In October 2017, the FDA granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for treatment of adult patients with relapsed or ...refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The objective response rate per independent review committee was 72% 95% confidence interval (CI), 62-81, with a CR rate of 51% (95% CI, 41-62). With a median follow-up of 7.9 months, the median DOR was not reached in patients achieving CR (95% CI, 8.1 months; not estimable, NE), whereas patients with partial remission had an estimated median DOR of 2.1 months (95% CI, 1.3-5.3). Among 108 patients evaluated for safety, serious adverse reactions occurred in 52%. Cytokine release syndrome and neurologic toxicities occurred in 94% and 87% of patients, respectively, leading to implementation of a risk evaluation and mitigation strategy.
In October 2021, the FDA approved brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with relapsed or ...refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). Approval was based on the phase II portion of ZUMA-3, a single-arm, open-label, multicenter trial that evaluated a single infusion of brexu-cel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was established on the basis of complete remission (CR) within 3 months after infusion and the duration of CR (DOCR). Among 54 patients in the efficacy analysis population, the CR rate was 52% (95% CI: 38, 66) with a median time-to-response of 56 days. With a median follow-up for responders of 7.1 months, the median DOCR was not reached. For all leukapheresed patients in the phase II portion of this trial (n = 71), the CR rate was 41% (95% CI: 29, 53). Among the 78 patients treated with the approved dose of brexu-cel, serious adverse reactions occurred in 79% and fatal adverse reactions occurred in 5% and included cerebral edema and infections. Cytokine release syndrome occurred in 92% (grade ≥3, 26%) and neurologic toxicities occurred in 87% (grade ≥3, 35%), leading to implementation of a risk evaluation and mitigation strategy (REMS). Postmarketing study with 15 years of follow-up will further evaluate long-term safety in adult patients with relapsed or refractory B-ALL.
In March 2021, the U.S. Food and Drug Administration granted accelerated approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor T-cell therapy, for the treatment of adult ...patients with relapsed or refractory follicular lymphoma (r/r FL) after at least 2 lines of systemic therapy. Approval was based on ZUMA-5, a single-arm, open-label, multicenter trial that evaluated a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was based on objective response rate (ORR) and duration of response (DOR) as determined by an independent review committee. Among 81 patients in the primary efficacy analysis, having a median of 3 (range 2-9) prior lines of systemic therapy, the ORR was 91% (95% confidence interval CI: 83-96) with a complete remission (CR) rate of 60% and a median time-to-response of 1 month. The median DOR was not reached, and the 1-year rate of continued remission was 76% (95% CI: 64-85). For all leukapheresed patients with FL in this trial (n = 123), the ORR was 89% (95% CI: 83-94) with a CR rate of 62%. Among 146 patients with indolent lymphoma evaluated for safety, cytokine release syndrome occurred in 84% (Grade ≥3, 8%) and neurological toxicities occurred in 77% (Grade ≥3, 21%), leading to implementation of a risk evaluation and mitigation strategy. Serious adverse reactions occurred in 48%. Post-marketing studies will further evaluate clinical benefit in patients with r/r FL and long-term safety.
Abstract
Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration’s (FDA’s) benefit-risk assessment of cancer therapeutics by quantifying symptom and ...functional outcomes from the patient’s perspective.
This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling.
We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report.
PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute’s Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient’s perspective, in pediatric oncology trials.
Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration’s (FDA’s) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional ...outcomes from the patient’s perspective. This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling. We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report. PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute’s Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient’s perspective, in pediatric oncology trials.
Abstract
Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration’s (FDA’s) benefit-risk assessment of cancer therapeutics by quantifying symptom and ...functional outcomes from the patient’s perspective.
This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling.
We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report.
PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute’s Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient’s perspective, in pediatric oncology trials.
Introduction: In recent years, there has been increased interest in patient experience data, including PROs. To determine how and where PRO data are being assessed and communicated as part of ...approval of a marketing application, we examined approvals in the Center of Drugs Evaluation and Research in the Office of Hematology and Oncology Products as well as the Center for Biologics Evaluation and Research. Here we report on PRO data from malignant and benign hematology indications.
Method: New Molecular Entity (NME) and Supplemental applications with new indications approved between 2017 and 2018 were examined. We reviewed sponsor's clinical study reports (CSRs) for inclusion of PRO data. We assessed FDA review of this data by determining how often PRO data were incorporated in the Prescribing Information (label) and/or final FDA Clinical Reviews.
Results: From 2017 to 2018 a total of 31 NMEs and 33 supplemental applications were approved for benign and malignant hematology indications (Figure 1). Of the 10 benign hematology NMEs and BLAs approved, 3 (30%) contained PRO data in the sponsor's CSR, and FDA included the PRO data in all three FDA clinical reviews with one application (Emicizumab) having PRO data incorporated in the FDA product labeling. Emicizumab's label captured disease symptoms and physical functioning, prespecified secondary endpoints in the trial.
Of the 15 malignant hematology NMEs and BLAs approved, 7 (47%) contained PRO data in the sponsor's CSR. Of the 7 submissions that contained PRO data, 6 (86%) included PRO data in the FDA clinical review and PRO data were incorporated into the label for one application. Rituxan Hycela's label captured patient preference supported by a large randomized clinical trial with preference as the primary objective.
Of the 8 supplemental indications for benign hematology, 3 (38%) of the applications contained PRO data in the sponsor's CSR and FDA included the PRO in all three FDA clinical reviews with one application (Feraheme) having PRO data incorporated in the FDA product labeling. Feraheme captured descriptive disease symptom data.
Of the 20 applications submitted for supplemental indications for hematologic malignancies, 13 (65%) contained PRO data in the sponsor's CSR. Twelve of the 13 applications that contained PRO data (92%) had this data discussed in the FDA clinical review, and one application (ibrutinib) incorporated PRO data in FDA product labeling. Ibrutinib captured descriptive disease symptom data.
Discussion: When PRO data were included in efficacy submissions to FDA, a large portion of FDA clinical reviews included discussion of this information. PRO data were included in the label more frequently for benign indications compared to malignant indications. When in the label, PRO data tended to refer to disease symptoms and physical function, both of which have been specified as being part of FDA's proposed core outcome set for cancer.
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No relevant conflicts of interest to declare.
Background: With recent FDA approvals of CAR T cell therapy for the treatment of relapsed/refractory aggressive B cell non-Hodgkin lymphoma, an increasing number of older adults will be treated with ...this therapy. An improved understanding of the safety of CAR T cell therapy in this population is important to inform clinical decision making for the treatment of older subjects.
Methods: Data from two prospective single arm studies (n=214) of two approved CART cell products for the treatment of relapsed/refractory lymphoma were pooled and analyzed. Rates of cytokine release syndrome (CRS), as well as severity and treatment modalities (oxygen, vasopressor support, tocilizumab and steroids) were pooled and analyzed by age. Selected neuropsychiatric events were pooled and analyzed by age.
Results: Age was balanced between the two studies. The median age of subjects was 58 years (range 22-76 years). Of the 214 total subjects, 24% were 65 years of age and older.
CRS and neurotoxicity were evaluated in the subjects who received treatment with CAR T cell therapy. (Table 1).
*Two studies employed different grading methods for CRS; Lee's criteria (Lee DW et al, Blood 2014) and U Penn criteria (Porter DL et al, Blood 2014)
Conclusions: This exploratory analysis suggests overall similar rates of CRS and grade 2 and higher CRS in subjects less than 65 years as compared to 65 years of age and older. There appears to be an overall higher rate of encephalopathy and grade 3 and higher delirium/encephalopathy in adults 65 years and older compared to less than 65 years of age. The inclusion of greater numbers of patients ≥ 65 years of age in clinical trials will further inform clinicians about the safety and efficacy of CAR T cell therapy in older adults.
Table 1: Adverse Events by Age in subjects treated with CART cell therapy
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No relevant conflicts of interest to declare.
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