Refractory Systemic Anaplastic Large Cell Research Articles

Population Pharmacokinetics (PPK) and Exposure-Response to Support Body Surface Area (BSA)-Based Dosing of Brentuximab Vedotin in Pediatric Patients with Advanced-Stage Newly-Diagnosed Hodgkin Lymphoma (HL)

Introduction Brentuximab vedotin is an antibody-drug conjugate (ADC), consisting of antibody cAC10 specific to human CD30 and the antimicrotubule agent monomethyl auristatin E (MMAE), conjugated by a protease-cleavable linker. PPK models were developed to identify factors impacting the pharmacokinetics of ADC and MMAE, and exposure-response analyses were performed to assess the risk-benefit profiles of brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A+AVD) to support BSA-based dosing of brentuximab vedotin in pediatric patients with advanced-stage newly-diagnosed HL. Methods Data from two open-label phase 1/2 pediatric studies were included in the PPK analysis: study C25002 (NCT01492088), which was a dose-escalation study (brentuximab vedotin 1.4-1.8 mg/kg every 3 weeks) in patients with relapsed or refractory systemic anaplastic large cell lymphoma or HL, and study C25004 (NCT02979522) in patients with advanced-stage, newly-diagnosed HL (brentuximab vedotin 48 mg/m2 every 2 weeks [Q2W] +AVD; A 25 mg/m2, V 6 mg/m2, D 375 mg/m2). Samples for measuring ADC and MMAE concentrations and immunogenicity assessment were collected. Sources of brentuximab vedotin pharmacokinetic variability were quantified using nonlinear mixed-effects modeling. ADC exposures achieved by BSA-based dosing of brentuximab vedotin in pediatric patients were compared to those in adults who received weight-based dosing of brentuximab vedotin in the ECHELON-1 trial (NCT01712490). Exposure-response analyses included patients in study C25004 treated with brentuximab vedotin 48 mg/m2 Q2W in combination with AVD. Relationships between ADC/MMAE exposures, progression-free survival (PFS), and incidence of adverse events (AEs) were analyzed by logistic regression in patients receiving A+AVD. Results Data from 95 patients (6-17 years) informed pharmacokinetics models of ADC (linear 3-compartment with zero-order input and first-order elimination) and MMAE (2-compartment with first-order elimination and formation of MMAE from ADC). BSA (0.79-2.03 m2) and albumin level (23-51 g/L) were significant covariates for clearance of ADC and MMAE. Age, body weight, sex, and race were not identified as covariates for ADC and MMAE pharmacokinetics. Albumin concentrations did not result in clinically meaningful change in clearance of ADC and MMAE. BSA-based brentuximab vedotin dosing resulted in similar systemic exposures of ADC and MMAE across age groups (<12 [n=23], 12-16 [n=56], and >16 years [n=16]). In exposure-response analyses (n=59), steady-state ADC exposures (area under the curve [AUC]) with BSA-based dosing of brentuximab vedotin at 48 mg/m2 Q2W in pediatric patients were comparable to those with weight-based dosing of brentuximab vedotin at 1.2 mg/kg Q2W in adults in the ECHELON-1 trial (Figure). A significant increase (p<0.05) in the incidence of febrile neutropenia was related to increasing exposure of MMAE, consistent with what has been observed in adult patients. No apparent relationship was identified between ADC exposure and the incidence of peripheral neuropathy, grade ≥3 neutropenia, febrile neutropenia, or grade ≥3 treatment-emergent AEs, or between ADC/MMAE exposure and PFS. Conclusions PPK and exposure-response analyses support brentuximab vedotin 48 mg/m2 Q2W in combination with AVD as a treatment option for pediatric patients with advanced-stage newly-diagnosed HL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

FDA approval summary: Crizotinib for pediatric and young adult patients with relapsed or refractory systemic anaplastic large cell lymphoma.

In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single-arm trial of crizotinib monotherapy that included 26 patients, aged 1-20years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies.

Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma

AbstractThis pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.

Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

CE2 - Cost-Effectiveness of Brentuximab Vedotin in Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma in Taiwan

CE2 - Cost-Effectiveness of Brentuximab Vedotin in Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma in Taiwan

Cost-effectiveness of brentuximab vedotin in relapsed or refractory systemic anaplastic large cell lymphoma.

18 Background: Systemic anaplastic large cell lymphoma (sALCL) is a rare T-cell lymphoma. For patients who fail front-line therapy, outcomes are poor and there is no current defined standard of care. Brentuximab vedotin has demonstrated high objective response rates and is approved for patients with relapsed or refractory (R/R) sALCL. However, the cost-effectiveness of brentuximab vedotin compared with conventional chemotherapy has not been explored. Methods: A lifetime Excel-based partitioned survival model was used to compare survival outcomes from the pivotal phase-2 single-arm brentuximab vedotin trial of 58 R/R sALCL patients with good Eastern Corporative Oncology Group (ECOG) performance status after one or more prior therapies (SG035-0004); with 40 sALCL patients from a Canadian cancer registry receiving first-line conventional salvage chemotherapy (65% with ECOG 0 or 1) between 1980 and 2012 and followed for up to 20 years. Extrapolation of brentuximab vedotin survival after the trial period assumed the same rate of change as for conventional chemotherapy. A United Kingdom National Health Service perspective was adopted. Costs included drug acquisition and administration, and medical care for adverse events and pre- and post-progression. Utility values elicited by response and by progression, and disutilities associated with adverse events were applied to estimate quality-adjusted life years (QALYs). Results: The incremental cost-effectiveness ratio (ICER) for brentuximab vedotin was £35,390 per QALY gained versus conventional chemotherapy. ICERs were between £28,112 and £61,921 across a range of alternative model assumptions. Comparing only first-line salvage patients in both groups reduced the ICER to £26,766. Conversely, considering only patients with good ECOG performance status increased the ICER to £38,186. Using probabilistic sensitivity analysis, at willingness-to-pay of £38,000, the probability that brentuximab vedotin is cost-effective was &gt; 50%. Conclusions: Brentuximab vedotin may represent a cost-effective intervention compared to conventional chemotherapy for this patient population with limited therapeutic options.

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.

Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Abstract SY28-02: Tumor targeting with antimitotic monoclonal antibody drug conjugates.

Abstract Monoclonal antibodies (mAbs) have played a major role in cancer medicine, with active drugs such as trastuzumab, cetuximab, bevacizumab and rituximab in a wide range of therapeutic applications. The mechanism of activity of these agents involves cell signaling, effector functions through interactions with Fcγ receptor positive cells, and complement fixation. The activity of mAbs can be enhanced through the generation of antibody drug conjugates (ADCs) that are capable of delivering cytotoxic agents with some degree of selectivity to tumor cells. Early work in this field involved the use of clinically approved anticancer drugs that generally were low in potency. Consequently, the resulting ADCs had suboptimal activities. Because of this, significant attention was directed towards the identification of appropriate drugs for targeted delivery, the most successful being antimitotic drugs such as monomethyl auristatin E (MMAE), and maytansinoids. These drugs inhibit tubulin polymerization and arrest cell growth in a cell-cycle dependent manner. Successful delivery of these agents requires drug, linker, and conjugation optimization, in addition to judicious selection of an antigen target on tumor cell surfaces. Brentuximab vedotin, a conjugate comprised of the anti-CD30 mAb cAC10 conjugated with MMAE through a highly stable peptide linker, is an example of how addressing these considerations can lead to ADCs with pronounced clinical efficacy. In August 2011, brentuximab vedotin received accelerated approval by the US Food and Drug Administration for use in relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, two diseases with significant unmet medical needs. An overview of how this targeted antimitotic drug was developed and how we are extending the technology will be provided. Citation Format: Peter Senter. Tumor targeting with antimitotic monoclonal antibody drug conjugates. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY28-02. doi:10.1158/1538-7445.AM2013-SY28-02

Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Resolution of malignant cutaneous lesions with brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma

Resolution of malignant cutaneous lesions with brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma

Durable remissions with brentuximab vedotin (SGN-35): Updated results of a phase II study in patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

8032 Background: sALCL is a CD30-expressing malignancy comprising ~2-3% of all NHL cases. Brentuximab vedotin consists of an anti-CD30 antibody conjugated by a plasma-stable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Brentuximab vedotin selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing MMAE. Methods: A phase II, single-arm, multicenter study evaluated the efficacy and safety of brentuximab vedotin in patients (pts) with relapsed or refractory sALCL. Pts received brentuximab vedotin 1.8 mg/kg q3 weeks (wks) as a 30‐minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per an independent review facility (IRF) according to Cheson 2007. Results: 58 pts were enrolled; 57% were male, median age was 52 yrs (range 14–76 yrs). 72% of pts had ALK negative sALCL. Pts had received a median of 2 (range 1–6) prior systemic therapies. 62% of pts had primary refractory disease, 50% were refractory to their most recent prior therapy, and 22% had never responded to any prior therapy. At the time of primary efficacy analysis, ORR per IRF was 86% (50 of 58 pts) with CRs in 53% of pts (31 of 58). Median duration of objective response had not yet been reached; the duration ranged from 0.3 to 45.3 wks. Of 15 pts with malignant cutaneous lesions at baseline, 14 (93%) had resolution of all lesions; median time to resolution was 4.9 wks. After achieving a remission with brentuximab vedotin, 7 pts received an allogeneic stem cell transplant (SCT) and 7 pts had an autologous SCT. Treatment-related adverse events (AEs) of any grade in ≥15% of pts were peripheral sensory neuropathy (36%), nausea (24%), fatigue (22%), diarrhea (19%), and neutropenia (17%). AEs ≥ Grade 3 in ≥10% of patients were neutropenia (21%); thrombocytopenia (14%), and peripheral sensory neuropathy (10%). No treatment-related Grade 5 events were observed. Conclusions: Brentuximab vedotin induced objective responses in 86% of pts with highly refractory sALCL, including a high proportion of CRs, with manageable AEs. Updated response durability and safety will be presented at the meeting.

Complete Remissions with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

AbstractAbstract 961 Background:Systemic anaplastic large cell lymphoma (sALCL) is a CD30-expressing malignancy comprising approximately 2–3% of all cases of non-Hodgkin lymphoma. The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the highly potent antimicrotubule agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell. In phase 1 studies, brentuximab vedotin demonstrated good tolerability and notable antitumor activity in patients with relapsed or refractory sALCL: 6 of 7 treated patients achieved complete remissions (CR). Methods:A phase 2, single-arm, multicenter study was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL. Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of antitumor efficacy was based on objective response assessments according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results:A total of 58 patients were treated in this study; interim data are presented for the first 30 treated patients. 53% of patients were female and median age was 55 years (range 14–71). The majority of patients had ALK-1 negative tumor (70%, or n=21) and 4 patients (13%) had bone marrow involvement at baseline. The median number of prior chemotherapy regimens was 2 (range 1–6) and 8 patients (27%) had failed previous autologous hematopoietic stem cell transplant (SCT). 19 patients (63%) had primary refractory disease, and 16 patients (53%) had not responded to the most recent prior therapy. The objective response rate (ORR) by investigator assessment was 87%; 57% of patients achieved a CR (n=17) and 30% of patients achieved a partial remission (PR; n=9). The remaining patients had stable disease (n=3) or were not evaluable for response (n=1). Similar proportions of ALK-1 negative and ALK-1 positive patients achieved CR and PR. Reduction in tumor burden was observed in 97% of patients. The median time to objective response was 6 weeks (range 5–12) and the duration of objective responses currently range from 4–36 weeks, with responses ongoing in 18 patients. B symptoms resolved in 9 of 10 patients (90%) who had these symptoms at baseline. After achieving a CR with brentuximab vedotin, 10 patients (33%) went on to receive an autologous or allogeneic SCT. The most common (>20%) adverse events (AEs) of any grade were nausea (47%), diarrhea (40%), peripheral sensory neuropathy (40%), pyrexia (33%), dyspnea (30%), fatigue (27%), insomnia (23%), and neutropenia (23%). Grade 3/4 AEs considered related to brentuximab vedotin observed in >1 patient were neutropenia (17%), peripheral sensory neuropathy (13%), diarrhea (7%), and anemia (7%); no treatment-related Grade 5 events were observed. 7 patients (23%) discontinued treatment due to an AE. Conclusion:In this interim analysis of 30 patients with relapsed or refractory sALCL, the investigator-assessed ORR was 87% and the CR rate was 57%. Brentuximab vedotin treatment was associated with manageable AEs; the most common in the study were nausea, diarrhea, and peripheral sensory neuropathy. The rate of complete remissions observed thus far in this study with single-agent treatment suggests that brentuximab vedotin has potential for the treatment of sALCL. Results of the independent assessment of response for all patients, duration of response, progression-free survival, and updated safety data will be presented at the meeting. Disclosures:Shustov:Seattle Genetics, Inc.: Research Funding, Steering Committee member. Off Label Use: The clinical trial uses an investigational drug, brentuximab vedotin (SGN-35). Advani:Seattle Genetics, Inc.: Research Funding. Brice:Seattle Genetics, Inc.: Research Funding. Bartlett:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Research Funding; Roche: Consultancy; Biogen Idec: Consultancy; Amgen: Consultancy. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Honoraria, Speakers Bureau; Millennium: Speakers Bureau; Cephalon: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.