat our patients with pseudocirrhosis, we first wanted to understand the natural history of this condition, including which patients develop it, what treatments they have received, and what complications are most frequent,” said Dr. Huppert, MD, who is a hematology/oncology fellow at the University of California, San Francisco.
The study was retrospective, making it impossible to determine causality. “It is possible that the biology of HR+ disease predisposes patients to the development of pseudocirrhosis through mechanisms that are not yet elucidated. Alternatively, this may be due to the fact that patients with HR+ disease tend to have longer survival and are on systemic therapy for longer periods of time, allowing more time for pseudocirrhosis to develop in response to systemic therapy,” Dr. Huppert said.
In future work, Dr. Huppert plans to examine a control arm of patients with liver disease who do not develop pseudocirrhosis to gain a better understanding of factors that might cause the condition. She also hopes to work with hepatologists to determine if new antifibrosis agents might be applicable to pseudocirrhosis. “There may be interesting things we can learn from other disease states and apply to this condition,” she said.
The researchers analyzed data from 120 patients with pseudocirrhosis. 82.5% of patients were HR+/HER2–, 11.7% were HR+/HER2+, 2.5% were HR–/HER2+, and 3.3% were triple negative. Liver metastases were present in all patients, and 82.5% had more than 15 liver lesions.
A total of 92.5% of patients had previously undergone chemotherapy before pseudocirrhosis was identified, and the median time to diagnosis of pseudocirrhosis after diagnosis of liver metastases was 18.7 months. 50% of patients with pseudocirrhosis had stable or responding disease. After pseudocirrhosis diagnosis, patients underwent a median of 1.0 additional lines of therapy, and the median overall survival following pseudocirrhosis diagnosis was 7.9 months. A total of 80.8% of patients went on to be diagnosed with ascites, 17.5% with esophageal varices, 21.7% with splenomegaly, 10.0% with gastrointestinal bleeding, and 9.2% with hepatic encephalopathy.
Patients with radiographic evidence of ascites survived an average of 42.8 months after metastatic breast cancer diagnosis, while those without ascites survived an average of 76.2 months (P < .001).
Specialty care was rare: Just 7.5% of patients received a GI/hepatology consultation.
Dr. Huppert has no relevant financial disclosures.
CHICAGO – Pseudocirrhosis appears radiographically similar to cirrhosis, but lacks its classic pathologic features.
The study is the largest cohort of patients with pseudocirrhosis studied to date. “It provides important clinical information about the natural history of this condition to help oncologists better understand which patients develop this condition and what complications are most common. Interestingly, we found that patients who developed ascites had a worse overall survival than patients who did not develop ascites, which was not previously reported,” said Laura Huppert, MD, who presented the findings during a poster session at the annual meeting of the American Society of Clinical Oncology.
Pseudocirrhosis is commonly found in patients with metastatic breast cancer and can lead to ascites and varices, among other complications. “These problems can be quite debilitating and even life-threatening for our patients. In order to better diagnose and treat our patients with pseudocirrhosis, we first wanted to understand the natural history of this condition, including which patients develop it, what treatments they have received, and what complications are most frequent,” said Dr. Huppert, MD, who is a hematology/oncology fellow at the University of California, San Francisco.
The study was retrospective, making it impossible to determine causality. “It is possible that the biology of HR+ disease predisposes patients to the development of pseudocirrhosis through mechanisms that are not yet elucidated. Alternatively, this may be due to the fact that patients with HR+ disease tend to have longer survival and are on systemic therapy for longer periods of time, allowing more time for pseudocirrhosis to develop in response to systemic therapy,” Dr. Huppert said.
In future work, Dr. Huppert plans to examine a control arm of patients with liver disease who do not develop pseudocirrhosis to gain a better understanding of factors that might cause the condition. She also hopes to work with hepatologists to determine if new antifibrosis agents might be applicable to pseudocirrhosis. “There may be interesting things we can learn from other disease states and apply to this condition,” she said.
The researchers analyzed data from 120 patients with pseudocirrhosis. 82.5% of patients were HR+/HER2–, 11.7% were HR+/HER2+, 2.5% were HR–/HER2+, and 3.3% were triple negative. Liver metastases were present in all patients, and 82.5% had more than 15 liver lesions.
A total of 92.5% of patients had previously undergone chemotherapy before pseudocirrhosis was identified, and the median time to diagnosis of pseudocirrhosis after diagnosis of liver metastases was 18.7 months. 50% of patients with pseudocirrhosis had stable or responding disease. After pseudocirrhosis diagnosis, patients underwent a median of 1.0 additional lines of therapy, and the median overall survival following pseudocirrhosis diagnosis was 7.9 months. A total of 80.8% of patients went on to be diagnosed with ascites, 17.5% with esophageal varices, 21.7% with splenomegaly, 10.0% with gastrointestinal bleeding, and 9.2% with hepatic encephalopathy.
Patients with radiographic evidence of ascites survived an average of 42.8 months after metastatic breast cancer diagnosis, while those without ascites survived an average of 76.2 months (P < .001).
Specialty care was rare: Just 7.5% of patients received a GI/hepatology consultation.
Dr. Huppert has no relevant financial disclosures.
CHICAGO – Pseudocirrhosis appears radiographically similar to cirrhosis, but lacks its classic pathologic features.
The study is the largest cohort of patients with pseudocirrhosis studied to date. “It provides important clinical information about the natural history of this condition to help oncologists better understand which patients develop this condition and what complications are most common. Interestingly, we found that patients who developed ascites had a worse overall survival than patients who did not develop ascites, which was not previously reported,” said Laura Huppert, MD, who presented the findings during a poster session at the annual meeting of the American Society of Clinical Oncology.
Pseudocirrhosis is commonly found in patients with metastatic breast cancer and can lead to ascites and varices, among other complications. “These problems can be quite debilitating and even life-threatening for our patients. In order to better diagnose and treat our patients with pseudocirrhosis, we first wanted to understand the natural history of this condition, including which patients develop it, what treatments they have received, and what complications are most frequent,” said Dr. Huppert, MD, who is a hematology/oncology fellow at the University of California, San Francisco.
The study was retrospective, making it impossible to determine causality. “It is possible that the biology of HR+ disease predisposes patients to the development of pseudocirrhosis through mechanisms that are not yet elucidated. Alternatively, this may be due to the fact that patients with HR+ disease tend to have longer survival and are on systemic therapy for longer periods of time, allowing more time for pseudocirrhosis to develop in response to systemic therapy,” Dr. Huppert said.
In future work, Dr. Huppert plans to examine a control arm of patients with liver disease who do not develop pseudocirrhosis to gain a better understanding of factors that might cause the condition. She also hopes to work with hepatologists to determine if new antifibrosis agents might be applicable to pseudocirrhosis. “There may be interesting things we can learn from other disease states and apply to this condition,” she said.
The researchers analyzed data from 120 patients with pseudocirrhosis. 82.5% of patients were HR+/HER2–, 11.7% were HR+/HER2+, 2.5% were HR–/HER2+, and 3.3% were triple negative. Liver metastases were present in all patients, and 82.5% had more than 15 liver lesions.
A total of 92.5% of patients had previously undergone chemotherapy before pseudocirrhosis was identified, and the median time to diagnosis of pseudocirrhosis after diagnosis of liver metastases was 18.7 months. 50% of patients with pseudocirrhosis had stable or responding disease. After pseudocirrhosis diagnosis, patients underwent a median of 1.0 additional lines of therapy, and the median overall survival following pseudocirrhosis diagnosis was 7.9 months. A total of 80.8% of patients went on to be diagnosed with ascites, 17.5% with esophageal varices, 21.7% with splenomegaly, 10.0% with gastrointestinal bleeding, and 9.2% with hepatic encephalopathy.
Patients with radiographic evidence of ascites survived an average of 42.8 months after metastatic breast cancer diagnosis, while those without ascites survived an average of 76.2 months (P < .001).
Specialty care was rare: Just 7.5% of patients received a GI/hepatology consultation.
Dr. Huppert has no relevant financial disclosures.
AT ASCO 2022
Excess weight may ward off infection in breast cancer treatment
– a potentially deadly outcome that can occur as a result of chemotherapy treatment.
The study was presented at the annual meeting of the American Society of Clinical Oncology.
It is known that body mass index can affect breast cancer risk and prognosis, but it is not known if BMI can affect how well endocrine therapy works in a given patient. In the PALLAS clinical trial, Georg Pfeiler, MD, Medical University of Vienna, and colleagues, conducted an analysis of 5,698 patients with early hormone receptor–positive breast cancer receiving endocrine therapy with or without palbociclib. Dr. Pfeiler found that women who are overweight or obese had significantly less frequent and less severe cases of neutropenia. With fewer or less severe cases of neutropenia, there were also fewer interruptions in palbociclib treatment.
“One explanation for the lower discontinuation rates may be that the distributional volume of the drug is higher in overweight and obese patients leading to lower serum drug concentrations. It could also be influenced by differences in pharmacokinetics with respect to hyperinsulinemia,” said Dr. Pfeiler, who leads the Oncological Breast Outpatient Clinic and Bone Health Outpatient Clinic at the Medical University of Vienna.
The PALLAS trial compared the combination of palbociclib and adjuvant endocrine therapy with endocrine therapy alone in 5,698 women with early breast cancer. Patients were categorized according to BMI as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9), overweight (BMI, 25-29.9), and obese (> 30). The investigators analyzed differences in adverse events, time to early discontinuation of palbociclib, and in time to invasive disease-free survival.
At baseline, of 5,698 patients, 68 (1.2%) were underweight, 2,082 (36.5%) were of normal weight, 1,818 (31.9%) were overweight, and, 1,730 (30.4%) were obese. In patients treated with palbociclib, neutropenia was the primary toxicity leading to treatment discontinuation with rates of 21.1% in normal-weight patients, 14.0% of overweight patients, and 5.9% of obese patients, respectively.
Significantly different rates of all-grade neutropenia were observed in normal weight, overweight, and obese participants with regard to total (88.5%, 85.7% and 74.7%), as well as grade 3 (64.1%, 62.0% and 43.9%) and grade 4 neutropenia (7.0%, 3.6% and 2.0%), respectively. The lower frequency and severity of neutropenia observed in overweight and obese patients was associated with a significantly lower treatment discontinuation rate over time when compared with normal-weight patients (overweight vs. normal weight: HR, 0.73; 95% CI 0.63-0.84; P < .0001, and obese vs. normal weight: HR, 0.65; 95% CI, 0.56-0.75; P < .0001). There was, however, despite these observations, no statistically significant improvement in invasive disease survival with the addition of palbociclib to endocrine therapy in any weight category (normal weight: HR, 0.84; 95% CI 0.63-1.12; overweight: HR, 1.10; 95% CI 0.82-1.49; and obese: HR, 0.95; 95% CI, 0.69-1.30).
“This is an early analysis, and should be interpreted with caution, especially with regard to disease outcomes. The findings may reduce concerns over hematologic side effects in the overweight and obese. In the future there may be an important impact if it turns out after longer-term follow-up that palbociclib has been underdosed in the overweight and obese. We may need BMI-adapted dose management,” said Dr. Pfeiler, who is currently working on a longer-term follow-up study of the PALLAS group.
The analysis found no significant correlation between weight and occurrence of invasive disease events.
Dr. Pfeiler disclosed honoraria and grants from Pfizer. The study was funded by Alliance Foundation Trials.
– a potentially deadly outcome that can occur as a result of chemotherapy treatment.
The study was presented at the annual meeting of the American Society of Clinical Oncology.
It is known that body mass index can affect breast cancer risk and prognosis, but it is not known if BMI can affect how well endocrine therapy works in a given patient. In the PALLAS clinical trial, Georg Pfeiler, MD, Medical University of Vienna, and colleagues, conducted an analysis of 5,698 patients with early hormone receptor–positive breast cancer receiving endocrine therapy with or without palbociclib. Dr. Pfeiler found that women who are overweight or obese had significantly less frequent and less severe cases of neutropenia. With fewer or less severe cases of neutropenia, there were also fewer interruptions in palbociclib treatment.
“One explanation for the lower discontinuation rates may be that the distributional volume of the drug is higher in overweight and obese patients leading to lower serum drug concentrations. It could also be influenced by differences in pharmacokinetics with respect to hyperinsulinemia,” said Dr. Pfeiler, who leads the Oncological Breast Outpatient Clinic and Bone Health Outpatient Clinic at the Medical University of Vienna.
The PALLAS trial compared the combination of palbociclib and adjuvant endocrine therapy with endocrine therapy alone in 5,698 women with early breast cancer. Patients were categorized according to BMI as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9), overweight (BMI, 25-29.9), and obese (> 30). The investigators analyzed differences in adverse events, time to early discontinuation of palbociclib, and in time to invasive disease-free survival.
At baseline, of 5,698 patients, 68 (1.2%) were underweight, 2,082 (36.5%) were of normal weight, 1,818 (31.9%) were overweight, and, 1,730 (30.4%) were obese. In patients treated with palbociclib, neutropenia was the primary toxicity leading to treatment discontinuation with rates of 21.1% in normal-weight patients, 14.0% of overweight patients, and 5.9% of obese patients, respectively.
Significantly different rates of all-grade neutropenia were observed in normal weight, overweight, and obese participants with regard to total (88.5%, 85.7% and 74.7%), as well as grade 3 (64.1%, 62.0% and 43.9%) and grade 4 neutropenia (7.0%, 3.6% and 2.0%), respectively. The lower frequency and severity of neutropenia observed in overweight and obese patients was associated with a significantly lower treatment discontinuation rate over time when compared with normal-weight patients (overweight vs. normal weight: HR, 0.73; 95% CI 0.63-0.84; P < .0001, and obese vs. normal weight: HR, 0.65; 95% CI, 0.56-0.75; P < .0001). There was, however, despite these observations, no statistically significant improvement in invasive disease survival with the addition of palbociclib to endocrine therapy in any weight category (normal weight: HR, 0.84; 95% CI 0.63-1.12; overweight: HR, 1.10; 95% CI 0.82-1.49; and obese: HR, 0.95; 95% CI, 0.69-1.30).
“This is an early analysis, and should be interpreted with caution, especially with regard to disease outcomes. The findings may reduce concerns over hematologic side effects in the overweight and obese. In the future there may be an important impact if it turns out after longer-term follow-up that palbociclib has been underdosed in the overweight and obese. We may need BMI-adapted dose management,” said Dr. Pfeiler, who is currently working on a longer-term follow-up study of the PALLAS group.
The analysis found no significant correlation between weight and occurrence of invasive disease events.
Dr. Pfeiler disclosed honoraria and grants from Pfizer. The study was funded by Alliance Foundation Trials.
– a potentially deadly outcome that can occur as a result of chemotherapy treatment.
The study was presented at the annual meeting of the American Society of Clinical Oncology.
It is known that body mass index can affect breast cancer risk and prognosis, but it is not known if BMI can affect how well endocrine therapy works in a given patient. In the PALLAS clinical trial, Georg Pfeiler, MD, Medical University of Vienna, and colleagues, conducted an analysis of 5,698 patients with early hormone receptor–positive breast cancer receiving endocrine therapy with or without palbociclib. Dr. Pfeiler found that women who are overweight or obese had significantly less frequent and less severe cases of neutropenia. With fewer or less severe cases of neutropenia, there were also fewer interruptions in palbociclib treatment.
“One explanation for the lower discontinuation rates may be that the distributional volume of the drug is higher in overweight and obese patients leading to lower serum drug concentrations. It could also be influenced by differences in pharmacokinetics with respect to hyperinsulinemia,” said Dr. Pfeiler, who leads the Oncological Breast Outpatient Clinic and Bone Health Outpatient Clinic at the Medical University of Vienna.
The PALLAS trial compared the combination of palbociclib and adjuvant endocrine therapy with endocrine therapy alone in 5,698 women with early breast cancer. Patients were categorized according to BMI as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9), overweight (BMI, 25-29.9), and obese (> 30). The investigators analyzed differences in adverse events, time to early discontinuation of palbociclib, and in time to invasive disease-free survival.
At baseline, of 5,698 patients, 68 (1.2%) were underweight, 2,082 (36.5%) were of normal weight, 1,818 (31.9%) were overweight, and, 1,730 (30.4%) were obese. In patients treated with palbociclib, neutropenia was the primary toxicity leading to treatment discontinuation with rates of 21.1% in normal-weight patients, 14.0% of overweight patients, and 5.9% of obese patients, respectively.
Significantly different rates of all-grade neutropenia were observed in normal weight, overweight, and obese participants with regard to total (88.5%, 85.7% and 74.7%), as well as grade 3 (64.1%, 62.0% and 43.9%) and grade 4 neutropenia (7.0%, 3.6% and 2.0%), respectively. The lower frequency and severity of neutropenia observed in overweight and obese patients was associated with a significantly lower treatment discontinuation rate over time when compared with normal-weight patients (overweight vs. normal weight: HR, 0.73; 95% CI 0.63-0.84; P < .0001, and obese vs. normal weight: HR, 0.65; 95% CI, 0.56-0.75; P < .0001). There was, however, despite these observations, no statistically significant improvement in invasive disease survival with the addition of palbociclib to endocrine therapy in any weight category (normal weight: HR, 0.84; 95% CI 0.63-1.12; overweight: HR, 1.10; 95% CI 0.82-1.49; and obese: HR, 0.95; 95% CI, 0.69-1.30).
“This is an early analysis, and should be interpreted with caution, especially with regard to disease outcomes. The findings may reduce concerns over hematologic side effects in the overweight and obese. In the future there may be an important impact if it turns out after longer-term follow-up that palbociclib has been underdosed in the overweight and obese. We may need BMI-adapted dose management,” said Dr. Pfeiler, who is currently working on a longer-term follow-up study of the PALLAS group.
The analysis found no significant correlation between weight and occurrence of invasive disease events.
Dr. Pfeiler disclosed honoraria and grants from Pfizer. The study was funded by Alliance Foundation Trials.
FROM ASCO 2022
Women with HER2+ metastatic breast cancer are living longer
When a patient first presents to a doctor with signs and symptoms of having breast cancer that has metastasized to other parts of the body, the prospects of long-term survival are dim. But now, a new study presented at the annual meeting of the American Society of Clinical Oncology suggests that women with metastatic HER2+ breast cancer are generally living longer, compared with women treated in previous years.
Between 2010 and 2018, the overall survival for 5,576 women (99% women) with HER2+ metastatic breast cancer enrolled in this study improved 5.6% each year of the study. The study also showed a 6.4% improvement in breast cancer–specific death rates year over year.
“These highlights coincide with significant therapeutic advances for HER2+ metastatic breast cancer over the past decade. We need to continue our research efforts to identify better treatments for our patients so we can continue to improve the prognosis of these patients,” said study author Jose Pablo Leone, MD, a medical oncologist with Dana-Farber Cancer Institute, Boston.
The study, which is based on an evaluation of data from the Surveillance, Epidemiology and End Results database, found factors associated with shorter survival included older age, Black race, lower income, and the presence of visceral or brain metastases. Long-term survival of more than 5 years was associated with younger age, White race, and higher income, but also having fewer metastatic sites and estrogen receptor (ER)/progesterone receptor (PR) positivity.
“We also found specific factors that were only associated with shorter overall survival, such as the presence of metastases in the brain, liver, or lung. The lack of metastasis in these sites was not associated with longer overall survival. In contrast, a lower number of metastatic sites, regardless of the location of those sites were associated with longer overall survival but not short-term survival,” Dr. Leone said.
A total of 63.3% of patients in the study survived less than 2 years while 37.8% lived 5 years or more, and 26.8% lived longer than 8 years. Factors associated with less than 2 years in overall survival were older age (odds ratio, 3.76), Black race (OR 1.5), nonductal nonlobular (OR, 4.64), brain metastases (OR, 2.95), liver metastases (OR, 1.98), lung metastases (OR, 1.56), ER/PR negativity (OR, 1.74), and lower income (OR, 1.62). Factors associated with longer survival of 5 years or more included younger age (OR, 2.85), White race (OR, 1.7), fewer metastatic organ sites (OR, 2.6), ER/PR positivity (OR, 1.27), and higher income (OR, 3.31).
Dr. Leone said that, while involvement of specific visceral sites (brain, liver, lung) was associated with shorter overall survival, the odds of living longer than 5 years was not associated with those sites. In contrast, the number of sites was associated with longer overall survival, but not shorter overall survival regardless of location. “While fewer number of metastatic sites were associated with higher odds of overall survival greater than 5 years, the number of metastatic sites was not associated with the odds of overall survival of being less than 2 years,” he said.
A limitation of the study included the retrospective nature of the study. “Treatment data are unavailable, so we cannot quantify the impact of various treatments on the odds of survival,” Dr. Leone said.
This study was not funded.
When a patient first presents to a doctor with signs and symptoms of having breast cancer that has metastasized to other parts of the body, the prospects of long-term survival are dim. But now, a new study presented at the annual meeting of the American Society of Clinical Oncology suggests that women with metastatic HER2+ breast cancer are generally living longer, compared with women treated in previous years.
Between 2010 and 2018, the overall survival for 5,576 women (99% women) with HER2+ metastatic breast cancer enrolled in this study improved 5.6% each year of the study. The study also showed a 6.4% improvement in breast cancer–specific death rates year over year.
“These highlights coincide with significant therapeutic advances for HER2+ metastatic breast cancer over the past decade. We need to continue our research efforts to identify better treatments for our patients so we can continue to improve the prognosis of these patients,” said study author Jose Pablo Leone, MD, a medical oncologist with Dana-Farber Cancer Institute, Boston.
The study, which is based on an evaluation of data from the Surveillance, Epidemiology and End Results database, found factors associated with shorter survival included older age, Black race, lower income, and the presence of visceral or brain metastases. Long-term survival of more than 5 years was associated with younger age, White race, and higher income, but also having fewer metastatic sites and estrogen receptor (ER)/progesterone receptor (PR) positivity.
“We also found specific factors that were only associated with shorter overall survival, such as the presence of metastases in the brain, liver, or lung. The lack of metastasis in these sites was not associated with longer overall survival. In contrast, a lower number of metastatic sites, regardless of the location of those sites were associated with longer overall survival but not short-term survival,” Dr. Leone said.
A total of 63.3% of patients in the study survived less than 2 years while 37.8% lived 5 years or more, and 26.8% lived longer than 8 years. Factors associated with less than 2 years in overall survival were older age (odds ratio, 3.76), Black race (OR 1.5), nonductal nonlobular (OR, 4.64), brain metastases (OR, 2.95), liver metastases (OR, 1.98), lung metastases (OR, 1.56), ER/PR negativity (OR, 1.74), and lower income (OR, 1.62). Factors associated with longer survival of 5 years or more included younger age (OR, 2.85), White race (OR, 1.7), fewer metastatic organ sites (OR, 2.6), ER/PR positivity (OR, 1.27), and higher income (OR, 3.31).
Dr. Leone said that, while involvement of specific visceral sites (brain, liver, lung) was associated with shorter overall survival, the odds of living longer than 5 years was not associated with those sites. In contrast, the number of sites was associated with longer overall survival, but not shorter overall survival regardless of location. “While fewer number of metastatic sites were associated with higher odds of overall survival greater than 5 years, the number of metastatic sites was not associated with the odds of overall survival of being less than 2 years,” he said.
A limitation of the study included the retrospective nature of the study. “Treatment data are unavailable, so we cannot quantify the impact of various treatments on the odds of survival,” Dr. Leone said.
This study was not funded.
When a patient first presents to a doctor with signs and symptoms of having breast cancer that has metastasized to other parts of the body, the prospects of long-term survival are dim. But now, a new study presented at the annual meeting of the American Society of Clinical Oncology suggests that women with metastatic HER2+ breast cancer are generally living longer, compared with women treated in previous years.
Between 2010 and 2018, the overall survival for 5,576 women (99% women) with HER2+ metastatic breast cancer enrolled in this study improved 5.6% each year of the study. The study also showed a 6.4% improvement in breast cancer–specific death rates year over year.
“These highlights coincide with significant therapeutic advances for HER2+ metastatic breast cancer over the past decade. We need to continue our research efforts to identify better treatments for our patients so we can continue to improve the prognosis of these patients,” said study author Jose Pablo Leone, MD, a medical oncologist with Dana-Farber Cancer Institute, Boston.
The study, which is based on an evaluation of data from the Surveillance, Epidemiology and End Results database, found factors associated with shorter survival included older age, Black race, lower income, and the presence of visceral or brain metastases. Long-term survival of more than 5 years was associated with younger age, White race, and higher income, but also having fewer metastatic sites and estrogen receptor (ER)/progesterone receptor (PR) positivity.
“We also found specific factors that were only associated with shorter overall survival, such as the presence of metastases in the brain, liver, or lung. The lack of metastasis in these sites was not associated with longer overall survival. In contrast, a lower number of metastatic sites, regardless of the location of those sites were associated with longer overall survival but not short-term survival,” Dr. Leone said.
A total of 63.3% of patients in the study survived less than 2 years while 37.8% lived 5 years or more, and 26.8% lived longer than 8 years. Factors associated with less than 2 years in overall survival were older age (odds ratio, 3.76), Black race (OR 1.5), nonductal nonlobular (OR, 4.64), brain metastases (OR, 2.95), liver metastases (OR, 1.98), lung metastases (OR, 1.56), ER/PR negativity (OR, 1.74), and lower income (OR, 1.62). Factors associated with longer survival of 5 years or more included younger age (OR, 2.85), White race (OR, 1.7), fewer metastatic organ sites (OR, 2.6), ER/PR positivity (OR, 1.27), and higher income (OR, 3.31).
Dr. Leone said that, while involvement of specific visceral sites (brain, liver, lung) was associated with shorter overall survival, the odds of living longer than 5 years was not associated with those sites. In contrast, the number of sites was associated with longer overall survival, but not shorter overall survival regardless of location. “While fewer number of metastatic sites were associated with higher odds of overall survival greater than 5 years, the number of metastatic sites was not associated with the odds of overall survival of being less than 2 years,” he said.
A limitation of the study included the retrospective nature of the study. “Treatment data are unavailable, so we cannot quantify the impact of various treatments on the odds of survival,” Dr. Leone said.
This study was not funded.
FROM ASCO 2022
Panitumumab beats bevacizumab in left-sided mCRC
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
International trial finds best regimen for Ewing sarcoma
CHICAGO -- (RR-ES) in the practice-changing rEECur trial.
This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with the rare and deadly disease.
The study results are expected to change the standard of care and be practice-changing on a global scale, commented Julie Gralow, MD, chief medical officer at the annual meeting of the American Society of Clinical Oncology, where the results were presented June 5 during a plenary session.
Ewing sarcoma is a very rare cancer of the bone and soft tissue that mainly affects children and young adults, particularly in the second decade of life, explained lead author Martin McCabe, MD, clinical senior lecturer in pediatric, teenage, and young adult cancer at the University of Manchester (England). The incidence rate is 3.2 per million people under age 25 years, he said.
Dr. Gralow explained in an interview that treatment of Ewing sarcoma differs from one cancer center to another. Several different chemotherapy regimens are being used, all based on single-arm trials, with no consensus on which is best.
This international trial set out to answer that question and compared four different regimens. Participating centers were “able to solve a question by partnering, coming together, and even in a very rare population get enough patients to define the winner,” she said.
Earlier findings from this trial had shown that ifosfamide had improved survival, compared with gemcitabine and docetaxel and compared with irinotecan and temozolomide.
At the meeting, results of the comparison of ifosfamide versus a combination of topotecan and cyclophosphamide (TC) were presented.
Median overall survival was 15.4 versus 10.5 months with ifosfamide versus TC, and 1-year overall survival was 55% versus 45%, respectively, for a 94% probability that ifosfamide is better than TC for overall survival, Dr. McCabe reported.
Median event-free survival was 16.8 months in 73 patients in the ifosfamide group versus 10.4 months for 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. “Given the observed data, there is a 96% probability that ifosfamide is better than TC for event-free survival,” he said.
High-dose ifosfamide prolonged median event-free survival by 5.7 months, compared with 3.7 months for TC.
Notably, greater event-free survival and overall survival differences were observed for patients under age 14 years, compared with those aged 14 and older, Dr. McCabe noted.
As for toxicity, similar rates of neutropenic infections were seen in the two groups, but more severe renal and brain toxicity were observed with ifosfamide, with both occurring in less than 10% of patients, he said.
Despite the practice-changing results, Dr. McCabe stressed that the “differences [between treatments] are quite small, and what we actually need is better drugs to cure more patients.”
The rEEcur trial is continuing to recruit patients to the ifosfamide group, and a fifth chemotherapy group of carboplatin and etoposide has been added.
Later this year, investigators also plan to add a new group with a molecular targeted therapeutic.
Important global collaboration
Dr. Gralow emphasized the global collaboration that was behind this trial, which set out to answer important questions about how best to treat a rare disease. “In this really terrific collaboration ... there was an agreement to test all these regimens that are commonly used, and so we now have data on efficacy and toxicity.”
“It’s a really important concept in rare diseases: If we all work together, we actually can study them and get answers,” she said.
“I think pediatricians and oncologists are [now] better able to talk about the risks and benefits [of the regimens],” she added.
Vicki L. Keedy, MD, an ASCO Expert in sarcoma, concurred. The findings from the rEECur trial “could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data,” she commented in an ASCO press release.
A version of this article first appeared on Medscape.com.
CHICAGO -- (RR-ES) in the practice-changing rEECur trial.
This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with the rare and deadly disease.
The study results are expected to change the standard of care and be practice-changing on a global scale, commented Julie Gralow, MD, chief medical officer at the annual meeting of the American Society of Clinical Oncology, where the results were presented June 5 during a plenary session.
Ewing sarcoma is a very rare cancer of the bone and soft tissue that mainly affects children and young adults, particularly in the second decade of life, explained lead author Martin McCabe, MD, clinical senior lecturer in pediatric, teenage, and young adult cancer at the University of Manchester (England). The incidence rate is 3.2 per million people under age 25 years, he said.
Dr. Gralow explained in an interview that treatment of Ewing sarcoma differs from one cancer center to another. Several different chemotherapy regimens are being used, all based on single-arm trials, with no consensus on which is best.
This international trial set out to answer that question and compared four different regimens. Participating centers were “able to solve a question by partnering, coming together, and even in a very rare population get enough patients to define the winner,” she said.
Earlier findings from this trial had shown that ifosfamide had improved survival, compared with gemcitabine and docetaxel and compared with irinotecan and temozolomide.
At the meeting, results of the comparison of ifosfamide versus a combination of topotecan and cyclophosphamide (TC) were presented.
Median overall survival was 15.4 versus 10.5 months with ifosfamide versus TC, and 1-year overall survival was 55% versus 45%, respectively, for a 94% probability that ifosfamide is better than TC for overall survival, Dr. McCabe reported.
Median event-free survival was 16.8 months in 73 patients in the ifosfamide group versus 10.4 months for 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. “Given the observed data, there is a 96% probability that ifosfamide is better than TC for event-free survival,” he said.
High-dose ifosfamide prolonged median event-free survival by 5.7 months, compared with 3.7 months for TC.
Notably, greater event-free survival and overall survival differences were observed for patients under age 14 years, compared with those aged 14 and older, Dr. McCabe noted.
As for toxicity, similar rates of neutropenic infections were seen in the two groups, but more severe renal and brain toxicity were observed with ifosfamide, with both occurring in less than 10% of patients, he said.
Despite the practice-changing results, Dr. McCabe stressed that the “differences [between treatments] are quite small, and what we actually need is better drugs to cure more patients.”
The rEEcur trial is continuing to recruit patients to the ifosfamide group, and a fifth chemotherapy group of carboplatin and etoposide has been added.
Later this year, investigators also plan to add a new group with a molecular targeted therapeutic.
Important global collaboration
Dr. Gralow emphasized the global collaboration that was behind this trial, which set out to answer important questions about how best to treat a rare disease. “In this really terrific collaboration ... there was an agreement to test all these regimens that are commonly used, and so we now have data on efficacy and toxicity.”
“It’s a really important concept in rare diseases: If we all work together, we actually can study them and get answers,” she said.
“I think pediatricians and oncologists are [now] better able to talk about the risks and benefits [of the regimens],” she added.
Vicki L. Keedy, MD, an ASCO Expert in sarcoma, concurred. The findings from the rEECur trial “could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data,” she commented in an ASCO press release.
A version of this article first appeared on Medscape.com.
CHICAGO -- (RR-ES) in the practice-changing rEECur trial.
This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with the rare and deadly disease.
The study results are expected to change the standard of care and be practice-changing on a global scale, commented Julie Gralow, MD, chief medical officer at the annual meeting of the American Society of Clinical Oncology, where the results were presented June 5 during a plenary session.
Ewing sarcoma is a very rare cancer of the bone and soft tissue that mainly affects children and young adults, particularly in the second decade of life, explained lead author Martin McCabe, MD, clinical senior lecturer in pediatric, teenage, and young adult cancer at the University of Manchester (England). The incidence rate is 3.2 per million people under age 25 years, he said.
Dr. Gralow explained in an interview that treatment of Ewing sarcoma differs from one cancer center to another. Several different chemotherapy regimens are being used, all based on single-arm trials, with no consensus on which is best.
This international trial set out to answer that question and compared four different regimens. Participating centers were “able to solve a question by partnering, coming together, and even in a very rare population get enough patients to define the winner,” she said.
Earlier findings from this trial had shown that ifosfamide had improved survival, compared with gemcitabine and docetaxel and compared with irinotecan and temozolomide.
At the meeting, results of the comparison of ifosfamide versus a combination of topotecan and cyclophosphamide (TC) were presented.
Median overall survival was 15.4 versus 10.5 months with ifosfamide versus TC, and 1-year overall survival was 55% versus 45%, respectively, for a 94% probability that ifosfamide is better than TC for overall survival, Dr. McCabe reported.
Median event-free survival was 16.8 months in 73 patients in the ifosfamide group versus 10.4 months for 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. “Given the observed data, there is a 96% probability that ifosfamide is better than TC for event-free survival,” he said.
High-dose ifosfamide prolonged median event-free survival by 5.7 months, compared with 3.7 months for TC.
Notably, greater event-free survival and overall survival differences were observed for patients under age 14 years, compared with those aged 14 and older, Dr. McCabe noted.
As for toxicity, similar rates of neutropenic infections were seen in the two groups, but more severe renal and brain toxicity were observed with ifosfamide, with both occurring in less than 10% of patients, he said.
Despite the practice-changing results, Dr. McCabe stressed that the “differences [between treatments] are quite small, and what we actually need is better drugs to cure more patients.”
The rEEcur trial is continuing to recruit patients to the ifosfamide group, and a fifth chemotherapy group of carboplatin and etoposide has been added.
Later this year, investigators also plan to add a new group with a molecular targeted therapeutic.
Important global collaboration
Dr. Gralow emphasized the global collaboration that was behind this trial, which set out to answer important questions about how best to treat a rare disease. “In this really terrific collaboration ... there was an agreement to test all these regimens that are commonly used, and so we now have data on efficacy and toxicity.”
“It’s a really important concept in rare diseases: If we all work together, we actually can study them and get answers,” she said.
“I think pediatricians and oncologists are [now] better able to talk about the risks and benefits [of the regimens],” she added.
Vicki L. Keedy, MD, an ASCO Expert in sarcoma, concurred. The findings from the rEECur trial “could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data,” she commented in an ASCO press release.
A version of this article first appeared on Medscape.com.
AT ASCO 2022
‘Extremely exciting’ study results guide MM treatment options
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASCO 2022