Dataset Information

Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.

ABSTRACT: To simulate clinical trials to assess overall survival (OS) benefit of bevacizumab in combination with chemotherapy in selected patients with gastric cancer (GC), a modeling framework linking OS with tumor growth inhibition (TGI) metrics and baseline patient characteristics was developed. Various TGI metrics were estimated using TGI models and data from two phase III studies comparing bevacizumab plus chemotherapy vs. chemotherapy as first-line therapy in 976 GC patients. Time-to-tumor-growth (TTG) was the best TGI metric to predict OS. TTG, Eastern Cooperative Oncology Group (ECOG) score, albumin level, and Asian ethnicity were significant covariates in the final OS model. The model correctly predicted a decreased hazard ratio favorable to bevacizumab in patients with high baseline plasma VEGF-A above the median of 113.4 ng/L. Based on trial simulations, in trials enrolling patients with elevated baseline plasma VEGF-A (500 patients per arm), the expected hazard ratio was 0.82 (95% prediction interval: 0.70-0.95), independent of ethnicity.

SUBMITTER: Han K

PROVIDER: S-EPMC4961078 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.

Han Kelong K Claret L L Piao Y Y Hegde P P Joshi A A Powell J R JR Jin J J Bruno R R

CPT: pharmacometrics & systems pharmacology 20160712 7

To simulate clinical trials to assess overall survival (OS) benefit of bevacizumab in combination with chemotherapy in selected patients with gastric cancer (GC), a modeling framework linking OS with tumor growth inhibition (TGI) metrics and baseline patient characteristics was developed. Various TGI metrics were estimated using TGI models and data from two phase III studies comparing bevacizumab plus chemotherapy vs. chemotherapy as first-line therapy in 976 GC patients. Time-to-tumor-growth (T ...[more]

PMID: 27404946

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Project description:ImportanceThis study demonstrates that tislelizumab in combination with chemotherapy is associated with improved progression-free survival (PFS) in patients with advanced squamous non-small-cell lung cancer (sq-NSCLC).ObjectiveTo assess the efficacy and safety/tolerability of tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for patients with advanced sq-NSCLC.Design, setting, and participantsThis open-label, randomized phase 3 clinical trial was conducted at 46 sites in China between July 2018 and June 2019 and included patients with treatment-naive, histologically confirmed stage IIIB/IV sq-NSCLC. The data cutoff for these analyses was December 6, 2019; data extraction occurred on January 7, 2020.InterventionsPatients were randomized (1:1:1) to receive 1 of the following regimens intravenously on a 21-day cycle: tislelizumab (200 mg, day 1) plus paclitaxel (175 mg/m2, day 1) and carboplatin (area under the concentration of 5, day 1) (arm A); tislelizumab plus nab-paclitaxel (100 mg/m2, days 1, 8, and 15) and carboplatin (arm B); and paclitaxel and carboplatin (arm C). Patients were stratified by disease stage and tumor programmed cell death 1 ligand 1 (PD-L1) expression (<1% vs 1%-49% vs ≥50%).Main outcomes and measuresThe primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary end points included overall survival, investigator-assessed (INV) PFS, IRC-assessed objective response rate (ORR), and IRC-assessed duration of response, as well as the incidence and severity of adverse events (AEs).ResultsOverall, 355 patients (median [range] age, 62 [34-74] years; 330 men [91.7%]) with sq-NSCLC received treatment. After a median study follow-up of 8.6 months (95% CI, 8.1-9.0 months), IRC-assessed PFS was significantly improved with tislelizumab plus chemotherapy (arm A, 7.6 months; arm B, 7.6 months) vs chemotherapy alone (arm C, 5.5 months; hazard ratios were 0.524 (95% CI, 0.370-0.742; P < .001 [A vs C]) and 0.478 (95% CI, 0.336-0.679; P < .001 [B vs C]). Higher IRC-assessed ORR and longer IRC-assessed duration of response were observed in arms A (72.5%; 8.2 months) and B (74.8%; 8.6 months) vs C (49.6%; 4.2 months). No association was observed between PD-L1 expression and IRC-assessed PFS or ORR. Discontinuation of any treatment because of AEs was reported in 15 (12.5%; arm A), 35 (29.7%; arm B), and 18 (15.4%; arm C) patients. In each arm, the most common grade of 3 or greater AE was decreased neutrophil levels, which aligned with known chemotherapy toxic effects. Six treatment-related AEs leading to death occurred; however, no deaths were solely attributed to tislelizumab.Conclusions and relevanceIn this phase 3 randomized clinical trial, adding tislelizumab to chemotherapy was associated with significantly prolonged IRC-assessed PFS, higher IRC-assessed ORRs, and a manageable safety/tolerability profile in patients with advanced sq-NSCLC, regardless of PD-L1 expression.Trial registrationClinicalTrials.gov Identifier: NCT03594747.

Project description:PurposeResults from previous randomised controlled trials (RCTs) investigating whether the addition of bevacizumab to neoadjuvant chemotherapy (NAC) could statistically significantly increase the pathological complete response (pCR) and to identify which subgroup would benefit most from such regimens have produced conflicting results. This meta-analysis was designed to assess the efficacy and safety of bevacizumab plus chemotherapy compared with chemotherapy alone in the neoadjuvant setting.MethodsA literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane library was performed to identify eligible studies. The primary endpoint of interest was pCR. The secondary endpoints were clinical complete rate (cCR), surgery rate, breast-conserving surgery (BCS) rate, and toxicity. The meta-analysis was performed using Review Manager software version 5.3.ResultsNine RCTs matched the selection criteria, yielding a total of 4967 patients (bevacizumab plus chemotherapy: 50.1%, chemotherapy alone: 49.9%). The results of this meta-analysis demonstrated that the addition of bevacizumab to NAC significantly increased the pCR rate (odds ratio [OR] = 1.34 [1.18-1.54]; P < 0.0001) compared with chemotherapy alone. Subgroup analysis showed that the effect of bevacizumab was more pronounced in patients with HER2-negative cancer (OR = 1.34 [1.17-1.54]; P < 0.0001) compared with HER2-positive cancer (OR = 1.69 [0.90-3.20]; P = 0.11). Similarly, in patients with HER2-negative cancer, the effect of bevacizumab was also more pronounced in patients with HR-negative cancer (OR = 1.38 [1.09-1.74]; P = 0.007) compared with HR-positive cancer (OR = 1.36 [0.78-2.35]; P = 0.27). No significant differences were observed between the groups with respect to cCR, surgery rate, or BCS rate. Additionally bevacizumab was associated with a higher incidence of neutropenia, febrile neutropenia, and hand-foot syndrome.ConclusionsHigher proportions of patients achieved pCR when bevacizumab was added to NAC compared with when they received chemotherapy alone; acceptable toxicities were also found. Subgroup analysis demonstrated that patients with histologically confirmed HER2-negative and HR-negative breast cancer benefited the most.

Project description:ImportanceTreatment with atezolizumab plus bevacizumab may prolong overall survival among patients with unresectable hepatocellular carcinoma. However, to our knowledge, the cost-effectiveness of using this high-priced therapy for this indication is currently unknown.ObjectiveTo evaluate the cost-effectiveness of atezolizumab plus bevacizumab to treat unresectable hepatocellular carcinoma from the US payer perspective.Design, setting, and participantsThis economic evaluation used a partitioned survival model consisting of 3 discrete health states to assess the cost-effectiveness of treatment of hepatocellular carcinoma with atezolizumab plus bevacizumab vs sorafenib. The characteristics of patients in the model were similar to patients in a phase 3, open-label randomized clinical trial (IMbrave150) who had unresectable hepatocellular carcinoma and had not previously received systemic treatment. Key clinical data were generated from the IMbrave150 trial conducted between March 15, 2018, and January 30, 2019, and cost and health preference data were collected from the literature.Main outcomes and measuresCosts, quality-adjusted life-years (QALYs), incremental cost-utility ratios, incremental net health benefits, and incremental net monetary benefits were calculated for the 2 treatment strategies. Subgroup, 1-way sensitivity, and probabilistic sensitivity analyses were performed.ResultsTreatment of hepatocellular carcinoma with atezolizumab plus bevacizumab added 0.530 QALYs and resulted in an incremental cost of $89 807 compared with sorafenib therapy, which had an incremental cost-utility ratio of $169 223 per QALY gained. The incremental net health benefit was -0.068 QALYs, and the incremental net monetary benefit was -$10 202 at a willingness-to-pay threshold of $150 000/QALY. The probabilistic sensitivity analysis indicated that treatment with atezolizumab plus bevacizumab achieved a 35% probability of cost-effectiveness at a threshold of $150 000/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the hazard ratio of overall survival. The subgroup analysis found that treatment with atezolizumab plus bevacizumab was associated with preferred incremental net health benefits in several subgroups, including patients with hepatitis B and C.Conclusions and relevanceAtezolizumab plus bevacizumab treatment is unlikely to be a cost-effective option compared with sorafenib for patients with unresectable hepatocellular carcinoma. Reducing the prices of atezolizumab and bevacizumab may improve cost-effectiveness. The economic outcomes also may be improved by tailoring treatments based on individual patient factors.

Project description:ImportanceSafe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need.ObjectiveTo evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater.Design, setting, and participantsThe phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017.InterventionsPatients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2 twice daily), or chemotherapy plus placebo, every 3 weeks.Main outcomes and measuresPrimary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater.ResultsA total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03; P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17; P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02; P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively.Conclusions and relevanceThis phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested.Trial registrationClinicalTrials.gov Identifier: NCT02494583.

Dataset Information

Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.

Publications

Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.

Similar Datasets

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