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Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study.

ABSTRACT: The aim of this study was to investigate the clinical impact of sarcopenia on the efficacy of programmed death (PD)-1 inhibitors. We retrospectively reviewed the medical records of all patients treated with nivolumab or pembrolizumab between January 2016 and September 2018 for previously treated advanced non-small cell lung cancer (NSCLC). The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36?cm²/m² for males and 3.92?cm²/m² for females). A total of 42 patients were analysed. The prevalence of sarcopenia was 52.4%. Sarcopenia was significantly associated with poorer progression-free survival (PFS) (median, 2.1 vs. 6.8 months, p?=?0.004). Compared to patients with sarcopenia, those without sarcopenia had a higher overall response rate (40.0% vs. 9.1%, p?=?0.025) and 1-year PFS rate (38.1% vs. 10.1%). In conclusion, sarcopenia at baseline as determined using computed tomography is a significant predictor of worse outcome in patients with advanced NSCLC receiving PD-1 blockade. Screening for sarcopenia may help identify patients more likely to achieve a long-term response in routine clinical practice.

SUBMITTER: Shiroyama T

PROVIDER: S-EPMC6385253 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study.

Shiroyama Takayuki T Nagatomo Izumi I Koyama Shohei S Hirata Haruhiko H Nishida Sumiyuki S Miyake Kotaro K Fukushima Kiyoharu K Shirai Yuya Y Mitsui Yuichi Y Takata So S Masuhiro Kentaro K Yaga Moto M Iwahori Kota K Takeda Yoshito Y Kida Hiroshi H Kumanogoh Atsushi A

Scientific reports 20190221 1

The aim of this study was to investigate the clinical impact of sarcopenia on the efficacy of programmed death (PD)-1 inhibitors. We retrospectively reviewed the medical records of all patients treated with nivolumab or pembrolizumab between January 2016 and September 2018 for previously treated advanced non-small cell lung cancer (NSCLC). The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography was assessed to calculate the psoas mus ...[more]

PMID: 30792455

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Project description:Importance:Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown. Objectives:To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. Design, Setting, and Participants:In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. Interventions:The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. Main Outcomes and Measures:The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Results:Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350]; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Conclusions and Relevance:Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

Project description:BackgroundThe present study aimed to investigate the determinant factors of survival in patients with pretreated advanced stage non-small cell lung cancer (NSCLC) who received anti-PD-1/PD-L1 therapy.MethodsIn this observational retrospective study, the clinical profiles and laboratory parameters of patients with NSCLC treated with anti-PD-1/PD-L1 therapy were consecutively collected. Lung Immune Prognostic Index (LIPI) was calculated based on the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase level (LDH). Modified Glasgow Prognostic Score (mGPS) was calculated based on serum C reactive protein and albumin, and tumor mutation burden (TMB) was calculated using a targeted next-generation sequencing panel based on 422 cancer-relevant genes. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. The Cox regression model was used to identify the potential determinant factors of survival benefit. Trained oncologists at Sun Yat-sen University Cancer Center followed all of the participants through visits to doctors' offices or via telephone calls to determine their clinical status.ResultsSeventy-three patients were included in our study. With a median follow up time of 637 days, there was a significant difference in PFS between patients with high TMB compared to those with low TMB (3.7 vs. 2.1 months; P=0.004), while no significant difference was found in OS (14.0 vs. 16.4 months; P=0.972). Patients with a good LIPI score had a significantly longer OS compared to patients with a poor LIPI score (19.2 vs. 12.6 months; P=0.010). The median OS in patients with a good and a poor mGPS was 16.8 and 4.3 months, respectively (P=0.029). In multivariate analysis, TMB was found to be significantly associated with PFS (HR, 0.38; 95% CI: 0.21-0.69; P=0.002), while LIPI score was found to be significantly associated with OS (HR, 0.50; 95% CI: 0.28-0.89; P=0.012).ConclusionsIn the present study, LIPI score was a significant determinant of OS in patients with advanced NSCLC who received ICIs; however, TMB was only associated with PFS and not associated with OS.

Project description:The era of immunotherapy has changed the face of how we approach treatment for many oncologic and hematologic malignancies. Lung cancer has been in the forefront of checkpoint inhibition for the past 2 years and has paved the path for other subspecialties. While PD-1 inhibitors nivolumab and pembrolizumab have been approved for non-small cell lung cancer (NSCLC), this review focuses on atezolizumab, its landmark studies, and ongoing trials. Atezolizumab is the first programmed death ligand 1 (PD-L1) inhibitor to receive US Food and Drug Administration (FDA) approval for metastatic NSCLC patients who have progressed on frontline chemotherapy. This approval was based on two open-label Phase II multicenter trials, POPLAR (NCT01903993) and BIRCH (NCT02031458). Both studies revealed a benefit in overall survival (OS), progression-free survival, and response rate in the atezolizumab arm when compared to single-agent docetaxol. There were also fewest Grade 3-5 treatment-related adverse events (TRAEs) in the atezolizumab cohort. The open-label randomized Phase III OAK trial (NCT02008227) further established the role of atezolizumab in previously treated NSCLC. This study compared atezolizumab with docetaxel in patients with advanced NSCLC (squamous or nonsquamous histologies) who had progressed on one to two prior chemotherapy regimens. OS in the PD-L1-enriched population was superior in the atezolizumab arm (n=241) at 15.7 months compared with docetaxel (n=222) at 10.3 months (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.58-0.93; p=0.0102). Patients lacking PD-L1 also had survival benefit with atezolizumab with a median OS (mOS) of 12.6 months versus 8.9 months with chemotherapy (HR 0.75, 95% CI 0.59-0.96). Benefit was noted in both squamous and nonsquamous NSCLC subsets and regardless of PD-L1 expressivity. As seen in the POPLAR and BIRCH studies, the toxicity profile was significantly better with immunotherapy. The future is unfolding rapidly as new checkpoint inhibitors are gaining FDA approval. It is still not known if these agents will be used in combination with chemotherapy, with other immune-modulating agents, radiation therapy, or all of the above. The results of these studies investigating their use in combination with chemotherapy agents, with other immunotherapy agents such as CTLA-4 inhibitors, and with radiation therapy, are eagerly awaited.

Project description:BackgroundPlasma D-dimer is of great significance for the clinical exclusion of tumor-related thrombosis. Previous studies have shown its predictive role in non-small cell lung cancer (NSCLC) treated with chemotherapy. However, whether pretreatment D-dimer could predict the efficacy and prognosis in NSCLC patients treated with immune checkpoint inhibitors (ICIs) remains unclear.MethodsAdvanced NSCLC patients treated with ICIs at the Chinese PLA General Hospital between January 2015 and March 2019 were enrolled. Patients were divided into a pretreatment normal D-dimer group (≤0.5 µg/mL) and high D-dimer group (>0.5 µg/mL). Optimization-based approach was applied to balance baseline covariates between the 2 groups, including age, sex, histological type, smoking history, stage, Eastern Cooperative Oncology Group Performance Status (ECOG PS), lines of treatment, ICI drugs, brain metastasis, treatment type, and D-dimer levels. Kaplan-Meier analysis and Cox proportional hazards model were used for analyzing survival data, including progression-free survival (PFS, the time from initial ICI treatment to PD or death), overall survival (OS, the time between initial ICI treatment and death), and hazard ratio (HR). Follow-up of all patients was performed by searching electronic medical records and counseling telephone. The follow-up cut-off date was July 6, 2020.ResultsThis study included 277 advanced NSCLC patients. Among the enrolled patients, 23.1% were female, 64.6% had non-squamous cell lung cancer, and 79.4% were stage IV. Univariate and multivariate analysis showed that pretreatment high D-dimer levels were independently associated with shortened PFS and OS (P<0.01). Subgroup analysis confirmed that pretreatment high D-dimer levels were associated with poor prognosis in most subsets. After balancing baseline covariates between the high D-dimer group and normal D-dimer group, the results indicated that patients with pretreatment high D-dimer levels had significantly shorter PFS [median: 6.4 vs. 11.5 months; HR, 1.70; 95% confidence ratio (CI): 1.25-2.37; P<0.001] and OS (median: 12.7 vs. 30.4 months; HR, 2.29; 95% CI: 1.54-3.41; P<0.001) than those with pretreatment normal D-dimer levels.ConclusionsPretreatment plasma D-dimer could serve as a convenient prognostic biomarker for advanced NSCLC patients receiving ICI treatment. Patients with pretreatment high D-dimer levels may have poor PFS and OS.

Dataset Information

Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study.

Publications

Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study.

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