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First-line immune checkpoint inhibitors for extensive stage small-cell lung cancer: clinical developments and future directions.

ABSTRACT: Small-cell lung cancer (SCLC) is an aggressive and rapidly growing disease with poor prognosis. Despite intense efforts to improve clinical outcomes, platinum/etoposide chemotherapy has remained the most effective regimen for first-line extensive disease SCLC for decades. The addition of immune checkpoint inhibitors, and specifically programmed death-ligand 1 inhibitors, to standard platinum/etoposide, significantly improves survival and represents a promising advance in this field. However, identification of a predictive biomarker to refine patient selection is an area of unmet need. Further understanding of tumour immunity and mechanism of resistance is required to design novel strategies that improve survival. In this review, we describe recent developments and future directions on first-line immune checkpoint blockade for extensive disease-SCLC.

SUBMITTER: Ortega-Franco A

PROVIDER: S-EPMC7811117 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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First-line immune checkpoint inhibitors for extensive stage small-cell lung cancer: clinical developments and future directions.

Ortega-Franco A A Ackermann C C Paz-Ares L L Califano R R

ESMO open 20210113 1

Small-cell lung cancer (SCLC) is an aggressive and rapidly growing disease with poor prognosis. Despite intense efforts to improve clinical outcomes, platinum/etoposide chemotherapy has remained the most effective regimen for first-line extensive disease SCLC for decades. The addition of immune checkpoint inhibitors, and specifically programmed death-ligand 1 inhibitors, to standard platinum/etoposide, significantly improves survival and represents a promising advance in this field. However, ide ...[more]

PMID: 33450659

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Project description:Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46-0.98 for nivolumab, HR = 0.70, 95% CI = 0.54-0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59-0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46-0.92 for nivolumab, HR = 0.77, 95% CI = 0.61-0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65-0.94 for durvalumab, HR = 0.75, 95% CI = 0.61-0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3-4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3-4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

Project description:Introduction: This study evaluated the cost-effectiveness of atezolizumab + chemotherapy vs. chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (SCLC) in the United States (US). Methods: The three health states partitioned survival (PS) model was used over the lifetime. Effectiveness and safety data were derived from the IMpower133 trial. The parametric survival model and mixture cure model were used for the atezolizumab + chemotherapy group to explore the long-term uncertainty of the effect of immunotherapy, and the parametric survival model was used for the chemotherapy group. Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from previous studies. Sensitivity analyses were performed to observe model stability. Results: If the mixture cure model was considered for the intervention group, compared with chemotherapy alone, atezolizumab + chemotherapy yielded an additional 0.11 quality-adjusted life-years (QALYs), with an incremental cost of US$84,257. The incremental cost-utility ratio (ICUR) was US$785,848/QALY. If the parametric survival model was considered for the intervention group, atezolizumab + chemotherapy yielded an additional 0.10 QALYs, with an incremental cost of US$84,257; the ICUR was US$827,610/QALY. In the one-way sensitivity analysis, progression-free (PF) and postprogression (PP) utilities were the main drivers. In the scenario analysis (PF utility = 0.673, PP utility = 0.473), the results showed that the ICUR was US$910,557/QALY and US$965,607/QALY when the mixture cure model and parametric survival model was considered for the intervention group, respectively. In the PSA, the probabilities that atezolizumab + chemotherapy would not be cost-effective were 100% if the willingness-to-pay threshold was US$100,000/QALY. Conclusions: The findings of the present analysis suggest that atezolizumab + chemotherapy is not cost-effective in patients receiving first-line treatment for extensive-stage SCLC in the US.

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First-line immune checkpoint inhibitors for extensive stage small-cell lung cancer: clinical developments and future directions.

Publications

First-line immune checkpoint inhibitors for extensive stage small-cell lung cancer: clinical developments and future directions.

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