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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
First-in-class ADC has benefit across mTNBC subgroups
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
FROM SABCS 2020
Phase 1 study shows feasibility, safety, efficacy of STAR T cells for ALL
A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
Remission can be improved
While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.
The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.
The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m2 per day) and cyclophosphamide (250mg/m2 per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
100% MRD negative
On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.
Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.
Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 104 copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
STAR holds promise
Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.
Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”
Dr. Lu reported that she had no relevant disclosures.
SOURCE: Lu P et al. ASH 2020, Abstract 270.
A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
Remission can be improved
While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.
The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.
The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m2 per day) and cyclophosphamide (250mg/m2 per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
100% MRD negative
On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.
Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.
Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 104 copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
STAR holds promise
Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.
Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”
Dr. Lu reported that she had no relevant disclosures.
SOURCE: Lu P et al. ASH 2020, Abstract 270.
A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
Remission can be improved
While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.
The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.
The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m2 per day) and cyclophosphamide (250mg/m2 per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
100% MRD negative
On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.
Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.
Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 104 copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
STAR holds promise
Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.
Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”
Dr. Lu reported that she had no relevant disclosures.
SOURCE: Lu P et al. ASH 2020, Abstract 270.
FROM ASH 2020
IBD: Fecal calprotectin’s role in guiding treatment debated
Questions on fecal calprotectin’s usefulness as a measure of intestinal inflammation in inflammatory bowel disease (IBD) dominated the viewer chat after the opening session of Advances in Inflammatory Bowel Diseases 2020 Annual Meeting.
The measure is often used to differentiate irritable bowel syndrome (IBS) from IBD.
Panelists differed on how predictive fecal calprotectin is for disease status and what information the stool concentration of calprotectin imparts. Several experts discussed calprotectin cutoffs for when disease would be considered in remission or when a colonoscopy is needed for evaluation.
Bruce E. Sands, MD, of the Icahn School of Medicine at Mount Sinai, New York, said about the noninvasive test: “It can be very tricky to use.”
Variation by time of day, by person
He explained that there can be individual differences, and that the concentration may be different in the first stool of the day compared with the last.
“There’s a lot of variation, which makes the cutoffs good on average for populations but a little bit more difficult to apply to individuals,” he said.
Dr. Sands said the marker has more merit for people with large-bowel inflammation but is not quite as accurate a marker for patients with exclusively small-bowel inflammation.
Moderator Steven Hanauer, MD, professor of medicine, gastroenterology, and hepatology at Northwestern University, Chicago, asked Dr. Sands what his next move would be if a patient had a concentration of 160 mcg/mg.
Sands called concentrations between 150 and 250 mcg/mg “a gray zone.”
“That usually indicates for me a need to evaluate with a colonoscopy,” he said.
“If we’re talking about using fecal calprotectin to rule out IBS, the cutoff there is more like 50, 55. But that isn’t how we’re generally using it as IBD practitioners.”
Sunanda V. Kane, MD, MSPH, a gastroenterologist with the Mayo Clinic in Rochester, Minn., said in an interview that 160 mcg/mg in a patient with IBD “means to me likely some minimal disease but not enough for me to make drastic changes to a medical regimen.”
She said about the measure, “We need to understand its limitations as well as strengths. Right now, insurance companies consider it ‘experimental’ and a lot of companies will not cover it. Ironically, they will cover the cost of a colonoscopy but not a stool test.”
Use as a benchmark
Dr. Sands said if he’s doing a colonoscopy to establish that the patient is in remission and knows what the fecal calprotectin level is at the time, he uses it as a benchmark for the future to judge whether the patient is deviating from remission.
He added that the negative predictive value of fecal calprotectin with a cutoff of 100 mcg/mg is “actually pretty good so you can avoid a number of unnecessary colonoscopies to look for recurrence.”
William J. Sandborn, MD, of the University of California, San Diego, said about the marker, “We use it some, but a cutoff of 50 is very specific. You can think of that as equivalent to a Mayo endoscopy score of 0 in ulcerative colitis and probably histologic remission.”
Cutoffs above 50 mcg/mg are “not very clear,” he said.
He said given the lack of consensus on the panel, “others might take some pause about that discomfort.”
Dr. Sandborn pointed out that little is known about elevated calprotectin in ulcerative proctitis and whether it is elevated in Crohn’s ileitis.
Dr. Kane said other factors will affect fecal calprotectin levels.
“We have some data to say that if you are on a proton pump inhibitor that that changes fecal calprotectin levels. Patients who have inflamed pseudopolyps may have quiescent disease around the pseudopolyps that may elevate the fecal calprotectin.”
But it can have particular benefit in some patient populations, she said.
She pointed to a study that concluded calprotectin levels can be used in pregnant ulcerative colitis patients to gauge disease activity noninvasively.
Dr. Sands, Dr. Sandborn, Dr. Kane, and Dr. Hanauer have disclosed having no relevant financial relationships.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A version of this article originally appeared on Medscape.com.
Questions on fecal calprotectin’s usefulness as a measure of intestinal inflammation in inflammatory bowel disease (IBD) dominated the viewer chat after the opening session of Advances in Inflammatory Bowel Diseases 2020 Annual Meeting.
The measure is often used to differentiate irritable bowel syndrome (IBS) from IBD.
Panelists differed on how predictive fecal calprotectin is for disease status and what information the stool concentration of calprotectin imparts. Several experts discussed calprotectin cutoffs for when disease would be considered in remission or when a colonoscopy is needed for evaluation.
Bruce E. Sands, MD, of the Icahn School of Medicine at Mount Sinai, New York, said about the noninvasive test: “It can be very tricky to use.”
Variation by time of day, by person
He explained that there can be individual differences, and that the concentration may be different in the first stool of the day compared with the last.
“There’s a lot of variation, which makes the cutoffs good on average for populations but a little bit more difficult to apply to individuals,” he said.
Dr. Sands said the marker has more merit for people with large-bowel inflammation but is not quite as accurate a marker for patients with exclusively small-bowel inflammation.
Moderator Steven Hanauer, MD, professor of medicine, gastroenterology, and hepatology at Northwestern University, Chicago, asked Dr. Sands what his next move would be if a patient had a concentration of 160 mcg/mg.
Sands called concentrations between 150 and 250 mcg/mg “a gray zone.”
“That usually indicates for me a need to evaluate with a colonoscopy,” he said.
“If we’re talking about using fecal calprotectin to rule out IBS, the cutoff there is more like 50, 55. But that isn’t how we’re generally using it as IBD practitioners.”
Sunanda V. Kane, MD, MSPH, a gastroenterologist with the Mayo Clinic in Rochester, Minn., said in an interview that 160 mcg/mg in a patient with IBD “means to me likely some minimal disease but not enough for me to make drastic changes to a medical regimen.”
She said about the measure, “We need to understand its limitations as well as strengths. Right now, insurance companies consider it ‘experimental’ and a lot of companies will not cover it. Ironically, they will cover the cost of a colonoscopy but not a stool test.”
Use as a benchmark
Dr. Sands said if he’s doing a colonoscopy to establish that the patient is in remission and knows what the fecal calprotectin level is at the time, he uses it as a benchmark for the future to judge whether the patient is deviating from remission.
He added that the negative predictive value of fecal calprotectin with a cutoff of 100 mcg/mg is “actually pretty good so you can avoid a number of unnecessary colonoscopies to look for recurrence.”
William J. Sandborn, MD, of the University of California, San Diego, said about the marker, “We use it some, but a cutoff of 50 is very specific. You can think of that as equivalent to a Mayo endoscopy score of 0 in ulcerative colitis and probably histologic remission.”
Cutoffs above 50 mcg/mg are “not very clear,” he said.
He said given the lack of consensus on the panel, “others might take some pause about that discomfort.”
Dr. Sandborn pointed out that little is known about elevated calprotectin in ulcerative proctitis and whether it is elevated in Crohn’s ileitis.
Dr. Kane said other factors will affect fecal calprotectin levels.
“We have some data to say that if you are on a proton pump inhibitor that that changes fecal calprotectin levels. Patients who have inflamed pseudopolyps may have quiescent disease around the pseudopolyps that may elevate the fecal calprotectin.”
But it can have particular benefit in some patient populations, she said.
She pointed to a study that concluded calprotectin levels can be used in pregnant ulcerative colitis patients to gauge disease activity noninvasively.
Dr. Sands, Dr. Sandborn, Dr. Kane, and Dr. Hanauer have disclosed having no relevant financial relationships.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A version of this article originally appeared on Medscape.com.
Questions on fecal calprotectin’s usefulness as a measure of intestinal inflammation in inflammatory bowel disease (IBD) dominated the viewer chat after the opening session of Advances in Inflammatory Bowel Diseases 2020 Annual Meeting.
The measure is often used to differentiate irritable bowel syndrome (IBS) from IBD.
Panelists differed on how predictive fecal calprotectin is for disease status and what information the stool concentration of calprotectin imparts. Several experts discussed calprotectin cutoffs for when disease would be considered in remission or when a colonoscopy is needed for evaluation.
Bruce E. Sands, MD, of the Icahn School of Medicine at Mount Sinai, New York, said about the noninvasive test: “It can be very tricky to use.”
Variation by time of day, by person
He explained that there can be individual differences, and that the concentration may be different in the first stool of the day compared with the last.
“There’s a lot of variation, which makes the cutoffs good on average for populations but a little bit more difficult to apply to individuals,” he said.
Dr. Sands said the marker has more merit for people with large-bowel inflammation but is not quite as accurate a marker for patients with exclusively small-bowel inflammation.
Moderator Steven Hanauer, MD, professor of medicine, gastroenterology, and hepatology at Northwestern University, Chicago, asked Dr. Sands what his next move would be if a patient had a concentration of 160 mcg/mg.
Sands called concentrations between 150 and 250 mcg/mg “a gray zone.”
“That usually indicates for me a need to evaluate with a colonoscopy,” he said.
“If we’re talking about using fecal calprotectin to rule out IBS, the cutoff there is more like 50, 55. But that isn’t how we’re generally using it as IBD practitioners.”
Sunanda V. Kane, MD, MSPH, a gastroenterologist with the Mayo Clinic in Rochester, Minn., said in an interview that 160 mcg/mg in a patient with IBD “means to me likely some minimal disease but not enough for me to make drastic changes to a medical regimen.”
She said about the measure, “We need to understand its limitations as well as strengths. Right now, insurance companies consider it ‘experimental’ and a lot of companies will not cover it. Ironically, they will cover the cost of a colonoscopy but not a stool test.”
Use as a benchmark
Dr. Sands said if he’s doing a colonoscopy to establish that the patient is in remission and knows what the fecal calprotectin level is at the time, he uses it as a benchmark for the future to judge whether the patient is deviating from remission.
He added that the negative predictive value of fecal calprotectin with a cutoff of 100 mcg/mg is “actually pretty good so you can avoid a number of unnecessary colonoscopies to look for recurrence.”
William J. Sandborn, MD, of the University of California, San Diego, said about the marker, “We use it some, but a cutoff of 50 is very specific. You can think of that as equivalent to a Mayo endoscopy score of 0 in ulcerative colitis and probably histologic remission.”
Cutoffs above 50 mcg/mg are “not very clear,” he said.
He said given the lack of consensus on the panel, “others might take some pause about that discomfort.”
Dr. Sandborn pointed out that little is known about elevated calprotectin in ulcerative proctitis and whether it is elevated in Crohn’s ileitis.
Dr. Kane said other factors will affect fecal calprotectin levels.
“We have some data to say that if you are on a proton pump inhibitor that that changes fecal calprotectin levels. Patients who have inflamed pseudopolyps may have quiescent disease around the pseudopolyps that may elevate the fecal calprotectin.”
But it can have particular benefit in some patient populations, she said.
She pointed to a study that concluded calprotectin levels can be used in pregnant ulcerative colitis patients to gauge disease activity noninvasively.
Dr. Sands, Dr. Sandborn, Dr. Kane, and Dr. Hanauer have disclosed having no relevant financial relationships.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A version of this article originally appeared on Medscape.com.
Adding atezolizumab to chemo doesn’t worsen QOL in early TNBC
In the randomized phase 3 trial, patients received neoadjuvant atezolizumab or placebo plus chemotherapy, followed by surgery and adjuvant atezolizumab or observation.
An analysis of patient-reported outcomes showed that, after a brief decline in health-related quality of life (HRQOL) in both the atezolizumab and control arms, the burden of treatment eased and then remained similar throughout follow-up.
“Treatment-related symptoms in both arms were similar, and the addition of atezolizumab to chemotherapy was tolerable, with no additional treatment side-effect bother reported,” said Elizabeth Mittendorf, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
She presented these results in an oral abstract presentation during the 2020 San Antonio Breast Cancer Symposium.
Initial results
Primary results of the IMpassion031 trial were reported at ESMO 2020 and published in The Lancet.
The trial enrolled patients with treatment-naive early TNBC, and they were randomized to receive chemotherapy plus atezolizumab or placebo. Atezolizumab was given at 840 mg intravenously every 2 weeks.
Chemotherapy consisted of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks. Patients then underwent surgery, which was followed by either atezolizumab maintenance or observation.
The addition of atezolizumab was associated with a 17% improvement in the rate of pathological complete response (pCR) in the intention-to-treat population.
Among patients positive for PD-L1, atezolizumab was associated with a 20% improvement in pCR rate.
Patients have their say
At SABCS 2020, Dr. Mittendorf presented patient-reported outcomes (PRO) for 161 patients randomized to atezolizumab plus chemotherapy and 167 assigned to placebo plus chemotherapy.
The outcome measures – including role function (the ability to work or pursue common everyday activities), physical function, emotional and social function, and HRQOL – came from scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
The exploratory PRO endpoints were mean function and disease- or treatment-related symptoms as well as mean change from baseline in these symptoms.
At baseline, mean physical function scores were high in both arms, at approximately 90%. They dropped to about 65% in each arm by cycle 5 and rebounded to about 80% by cycle 7.
“The change was clinically meaningful, in that the dip was greater than 10 points,” Dr. Mittendorf said. “As patients completed neoadjuvant therapy and were in the adjuvant phase of the study, there was an increase and stabilization with respect to their physical function.”
Similarly, role function declined from 89% in each arm at baseline to a nadir of about 55% in the placebo arm and 50% in the atezolizumab arm. After cycle 5, role function levels began to increase in both arms and remained above 70% from cycle 7 onward.
Role function did not completely recover or stabilize among patients in the atezolizumab arm, “and we attribute this to the fact that these patients continue to receive atezolizumab, which requires that they come to clinic for that therapy, thereby potentially impacting role function,” Dr. Mittendorf said.
She reported that HRQOL declined from a median of nearly 80% at baseline in both arms to a nadir of 62% in the placebo arm and 52% in the atezolizumab arm by cycle 5. HRQOL rebounded starting at cycle 6 and stabilized thereafter, with little daylight between the treatment arms at the most recent follow-up.
The investigators saw worsening of the treatment-related symptoms fatigue, nausea/vomiting, and diarrhea in each arm, with the highest level of symptoms except pain reported at cycle 5. The highest reported pain level was seen at cycle 4.
In each arm, the symptoms declined and stabilized in the adjuvant setting, with mean values at week 16 similar to those reported at baseline for most symptoms. The exception was fatigue, which remained slightly elevated in both arms.
Regarding side-effect bother, a similar proportion of patients in each arm reported increased level of bother by visit during the neoadjuvant phase. However, no additional side-effect bother was reported by patients receiving maintenance atezolizumab, compared with patients in the placebo arm, who were followed with observation alone.
‘Reassuring’ data
“What we can conclude from the PRO in IMpassion031 is that early breast cancer patients are relatively asymptomatic. They do have a good baseline quality of life and very good functioning. The neoadjuvant therapy certainly has deterioration in quality of life and functioning, but this is transient, and there was no evident burden from the atezolizumab,” said invited discussant Sylvia Adams, MD, of New York University.
She said it’s reassuring to see the addition of atezolizumab did not adversely affect HRQOL but added that the study “also shows that chemotherapy has a major impact on well-being, as expected.”
Questions and problems that still need to be addressed regarding the use of immunotherapies in early TNBC include whether every patient needs chemotherapy or immunotherapy, a lack of predictive biomarkers, whether increases in pCR rates after neoadjuvant immunotherapy and chemotherapy will translate into improved survival, and the optimal chemotherapy backbone and schedule, she said.
IMpassion031 is sponsored by F. Hoffman-LaRoche. Dr. Mittendorf disclosed relationships with Roche/Genentech, GlaxoSmithKline, Physicians’ Education Resource, AstraZeneca, Exact Sciences, Merck, Peregrine Pharmaceuticals, SELLAS Life Sciences, TapImmune, EMD Serono, Galena Biopharma, Bristol Myers Squibb, and Lilly. Dr. Adams disclosed relationships with Genentech, Bristol Myers Squibb, Merck, Amgen, Celgene, and Novartis.
SOURCE: Mittendorf E at al. SABCS 2020, Abstract GS3-02.
In the randomized phase 3 trial, patients received neoadjuvant atezolizumab or placebo plus chemotherapy, followed by surgery and adjuvant atezolizumab or observation.
An analysis of patient-reported outcomes showed that, after a brief decline in health-related quality of life (HRQOL) in both the atezolizumab and control arms, the burden of treatment eased and then remained similar throughout follow-up.
“Treatment-related symptoms in both arms were similar, and the addition of atezolizumab to chemotherapy was tolerable, with no additional treatment side-effect bother reported,” said Elizabeth Mittendorf, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
She presented these results in an oral abstract presentation during the 2020 San Antonio Breast Cancer Symposium.
Initial results
Primary results of the IMpassion031 trial were reported at ESMO 2020 and published in The Lancet.
The trial enrolled patients with treatment-naive early TNBC, and they were randomized to receive chemotherapy plus atezolizumab or placebo. Atezolizumab was given at 840 mg intravenously every 2 weeks.
Chemotherapy consisted of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks. Patients then underwent surgery, which was followed by either atezolizumab maintenance or observation.
The addition of atezolizumab was associated with a 17% improvement in the rate of pathological complete response (pCR) in the intention-to-treat population.
Among patients positive for PD-L1, atezolizumab was associated with a 20% improvement in pCR rate.
Patients have their say
At SABCS 2020, Dr. Mittendorf presented patient-reported outcomes (PRO) for 161 patients randomized to atezolizumab plus chemotherapy and 167 assigned to placebo plus chemotherapy.
The outcome measures – including role function (the ability to work or pursue common everyday activities), physical function, emotional and social function, and HRQOL – came from scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
The exploratory PRO endpoints were mean function and disease- or treatment-related symptoms as well as mean change from baseline in these symptoms.
At baseline, mean physical function scores were high in both arms, at approximately 90%. They dropped to about 65% in each arm by cycle 5 and rebounded to about 80% by cycle 7.
“The change was clinically meaningful, in that the dip was greater than 10 points,” Dr. Mittendorf said. “As patients completed neoadjuvant therapy and were in the adjuvant phase of the study, there was an increase and stabilization with respect to their physical function.”
Similarly, role function declined from 89% in each arm at baseline to a nadir of about 55% in the placebo arm and 50% in the atezolizumab arm. After cycle 5, role function levels began to increase in both arms and remained above 70% from cycle 7 onward.
Role function did not completely recover or stabilize among patients in the atezolizumab arm, “and we attribute this to the fact that these patients continue to receive atezolizumab, which requires that they come to clinic for that therapy, thereby potentially impacting role function,” Dr. Mittendorf said.
She reported that HRQOL declined from a median of nearly 80% at baseline in both arms to a nadir of 62% in the placebo arm and 52% in the atezolizumab arm by cycle 5. HRQOL rebounded starting at cycle 6 and stabilized thereafter, with little daylight between the treatment arms at the most recent follow-up.
The investigators saw worsening of the treatment-related symptoms fatigue, nausea/vomiting, and diarrhea in each arm, with the highest level of symptoms except pain reported at cycle 5. The highest reported pain level was seen at cycle 4.
In each arm, the symptoms declined and stabilized in the adjuvant setting, with mean values at week 16 similar to those reported at baseline for most symptoms. The exception was fatigue, which remained slightly elevated in both arms.
Regarding side-effect bother, a similar proportion of patients in each arm reported increased level of bother by visit during the neoadjuvant phase. However, no additional side-effect bother was reported by patients receiving maintenance atezolizumab, compared with patients in the placebo arm, who were followed with observation alone.
‘Reassuring’ data
“What we can conclude from the PRO in IMpassion031 is that early breast cancer patients are relatively asymptomatic. They do have a good baseline quality of life and very good functioning. The neoadjuvant therapy certainly has deterioration in quality of life and functioning, but this is transient, and there was no evident burden from the atezolizumab,” said invited discussant Sylvia Adams, MD, of New York University.
She said it’s reassuring to see the addition of atezolizumab did not adversely affect HRQOL but added that the study “also shows that chemotherapy has a major impact on well-being, as expected.”
Questions and problems that still need to be addressed regarding the use of immunotherapies in early TNBC include whether every patient needs chemotherapy or immunotherapy, a lack of predictive biomarkers, whether increases in pCR rates after neoadjuvant immunotherapy and chemotherapy will translate into improved survival, and the optimal chemotherapy backbone and schedule, she said.
IMpassion031 is sponsored by F. Hoffman-LaRoche. Dr. Mittendorf disclosed relationships with Roche/Genentech, GlaxoSmithKline, Physicians’ Education Resource, AstraZeneca, Exact Sciences, Merck, Peregrine Pharmaceuticals, SELLAS Life Sciences, TapImmune, EMD Serono, Galena Biopharma, Bristol Myers Squibb, and Lilly. Dr. Adams disclosed relationships with Genentech, Bristol Myers Squibb, Merck, Amgen, Celgene, and Novartis.
SOURCE: Mittendorf E at al. SABCS 2020, Abstract GS3-02.
In the randomized phase 3 trial, patients received neoadjuvant atezolizumab or placebo plus chemotherapy, followed by surgery and adjuvant atezolizumab or observation.
An analysis of patient-reported outcomes showed that, after a brief decline in health-related quality of life (HRQOL) in both the atezolizumab and control arms, the burden of treatment eased and then remained similar throughout follow-up.
“Treatment-related symptoms in both arms were similar, and the addition of atezolizumab to chemotherapy was tolerable, with no additional treatment side-effect bother reported,” said Elizabeth Mittendorf, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
She presented these results in an oral abstract presentation during the 2020 San Antonio Breast Cancer Symposium.
Initial results
Primary results of the IMpassion031 trial were reported at ESMO 2020 and published in The Lancet.
The trial enrolled patients with treatment-naive early TNBC, and they were randomized to receive chemotherapy plus atezolizumab or placebo. Atezolizumab was given at 840 mg intravenously every 2 weeks.
Chemotherapy consisted of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks. Patients then underwent surgery, which was followed by either atezolizumab maintenance or observation.
The addition of atezolizumab was associated with a 17% improvement in the rate of pathological complete response (pCR) in the intention-to-treat population.
Among patients positive for PD-L1, atezolizumab was associated with a 20% improvement in pCR rate.
Patients have their say
At SABCS 2020, Dr. Mittendorf presented patient-reported outcomes (PRO) for 161 patients randomized to atezolizumab plus chemotherapy and 167 assigned to placebo plus chemotherapy.
The outcome measures – including role function (the ability to work or pursue common everyday activities), physical function, emotional and social function, and HRQOL – came from scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
The exploratory PRO endpoints were mean function and disease- or treatment-related symptoms as well as mean change from baseline in these symptoms.
At baseline, mean physical function scores were high in both arms, at approximately 90%. They dropped to about 65% in each arm by cycle 5 and rebounded to about 80% by cycle 7.
“The change was clinically meaningful, in that the dip was greater than 10 points,” Dr. Mittendorf said. “As patients completed neoadjuvant therapy and were in the adjuvant phase of the study, there was an increase and stabilization with respect to their physical function.”
Similarly, role function declined from 89% in each arm at baseline to a nadir of about 55% in the placebo arm and 50% in the atezolizumab arm. After cycle 5, role function levels began to increase in both arms and remained above 70% from cycle 7 onward.
Role function did not completely recover or stabilize among patients in the atezolizumab arm, “and we attribute this to the fact that these patients continue to receive atezolizumab, which requires that they come to clinic for that therapy, thereby potentially impacting role function,” Dr. Mittendorf said.
She reported that HRQOL declined from a median of nearly 80% at baseline in both arms to a nadir of 62% in the placebo arm and 52% in the atezolizumab arm by cycle 5. HRQOL rebounded starting at cycle 6 and stabilized thereafter, with little daylight between the treatment arms at the most recent follow-up.
The investigators saw worsening of the treatment-related symptoms fatigue, nausea/vomiting, and diarrhea in each arm, with the highest level of symptoms except pain reported at cycle 5. The highest reported pain level was seen at cycle 4.
In each arm, the symptoms declined and stabilized in the adjuvant setting, with mean values at week 16 similar to those reported at baseline for most symptoms. The exception was fatigue, which remained slightly elevated in both arms.
Regarding side-effect bother, a similar proportion of patients in each arm reported increased level of bother by visit during the neoadjuvant phase. However, no additional side-effect bother was reported by patients receiving maintenance atezolizumab, compared with patients in the placebo arm, who were followed with observation alone.
‘Reassuring’ data
“What we can conclude from the PRO in IMpassion031 is that early breast cancer patients are relatively asymptomatic. They do have a good baseline quality of life and very good functioning. The neoadjuvant therapy certainly has deterioration in quality of life and functioning, but this is transient, and there was no evident burden from the atezolizumab,” said invited discussant Sylvia Adams, MD, of New York University.
She said it’s reassuring to see the addition of atezolizumab did not adversely affect HRQOL but added that the study “also shows that chemotherapy has a major impact on well-being, as expected.”
Questions and problems that still need to be addressed regarding the use of immunotherapies in early TNBC include whether every patient needs chemotherapy or immunotherapy, a lack of predictive biomarkers, whether increases in pCR rates after neoadjuvant immunotherapy and chemotherapy will translate into improved survival, and the optimal chemotherapy backbone and schedule, she said.
IMpassion031 is sponsored by F. Hoffman-LaRoche. Dr. Mittendorf disclosed relationships with Roche/Genentech, GlaxoSmithKline, Physicians’ Education Resource, AstraZeneca, Exact Sciences, Merck, Peregrine Pharmaceuticals, SELLAS Life Sciences, TapImmune, EMD Serono, Galena Biopharma, Bristol Myers Squibb, and Lilly. Dr. Adams disclosed relationships with Genentech, Bristol Myers Squibb, Merck, Amgen, Celgene, and Novartis.
SOURCE: Mittendorf E at al. SABCS 2020, Abstract GS3-02.
FROM SABCS 2020
Pregnancy after breast cancer is rockier but doesn’t increase recurrence risk
Breast cancer survivors are less likely to get pregnant and have higher risks of some delivery and fetal complications, according to a meta-analysis reported at the 2020 San Antonio Breast Cancer Symposium.
However, the data also showed that pregnancy does not increase the risk of cancer recurrence.
“With the availability of more effective anticancer treatments, survivorship and addressing the treatments’ potential long-term toxicities has gained substantial attention,” said study investigator Matteo Lambertini, MD, PhD, of University of Genova (Italy) – IRCCS Policlinico San Martino Hospital.
“Returning to a normal life after cancer diagnosis and treatment should be considered, in the 21st century, as a crucial ambition in cancer care,” Dr. Lambertini added. “In patients diagnosed during their reproductive years, this includes the possibility to complete their family planning. Due to the constant rise in age at first pregnancy over the past years, many women are diagnosed with breast cancer before completing their reproductive plans.”
In that context, certain cancer treatments have the potential to reduce fertility. In addition, many women need prolonged hormone therapy, and conception is contraindicated while they are receiving it.
Study results
Dr. Lambertini and colleagues performed a meta-analysis using data from 39 studies that included a total of 114,573 breast cancer patients and 8,093,401 women from the general population.
Results showed that breast cancer survivors were much less likely than women in the general population to become pregnant (relative risk, 0.40; P < .001).
However, “the majority of the studies included in our meta-analysis did not capture the information on how many women tried to get pregnant,” Dr. Lambertini cautioned.
In the few studies that did, more than half of women trying to conceive did become pregnant, and most of them were able to do so naturally, without need for assisted reproductive technologies.
On the flip side, analyses also showed that pregnancies occurred in some women who did not want to conceive, underscoring the importance of comprehensive oncofertility counseling that addresses not only fertility preservation, but also contraception, Dr. Lambertini said.
Among women who became pregnant, breast cancer survivors did not have higher odds of spontaneous abortion or complications such as preeclampsia, and their infants were not significantly more likely to have congenital abnormalities.
However, the breast cancer survivor group did have higher odds of cesarean birth (odds ratio, 1.14; P = .007), low birth weight (OR, 1.50; P < .001), preterm birth (OR, 1.45; P = .006), and infants small for gestational age (OR, 1.16; P = .039).
In stratified analysis, the higher risk of having an infant with low birth weight was significant only for women who had received chemotherapy, and the higher risk of having an infant small for gestational age was significant only for women who had received chemotherapy or who had a late pregnancy (more than 2 years to 5 years after cancer diagnosis).
Among breast cancer survivors, those who became pregnant actually had lower risks of disease-free survival events (hazard ratio, 0.73; P = .016) and death (HR, 0.56; P < .001). Findings were similar in the subset of studies that adjusted for the so-called healthy mother effect.
Pregnancy did not significantly affect disease-free survival among women with hormone receptor–positive disease and appeared protective among women with hormone receptor–negative disease (HR, 0.72).
Pregnancy also appeared safe in terms of overall survival, irrespective of survivors’ BRCA status, nodal status, receipt of chemotherapy, pregnancy outcome (completed vs. abortion), and pregnancy interval.
This study was limited by the lack of patient-level data and by the fact that most of the included studies had a retrospective design, Dr. Lambertini acknowledged.
Close monitoring, early discussions are key
“Results of this meta-analysis provide reassuring, updated evidence on the feasibility and safety of conceiving in young women with prior breast cancer diagnosis. They provide crucial information for improving the oncofertility counseling of young breast cancer patients, helping them and their treating physicians in making evidence-based decisions on future family planning,” Dr. Lambertini commented.
“The higher risk of delivery and fetal complications … calls for ensuring a closer monitoring of these pregnancies,” he added. “The lack of detrimental prognostic effect of pregnancy after breast cancer following appropriate treatment and follow-up strongly voices the need for a deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”
“The findings provide further support regarding the safety of pregnancy following a breast cancer diagnosis,” agreed Halle Moore, MD, of Cleveland Clinic Taussig Cancer Institute in Ohio, who was not involved in this study.
“I would add that we still have a lot to learn about optimal timing of pregnancy with respect to breast cancer treatment for women with hormone-sensitive breast cancer treated with endocrine therapy,” she said.
The study’s results serve as a reminder that providers should be routinely discussing future pregnancy wishes and fertility preservation options with breast cancer patients at the time of initial diagnosis, Dr. Moore said.
“The earlier we identify an interest in future fertility, the more we can do to improve the chances for a successful pregnancy outcome,” she elaborated. “It is important to assess interest in future pregnancy as soon as possible when a young woman is diagnosed with breast cancer, as fertility preservation options are most likely to be successful when applied prior to chemotherapy or hormonal treatment for breast cancer.”
“The findings also suggest that involvement of a high-risk obstetrics team should be considered for pregnant breast cancer survivors,” Dr. Moore noted.
This research was funded by the Italian Ministry of Health and the Italian Association for Cancer Research. Dr. Lambertini and Dr. Moore disclosed no conflicts of interest. Eva Blondeaux, MD, of University of Genova – IRCCS Policlinico San Martino Hospital, who presented this research at the meeting, disclosed no conflicts as well.
SOURCE: Blondeaux e et al. SABCS 2020, Abstract GS3-09.
Breast cancer survivors are less likely to get pregnant and have higher risks of some delivery and fetal complications, according to a meta-analysis reported at the 2020 San Antonio Breast Cancer Symposium.
However, the data also showed that pregnancy does not increase the risk of cancer recurrence.
“With the availability of more effective anticancer treatments, survivorship and addressing the treatments’ potential long-term toxicities has gained substantial attention,” said study investigator Matteo Lambertini, MD, PhD, of University of Genova (Italy) – IRCCS Policlinico San Martino Hospital.
“Returning to a normal life after cancer diagnosis and treatment should be considered, in the 21st century, as a crucial ambition in cancer care,” Dr. Lambertini added. “In patients diagnosed during their reproductive years, this includes the possibility to complete their family planning. Due to the constant rise in age at first pregnancy over the past years, many women are diagnosed with breast cancer before completing their reproductive plans.”
In that context, certain cancer treatments have the potential to reduce fertility. In addition, many women need prolonged hormone therapy, and conception is contraindicated while they are receiving it.
Study results
Dr. Lambertini and colleagues performed a meta-analysis using data from 39 studies that included a total of 114,573 breast cancer patients and 8,093,401 women from the general population.
Results showed that breast cancer survivors were much less likely than women in the general population to become pregnant (relative risk, 0.40; P < .001).
However, “the majority of the studies included in our meta-analysis did not capture the information on how many women tried to get pregnant,” Dr. Lambertini cautioned.
In the few studies that did, more than half of women trying to conceive did become pregnant, and most of them were able to do so naturally, without need for assisted reproductive technologies.
On the flip side, analyses also showed that pregnancies occurred in some women who did not want to conceive, underscoring the importance of comprehensive oncofertility counseling that addresses not only fertility preservation, but also contraception, Dr. Lambertini said.
Among women who became pregnant, breast cancer survivors did not have higher odds of spontaneous abortion or complications such as preeclampsia, and their infants were not significantly more likely to have congenital abnormalities.
However, the breast cancer survivor group did have higher odds of cesarean birth (odds ratio, 1.14; P = .007), low birth weight (OR, 1.50; P < .001), preterm birth (OR, 1.45; P = .006), and infants small for gestational age (OR, 1.16; P = .039).
In stratified analysis, the higher risk of having an infant with low birth weight was significant only for women who had received chemotherapy, and the higher risk of having an infant small for gestational age was significant only for women who had received chemotherapy or who had a late pregnancy (more than 2 years to 5 years after cancer diagnosis).
Among breast cancer survivors, those who became pregnant actually had lower risks of disease-free survival events (hazard ratio, 0.73; P = .016) and death (HR, 0.56; P < .001). Findings were similar in the subset of studies that adjusted for the so-called healthy mother effect.
Pregnancy did not significantly affect disease-free survival among women with hormone receptor–positive disease and appeared protective among women with hormone receptor–negative disease (HR, 0.72).
Pregnancy also appeared safe in terms of overall survival, irrespective of survivors’ BRCA status, nodal status, receipt of chemotherapy, pregnancy outcome (completed vs. abortion), and pregnancy interval.
This study was limited by the lack of patient-level data and by the fact that most of the included studies had a retrospective design, Dr. Lambertini acknowledged.
Close monitoring, early discussions are key
“Results of this meta-analysis provide reassuring, updated evidence on the feasibility and safety of conceiving in young women with prior breast cancer diagnosis. They provide crucial information for improving the oncofertility counseling of young breast cancer patients, helping them and their treating physicians in making evidence-based decisions on future family planning,” Dr. Lambertini commented.
“The higher risk of delivery and fetal complications … calls for ensuring a closer monitoring of these pregnancies,” he added. “The lack of detrimental prognostic effect of pregnancy after breast cancer following appropriate treatment and follow-up strongly voices the need for a deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”
“The findings provide further support regarding the safety of pregnancy following a breast cancer diagnosis,” agreed Halle Moore, MD, of Cleveland Clinic Taussig Cancer Institute in Ohio, who was not involved in this study.
“I would add that we still have a lot to learn about optimal timing of pregnancy with respect to breast cancer treatment for women with hormone-sensitive breast cancer treated with endocrine therapy,” she said.
The study’s results serve as a reminder that providers should be routinely discussing future pregnancy wishes and fertility preservation options with breast cancer patients at the time of initial diagnosis, Dr. Moore said.
“The earlier we identify an interest in future fertility, the more we can do to improve the chances for a successful pregnancy outcome,” she elaborated. “It is important to assess interest in future pregnancy as soon as possible when a young woman is diagnosed with breast cancer, as fertility preservation options are most likely to be successful when applied prior to chemotherapy or hormonal treatment for breast cancer.”
“The findings also suggest that involvement of a high-risk obstetrics team should be considered for pregnant breast cancer survivors,” Dr. Moore noted.
This research was funded by the Italian Ministry of Health and the Italian Association for Cancer Research. Dr. Lambertini and Dr. Moore disclosed no conflicts of interest. Eva Blondeaux, MD, of University of Genova – IRCCS Policlinico San Martino Hospital, who presented this research at the meeting, disclosed no conflicts as well.
SOURCE: Blondeaux e et al. SABCS 2020, Abstract GS3-09.
Breast cancer survivors are less likely to get pregnant and have higher risks of some delivery and fetal complications, according to a meta-analysis reported at the 2020 San Antonio Breast Cancer Symposium.
However, the data also showed that pregnancy does not increase the risk of cancer recurrence.
“With the availability of more effective anticancer treatments, survivorship and addressing the treatments’ potential long-term toxicities has gained substantial attention,” said study investigator Matteo Lambertini, MD, PhD, of University of Genova (Italy) – IRCCS Policlinico San Martino Hospital.
“Returning to a normal life after cancer diagnosis and treatment should be considered, in the 21st century, as a crucial ambition in cancer care,” Dr. Lambertini added. “In patients diagnosed during their reproductive years, this includes the possibility to complete their family planning. Due to the constant rise in age at first pregnancy over the past years, many women are diagnosed with breast cancer before completing their reproductive plans.”
In that context, certain cancer treatments have the potential to reduce fertility. In addition, many women need prolonged hormone therapy, and conception is contraindicated while they are receiving it.
Study results
Dr. Lambertini and colleagues performed a meta-analysis using data from 39 studies that included a total of 114,573 breast cancer patients and 8,093,401 women from the general population.
Results showed that breast cancer survivors were much less likely than women in the general population to become pregnant (relative risk, 0.40; P < .001).
However, “the majority of the studies included in our meta-analysis did not capture the information on how many women tried to get pregnant,” Dr. Lambertini cautioned.
In the few studies that did, more than half of women trying to conceive did become pregnant, and most of them were able to do so naturally, without need for assisted reproductive technologies.
On the flip side, analyses also showed that pregnancies occurred in some women who did not want to conceive, underscoring the importance of comprehensive oncofertility counseling that addresses not only fertility preservation, but also contraception, Dr. Lambertini said.
Among women who became pregnant, breast cancer survivors did not have higher odds of spontaneous abortion or complications such as preeclampsia, and their infants were not significantly more likely to have congenital abnormalities.
However, the breast cancer survivor group did have higher odds of cesarean birth (odds ratio, 1.14; P = .007), low birth weight (OR, 1.50; P < .001), preterm birth (OR, 1.45; P = .006), and infants small for gestational age (OR, 1.16; P = .039).
In stratified analysis, the higher risk of having an infant with low birth weight was significant only for women who had received chemotherapy, and the higher risk of having an infant small for gestational age was significant only for women who had received chemotherapy or who had a late pregnancy (more than 2 years to 5 years after cancer diagnosis).
Among breast cancer survivors, those who became pregnant actually had lower risks of disease-free survival events (hazard ratio, 0.73; P = .016) and death (HR, 0.56; P < .001). Findings were similar in the subset of studies that adjusted for the so-called healthy mother effect.
Pregnancy did not significantly affect disease-free survival among women with hormone receptor–positive disease and appeared protective among women with hormone receptor–negative disease (HR, 0.72).
Pregnancy also appeared safe in terms of overall survival, irrespective of survivors’ BRCA status, nodal status, receipt of chemotherapy, pregnancy outcome (completed vs. abortion), and pregnancy interval.
This study was limited by the lack of patient-level data and by the fact that most of the included studies had a retrospective design, Dr. Lambertini acknowledged.
Close monitoring, early discussions are key
“Results of this meta-analysis provide reassuring, updated evidence on the feasibility and safety of conceiving in young women with prior breast cancer diagnosis. They provide crucial information for improving the oncofertility counseling of young breast cancer patients, helping them and their treating physicians in making evidence-based decisions on future family planning,” Dr. Lambertini commented.
“The higher risk of delivery and fetal complications … calls for ensuring a closer monitoring of these pregnancies,” he added. “The lack of detrimental prognostic effect of pregnancy after breast cancer following appropriate treatment and follow-up strongly voices the need for a deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”
“The findings provide further support regarding the safety of pregnancy following a breast cancer diagnosis,” agreed Halle Moore, MD, of Cleveland Clinic Taussig Cancer Institute in Ohio, who was not involved in this study.
“I would add that we still have a lot to learn about optimal timing of pregnancy with respect to breast cancer treatment for women with hormone-sensitive breast cancer treated with endocrine therapy,” she said.
The study’s results serve as a reminder that providers should be routinely discussing future pregnancy wishes and fertility preservation options with breast cancer patients at the time of initial diagnosis, Dr. Moore said.
“The earlier we identify an interest in future fertility, the more we can do to improve the chances for a successful pregnancy outcome,” she elaborated. “It is important to assess interest in future pregnancy as soon as possible when a young woman is diagnosed with breast cancer, as fertility preservation options are most likely to be successful when applied prior to chemotherapy or hormonal treatment for breast cancer.”
“The findings also suggest that involvement of a high-risk obstetrics team should be considered for pregnant breast cancer survivors,” Dr. Moore noted.
This research was funded by the Italian Ministry of Health and the Italian Association for Cancer Research. Dr. Lambertini and Dr. Moore disclosed no conflicts of interest. Eva Blondeaux, MD, of University of Genova – IRCCS Policlinico San Martino Hospital, who presented this research at the meeting, disclosed no conflicts as well.
SOURCE: Blondeaux e et al. SABCS 2020, Abstract GS3-09.
FROM SABCS 2020
Synthetic lethality: Triple combination is a viable strategy for B-cell malignancies
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
FROM ASH 2020
Wearable device clears a first ‘milestone’ in seizure detection
The new findings have the potential to revolutionize the management of patients with epilepsy, according to the researchers. “We have set a first benchmark for automatic detection of a variety of epileptic seizures using wearable sensors and deep-learning algorithms. In other words, we have shown for the first time that it’s possible to do this,” said study investigator Jianbin Tang, MA, data science project lead, IBM Research Australia, Victoria.
The findings were presented at the American Epilepsy Society’s annual meeting, held online this year because of the COVID-19 pandemic.
Accurate monitoring of seizures is important for assessing risk, injury prevention, and treatment response evaluation. Currently, video EEG is the gold standard for seizure detection, but it requires a hospital stay, is often costly, and can be stigmatizing, said Mr. Tang.
An advance in detecting seizure types
Recent advances in non-EEG wearable devices show promise in detecting generalized onset tonic-clonic and focal to bilateral tonic-clonic seizures, but it’s not clear if they have the ability to detect other seizure types. “We hope to fill this gap by expanding wearable seizure detection to additional seizure types,” said Mr. Tang.
Seizure tracking outside the hospital setting largely “relies on manually annotated family and patient reports, which often can be unreliable due to missed seizures and problems recalling seizures,” he said.
The study included 75 children (44% were female; mean age was 11.1 years) admitted to a long-term EEG monitoring unit at a single center for a 24-hour stay. Patients wore the detector on the ankle or wrist. The device continuously collected data on functions such as sweating, heart rate, movement, and temperature.
With part of the dataset, researchers trained deep-learning algorithms to automatically detect seizure segments. They then validated the performance of the detection algorithms on the remainder of the dataset.
The analysis was based on data from 722 epileptic seizures of all types including focal and generalized, motor and nonmotor. Seizures occurred throughout the day and during the night while patients were awake or asleep.
When a seizure is detected, the system triggers a real-time alert and will store the information about the detected seizure in a repository, said Mr. Tang.
The signals were initially stored in the wristband and then securely uploaded to the Cloud. From there, the signal files were downloaded by the investigators for analysis and interpretation. All data were entirely anonymized and de-identified. Researchers used Area Under Curve–Receiver Operating Characteristic (AUC-ROC) to assess performance.
“Our best performing detection models reach an AUC-ROC of 67.59%, which represents a decent performance level,” said Mr. Tang. “There certainly is room for performance improvement and we are already working on this,” he added.
The device performed “better than chance,” which is a “standard technical term” in the field of machine learning and is “the first hurdle any machine-learning model needs to take to be considered useful.” The investigators noted that such automatic seizure detection “is feasible across a broad spectrum of epileptic seizure types,” said Mr. Tang. “This is a first and has not been shown before.”
The study suggests that the noninvasive wearable device could be used at home, at school, and in other everyday settings outside the clinic. “This could one day provide patients, caregivers, and clinicians with reliable seizure reports,” said Mr. Tang.
He said he believes the device might be especially useful in detecting frequent or subtle seizures, which are easy to miss. Patients requiring medication evaluation and rescue medication and those at risk of status epilepticus may be good candidates.
The researchers don’t expect wearable technology to totally replace EEG but see it as “a useful complementary tool to track seizures continuously at times or in settings where EEG monitoring is not available,” said Mr. Tang.
‘Important milestone’
Commenting on the research, Benjamin H. Brinkmann, PhD, associate professor of neurology at the Mayo Clinic in Rochester, Minn., said the investigators “have done very good work applying state of the art machine learning techniques” to the “important problem” of accurately detecting seizures.
Dr. Brinkmann is part of the Epilepsy Foundation–sponsored “My Seizure Gauge” project that’s evaluating various wearable devices, including the Empatica E4 wristband and the Fitbit Charge 3, to determine what measurements are needed for reliable seizure forecasting.
“Previously, no one knew whether seizure prediction was possible with these devices, and the fact that this group was able to achieve ‘better-than-chance’ prediction accuracy is an important milestone.”
However, he emphasized that there is still a great deal of work to be done to determine, for example, if seizure prediction with these devices can be accurate enough to be clinically useful. “For example, if the system generates too many false-positive predictions, patients won’t use it.”
In addition, the findings need to be replicated and recordings extended to 6 months or more to determine whether they are helpful to patients long term and in the home environment, said Dr. Brinkmann.
The investigators and Dr. Brinkmann have disclosed having no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The new findings have the potential to revolutionize the management of patients with epilepsy, according to the researchers. “We have set a first benchmark for automatic detection of a variety of epileptic seizures using wearable sensors and deep-learning algorithms. In other words, we have shown for the first time that it’s possible to do this,” said study investigator Jianbin Tang, MA, data science project lead, IBM Research Australia, Victoria.
The findings were presented at the American Epilepsy Society’s annual meeting, held online this year because of the COVID-19 pandemic.
Accurate monitoring of seizures is important for assessing risk, injury prevention, and treatment response evaluation. Currently, video EEG is the gold standard for seizure detection, but it requires a hospital stay, is often costly, and can be stigmatizing, said Mr. Tang.
An advance in detecting seizure types
Recent advances in non-EEG wearable devices show promise in detecting generalized onset tonic-clonic and focal to bilateral tonic-clonic seizures, but it’s not clear if they have the ability to detect other seizure types. “We hope to fill this gap by expanding wearable seizure detection to additional seizure types,” said Mr. Tang.
Seizure tracking outside the hospital setting largely “relies on manually annotated family and patient reports, which often can be unreliable due to missed seizures and problems recalling seizures,” he said.
The study included 75 children (44% were female; mean age was 11.1 years) admitted to a long-term EEG monitoring unit at a single center for a 24-hour stay. Patients wore the detector on the ankle or wrist. The device continuously collected data on functions such as sweating, heart rate, movement, and temperature.
With part of the dataset, researchers trained deep-learning algorithms to automatically detect seizure segments. They then validated the performance of the detection algorithms on the remainder of the dataset.
The analysis was based on data from 722 epileptic seizures of all types including focal and generalized, motor and nonmotor. Seizures occurred throughout the day and during the night while patients were awake or asleep.
When a seizure is detected, the system triggers a real-time alert and will store the information about the detected seizure in a repository, said Mr. Tang.
The signals were initially stored in the wristband and then securely uploaded to the Cloud. From there, the signal files were downloaded by the investigators for analysis and interpretation. All data were entirely anonymized and de-identified. Researchers used Area Under Curve–Receiver Operating Characteristic (AUC-ROC) to assess performance.
“Our best performing detection models reach an AUC-ROC of 67.59%, which represents a decent performance level,” said Mr. Tang. “There certainly is room for performance improvement and we are already working on this,” he added.
The device performed “better than chance,” which is a “standard technical term” in the field of machine learning and is “the first hurdle any machine-learning model needs to take to be considered useful.” The investigators noted that such automatic seizure detection “is feasible across a broad spectrum of epileptic seizure types,” said Mr. Tang. “This is a first and has not been shown before.”
The study suggests that the noninvasive wearable device could be used at home, at school, and in other everyday settings outside the clinic. “This could one day provide patients, caregivers, and clinicians with reliable seizure reports,” said Mr. Tang.
He said he believes the device might be especially useful in detecting frequent or subtle seizures, which are easy to miss. Patients requiring medication evaluation and rescue medication and those at risk of status epilepticus may be good candidates.
The researchers don’t expect wearable technology to totally replace EEG but see it as “a useful complementary tool to track seizures continuously at times or in settings where EEG monitoring is not available,” said Mr. Tang.
‘Important milestone’
Commenting on the research, Benjamin H. Brinkmann, PhD, associate professor of neurology at the Mayo Clinic in Rochester, Minn., said the investigators “have done very good work applying state of the art machine learning techniques” to the “important problem” of accurately detecting seizures.
Dr. Brinkmann is part of the Epilepsy Foundation–sponsored “My Seizure Gauge” project that’s evaluating various wearable devices, including the Empatica E4 wristband and the Fitbit Charge 3, to determine what measurements are needed for reliable seizure forecasting.
“Previously, no one knew whether seizure prediction was possible with these devices, and the fact that this group was able to achieve ‘better-than-chance’ prediction accuracy is an important milestone.”
However, he emphasized that there is still a great deal of work to be done to determine, for example, if seizure prediction with these devices can be accurate enough to be clinically useful. “For example, if the system generates too many false-positive predictions, patients won’t use it.”
In addition, the findings need to be replicated and recordings extended to 6 months or more to determine whether they are helpful to patients long term and in the home environment, said Dr. Brinkmann.
The investigators and Dr. Brinkmann have disclosed having no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The new findings have the potential to revolutionize the management of patients with epilepsy, according to the researchers. “We have set a first benchmark for automatic detection of a variety of epileptic seizures using wearable sensors and deep-learning algorithms. In other words, we have shown for the first time that it’s possible to do this,” said study investigator Jianbin Tang, MA, data science project lead, IBM Research Australia, Victoria.
The findings were presented at the American Epilepsy Society’s annual meeting, held online this year because of the COVID-19 pandemic.
Accurate monitoring of seizures is important for assessing risk, injury prevention, and treatment response evaluation. Currently, video EEG is the gold standard for seizure detection, but it requires a hospital stay, is often costly, and can be stigmatizing, said Mr. Tang.
An advance in detecting seizure types
Recent advances in non-EEG wearable devices show promise in detecting generalized onset tonic-clonic and focal to bilateral tonic-clonic seizures, but it’s not clear if they have the ability to detect other seizure types. “We hope to fill this gap by expanding wearable seizure detection to additional seizure types,” said Mr. Tang.
Seizure tracking outside the hospital setting largely “relies on manually annotated family and patient reports, which often can be unreliable due to missed seizures and problems recalling seizures,” he said.
The study included 75 children (44% were female; mean age was 11.1 years) admitted to a long-term EEG monitoring unit at a single center for a 24-hour stay. Patients wore the detector on the ankle or wrist. The device continuously collected data on functions such as sweating, heart rate, movement, and temperature.
With part of the dataset, researchers trained deep-learning algorithms to automatically detect seizure segments. They then validated the performance of the detection algorithms on the remainder of the dataset.
The analysis was based on data from 722 epileptic seizures of all types including focal and generalized, motor and nonmotor. Seizures occurred throughout the day and during the night while patients were awake or asleep.
When a seizure is detected, the system triggers a real-time alert and will store the information about the detected seizure in a repository, said Mr. Tang.
The signals were initially stored in the wristband and then securely uploaded to the Cloud. From there, the signal files were downloaded by the investigators for analysis and interpretation. All data were entirely anonymized and de-identified. Researchers used Area Under Curve–Receiver Operating Characteristic (AUC-ROC) to assess performance.
“Our best performing detection models reach an AUC-ROC of 67.59%, which represents a decent performance level,” said Mr. Tang. “There certainly is room for performance improvement and we are already working on this,” he added.
The device performed “better than chance,” which is a “standard technical term” in the field of machine learning and is “the first hurdle any machine-learning model needs to take to be considered useful.” The investigators noted that such automatic seizure detection “is feasible across a broad spectrum of epileptic seizure types,” said Mr. Tang. “This is a first and has not been shown before.”
The study suggests that the noninvasive wearable device could be used at home, at school, and in other everyday settings outside the clinic. “This could one day provide patients, caregivers, and clinicians with reliable seizure reports,” said Mr. Tang.
He said he believes the device might be especially useful in detecting frequent or subtle seizures, which are easy to miss. Patients requiring medication evaluation and rescue medication and those at risk of status epilepticus may be good candidates.
The researchers don’t expect wearable technology to totally replace EEG but see it as “a useful complementary tool to track seizures continuously at times or in settings where EEG monitoring is not available,” said Mr. Tang.
‘Important milestone’
Commenting on the research, Benjamin H. Brinkmann, PhD, associate professor of neurology at the Mayo Clinic in Rochester, Minn., said the investigators “have done very good work applying state of the art machine learning techniques” to the “important problem” of accurately detecting seizures.
Dr. Brinkmann is part of the Epilepsy Foundation–sponsored “My Seizure Gauge” project that’s evaluating various wearable devices, including the Empatica E4 wristband and the Fitbit Charge 3, to determine what measurements are needed for reliable seizure forecasting.
“Previously, no one knew whether seizure prediction was possible with these devices, and the fact that this group was able to achieve ‘better-than-chance’ prediction accuracy is an important milestone.”
However, he emphasized that there is still a great deal of work to be done to determine, for example, if seizure prediction with these devices can be accurate enough to be clinically useful. “For example, if the system generates too many false-positive predictions, patients won’t use it.”
In addition, the findings need to be replicated and recordings extended to 6 months or more to determine whether they are helpful to patients long term and in the home environment, said Dr. Brinkmann.
The investigators and Dr. Brinkmann have disclosed having no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM AES 2020
RxPONDER: Even more women may forgo chemo for breast cancer
More women with early-stage breast cancer may safely forgo chemotherapy, suggests an interim analysis of the large-scale phase 3 RxPONDER trial, presented at the San Antonio Breast Cancer Symposium 2020.
The investigators reported that adding chemotherapy to endocrine therapy did not improve outcomes for postmenopausal women with low-risk, node-positive, hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer in comparison with endocrine therapy alone.
These results are akin to those from the TAILORx trial. The results of that trial were first presented in 2018 and have changed practice for women with early-stage disease who have no lymph node involvement.
Clinicians celebrated the new results for women with lymph node–positive disease.
“RxPonder: practice changing!!!” tweeted meeting attendee Sarah Sammons, MD, Duke Cancer Center, Durham, N.C.
“Data from RxPonder are the most clinically important this year at @SABCSSanAntonio,” tweeted Hal Burstein, MD, Dana Farber Cancer Institute, Boston, who was not involved in the study.
“This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions,” asserted study lead author Kevin Kalinsky, MD, Winship Cancer Institute of Emory University, Atlanta, during a meeting press conference.
But the trial, run by the SWOG Cancer Research Network, was not without controversy.
That’s because the trial also included premenopausal women whose disease characteristics were the same and who were found to have benefited from chemotherapy.
It was not clear whether the benefit was from chemotherapy’s cytotoxicity or its endocrine effects/ovarian suppression (which limits the production of estrogen, a breast cell stimulant) in these young women. But multiple experts asserted that the effect was very likely from ovarian suppression.
“There are less toxic ways than chemo to suppress ovarian function,” tweeted Tatiana Prowell, MD, Johns Hopkins University, Baltimore, who is not a study investigator.
Some experts strongly doubted the findings in premenopausal women.
“I hate to come away with the message that all [low-risk, node-positive] premenopausal patients should get chemotherapy,” summarized C. Kent Osborne, MD, Baylor College of Medicine, Houston, who is codirector of SABCS and was not involved in the study.
RxPONDER will follow patients for 15 years, so additional data and insights will follow, observed SWOG in a press statement.
Women had limited positive nodes
RxPONDER, or SWOG S1007, involved more than 5000 women who had HR+, HER2– breast cancer with involvement of one to three lymph nodes. The patients’ recurrence score was ≤25 on a 21-tumor gene expression assay (Oncotype Dx), which is characterized as low risk.
Approximately 20% of U.S. women with nonmetastatic HR+, HER2– breast cancer present with involvement of one to three lymph nodes, Dr. Kalinsky noted.
Study participants were randomly assigned to receive either standard chemotherapy plus endocrine therapy or endocrine therapy alone. Follow-up was for a median of 5 years before the current preplanned analysis.
Over a median follow-up of 5.1 years, there were 447 observed invasive disease-free survival (IDFS) events, the primary endpoint, which is 54% of the expected number at final analysis.
Across the whole cohort, adding chemotherapy to endocrine therapy was associated with a significant improvement in IDFS, with a 5-year rate of 92.4% vs 91.0% for endocrine therapy (P = .026).
Among the postmenopausal women, no such improvement was seen. The 5-year IDFS rate was 91.6% with chemotherapy plus endocrine therapy and 91.9% with endocrine therapy alone (P = .82).
Among premenopausal women, there was improvement in IDFS. The 5-year rate was 94.2% with chemotherapy plus endocrine therapy and 89.0% for endocrine therapy alone (P = .0004).
These differences were reflected in the results for overall survival. For postmenopausal women, there was a nonsignificant difference in 5-year overall survival rates (96.2% vs. 96.1%).
On the other hand, for premenopausal women, there was a significant difference in 5-year overall survival rates (98.6% vs. 97.3%; P = .032).
Stratifying patients by recurrence score, 0-13 versus 14-25, and by involvement of one versus two to three nodes did not have a major impact on the results, said Dr. Kalinsky, who also noted that future analyses will include quality of life and other outcomes.
More about endocrine therapy in RxPONDER
Dr. Osborne said that premenopausal women in RxPONDER were “nearly always” prescribed tamoxifen.
However, he observed that the current standard approach to treatment in this age group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, “both of which have been shown to be superior to tamoxifen alone in this subgroup.
“Since the adjuvant chemotherapy causes ovarian suppression in many premenopausal patients,” he said, “these patients then, in fact, received ovarian suppression plus tamoxifen,” rather than tamoxifen alone for the group that did not receive chemotherapy.
Dr. Osborne asked a question that came up again and again during the postpresentation discussion: “Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” he said.
Dr. Kalinsky replied that whether the difference in benefit of chemotherapy in premenopausal women “was a direct benefit, meaning that there’s something about the biology difference” between tumors in premenopausal versus postmenopausal women, “or whether this was an indirect effect, meaning impacting rates of amenorrhea... is not specifically how this study was designed.”
However, an exploratory landmark analysis at 6 months suggested that the use of ovarian suppression with endocrine therapy did not have an effect on outcomes.
Dr. Osborne said he is nevertheless “still skeptical that chemotherapy works differently in premenopausal women. Until we show that it’s not an endocrine effect ... I just can’t imagine why that group of patients, even the ones with very low Oncotype [score], would have a different response to chemotherapy.”
He added: “If I can think of a rationale ... I would believe it, but right now, I’m a little bit skeptical.”
Virginia Kaklamani, MD, of the University of Texas Health San Antonio Cancer Center, San Antonio, who is a meeting codirector, said she wanted to “second that.
“I honestly think that this is an OFS [ovarian function suppression effect] that we are seeing. We have several clinical trials that have been done looking at ovarian function suppression versus not ... showing that [it] can help as much as chemotherapy.”
Dr. Kaklamani continued: “Unfortunately, the arms to those trials were not perfect for now, and this is going to be an unanswered question until we have a large trial comparing OFS to chemotherapy.”
The study was sponsored by the National Cancer Institute, the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Exact Sciences. Dr. Kalinsky, Dr. Osborne, and Dr. Kaklamani report financial ties to multiple pharmaceutical companies.
This article first appeared on Medscape.com.
More women with early-stage breast cancer may safely forgo chemotherapy, suggests an interim analysis of the large-scale phase 3 RxPONDER trial, presented at the San Antonio Breast Cancer Symposium 2020.
The investigators reported that adding chemotherapy to endocrine therapy did not improve outcomes for postmenopausal women with low-risk, node-positive, hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer in comparison with endocrine therapy alone.
These results are akin to those from the TAILORx trial. The results of that trial were first presented in 2018 and have changed practice for women with early-stage disease who have no lymph node involvement.
Clinicians celebrated the new results for women with lymph node–positive disease.
“RxPonder: practice changing!!!” tweeted meeting attendee Sarah Sammons, MD, Duke Cancer Center, Durham, N.C.
“Data from RxPonder are the most clinically important this year at @SABCSSanAntonio,” tweeted Hal Burstein, MD, Dana Farber Cancer Institute, Boston, who was not involved in the study.
“This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions,” asserted study lead author Kevin Kalinsky, MD, Winship Cancer Institute of Emory University, Atlanta, during a meeting press conference.
But the trial, run by the SWOG Cancer Research Network, was not without controversy.
That’s because the trial also included premenopausal women whose disease characteristics were the same and who were found to have benefited from chemotherapy.
It was not clear whether the benefit was from chemotherapy’s cytotoxicity or its endocrine effects/ovarian suppression (which limits the production of estrogen, a breast cell stimulant) in these young women. But multiple experts asserted that the effect was very likely from ovarian suppression.
“There are less toxic ways than chemo to suppress ovarian function,” tweeted Tatiana Prowell, MD, Johns Hopkins University, Baltimore, who is not a study investigator.
Some experts strongly doubted the findings in premenopausal women.
“I hate to come away with the message that all [low-risk, node-positive] premenopausal patients should get chemotherapy,” summarized C. Kent Osborne, MD, Baylor College of Medicine, Houston, who is codirector of SABCS and was not involved in the study.
RxPONDER will follow patients for 15 years, so additional data and insights will follow, observed SWOG in a press statement.
Women had limited positive nodes
RxPONDER, or SWOG S1007, involved more than 5000 women who had HR+, HER2– breast cancer with involvement of one to three lymph nodes. The patients’ recurrence score was ≤25 on a 21-tumor gene expression assay (Oncotype Dx), which is characterized as low risk.
Approximately 20% of U.S. women with nonmetastatic HR+, HER2– breast cancer present with involvement of one to three lymph nodes, Dr. Kalinsky noted.
Study participants were randomly assigned to receive either standard chemotherapy plus endocrine therapy or endocrine therapy alone. Follow-up was for a median of 5 years before the current preplanned analysis.
Over a median follow-up of 5.1 years, there were 447 observed invasive disease-free survival (IDFS) events, the primary endpoint, which is 54% of the expected number at final analysis.
Across the whole cohort, adding chemotherapy to endocrine therapy was associated with a significant improvement in IDFS, with a 5-year rate of 92.4% vs 91.0% for endocrine therapy (P = .026).
Among the postmenopausal women, no such improvement was seen. The 5-year IDFS rate was 91.6% with chemotherapy plus endocrine therapy and 91.9% with endocrine therapy alone (P = .82).
Among premenopausal women, there was improvement in IDFS. The 5-year rate was 94.2% with chemotherapy plus endocrine therapy and 89.0% for endocrine therapy alone (P = .0004).
These differences were reflected in the results for overall survival. For postmenopausal women, there was a nonsignificant difference in 5-year overall survival rates (96.2% vs. 96.1%).
On the other hand, for premenopausal women, there was a significant difference in 5-year overall survival rates (98.6% vs. 97.3%; P = .032).
Stratifying patients by recurrence score, 0-13 versus 14-25, and by involvement of one versus two to three nodes did not have a major impact on the results, said Dr. Kalinsky, who also noted that future analyses will include quality of life and other outcomes.
More about endocrine therapy in RxPONDER
Dr. Osborne said that premenopausal women in RxPONDER were “nearly always” prescribed tamoxifen.
However, he observed that the current standard approach to treatment in this age group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, “both of which have been shown to be superior to tamoxifen alone in this subgroup.
“Since the adjuvant chemotherapy causes ovarian suppression in many premenopausal patients,” he said, “these patients then, in fact, received ovarian suppression plus tamoxifen,” rather than tamoxifen alone for the group that did not receive chemotherapy.
Dr. Osborne asked a question that came up again and again during the postpresentation discussion: “Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” he said.
Dr. Kalinsky replied that whether the difference in benefit of chemotherapy in premenopausal women “was a direct benefit, meaning that there’s something about the biology difference” between tumors in premenopausal versus postmenopausal women, “or whether this was an indirect effect, meaning impacting rates of amenorrhea... is not specifically how this study was designed.”
However, an exploratory landmark analysis at 6 months suggested that the use of ovarian suppression with endocrine therapy did not have an effect on outcomes.
Dr. Osborne said he is nevertheless “still skeptical that chemotherapy works differently in premenopausal women. Until we show that it’s not an endocrine effect ... I just can’t imagine why that group of patients, even the ones with very low Oncotype [score], would have a different response to chemotherapy.”
He added: “If I can think of a rationale ... I would believe it, but right now, I’m a little bit skeptical.”
Virginia Kaklamani, MD, of the University of Texas Health San Antonio Cancer Center, San Antonio, who is a meeting codirector, said she wanted to “second that.
“I honestly think that this is an OFS [ovarian function suppression effect] that we are seeing. We have several clinical trials that have been done looking at ovarian function suppression versus not ... showing that [it] can help as much as chemotherapy.”
Dr. Kaklamani continued: “Unfortunately, the arms to those trials were not perfect for now, and this is going to be an unanswered question until we have a large trial comparing OFS to chemotherapy.”
The study was sponsored by the National Cancer Institute, the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Exact Sciences. Dr. Kalinsky, Dr. Osborne, and Dr. Kaklamani report financial ties to multiple pharmaceutical companies.
This article first appeared on Medscape.com.
More women with early-stage breast cancer may safely forgo chemotherapy, suggests an interim analysis of the large-scale phase 3 RxPONDER trial, presented at the San Antonio Breast Cancer Symposium 2020.
The investigators reported that adding chemotherapy to endocrine therapy did not improve outcomes for postmenopausal women with low-risk, node-positive, hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer in comparison with endocrine therapy alone.
These results are akin to those from the TAILORx trial. The results of that trial were first presented in 2018 and have changed practice for women with early-stage disease who have no lymph node involvement.
Clinicians celebrated the new results for women with lymph node–positive disease.
“RxPonder: practice changing!!!” tweeted meeting attendee Sarah Sammons, MD, Duke Cancer Center, Durham, N.C.
“Data from RxPonder are the most clinically important this year at @SABCSSanAntonio,” tweeted Hal Burstein, MD, Dana Farber Cancer Institute, Boston, who was not involved in the study.
“This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions,” asserted study lead author Kevin Kalinsky, MD, Winship Cancer Institute of Emory University, Atlanta, during a meeting press conference.
But the trial, run by the SWOG Cancer Research Network, was not without controversy.
That’s because the trial also included premenopausal women whose disease characteristics were the same and who were found to have benefited from chemotherapy.
It was not clear whether the benefit was from chemotherapy’s cytotoxicity or its endocrine effects/ovarian suppression (which limits the production of estrogen, a breast cell stimulant) in these young women. But multiple experts asserted that the effect was very likely from ovarian suppression.
“There are less toxic ways than chemo to suppress ovarian function,” tweeted Tatiana Prowell, MD, Johns Hopkins University, Baltimore, who is not a study investigator.
Some experts strongly doubted the findings in premenopausal women.
“I hate to come away with the message that all [low-risk, node-positive] premenopausal patients should get chemotherapy,” summarized C. Kent Osborne, MD, Baylor College of Medicine, Houston, who is codirector of SABCS and was not involved in the study.
RxPONDER will follow patients for 15 years, so additional data and insights will follow, observed SWOG in a press statement.
Women had limited positive nodes
RxPONDER, or SWOG S1007, involved more than 5000 women who had HR+, HER2– breast cancer with involvement of one to three lymph nodes. The patients’ recurrence score was ≤25 on a 21-tumor gene expression assay (Oncotype Dx), which is characterized as low risk.
Approximately 20% of U.S. women with nonmetastatic HR+, HER2– breast cancer present with involvement of one to three lymph nodes, Dr. Kalinsky noted.
Study participants were randomly assigned to receive either standard chemotherapy plus endocrine therapy or endocrine therapy alone. Follow-up was for a median of 5 years before the current preplanned analysis.
Over a median follow-up of 5.1 years, there were 447 observed invasive disease-free survival (IDFS) events, the primary endpoint, which is 54% of the expected number at final analysis.
Across the whole cohort, adding chemotherapy to endocrine therapy was associated with a significant improvement in IDFS, with a 5-year rate of 92.4% vs 91.0% for endocrine therapy (P = .026).
Among the postmenopausal women, no such improvement was seen. The 5-year IDFS rate was 91.6% with chemotherapy plus endocrine therapy and 91.9% with endocrine therapy alone (P = .82).
Among premenopausal women, there was improvement in IDFS. The 5-year rate was 94.2% with chemotherapy plus endocrine therapy and 89.0% for endocrine therapy alone (P = .0004).
These differences were reflected in the results for overall survival. For postmenopausal women, there was a nonsignificant difference in 5-year overall survival rates (96.2% vs. 96.1%).
On the other hand, for premenopausal women, there was a significant difference in 5-year overall survival rates (98.6% vs. 97.3%; P = .032).
Stratifying patients by recurrence score, 0-13 versus 14-25, and by involvement of one versus two to three nodes did not have a major impact on the results, said Dr. Kalinsky, who also noted that future analyses will include quality of life and other outcomes.
More about endocrine therapy in RxPONDER
Dr. Osborne said that premenopausal women in RxPONDER were “nearly always” prescribed tamoxifen.
However, he observed that the current standard approach to treatment in this age group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, “both of which have been shown to be superior to tamoxifen alone in this subgroup.
“Since the adjuvant chemotherapy causes ovarian suppression in many premenopausal patients,” he said, “these patients then, in fact, received ovarian suppression plus tamoxifen,” rather than tamoxifen alone for the group that did not receive chemotherapy.
Dr. Osborne asked a question that came up again and again during the postpresentation discussion: “Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” he said.
Dr. Kalinsky replied that whether the difference in benefit of chemotherapy in premenopausal women “was a direct benefit, meaning that there’s something about the biology difference” between tumors in premenopausal versus postmenopausal women, “or whether this was an indirect effect, meaning impacting rates of amenorrhea... is not specifically how this study was designed.”
However, an exploratory landmark analysis at 6 months suggested that the use of ovarian suppression with endocrine therapy did not have an effect on outcomes.
Dr. Osborne said he is nevertheless “still skeptical that chemotherapy works differently in premenopausal women. Until we show that it’s not an endocrine effect ... I just can’t imagine why that group of patients, even the ones with very low Oncotype [score], would have a different response to chemotherapy.”
He added: “If I can think of a rationale ... I would believe it, but right now, I’m a little bit skeptical.”
Virginia Kaklamani, MD, of the University of Texas Health San Antonio Cancer Center, San Antonio, who is a meeting codirector, said she wanted to “second that.
“I honestly think that this is an OFS [ovarian function suppression effect] that we are seeing. We have several clinical trials that have been done looking at ovarian function suppression versus not ... showing that [it] can help as much as chemotherapy.”
Dr. Kaklamani continued: “Unfortunately, the arms to those trials were not perfect for now, and this is going to be an unanswered question until we have a large trial comparing OFS to chemotherapy.”
The study was sponsored by the National Cancer Institute, the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Exact Sciences. Dr. Kalinsky, Dr. Osborne, and Dr. Kaklamani report financial ties to multiple pharmaceutical companies.
This article first appeared on Medscape.com.
FROM SABCS 2020
ZUMA-12 study shows frontline axi-cel has substantial activity in high-risk large B-cell lymphoma
Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.
The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.
While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.
Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
Longer follow-up needed
The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.
Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.
“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.
Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.
“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
Ongoing responses at 9 months
The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.
Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.
As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.
The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.
Median duration of response, progression-free survival, and overall survival have not been reached, he added.
Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.
All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.
ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.
Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.
The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.
While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.
Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
Longer follow-up needed
The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.
Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.
“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.
Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.
“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
Ongoing responses at 9 months
The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.
Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.
As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.
The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.
Median duration of response, progression-free survival, and overall survival have not been reached, he added.
Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.
All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.
ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.
Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.
The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.
While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.
Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
Longer follow-up needed
The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.
Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.
“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.
Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.
“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
Ongoing responses at 9 months
The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.
Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.
As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.
The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.
Median duration of response, progression-free survival, and overall survival have not been reached, he added.
Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.
All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.
ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.
FROM ASH 2020
Highly effective in Ph-negative B-cell ALL: Hyper-CVAD with sequential blinatumomab
Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.
Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.
While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.
The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
Study details
Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).
Complete responses
After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.
RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.
The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.
“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.
“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.
Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.
SOURCE: Short NG et al. ASH 2020, Abstract 464.
Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.
Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.
While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.
The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
Study details
Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).
Complete responses
After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.
RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.
The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.
“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.
“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.
Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.
SOURCE: Short NG et al. ASH 2020, Abstract 464.
Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.
Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.
While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.
The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
Study details
Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).
Complete responses
After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.
RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.
The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.
“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.
“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.
Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.
SOURCE: Short NG et al. ASH 2020, Abstract 464.
FROM ASH 2020