Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study.

BACKGROUND: In the EXIST-1 trial, initiated on Aug 10, 2009, more than 35% of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex had at least 50% reduction in SEGA volume after 9·6 months of treatment with everolimus. In this Article, we report interim data (up to Jan 11, 2013) to support longer-term tolerability and efficacy of everolimus from the continuing 4-year extension phase of EXIST-1. METHODS: We assessed data from a prospective, open-label extension of a multicentre, phase 3, randomised, double-blind, placebo-controlled study in patients with tuberous sclerosis complex who had SEGA that was growing and needed treatment. In this extension study, we included all patients who had been assigned everolimus during the double-blind, randomised phase of the trial and those patients who crossed over from the placebo group to receive everolimus during the randomised phase or at the start of the extension phase. All patients received oral everolimus at a starting dose of 4·5 mg/m(2) per day. Everolimus dose was subsequently adjusted subject to tolerability to attain blood trough concentrations of 5-15 ng/mL. An independent central radiology review team assessed SEGA response (at least a 50% reduction from baseline in total volume of all target SEGAs; the primary endpoint) by MRI at 12, 24, and 48 weeks, then every year thereafter in all patients who received at least one dose of everolimus. This study was registered with ClinicalTrials.gov, number NCT00789828. FINDINGS: Of the original 117 randomly assigned patients, 111 were given everolimus between Aug 20, 2009, and Jan 11, 2013 (date of data cutoff); we included these patients in our longer-term analysis. Median duration of everolimus exposure was 29·3 months (IQR 19·4-33·8). Median follow-up was 28·3 months (IQR 19·3-33·0). 54 (49%) patients had a response of 50% or greater reduction in SEGA volume (95% CI 39·0-58·3), and duration of response was between 2·1 and 31·1 months (median not reached). SEGA volume was reduced by 50% or more in 39 (37%) of 105 patients at 24 weeks, 48 (46%) of 104 patients at 48 weeks, 36 (47%) of 76 patients at 96 weeks, and 11 (38%) of 29 patients at 144 weeks. Stomatitis (48 [43%] patients) and mouth ulceration (33 [30%] patients) were the most frequent treatment-related adverse events; infections were the most commonly reported treatment-related serious adverse event, occurring in 15 (14%) patients. 35 (32%) patients reported treatment-related grade 3 or 4 adverse events, the most common of which were stomatitis (nine [8%]) and pneumonia (nine [8%]). 18 (16%) patients had treatment-related serious adverse events. Six (5%) patients withdrew because of adverse events. INTERPRETATION: These results support the longer-term use of everolimus in patients who have few treatment options and who need continued treatment for tuberous sclerosis complex and its varied manifestations. Reduction or stabilisation of tumour volume with everolimus will hopefully provide long-term clinical benefit in patients with SEGA. FUNDING: Novartis Pharmaceuticals.

Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.

IMPORTANCE: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS: EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS: Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS: No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE: Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01035229.

Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial.

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.

Industry's Giant Leap Into Cellular Therapy: Catalyzing Chimeric Antigen Receptor T Cell (CAR-T) Immunotherapy.

PURPOSE OF REVIEW: We describe the significant technological leap from bench to bedside that was achieved through a strong academic-industry collaboration between dedicated clinicians and researchers at the University of Pennsylvania, the Children's Hospital of Philadelphia, and Novartis to commercialize the chimeric antigen receptor T cell (CAR-T) therapy tisagenlecleucel (CTL019; Kymriah®; Novartis Pharma AG, Basel, Switzerland). RECENT FINDINGS: Tisagenlecleucel was the first CAR-T therapy and the first gene therapy to receive US Food and Drug Administration approval in 2017, with an initial indication for pediatric and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia, followed by approval in May 2018 for a second indication in adult patients with r/r diffuse large B cell lymphoma. Subsequent approvals in the European Union, Switzerland, and Canada soon followed. The tisagenlecleucel success story represents the development and commercialization of a first-of-its-kind personalized cellular therapy with a manufacturing process that supports commercial production and ongoing global clinical trials in a growing number of countries.

Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology.

BACKGROUND: In patients with solid tumours, daily everolimus dosing demonstrated dose proportionality and linear pharmacokinetics. A meta-analysis was conducted to characterise the relationship between everolimus Cmin and efficacy and safety and the effect of CYP3A4 and P-glycoprotein (PgP) substrate/inhibitor/inducer coadministration on everolimus trough concentration (Cmin). METHODS: Individual patient data from five phase 2/3 studies, in which steady state, predose pharmacokinetic samples were taken from patients with solid tumours administered everolimus 10mg/day, were pooled. FINDINGS: Efficacy and safety were evaluable for 945 and 938 patients, respectively. A 2-fold increase in everolimus Cmin increased the likelihood of tumour size reduction (odds ratio 1.40, 95% confidence interval (CI) 1.23-1.60), was associated with a trend for reduced risk of progression-free survival events (risk ratio [RR] 0.90, 95% CI 0.69-1.18) and increased the risk of grade ⩾3 pulmonary (RR 1.93, 95% CI 1.12-3.34), stomatitis (RR 1.49, 95% CI 1.05-2.10) and metabolic (RR 1.30, 95% CI 1.02-1.65) events. Coadministering everolimus with strong CYP3A4 and PgP inhibitors increased everolimus Cmin by 10% and 20%, respectively; coadministration with CYP3A4 inducers reduced Cmin by 7%. INTERPRETATION: A 2-fold increase in everolimus Cmin was associated with improved tumour size reduction and increased risk of high-grade pulmonary, metabolic and stomatitis events. FUNDING: Novartis Pharmaceuticals Corporation.

Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma.

PURPOSE: A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety. RESULTS: Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively). CONCLUSION: Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression.

Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib.

Dovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model-based approach. A semi-mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) responsible for dovitinib metabolism was described using an indirect response model. Simulation of dovitinib plasma concentration profiles following 4 intermittent dosing schedules suggested that intermittent dosing could prevent prolonged drug accumulation. Based on the simulated plasma profiles, PD response, and patient compliance, a 5-days-on/2-days-off intermittent dosing schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib plasma concentrations in this study confirmed the model predictions. Furthermore, dovitinib was well tolerated, and antitumor activity was observed as well in this new study. The 5-days-on/2-days-off dosing schedule is currently used in a dovitinib registration trial and other clinical trials.

Effects of hepatic impairment on the pharmacokinetics of everolimus: a single-dose, open-label, parallel-group study.

BACKGROUND: Although the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment. OBJECTIVE: The goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting. METHODS: A multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0-∞ geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment. RESULTS: Thirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0-∞ for patients with mild, moderate, and severe hepatic impairment increased by 1.60-, 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 µmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, ≤1 day in duration, and not everolimus related. CONCLUSIONS: Everolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591.

Safety of everolimus by treatment duration in patients with advanced renal cell cancer in an expanded access program.

OBJECTIVE: To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program. METHODS: Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors. RESULTS: The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates. CONCLUSION: Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations≥1 year and not associated with cumulative toxicity.

Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial.

BACKGROUND: Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy. OBJECTIVE: To evaluate the efficacy and safety of everolimus in elderly patients (those ≥ 65 and ≥ 70 yr of age) enrolled in RECORD-1. DESIGN, SETTING, AND PARTICIPANTS: The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n=416). INTERVENTION: Everolimus 10mg once daily (n=277) or placebo (n=139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity. MEASUREMENTS: Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety. RESULTS AND LIMITATIONS: In RECORD-1, 36.8% of patients were ≥ 65 yr and 17.5% were ≥ 70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation. CONCLUSIONS: Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.

An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy.

BACKGROUND AND OBJECTIVES: The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. PATIENTS AND METHODS: REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. RESULTS: A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. CONCLUSION: Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio.