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Research reveals new subtypes of DLBCL
New research helps explain why some patients with diffuse large B-cell lymphoma (DLBCL) respond well to immunochemotherapy and others do not.
Researchers analyzed samples from nearly 600 DLBCL patients and identified 4 new genetic subtypes of the disease.
Patients with 2 of these subtypes had overall survival (OS) rates that were roughly twice as high as OS rates in patients with the other 2 subtypes.
Louis M. Staudt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues described these findings in NEJM.
The researchers noted that the current subtypes of DLBCL—germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL—are associated with OS after treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients with ABC DLBCL have a much lower OS rate, on average, than patients with GCB DLBCL. However, even in the GCB subgroup, many patients relapse after treatment.
“The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy,” Dr Staudt said.
“And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
Dr Staudt and his colleagues analyzed tumor samples from 574 patients with DLBCL, performing exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to find recurrent aberrations.
The team also developed an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
In this way, they identified 4 genetic subtypes:
- MCD, which was named based on the co-occurrence of MYD88L265P and CD79B mutations
- BN2, whose name was based on the presence of BCL6 fusions and NOTCH2 mutations
- N1, named for NOTCH1 mutations
- EZB, named for EZH2 mutations and BCL2 translocations.
The researchers said aberrations in multiple genes distinguished each of these subtypes from other DLBCLs, and the subtypes differed phenotypically.
Patients with BN2 or EZB subtypes had much higher OS rates after receiving R-CHOP than patients with MCD or N1 subtypes. The predicted 5-year OS rates were 26% for MCD patients, 36% for N1 patients, 65% for BN2 patients, and 68% for EZB patients.
The researchers said they found evidence to suggest that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is amenable to therapeutic inhibition.
The team also noted that some of the subtypes they identified can be found in both ABC and GCB DLBCLs. For example, a patient could have ABC DLBCL, which is associated with a lower OS rate after R-CHOP, but also have the BN2 genetic subtype that responds well to R-CHOP.
“This shows we’ve gone beyond where we were,” Dr Staudt said. “Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the ‘bad’ type, and they need to be treated aggressively.”
“Now, we can implement this kind of classification and say that, even if a patient has the ‘bad’ ABC type, they have the ‘good’ genetic type, BN2. So there’s a much better chance of chemotherapy curing the disease.”
Data from this study will be shared through the National Cancer Institute’s Genomic Data Commons to make it available for future research.
Dr Staudt said he and his colleagues hope their new molecular classification will be used in clinical trials so that DLBCL treatment can move toward more targeted therapies.
“The goal is to find the right drug for the right person at the right time,” Dr Staudt said. “And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy.”
New research helps explain why some patients with diffuse large B-cell lymphoma (DLBCL) respond well to immunochemotherapy and others do not.
Researchers analyzed samples from nearly 600 DLBCL patients and identified 4 new genetic subtypes of the disease.
Patients with 2 of these subtypes had overall survival (OS) rates that were roughly twice as high as OS rates in patients with the other 2 subtypes.
Louis M. Staudt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues described these findings in NEJM.
The researchers noted that the current subtypes of DLBCL—germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL—are associated with OS after treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients with ABC DLBCL have a much lower OS rate, on average, than patients with GCB DLBCL. However, even in the GCB subgroup, many patients relapse after treatment.
“The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy,” Dr Staudt said.
“And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
Dr Staudt and his colleagues analyzed tumor samples from 574 patients with DLBCL, performing exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to find recurrent aberrations.
The team also developed an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
In this way, they identified 4 genetic subtypes:
- MCD, which was named based on the co-occurrence of MYD88L265P and CD79B mutations
- BN2, whose name was based on the presence of BCL6 fusions and NOTCH2 mutations
- N1, named for NOTCH1 mutations
- EZB, named for EZH2 mutations and BCL2 translocations.
The researchers said aberrations in multiple genes distinguished each of these subtypes from other DLBCLs, and the subtypes differed phenotypically.
Patients with BN2 or EZB subtypes had much higher OS rates after receiving R-CHOP than patients with MCD or N1 subtypes. The predicted 5-year OS rates were 26% for MCD patients, 36% for N1 patients, 65% for BN2 patients, and 68% for EZB patients.
The researchers said they found evidence to suggest that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is amenable to therapeutic inhibition.
The team also noted that some of the subtypes they identified can be found in both ABC and GCB DLBCLs. For example, a patient could have ABC DLBCL, which is associated with a lower OS rate after R-CHOP, but also have the BN2 genetic subtype that responds well to R-CHOP.
“This shows we’ve gone beyond where we were,” Dr Staudt said. “Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the ‘bad’ type, and they need to be treated aggressively.”
“Now, we can implement this kind of classification and say that, even if a patient has the ‘bad’ ABC type, they have the ‘good’ genetic type, BN2. So there’s a much better chance of chemotherapy curing the disease.”
Data from this study will be shared through the National Cancer Institute’s Genomic Data Commons to make it available for future research.
Dr Staudt said he and his colleagues hope their new molecular classification will be used in clinical trials so that DLBCL treatment can move toward more targeted therapies.
“The goal is to find the right drug for the right person at the right time,” Dr Staudt said. “And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy.”
New research helps explain why some patients with diffuse large B-cell lymphoma (DLBCL) respond well to immunochemotherapy and others do not.
Researchers analyzed samples from nearly 600 DLBCL patients and identified 4 new genetic subtypes of the disease.
Patients with 2 of these subtypes had overall survival (OS) rates that were roughly twice as high as OS rates in patients with the other 2 subtypes.
Louis M. Staudt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues described these findings in NEJM.
The researchers noted that the current subtypes of DLBCL—germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL—are associated with OS after treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Patients with ABC DLBCL have a much lower OS rate, on average, than patients with GCB DLBCL. However, even in the GCB subgroup, many patients relapse after treatment.
“The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy,” Dr Staudt said.
“And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
Dr Staudt and his colleagues analyzed tumor samples from 574 patients with DLBCL, performing exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to find recurrent aberrations.
The team also developed an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
In this way, they identified 4 genetic subtypes:
- MCD, which was named based on the co-occurrence of MYD88L265P and CD79B mutations
- BN2, whose name was based on the presence of BCL6 fusions and NOTCH2 mutations
- N1, named for NOTCH1 mutations
- EZB, named for EZH2 mutations and BCL2 translocations.
The researchers said aberrations in multiple genes distinguished each of these subtypes from other DLBCLs, and the subtypes differed phenotypically.
Patients with BN2 or EZB subtypes had much higher OS rates after receiving R-CHOP than patients with MCD or N1 subtypes. The predicted 5-year OS rates were 26% for MCD patients, 36% for N1 patients, 65% for BN2 patients, and 68% for EZB patients.
The researchers said they found evidence to suggest that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is amenable to therapeutic inhibition.
The team also noted that some of the subtypes they identified can be found in both ABC and GCB DLBCLs. For example, a patient could have ABC DLBCL, which is associated with a lower OS rate after R-CHOP, but also have the BN2 genetic subtype that responds well to R-CHOP.
“This shows we’ve gone beyond where we were,” Dr Staudt said. “Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the ‘bad’ type, and they need to be treated aggressively.”
“Now, we can implement this kind of classification and say that, even if a patient has the ‘bad’ ABC type, they have the ‘good’ genetic type, BN2. So there’s a much better chance of chemotherapy curing the disease.”
Data from this study will be shared through the National Cancer Institute’s Genomic Data Commons to make it available for future research.
Dr Staudt said he and his colleagues hope their new molecular classification will be used in clinical trials so that DLBCL treatment can move toward more targeted therapies.
“The goal is to find the right drug for the right person at the right time,” Dr Staudt said. “And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy.”
New genetic subtypes could facilitate precision medicine in DLBCL
Four genetic subtypes of diffuse large B-cell lymphoma (DLBCL) showed multiple distinct mutations, gene expression signatures, and treatment responses, researchers reported.
The findings “may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” Roland Schmitz, PhD, and his associates wrote in the New England Journal of Medicine.
Other DLBCL studies have focused on individual mutations, but therapeutic response probably hinges on “constellations of genetic aberrations,” wrote Dr. Schmitz of the National Cancer Institute and his associates.
Therefore, they used exome and transcriptome sequencing, deep amplicon resequencing of 372 genes, and DNA copy-number analysis to analyze 572 fresh-frozen DLBCL biopsy specimens, nearly all of which were treatment-naïve.
This multiplatform approach yielded four genetic subtypes: MCD, so named for its co-occurring MYD88L265P and CD79B mutations; BN2, which has BCL6 fusions and NOTCH2 mutations; N1, which has NOTCH1 mutations; and EZB, which has EZH2 mutations and BCL2 translocations. Most MCD and N1 specimens were activated B-cell–like (ABC) tumors, EZB specimens were primarily germinal-center B-cell–like (GCB) tumors, and BN2 specimens included ABC, GCB, and unclassified cases.
A closer look at 119 previously untreated patients linked genetic subtypes with significant differences in progression-free survival (P less than .0001) and overall survival (P = .0002) following R-CHOP or CHOP-like chemotherapy.
The BN2 and EZB subtypes “[had] much more favorable outcomes than the MCD and N1 subtypes,” Dr. Schmitz and his associates said. “Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on ‘chronic active’ B-cell receptor signaling that is amenable to therapeutic inhibition.”
Genetically subtyping DLBCL could help guide patients into appropriate clinical trials, the investigators wrote. For example, patients with the N1 subtype might be candidates for immune checkpoint inhibitor therapy, given N1’s prominent T-cell gene expression and poor response to R-CHOP.
Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
SOURCE: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
Four genetic subtypes of diffuse large B-cell lymphoma (DLBCL) showed multiple distinct mutations, gene expression signatures, and treatment responses, researchers reported.
The findings “may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” Roland Schmitz, PhD, and his associates wrote in the New England Journal of Medicine.
Other DLBCL studies have focused on individual mutations, but therapeutic response probably hinges on “constellations of genetic aberrations,” wrote Dr. Schmitz of the National Cancer Institute and his associates.
Therefore, they used exome and transcriptome sequencing, deep amplicon resequencing of 372 genes, and DNA copy-number analysis to analyze 572 fresh-frozen DLBCL biopsy specimens, nearly all of which were treatment-naïve.
This multiplatform approach yielded four genetic subtypes: MCD, so named for its co-occurring MYD88L265P and CD79B mutations; BN2, which has BCL6 fusions and NOTCH2 mutations; N1, which has NOTCH1 mutations; and EZB, which has EZH2 mutations and BCL2 translocations. Most MCD and N1 specimens were activated B-cell–like (ABC) tumors, EZB specimens were primarily germinal-center B-cell–like (GCB) tumors, and BN2 specimens included ABC, GCB, and unclassified cases.
A closer look at 119 previously untreated patients linked genetic subtypes with significant differences in progression-free survival (P less than .0001) and overall survival (P = .0002) following R-CHOP or CHOP-like chemotherapy.
The BN2 and EZB subtypes “[had] much more favorable outcomes than the MCD and N1 subtypes,” Dr. Schmitz and his associates said. “Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on ‘chronic active’ B-cell receptor signaling that is amenable to therapeutic inhibition.”
Genetically subtyping DLBCL could help guide patients into appropriate clinical trials, the investigators wrote. For example, patients with the N1 subtype might be candidates for immune checkpoint inhibitor therapy, given N1’s prominent T-cell gene expression and poor response to R-CHOP.
Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
SOURCE: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
Four genetic subtypes of diffuse large B-cell lymphoma (DLBCL) showed multiple distinct mutations, gene expression signatures, and treatment responses, researchers reported.
The findings “may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” Roland Schmitz, PhD, and his associates wrote in the New England Journal of Medicine.
Other DLBCL studies have focused on individual mutations, but therapeutic response probably hinges on “constellations of genetic aberrations,” wrote Dr. Schmitz of the National Cancer Institute and his associates.
Therefore, they used exome and transcriptome sequencing, deep amplicon resequencing of 372 genes, and DNA copy-number analysis to analyze 572 fresh-frozen DLBCL biopsy specimens, nearly all of which were treatment-naïve.
This multiplatform approach yielded four genetic subtypes: MCD, so named for its co-occurring MYD88L265P and CD79B mutations; BN2, which has BCL6 fusions and NOTCH2 mutations; N1, which has NOTCH1 mutations; and EZB, which has EZH2 mutations and BCL2 translocations. Most MCD and N1 specimens were activated B-cell–like (ABC) tumors, EZB specimens were primarily germinal-center B-cell–like (GCB) tumors, and BN2 specimens included ABC, GCB, and unclassified cases.
A closer look at 119 previously untreated patients linked genetic subtypes with significant differences in progression-free survival (P less than .0001) and overall survival (P = .0002) following R-CHOP or CHOP-like chemotherapy.
The BN2 and EZB subtypes “[had] much more favorable outcomes than the MCD and N1 subtypes,” Dr. Schmitz and his associates said. “Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on ‘chronic active’ B-cell receptor signaling that is amenable to therapeutic inhibition.”
Genetically subtyping DLBCL could help guide patients into appropriate clinical trials, the investigators wrote. For example, patients with the N1 subtype might be candidates for immune checkpoint inhibitor therapy, given N1’s prominent T-cell gene expression and poor response to R-CHOP.
Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
SOURCE: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
FROM NEJM
Key clinical point: Multiplatform analyses identified four new genetic subtypes of DLBCL.
Major finding: The subtypes were distinguishable based on multiple genetic aberrations, phenotypes, and treatment responses.
Study details: Study of 574 DLBCL samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes.
Disclosures: Funders included the National Institutes of Health, the National Cancer Institute, the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe), the Washington University in St. Louis, and the Kay Kendall Leukaemia Fund. Dr. Schmitz disclosed research funding from Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe).
Source: Schmitz et al. New Eng J Med. 2018 Apr 11. doi: 10.1056/NEJMoa1801445.
Tazemetostat exhibits antitumor activity in phase 1 trial
The EZH2 inhibitor tazemetostat demonstrated a “favorable safety profile and antitumor activity” in a phase 1 study, according to researchers.
The drug produced responses in 8 of 21 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including 3 complete responses (CRs).
The maximum tolerated dose of tazemetostat was not reached, and there were no fatal adverse events (AEs) related to treatment.
Grade 3/4 treatment-related AEs included thrombocytopenia, neutropenia, hepatocellular injury, and hypertension.
Antoine Italiano, MD, PhD, of Institut Bergonié in Bordeaux, France, and his colleagues reported these results in The Lancet Oncology. The trial was sponsored by Epizyme and Eisai.
The study enrolled 64 patients—43 with solid tumors and 21 with B-cell NHL. The following characteristics and dosing information pertain only to the patients with NHL.
Thirteen patients had diffuse large B-cell lymphoma (DLBCL), 7 had follicular lymphoma (FL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 62 (range, 53-70), and 71% were male. They had an ECOG performance status of 0 (62%) or 1 (38%).
Most patients had received at least 3 prior therapies—38% had 3, 14% had 4, and 33% had 5 or more prior therapies. Forty-eight percent had prior hematopoietic stem cell transplant.
The patients received escalating doses of tazemetostat twice daily—100 mg (n=1), 200 mg (n=2), 400 mg (n=1), 800 mg (n=8), and 1600 mg (n=4).
The remaining 5 patients were enrolled in a substudy to evaluate food effect. These patients received a single 200 mg dose on day -8 and day -1, with or without food, followed by 400 mg twice daily starting on day 1. Specific results on the food effects were not included in the paper.
Safety
In the entire study cohort, there was 1 dose-limiting toxicity—grade 4 thrombocytopenia—at the 1600 mg dose. The maximum tolerated dose of tazemetostat was not reached, but the researchers decided upon 800 mg twice daily as the recommended phase 2 dose.
Overall, 77% (n=49) of patients had treatment-related AEs. Grade 3/4 treatment-related AEs included thrombocytopenia (4%, n=2), neutropenia (4%, n=2), hepatocellular injury (2%, n=1), and hypertension (2%, n=1).
Serious treatment-related AEs were neutropenia in 1 patient (800 mg group) and anemia and thrombocytopenia in another patient (1600 mg group).
Seven patients (11%) had fatal AEs, but none were considered treatment-related. They included general physical health deterioration (1 at 200 mg, 1 at 1600 mg, and 2 at 400 mg), respiratory distress (2 at 400 mg), and septic shock (1 at 1600 mg).
Efficacy
Eight of the 21 NHL patients responded to treatment. Three patients had a CR—1 with DLBCL and 2 with FL. Of the 5 partial responders, 3 had DLBCL, 1 had FL, and 1 had MZL.
The median time to first response was 3.5 months, and the median duration of response was 12.4 months.
The 3 complete responders remained on tazemetostat beyond 27.6 months (FL patient), 28.8 months (FL patient), and 33.6 months (DLBCL patient).
Two of the 43 patients with solid tumors responded to tazemetostat—1 with a CR and 1 with a partial response.
The complete responder had an INI1-negative malignant rhabdoid tumor, and the partial responder had a SMARCA4-negative malignant rhabdoid tumor of the ovary.
“Today’s publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” Dr Italiano said. “I’m also encouraged by the preliminary antitumor activity observed in this study.”
The EZH2 inhibitor tazemetostat demonstrated a “favorable safety profile and antitumor activity” in a phase 1 study, according to researchers.
The drug produced responses in 8 of 21 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including 3 complete responses (CRs).
The maximum tolerated dose of tazemetostat was not reached, and there were no fatal adverse events (AEs) related to treatment.
Grade 3/4 treatment-related AEs included thrombocytopenia, neutropenia, hepatocellular injury, and hypertension.
Antoine Italiano, MD, PhD, of Institut Bergonié in Bordeaux, France, and his colleagues reported these results in The Lancet Oncology. The trial was sponsored by Epizyme and Eisai.
The study enrolled 64 patients—43 with solid tumors and 21 with B-cell NHL. The following characteristics and dosing information pertain only to the patients with NHL.
Thirteen patients had diffuse large B-cell lymphoma (DLBCL), 7 had follicular lymphoma (FL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 62 (range, 53-70), and 71% were male. They had an ECOG performance status of 0 (62%) or 1 (38%).
Most patients had received at least 3 prior therapies—38% had 3, 14% had 4, and 33% had 5 or more prior therapies. Forty-eight percent had prior hematopoietic stem cell transplant.
The patients received escalating doses of tazemetostat twice daily—100 mg (n=1), 200 mg (n=2), 400 mg (n=1), 800 mg (n=8), and 1600 mg (n=4).
The remaining 5 patients were enrolled in a substudy to evaluate food effect. These patients received a single 200 mg dose on day -8 and day -1, with or without food, followed by 400 mg twice daily starting on day 1. Specific results on the food effects were not included in the paper.
Safety
In the entire study cohort, there was 1 dose-limiting toxicity—grade 4 thrombocytopenia—at the 1600 mg dose. The maximum tolerated dose of tazemetostat was not reached, but the researchers decided upon 800 mg twice daily as the recommended phase 2 dose.
Overall, 77% (n=49) of patients had treatment-related AEs. Grade 3/4 treatment-related AEs included thrombocytopenia (4%, n=2), neutropenia (4%, n=2), hepatocellular injury (2%, n=1), and hypertension (2%, n=1).
Serious treatment-related AEs were neutropenia in 1 patient (800 mg group) and anemia and thrombocytopenia in another patient (1600 mg group).
Seven patients (11%) had fatal AEs, but none were considered treatment-related. They included general physical health deterioration (1 at 200 mg, 1 at 1600 mg, and 2 at 400 mg), respiratory distress (2 at 400 mg), and septic shock (1 at 1600 mg).
Efficacy
Eight of the 21 NHL patients responded to treatment. Three patients had a CR—1 with DLBCL and 2 with FL. Of the 5 partial responders, 3 had DLBCL, 1 had FL, and 1 had MZL.
The median time to first response was 3.5 months, and the median duration of response was 12.4 months.
The 3 complete responders remained on tazemetostat beyond 27.6 months (FL patient), 28.8 months (FL patient), and 33.6 months (DLBCL patient).
Two of the 43 patients with solid tumors responded to tazemetostat—1 with a CR and 1 with a partial response.
The complete responder had an INI1-negative malignant rhabdoid tumor, and the partial responder had a SMARCA4-negative malignant rhabdoid tumor of the ovary.
“Today’s publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” Dr Italiano said. “I’m also encouraged by the preliminary antitumor activity observed in this study.”
The EZH2 inhibitor tazemetostat demonstrated a “favorable safety profile and antitumor activity” in a phase 1 study, according to researchers.
The drug produced responses in 8 of 21 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including 3 complete responses (CRs).
The maximum tolerated dose of tazemetostat was not reached, and there were no fatal adverse events (AEs) related to treatment.
Grade 3/4 treatment-related AEs included thrombocytopenia, neutropenia, hepatocellular injury, and hypertension.
Antoine Italiano, MD, PhD, of Institut Bergonié in Bordeaux, France, and his colleagues reported these results in The Lancet Oncology. The trial was sponsored by Epizyme and Eisai.
The study enrolled 64 patients—43 with solid tumors and 21 with B-cell NHL. The following characteristics and dosing information pertain only to the patients with NHL.
Thirteen patients had diffuse large B-cell lymphoma (DLBCL), 7 had follicular lymphoma (FL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 62 (range, 53-70), and 71% were male. They had an ECOG performance status of 0 (62%) or 1 (38%).
Most patients had received at least 3 prior therapies—38% had 3, 14% had 4, and 33% had 5 or more prior therapies. Forty-eight percent had prior hematopoietic stem cell transplant.
The patients received escalating doses of tazemetostat twice daily—100 mg (n=1), 200 mg (n=2), 400 mg (n=1), 800 mg (n=8), and 1600 mg (n=4).
The remaining 5 patients were enrolled in a substudy to evaluate food effect. These patients received a single 200 mg dose on day -8 and day -1, with or without food, followed by 400 mg twice daily starting on day 1. Specific results on the food effects were not included in the paper.
Safety
In the entire study cohort, there was 1 dose-limiting toxicity—grade 4 thrombocytopenia—at the 1600 mg dose. The maximum tolerated dose of tazemetostat was not reached, but the researchers decided upon 800 mg twice daily as the recommended phase 2 dose.
Overall, 77% (n=49) of patients had treatment-related AEs. Grade 3/4 treatment-related AEs included thrombocytopenia (4%, n=2), neutropenia (4%, n=2), hepatocellular injury (2%, n=1), and hypertension (2%, n=1).
Serious treatment-related AEs were neutropenia in 1 patient (800 mg group) and anemia and thrombocytopenia in another patient (1600 mg group).
Seven patients (11%) had fatal AEs, but none were considered treatment-related. They included general physical health deterioration (1 at 200 mg, 1 at 1600 mg, and 2 at 400 mg), respiratory distress (2 at 400 mg), and septic shock (1 at 1600 mg).
Efficacy
Eight of the 21 NHL patients responded to treatment. Three patients had a CR—1 with DLBCL and 2 with FL. Of the 5 partial responders, 3 had DLBCL, 1 had FL, and 1 had MZL.
The median time to first response was 3.5 months, and the median duration of response was 12.4 months.
The 3 complete responders remained on tazemetostat beyond 27.6 months (FL patient), 28.8 months (FL patient), and 33.6 months (DLBCL patient).
Two of the 43 patients with solid tumors responded to tazemetostat—1 with a CR and 1 with a partial response.
The complete responder had an INI1-negative malignant rhabdoid tumor, and the partial responder had a SMARCA4-negative malignant rhabdoid tumor of the ovary.
“Today’s publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” Dr Italiano said. “I’m also encouraged by the preliminary antitumor activity observed in this study.”
Combo improves outcomes in MCL
A 2-drug combination can improve outcomes in patients with mantle cell lymphoma (MCL), according to researchers.
In a phase 2 trial of MCL patients, the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax produced an overall response rate of 71% and a complete response (CR) rate of 62%.
“This was in patients who we expected to have a poor outcome on conventional therapy, and in which treatment with either ibrutinib or venetoclax alone was expected to see only 21% of patients show a complete response,” said Constantine Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
The most common adverse events (AEs) in patients receiving venetoclax and ibrutinib were diarrhea (83%), fatigue (75%), and nausea/vomiting (71%). Fourteen patients (58%) had serious AEs, including 2 with tumor lysis syndrome.
Dr Tam and his colleagues reported these results in NEJM.
The study included 24 patients—23 with relapsed/refractory MCL and 1 with previously untreated MCL. They had a median age of 68 (range, 47-81).
Most patients had high-risk (75%) or intermediate-risk (21%) disease, according to the MCL International Prognostic Index. Half of patients (including the previously untreated patient) had a TP53 aberration, and 25% had an NF-κB pathway mutation.
The relapsed/refractory patients had a median of 2 prior therapies (range, 1-6), and 48% were refractory to their most recent therapy.
Patients received ibrutinib monotherapy at 560 mg daily for 4 weeks. Then, patients began receiving venetoclax as well, in increasing doses, up to 400 mg per day. Patients received treatment until progression or unacceptable toxicity.
Efficacy
The study’s primary endpoint was CR at week 16, as assessed without PET. This was to allow the researchers to compare CR results in this trial to CR results in the PCYC-1104-CA study, a phase 2 trial of ibrutinib monotherapy in MCL.
According to CT, the CR rate was 42% in patients who received venetoclax and ibrutinib. This is significantly higher than the 9% CR rate observed in the patients treated with ibrutinib alone (P<0.001).
However, according to PET/CT, the 16-week CR rate was 62% in patients who received venetoclax and ibrutinib, and the overall response rate was 71%.
Overall, the rate of minimal residual disease (MRD) negativity was 67% (n=16) in the bone marrow according to flow cytometry and 38% (n=9) in the blood according to allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). However, not all patients were evaluable for MRD.
Among evaluable patients with a CR, 93% (14/15) were MRD negative according to flow cytometry, and 82% (9/11) were negative according to ASO-PCR.
The median progression-free survival was not reached at a median follow-up of 15.9 months. The estimated progression-free survival was 75% at 12 months and 57% at 18 months.
The rate of overall survival was 79% at 12 months and 74% at 18 months.
“These very promising results have triggered additional and larger studies to better understand the synergistic benefits of the venetoclax-ibrutinib treatment combination in MCL patients,” Dr Tam said.
Safety
The most common AEs were diarrhea (83%); fatigue (75%); nausea/vomiting (71%); bleeding, bruising, or postoperative hemorrhage (54%); musculoskeletal or connective-tissue pain (50%); cough or dyspnea (46%); soft-tissue infection (42%); upper respiratory tract infection (42%); neutropenia (33%); and lower respiratory tract infection (33%).
Grade 3/4 AEs included neutropenia (33%), thrombocytopenia (17%), anemia (12%), diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), lower respiratory tract infection (8%), soft-tissue infection (8%), cough or dyspnea (4%), musculoskeletal or connective-tissue pain (4%), and bleeding, bruising, or postoperative hemorrhage (4%).
Serious AEs included diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), pyrexia (8%), pleural effusion (8%), cardiac failure (4%), and soft-tissue infection (4%).
The patients who developed tumor lysis syndrome were among the first 15 patients who started venetoclax at a dose of 50 mg per day. Because of these cases, the study protocol was amended to lower the starting dose of venetoclax to 20 mg daily. After that, there were no additional cases of tumor lysis syndrome.
There were 6 deaths during the study. Four were attributed to disease progression, 1 to malignant otitis externa, and 1 to cardiac failure in a patient in CR.
A 2-drug combination can improve outcomes in patients with mantle cell lymphoma (MCL), according to researchers.
In a phase 2 trial of MCL patients, the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax produced an overall response rate of 71% and a complete response (CR) rate of 62%.
“This was in patients who we expected to have a poor outcome on conventional therapy, and in which treatment with either ibrutinib or venetoclax alone was expected to see only 21% of patients show a complete response,” said Constantine Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
The most common adverse events (AEs) in patients receiving venetoclax and ibrutinib were diarrhea (83%), fatigue (75%), and nausea/vomiting (71%). Fourteen patients (58%) had serious AEs, including 2 with tumor lysis syndrome.
Dr Tam and his colleagues reported these results in NEJM.
The study included 24 patients—23 with relapsed/refractory MCL and 1 with previously untreated MCL. They had a median age of 68 (range, 47-81).
Most patients had high-risk (75%) or intermediate-risk (21%) disease, according to the MCL International Prognostic Index. Half of patients (including the previously untreated patient) had a TP53 aberration, and 25% had an NF-κB pathway mutation.
The relapsed/refractory patients had a median of 2 prior therapies (range, 1-6), and 48% were refractory to their most recent therapy.
Patients received ibrutinib monotherapy at 560 mg daily for 4 weeks. Then, patients began receiving venetoclax as well, in increasing doses, up to 400 mg per day. Patients received treatment until progression or unacceptable toxicity.
Efficacy
The study’s primary endpoint was CR at week 16, as assessed without PET. This was to allow the researchers to compare CR results in this trial to CR results in the PCYC-1104-CA study, a phase 2 trial of ibrutinib monotherapy in MCL.
According to CT, the CR rate was 42% in patients who received venetoclax and ibrutinib. This is significantly higher than the 9% CR rate observed in the patients treated with ibrutinib alone (P<0.001).
However, according to PET/CT, the 16-week CR rate was 62% in patients who received venetoclax and ibrutinib, and the overall response rate was 71%.
Overall, the rate of minimal residual disease (MRD) negativity was 67% (n=16) in the bone marrow according to flow cytometry and 38% (n=9) in the blood according to allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). However, not all patients were evaluable for MRD.
Among evaluable patients with a CR, 93% (14/15) were MRD negative according to flow cytometry, and 82% (9/11) were negative according to ASO-PCR.
The median progression-free survival was not reached at a median follow-up of 15.9 months. The estimated progression-free survival was 75% at 12 months and 57% at 18 months.
The rate of overall survival was 79% at 12 months and 74% at 18 months.
“These very promising results have triggered additional and larger studies to better understand the synergistic benefits of the venetoclax-ibrutinib treatment combination in MCL patients,” Dr Tam said.
Safety
The most common AEs were diarrhea (83%); fatigue (75%); nausea/vomiting (71%); bleeding, bruising, or postoperative hemorrhage (54%); musculoskeletal or connective-tissue pain (50%); cough or dyspnea (46%); soft-tissue infection (42%); upper respiratory tract infection (42%); neutropenia (33%); and lower respiratory tract infection (33%).
Grade 3/4 AEs included neutropenia (33%), thrombocytopenia (17%), anemia (12%), diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), lower respiratory tract infection (8%), soft-tissue infection (8%), cough or dyspnea (4%), musculoskeletal or connective-tissue pain (4%), and bleeding, bruising, or postoperative hemorrhage (4%).
Serious AEs included diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), pyrexia (8%), pleural effusion (8%), cardiac failure (4%), and soft-tissue infection (4%).
The patients who developed tumor lysis syndrome were among the first 15 patients who started venetoclax at a dose of 50 mg per day. Because of these cases, the study protocol was amended to lower the starting dose of venetoclax to 20 mg daily. After that, there were no additional cases of tumor lysis syndrome.
There were 6 deaths during the study. Four were attributed to disease progression, 1 to malignant otitis externa, and 1 to cardiac failure in a patient in CR.
A 2-drug combination can improve outcomes in patients with mantle cell lymphoma (MCL), according to researchers.
In a phase 2 trial of MCL patients, the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax produced an overall response rate of 71% and a complete response (CR) rate of 62%.
“This was in patients who we expected to have a poor outcome on conventional therapy, and in which treatment with either ibrutinib or venetoclax alone was expected to see only 21% of patients show a complete response,” said Constantine Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
The most common adverse events (AEs) in patients receiving venetoclax and ibrutinib were diarrhea (83%), fatigue (75%), and nausea/vomiting (71%). Fourteen patients (58%) had serious AEs, including 2 with tumor lysis syndrome.
Dr Tam and his colleagues reported these results in NEJM.
The study included 24 patients—23 with relapsed/refractory MCL and 1 with previously untreated MCL. They had a median age of 68 (range, 47-81).
Most patients had high-risk (75%) or intermediate-risk (21%) disease, according to the MCL International Prognostic Index. Half of patients (including the previously untreated patient) had a TP53 aberration, and 25% had an NF-κB pathway mutation.
The relapsed/refractory patients had a median of 2 prior therapies (range, 1-6), and 48% were refractory to their most recent therapy.
Patients received ibrutinib monotherapy at 560 mg daily for 4 weeks. Then, patients began receiving venetoclax as well, in increasing doses, up to 400 mg per day. Patients received treatment until progression or unacceptable toxicity.
Efficacy
The study’s primary endpoint was CR at week 16, as assessed without PET. This was to allow the researchers to compare CR results in this trial to CR results in the PCYC-1104-CA study, a phase 2 trial of ibrutinib monotherapy in MCL.
According to CT, the CR rate was 42% in patients who received venetoclax and ibrutinib. This is significantly higher than the 9% CR rate observed in the patients treated with ibrutinib alone (P<0.001).
However, according to PET/CT, the 16-week CR rate was 62% in patients who received venetoclax and ibrutinib, and the overall response rate was 71%.
Overall, the rate of minimal residual disease (MRD) negativity was 67% (n=16) in the bone marrow according to flow cytometry and 38% (n=9) in the blood according to allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). However, not all patients were evaluable for MRD.
Among evaluable patients with a CR, 93% (14/15) were MRD negative according to flow cytometry, and 82% (9/11) were negative according to ASO-PCR.
The median progression-free survival was not reached at a median follow-up of 15.9 months. The estimated progression-free survival was 75% at 12 months and 57% at 18 months.
The rate of overall survival was 79% at 12 months and 74% at 18 months.
“These very promising results have triggered additional and larger studies to better understand the synergistic benefits of the venetoclax-ibrutinib treatment combination in MCL patients,” Dr Tam said.
Safety
The most common AEs were diarrhea (83%); fatigue (75%); nausea/vomiting (71%); bleeding, bruising, or postoperative hemorrhage (54%); musculoskeletal or connective-tissue pain (50%); cough or dyspnea (46%); soft-tissue infection (42%); upper respiratory tract infection (42%); neutropenia (33%); and lower respiratory tract infection (33%).
Grade 3/4 AEs included neutropenia (33%), thrombocytopenia (17%), anemia (12%), diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), lower respiratory tract infection (8%), soft-tissue infection (8%), cough or dyspnea (4%), musculoskeletal or connective-tissue pain (4%), and bleeding, bruising, or postoperative hemorrhage (4%).
Serious AEs included diarrhea (12%), tumor lysis syndrome (8%), atrial fibrillation (8%), pyrexia (8%), pleural effusion (8%), cardiac failure (4%), and soft-tissue infection (4%).
The patients who developed tumor lysis syndrome were among the first 15 patients who started venetoclax at a dose of 50 mg per day. Because of these cases, the study protocol was amended to lower the starting dose of venetoclax to 20 mg daily. After that, there were no additional cases of tumor lysis syndrome.
There were 6 deaths during the study. Four were attributed to disease progression, 1 to malignant otitis externa, and 1 to cardiac failure in a patient in CR.
Duvelisib NDA granted priority review
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for duvelisib, a dual PI3K delta/gamma inhibitor.
With this NDA, Verastem, Inc., is seeking full approval of duvelisib for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval of the drug for the treatment of relapsed or refractory follicular lymphoma (FL).
The FDA expects to make a decision on the NDA by October 5, 2018.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The application for duvelisib is supported by data from DUO™, a randomized, phase 3 study of patients with relapsed or refractory CLL/SLL, and DYNAMO™, a phase 2 study of patients with refractory indolent non-Hodgkin lymphoma.
Phase 3 DUO trial
Results from DUO were presented at the 2017 ASH Annual Meeting in December.
This study included 319 CLL/SLL patients who were randomized 1:1 to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).
The study’s primary endpoint was met, as duvelisib conferred a significant improvement in median progression-free survival (PFS) over ofatumumab.
Per an independent review committee, the median PFS was 13.3 months with duvelisib and 9.9 months with ofatumumab (hazard ratio=0.52; P<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed.
The overall response rate was 73.8% with duvelisib and 45.3% with ofatumumab (P<0.0001). The complete response rate was 0.6% in both arms.
Overall survival (OS) was similar in the duvelisib and ofatumumab arms (hazard ratio=0.99; P=0.4807). The median OS was not reached in either arm.
The most common grade 3 or higher adverse events (AEs)—in the duvelisib and ofatumumab arms, respectively—were neutropenia (30% vs 17%), anemia (13% vs 5%), diarrhea (15% vs 1%), pneumonia (14% vs 1%), and colitis (12% vs 1%).
Thirty-five percent of patients discontinued duvelisib due to an AE.
Severe opportunistic infections occurred in 6% of duvelisib recipients—bronchopulmonary aspergillosis (n=4), fungal infection (n=2), Pneumocystis jirovecii pneumonia (n=2), and cytomegalovirus colitis (n=1).
There were 4 deaths related to duvelisib—staphylococcal pneumonia (n=2), general physical health deterioration (n=1), and sepsis (n=1).
Phase 2 DYNAMO trial
Results from DYNAMO were presented at the 22nd EHA Congress (abstract S777) in June 2017.
This trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.
There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).
The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate, per an independent review committee, was 43%. One patient achieved a complete response, and 35 had a partial response. The median duration of response was 7.9 months.
The median PFS was 8.3 months, and the median OS was 27.8 months.
The most common grade 3 or higher AEs were neutropenia (22%), anemia (13%), diarrhea (16%), lipase increase (10%), and thrombocytopenia (9%).
There were 2 serious opportunistic infections—Pneumocystis pneumonia and fungal pneumonia.
There were 3 deaths attributed to duvelisib—toxic epidermal necrolysis/sepsis syndrome (n=1), drug reaction/eosinophilia/systemic symptoms (n=1), and pneumonitis/pneumonia (n=1).
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for duvelisib, a dual PI3K delta/gamma inhibitor.
With this NDA, Verastem, Inc., is seeking full approval of duvelisib for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval of the drug for the treatment of relapsed or refractory follicular lymphoma (FL).
The FDA expects to make a decision on the NDA by October 5, 2018.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The application for duvelisib is supported by data from DUO™, a randomized, phase 3 study of patients with relapsed or refractory CLL/SLL, and DYNAMO™, a phase 2 study of patients with refractory indolent non-Hodgkin lymphoma.
Phase 3 DUO trial
Results from DUO were presented at the 2017 ASH Annual Meeting in December.
This study included 319 CLL/SLL patients who were randomized 1:1 to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).
The study’s primary endpoint was met, as duvelisib conferred a significant improvement in median progression-free survival (PFS) over ofatumumab.
Per an independent review committee, the median PFS was 13.3 months with duvelisib and 9.9 months with ofatumumab (hazard ratio=0.52; P<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed.
The overall response rate was 73.8% with duvelisib and 45.3% with ofatumumab (P<0.0001). The complete response rate was 0.6% in both arms.
Overall survival (OS) was similar in the duvelisib and ofatumumab arms (hazard ratio=0.99; P=0.4807). The median OS was not reached in either arm.
The most common grade 3 or higher adverse events (AEs)—in the duvelisib and ofatumumab arms, respectively—were neutropenia (30% vs 17%), anemia (13% vs 5%), diarrhea (15% vs 1%), pneumonia (14% vs 1%), and colitis (12% vs 1%).
Thirty-five percent of patients discontinued duvelisib due to an AE.
Severe opportunistic infections occurred in 6% of duvelisib recipients—bronchopulmonary aspergillosis (n=4), fungal infection (n=2), Pneumocystis jirovecii pneumonia (n=2), and cytomegalovirus colitis (n=1).
There were 4 deaths related to duvelisib—staphylococcal pneumonia (n=2), general physical health deterioration (n=1), and sepsis (n=1).
Phase 2 DYNAMO trial
Results from DYNAMO were presented at the 22nd EHA Congress (abstract S777) in June 2017.
This trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.
There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).
The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate, per an independent review committee, was 43%. One patient achieved a complete response, and 35 had a partial response. The median duration of response was 7.9 months.
The median PFS was 8.3 months, and the median OS was 27.8 months.
The most common grade 3 or higher AEs were neutropenia (22%), anemia (13%), diarrhea (16%), lipase increase (10%), and thrombocytopenia (9%).
There were 2 serious opportunistic infections—Pneumocystis pneumonia and fungal pneumonia.
There were 3 deaths attributed to duvelisib—toxic epidermal necrolysis/sepsis syndrome (n=1), drug reaction/eosinophilia/systemic symptoms (n=1), and pneumonitis/pneumonia (n=1).
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for duvelisib, a dual PI3K delta/gamma inhibitor.
With this NDA, Verastem, Inc., is seeking full approval of duvelisib for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval of the drug for the treatment of relapsed or refractory follicular lymphoma (FL).
The FDA expects to make a decision on the NDA by October 5, 2018.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The application for duvelisib is supported by data from DUO™, a randomized, phase 3 study of patients with relapsed or refractory CLL/SLL, and DYNAMO™, a phase 2 study of patients with refractory indolent non-Hodgkin lymphoma.
Phase 3 DUO trial
Results from DUO were presented at the 2017 ASH Annual Meeting in December.
This study included 319 CLL/SLL patients who were randomized 1:1 to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).
The study’s primary endpoint was met, as duvelisib conferred a significant improvement in median progression-free survival (PFS) over ofatumumab.
Per an independent review committee, the median PFS was 13.3 months with duvelisib and 9.9 months with ofatumumab (hazard ratio=0.52; P<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed.
The overall response rate was 73.8% with duvelisib and 45.3% with ofatumumab (P<0.0001). The complete response rate was 0.6% in both arms.
Overall survival (OS) was similar in the duvelisib and ofatumumab arms (hazard ratio=0.99; P=0.4807). The median OS was not reached in either arm.
The most common grade 3 or higher adverse events (AEs)—in the duvelisib and ofatumumab arms, respectively—were neutropenia (30% vs 17%), anemia (13% vs 5%), diarrhea (15% vs 1%), pneumonia (14% vs 1%), and colitis (12% vs 1%).
Thirty-five percent of patients discontinued duvelisib due to an AE.
Severe opportunistic infections occurred in 6% of duvelisib recipients—bronchopulmonary aspergillosis (n=4), fungal infection (n=2), Pneumocystis jirovecii pneumonia (n=2), and cytomegalovirus colitis (n=1).
There were 4 deaths related to duvelisib—staphylococcal pneumonia (n=2), general physical health deterioration (n=1), and sepsis (n=1).
Phase 2 DYNAMO trial
Results from DYNAMO were presented at the 22nd EHA Congress (abstract S777) in June 2017.
This trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.
There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).
The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate, per an independent review committee, was 43%. One patient achieved a complete response, and 35 had a partial response. The median duration of response was 7.9 months.
The median PFS was 8.3 months, and the median OS was 27.8 months.
The most common grade 3 or higher AEs were neutropenia (22%), anemia (13%), diarrhea (16%), lipase increase (10%), and thrombocytopenia (9%).
There were 2 serious opportunistic infections—Pneumocystis pneumonia and fungal pneumonia.
There were 3 deaths attributed to duvelisib—toxic epidermal necrolysis/sepsis syndrome (n=1), drug reaction/eosinophilia/systemic symptoms (n=1), and pneumonitis/pneumonia (n=1).
Project provides ‘unprecedented understanding’ of cancers
Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.
Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.
The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.
These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.
The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”
“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.
“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”
The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.
“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.
The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.
Cell of origin
In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.
The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.
“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.
“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”
“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.
“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”
Oncogenic processes
The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.
The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.
“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”
“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.
“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”
Signaling pathways
The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.
The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.
Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.
Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.
The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.
These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.
The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”
“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.
“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”
The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.
“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.
The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.
Cell of origin
In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.
The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.
“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.
“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”
“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.
“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”
Oncogenic processes
The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.
The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.
“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”
“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.
“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”
Signaling pathways
The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.
The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.
Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.
Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.
The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.
These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.
The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”
“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.
“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”
The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.
“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.
The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.
Cell of origin
In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.
The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.
“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.
“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”
“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.
“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”
Oncogenic processes
The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.
The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.
“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”
“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.
“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”
Signaling pathways
The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.
The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.
Lenalidomide yields responses in a rare cutaneous lymphoma
The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.
In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.
In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.
“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.
Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.
Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.
Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.
“However, it was a stringent goal, and other secondary evaluations have to be considered in this context, such as a 6-month disease control rate at 42%,” they wrote.
Reduced doses were associated with improved outcomes, they added. Comparing the nine patients who had lenalidomide dose reductions to those who did not, there was a higher likelihood of 6- to 11-month overall response rate (44.4% vs. 10.0%; P = .11) and lower risk of disease progression or death (hazard ratio, 0.54; 95% confidence interval, 0.19-1.59; P = .27).
Grade 3 adverse events were primarily hematologic, and two deaths occurred (pulmonary embolism and sepsis).
Taken together, the encouraging results at reduced doses, the advanced age of the patients, and the high rate of adverse events suggests a role for lenalidomide as a part of combination treatment for PCDLBCL, LT in future trials, the researchers concluded.
The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.
In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.
In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.
“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.
Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.
Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.
Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.
“However, it was a stringent goal, and other secondary evaluations have to be considered in this context, such as a 6-month disease control rate at 42%,” they wrote.
Reduced doses were associated with improved outcomes, they added. Comparing the nine patients who had lenalidomide dose reductions to those who did not, there was a higher likelihood of 6- to 11-month overall response rate (44.4% vs. 10.0%; P = .11) and lower risk of disease progression or death (hazard ratio, 0.54; 95% confidence interval, 0.19-1.59; P = .27).
Grade 3 adverse events were primarily hematologic, and two deaths occurred (pulmonary embolism and sepsis).
Taken together, the encouraging results at reduced doses, the advanced age of the patients, and the high rate of adverse events suggests a role for lenalidomide as a part of combination treatment for PCDLBCL, LT in future trials, the researchers concluded.
The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.
In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.
In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.
“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.
Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.
Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.
Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.
“However, it was a stringent goal, and other secondary evaluations have to be considered in this context, such as a 6-month disease control rate at 42%,” they wrote.
Reduced doses were associated with improved outcomes, they added. Comparing the nine patients who had lenalidomide dose reductions to those who did not, there was a higher likelihood of 6- to 11-month overall response rate (44.4% vs. 10.0%; P = .11) and lower risk of disease progression or death (hazard ratio, 0.54; 95% confidence interval, 0.19-1.59; P = .27).
Grade 3 adverse events were primarily hematologic, and two deaths occurred (pulmonary embolism and sepsis).
Taken together, the encouraging results at reduced doses, the advanced age of the patients, and the high rate of adverse events suggests a role for lenalidomide as a part of combination treatment for PCDLBCL, LT in future trials, the researchers concluded.
The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Key clinical point:
Major finding: Five of 19 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months.
Study details: A multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT.
Disclosures: The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
Source: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
Ibrutinib plus venetoclax is active in mantle cell lymphoma
In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.
Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.
“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.
The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.
Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.
In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.
The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).
Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.
Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.
In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.
“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.
The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.
Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.
Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.
In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.
Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.
“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.
The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.
Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.
In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.
The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).
Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.
Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.
In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.
“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.
The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.
Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.
Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.
In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.
Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.
“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.
The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.
Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.
In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.
The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).
Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.
Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.
In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.
“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.
The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.
Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.
Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Dual targeting of BTK and BCL2 with ibrutinib and venetoclax may improve complete response rate versus ibrutinib alone in patients with mantle cell lymphoma.
Major finding: Complete response rate at week 16 as assessed by CT was 42%, compared with 9% with ibrutinib monotherapy in a previous study (P less than .001).
Study details: A single-group phase 2 study of daily oral ibrutinib and venetoclax in 24 patients with mantle cell lymphoma (23 relapsed or refractory, 1 previously untreated), as compared with historical controls.
Disclosures: Janssen and AbbVie partially funded the study. Dr. Tam reported financial ties to Janssen, Abbvie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
Source: Tam C et al. N Engl J Med. 2018;378:1211-23.
VIDEO: How to prepare PTCL patients for transplant
LA JOLLA, CALIF. – according to Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York.
“If you’re really trying to go to transplant, you want a complete remission or close to it. So that’s often been combination chemotherapy. But I think what we’re learning is, when some of the newer agents are combined, we’re seeing higher complete response rates. And we’re doing a better job at picking subtype specific approaches,” Dr. Horwitz said in a video interview at the annual T-cell Lymphoma Forum.
Dr. Horwitz also explored the role for reduced-intensity regimens in older patients, the use of radiation conditioning, and which new agents look most promising in peripheral T-cell lymphoma.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
SOURCE: Horwitz SM. TCLF 2018.
LA JOLLA, CALIF. – according to Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York.
“If you’re really trying to go to transplant, you want a complete remission or close to it. So that’s often been combination chemotherapy. But I think what we’re learning is, when some of the newer agents are combined, we’re seeing higher complete response rates. And we’re doing a better job at picking subtype specific approaches,” Dr. Horwitz said in a video interview at the annual T-cell Lymphoma Forum.
Dr. Horwitz also explored the role for reduced-intensity regimens in older patients, the use of radiation conditioning, and which new agents look most promising in peripheral T-cell lymphoma.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
SOURCE: Horwitz SM. TCLF 2018.
LA JOLLA, CALIF. – according to Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York.
“If you’re really trying to go to transplant, you want a complete remission or close to it. So that’s often been combination chemotherapy. But I think what we’re learning is, when some of the newer agents are combined, we’re seeing higher complete response rates. And we’re doing a better job at picking subtype specific approaches,” Dr. Horwitz said in a video interview at the annual T-cell Lymphoma Forum.
Dr. Horwitz also explored the role for reduced-intensity regimens in older patients, the use of radiation conditioning, and which new agents look most promising in peripheral T-cell lymphoma.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
SOURCE: Horwitz SM. TCLF 2018.
REPORTING FROM TCLF 2018
ICER assesses value of CAR T-cell therapies
The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.
ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.
The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.
“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.
Net health benefit
ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).
The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.
The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.
Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.
The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.
Toxicity and uncertainty
The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”
In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.
Cost-effectiveness
The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.
For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.
For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.
For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.
The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.
Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).
Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.
However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.
Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.
This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.
“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.
Panel voting results
ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.
Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.
After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.
Policy recommendations
Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.
Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.
“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.
Some of ICER’s recommendations include:
- When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
- Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
- Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
- Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
- Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
- Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
- Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.
Additional recommendations and more details are available in ICER’s report.
About ICER
ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.
ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.
ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.
These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.
The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.
ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.
The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.
“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.
Net health benefit
ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).
The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.
The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.
Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.
The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.
Toxicity and uncertainty
The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”
In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.
Cost-effectiveness
The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.
For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.
For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.
For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.
The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.
Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).
Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.
However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.
Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.
This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.
“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.
Panel voting results
ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.
Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.
After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.
Policy recommendations
Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.
Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.
“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.
Some of ICER’s recommendations include:
- When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
- Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
- Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
- Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
- Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
- Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
- Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.
Additional recommendations and more details are available in ICER’s report.
About ICER
ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.
ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.
ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.
These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.
The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.
ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.
The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.
“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.
Net health benefit
ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).
The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.
The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.
Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.
The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.
Toxicity and uncertainty
The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”
In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.
Cost-effectiveness
The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.
For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.
For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.
For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.
The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.
Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).
Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.
However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.
Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.
This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.
“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.
Panel voting results
ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.
Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.
After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.
Policy recommendations
Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.
Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.
“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.
Some of ICER’s recommendations include:
- When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
- Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
- Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
- Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
- Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
- Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
- Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.
Additional recommendations and more details are available in ICER’s report.
About ICER
ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.
ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.
ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.
These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.