Optimal Management of First-Line Advanced Renal Cell Carcinoma: Focus on Pembrolizumab.
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ABSTRACT:
SUBMITTER: Singh A
PROVIDER: S-EPMC7231754 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Optimal Management of First-Line Advanced Renal Cell Carcinoma: Focus on Pembrolizumab.
Singh Abhay A Singh Inderpreet I Singh Namrata N Puzanov Igor I
OncoTargets and therapy 20200513
Renal cell carcinoma (RCC) is among the 10 most common cancers in the USA. One-third of the patients diagnosed with this cancer present with locally advanced or metastatic disease. In the past, advanced disease conferred poor survival outcomes; however, the treatment paradigm for RCC has been revolutionized twice since 2005. The initial wave of revolution came with the emergence of vascular endothelial growth factor (VEGF) inhibitors and a second wave arose more recently with the emergence and u ...[more]
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Project description:BackgroundIn this study, compared to sunitinib as one of the available treatment options, we aimed to evaluate the cost-effectiveness of lenvatinib plus pembrolizumab or everolimus as first-line treatment for advanced renal cell carcinoma (RCC) patients in a Chinese health system setting.MethodsA partitioned survival model was developed to simulate patient disease and death. Transition probabilities and adverse reaction data were obtained from the CLEAR trial. The utility value was derived from literature. Costs were based on the Chinese drug database and local charges. Sensitivity analyses and were performed to assess the robustness of the model. Outcomes were measured as quality-adjusted life-years (QALYs), cumulative cost (COST), and incremental cost-effectiveness ratio (ICER).ResultsThe model predicted that the expected mean result in the lenvatinib plus pembrolizumab group (2.60 QALYs) was superior to that in the sunitinib group (2.13 QALYs) to obtain 0.47 QALYs, but the corresponding cost was 1,253,130 yuan greater, resulting in an ICER of 2,657,025 RMB/QALYs. Compared with the sunitinib group, the lenvatinib plus everolimus group (2.17 QALYs) gained 0.04 QALYs, with an additional cost of 32,851 yuan, resulting in an ICER of 77,6202 RMB/QALYs.ConclusionsLenvatinib plus pembrolizumab or everolimus has no economic advantage over sunitinib in treating advanced RCC in the Chinese healthcare system.
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Project description:BACKGROUND:Thymic carcinomas (TCs) are rare aggressive tumors with no standard first-line treatment. This study was conducted to determine the optimal chemotherapy regimen for advanced TC. METHODS:This retrospective study included 67 patients treated for stage IV TC in 2006-2015. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS) with different chemotherapy regimens. Multivariate Cox regression analysis was used to identify factors associated with PFS, including metastatic status, radiotherapy post-chemotherapy, primary lesion resection before chemotherapy, and chemotherapy regimen. RESULTS:A total of 36 patients received a paclitaxel-platinum regimen, 31 received a gemcitabine-platinum regimen, 14 underwent primary lesion resection, and 33 underwent radiotherapy. ORR was 31% (11/36) and 29% (9/31) in the paclitaxel-platinum and gemcitabine-platinum groups, respectively (P = 0.890). Median PFS, one-year PFS rate, and two-year PFS rate were 7.0 months, 26%, and 6% with paclitaxel-platinum treatment and 12 months, 48%, and 24% with gemcitabine-platinum treatment (log-rank P = 0.030). Median PFS, one-year PFS rate, and two-year PFS rate were 18.0 months, 57%, and 33% with surgical resection and 7.3 months, 31%, and 7% without resection (log-rank P = 0.030). Median PFS, one-year PFS rate, and two-year PFS rate were 13.0 months, 52%, and 20% with radiotherapy and 4.3 months, 22%, and 7% without radiotherapy (log-rank P = 0.001). In multivariate analysis, metastatic status (hazard ratio [HR], 0.33, P = 0.004), surgical resection (HR, 0.32; P = 0.004), and radiotherapy (HR, 0.32; P < 0.001) were associated with superior PFS. CONCLUSIONS:Both gemcitabine-platinum and paclitaxel-platinum regimens were efficacious for advanced TC. Primary lesion resection and radiotherapy may also benefit selected patients.
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Project description:Since 2005, an abundance of targeted agents has been approved for the treatment of metastatic renal cell carcinoma (mRCC), without any specification as to what may be the most optimal first-line and second-line sequence. Hence, our objective was to critically examine the evidence supporting the use of first-line and second-line agents in the management of mRCC. Our review suggests that in first line, sunitinib and pazopanib represent treatment options for patients with favorable or intermediate-risk features and clear cell histology. Unfortunately, the Phase III trial cannot conclusively prove the noninferiority of pazopanib relative to sunitinib. Hence, the use of sunitinib as first-line standard of care remains justified. Pazopanib represents an option for specific patients in whom sunitinib might not be tolerated. In patients with poor-risk features, temsirolimus represents the only option supported with level 1 evidence. Less optimal alternatives include sunitinib and bevacizumab combined with interferon, based on the minimal inclusion of poor-risk patients in pivotal Phase III studies of these two molecules. In patients with non-clear cell mRCC, the use of temsirolimus is supported by Phase III data, unlike for any other molecule. In second line, the options consist of everolimus and axitinib. However, the axitinib data are substantially more robust given the inclusion of more patients considered as true second-line, and validly justify the choice of axitinib over everolimus. Nonetheless, the Phase III trial of everolimus may be considered as level 1 evidence for use as third-line or subsequent lines of therapy.
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Project description:BackgroundThe data from the phase III clinical trial KEYNOTE-426 indicated that pembrolizumab plus axitinib compared with sunitinib could generate clinical benefits in patients with previously untreated advanced renal cell carcinoma (RCC). Given the incremental clinical benefits, we examined the potential cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in the first-line setting for patients with advanced RCC from the U.S. payers' perspective.Materials and methodsCost and health outcomes were estimated at a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters, and additional subgroup analyses were performed as well.ResultsUpon our analyses, the total treatment costs in the pembrolizumab plus axitinib and sunitinib groups were $522,796 and $348,424 and the QALYs gained 2.90 and 1.72, respectively. In the base-case analysis, compared with receiving sunitinib, patients with advanced RCC receiving pembrolizumab plus axitinib gained 1.18 more QALYs at an incremental cost-effectiveness ratio of $148,676/QALY. The results of subgroup analyses demonstrated that pembrolizumab plus axitinib was most cost-effective for patients who had one organ with metastasis.ConclusionFirst-line treatment with pembrolizumab plus axitinib, compared with sunitinib, is a cost-effective strategy when the value of WTP is from $100,000 to $150,000 per QALY in patients with advanced RCC. For patients with one-organ metastasis and those in International Metastatic Renal Cell Carcinoma Database Consortium poor risk group, first-line treatment with pembrolizumab plus axitinib is more cost-effective than others.Implications for practiceThis was the first study to examine the cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in advanced renal cell carcinoma (RCC). This study found that first-line treatment with pembrolizumab plus axitinib is a cost-effective strategy when the value of willingness-to-pay is from $100,000 to $150,000 per quality-adjusted life-year in patients with advanced RCC from the U.S. payers' perspective.
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Project description:The treatment of patients with renal cell carcinoma (RCC) is evolving rapidly, with promising new regimens being developed and approved for patients with advanced disease, particularly the combination of tyrosine kinase inhibitors with immune checkpoint inhibitors. Within the last 6 months, favorable first-line setting results for patients with clear cell RCC have been reported for the combination of cabozantinib plus nivolumab in the phase III CheckMate 9ER study, leading to its regulatory approval, and lenvatinib plus pembrolizumab in the phase III CLEAR study. Additional systemic first-line treatments for clear cell RCC include axitinib plus pembrolizumab, pazopanib, and sunitinib for favorable-risk patients and ipilimumab plus nivolumab, axitinib plus pembrolizumab, axitinib plus avelumab, and cabozantinib for intermediate- or poor-risk patients. In this review of novel approaches for first-line treatment of advanced RCC, we present an overview of current treatment strategies, the basis behind emerging treatment approaches, a summary of key results from the pivotal studies using tyrosine kinase inhibitor and immune checkpoint inhibitor combination therapy, novel treatments and strategies under development, and efforts for identifying biomarkers to guide treatment decisions.
| S-EPMC8435931 | biostudies-literature
Project description:PurposePembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported.MethodsIn this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1.ResultsIn the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent.ConclusionSingle-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.
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Project description: Lung cancer is currently the malignant tumor with the highest incidence and mortality in the world, while non-small cell lung cancer (NSCLC) is the most common pathological type of lung caner. In the past few decades, the only treatment options available for advanced NSCLC patients have been targeted therapy or chemotherapy, but these therapies are inevitably tolerated by tumors. The discovery of immune checkpints that mediate the immune escape of tumor cells have been promoting a series of immune checkpoint inhibitors to be used in cancer treatment and achieved great results. Among them, pembrolizumab is currently the only PD-1 inhibitor approved for first-line treatment of NSCLC, whether it is monotherapy or combination therapy, for creditable performance in KEYNOTE studies. In this review, we systematically integrate the latest series of clinical trial results, pharmacological mechanisms, adverse events (AEs) and predictive biomarkers in the first-line treatment of NSCLC. We hope pembrolizumab could become a better choice for more clinicians and benefit more patients with advanced NSCLC.
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Project description:ImportanceCheckpoint inhibitor combination therapy represents a major advance in the first-line treatment of advanced renal cell carcinoma. Pembrolizumab-axitinib and nivolumab-ipilimumab have become standard of care options after demonstrating clinical efficacy against sunitinib in separate phase 3 trials. The cost-effectiveness of these regimens is unknown.ObjectiveTo evaluate the cost-effectiveness of pembrolizumab-axitinib and nivolumab- ipilimumab in the first-line treatment of advanced renal cell carcinoma.Design, setting, and participantsFor this economic evaluation, a primary microsimulation model was developed and run between August and December 2019. Separate analyses were conducted for an intermediate- and poor-risk patient population (base case) and a favorable-risk population (exploratory analysis) because prognosis is known to differ between risk groups; 100 000 patients with advanced renal cell carcinoma were simulated in each treatment arm. Survival, treatment regimens, and other relevant conditions were based on data from the phase 3 KEYNOTE-426 and CheckMate214 clinical trials. The study perspective was the US health care sector.Main outcomes and measuresAn incremental cost-effectiveness ratio was calculated for each of the 2 analyses and compared with a willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY).ResultsPembrolizumab-axitinib was estimated to add 0.60 QALYs compared with nivolumab-ipilimumab in the base case analysis (3.66 vs 3.05 QALYs) and 0.25 QALYs compared with nivolumab-ipilimumab in the exploratory analysis (4.55 vs 4.30 QALYs), and was more costly (base case analysis: $562 927 vs $458 961; exploratory analysis: $589 035 vs $470 403). The incremental cost-effectiveness ratio was $172 532 per QALY in the base case analysis and $468 682 per QALY in the exploratory analysis. One-way sensitivity analyses revealed that the base case model was most sensitive to first-line drug prices (incremental cost-effectiveness ratio at upper limit of nivolumab price and lower limits of axitinib and pembrolizumab prices: $89 983, $102 287, and $114 943 per QALY, respectively). The exploratory analysis model was most sensitive to overall survival rates (incremental cost-effectiveness ratio at lower limit of pembrolizumab-axitinib rate and upper limit of nivolumab-ipilimumab rate: $278 644 and $285 684 per QALY, respectively).Conclusions and relevanceThe findings suggest that pembrolizumab-axitinib treatment is associated with greater QALYs compared with nivolumab/ipilimumab treatment in patients with advanced renal cell carcinoma but may not be cost-effective. Price reductions may make the cost of pembrolizumab-axitinib proportional to its clinical value and less financially burdensome to the US health care system.
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Project description:PurposeProgrammed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non-clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC.MethodsPatients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1.ResultsAmong enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest).ConclusionFirst-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.
| S-EPMC8078262 | biostudies-literature
Project description:Pembrolizumab monotherapy has become the preferred treatment for patients with advanced non-small cell lung carcinoma (NSCLC) and a programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS) of at least 50%. However, little is known about the value of adding chemotherapy to pembrolizumab in this setting. Therefore, we performed an indirect comparison for pembrolizumab plus chemotherapy versus pembrolizumab, using the frequentist methods. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Data were retrieved from randomized trials comparing pembrolizumab plus chemotherapy or pembrolizumab monotherapy against chemotherapy. Five trials involving 1289 patients were included. Direct meta-analysis showed that both pembrolizumab plus chemotherapy (ORR: relative risk (RR) 2.16; PFS: hazard ratio (HR) 0.36; OS: HR 0.51) and pembrolizumab alone (ORR: RR 1.33; PFS: HR, 0.65; OS: HR 0.67) improved clinical outcomes compared with chemotherapy. Indirect comparison showed that pembrolizumab plus chemotherapy was superior to pembrolizumab alone, in terms of ORR (RR 1.62, 1.18-2.23) and PFS (HR 0.55, 0.32-0.97). A trend towards improved OS was also observed (HR 0.76, 0.51-1.14). In conclusion, the addition of chemotherapy to pembrolizumab further improves the outcomes of patients with advanced NSCLC and a PD-L1 TPS of at least 50%.
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