Dataset Information

Utilization of circulating cell-free DNA profiling to guide first-line chemotherapy in advanced lung squamous cell carcinoma.

ABSTRACT: Rationale: Platinum-based chemotherapy is one of treatment mainstay for patients with advanced lung squamous cell carcinoma (LUSC) but it is still a "one-size fits all" approach. Here, we aimed to investigate the predictive and monitoring role of circulating cell-free DNA (cfDNA) profiling for the outcome of first-line chemotherapy in patients with advanced LUSC. Methods: Peripheral blood samples of 155 patients from a phase IV trial and 42 cases from an external real-world cohort were prospectively collected. We generated a copy number variations-based classifier via machine learning algorithm to integrate molecular profiling of cfDNA, named RESPONSE SCORE (RS) to predict the treatment outcome. To monitor the treatment efficacy, cfDNA samples collected at different time points were subjected to an ultra-deep sequencing platform. Results: The results showed that patients with high RS showed substantially higher objective response rate than those with low RS in training set (P < 0.001), validation set (P < 0.001) and real-world cohort (P = 0.019). Furthermore, a significant difference was observed in both progression-free survival (training set, P < 0.001; validation set: P < 0.001; real-world cohort: P = 0.019) and overall survival (training set, P < 0.001; validation set: P = 0.037) between high and low RS group. Notably, variant allele frequency (VAF) calculated from an ultra-deep sequencing platform significantly reduced in patients experienced a complete or partial response after 2 cycles of chemotherapy (P < 0.001), while it significantly increased in these of non-responder (P < 0.001). Moreover, VAF undetectable after 2 cycles of chemotherapy was correlated with markedly better objective response rate (P < 0.001) and progression-free survival (P < 0.001) than those with detectable VAF. Conclusions: These findings indicated that the RS, a circulating cfDNA sequencing-based stratification index, could help to guide first-line chemotherapy in advanced LUSC. The change of VAF is valuable to monitor the treatment response.

SUBMITTER: Jiang T

PROVIDER: S-EPMC7681090 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Utilization of circulating cell-free DNA profiling to guide first-line chemotherapy in advanced lung squamous cell carcinoma.

Jiang Tao T Jiang Liyan L Dong Xiaorong X Gu Kangsheng K Pan Yueyin Y Shi Qin Q Zhang Guojun G Wang Huijuan H Zhang Xiaochun X Yang Nong N Li Yuping Y Xiong Jianping J Yi Tienan T Peng Min M Song Yong Y Fan Yun Y Cui Jiuwei J Chen Gongyan G Tan Wei W Zang Aimin A Guo Qisen Q Zhao Guangqiang G Wang Ziping Z He Jianxing J Yao Wenxiu W Wu Xiaohong X Chen Kai K Hu Xiaohua X Hu Chunhong C Yue Lu L Jiang Da D Wang Guangfa G Liu Junfeng J Yu Guohua G Li Junling J Zhang Henghui H Wu Lihong L Fang Lu L Liang Dandan D Zhao Yi Y Zhao Weihong W Xie Wenmin W Ren Shengxiang S Zhou Caicun C

Theranostics 20210101 1

<b>Rationale:</b> Platinum-based chemotherapy is one of treatment mainstay for patients with advanced lung squamous cell carcinoma (LUSC) but it is still a "one-size fits all" approach. Here, we aimed to investigate the predictive and monitoring role of circulating cell-free DNA (cfDNA) profiling for the outcome of first-line chemotherapy in patients with advanced LUSC. <b>Methods:</b> Peripheral blood samples of 155 patients from a phase IV trial and 42 cases from an external real-world cohort ...[more]

PMID: 33391473

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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:BackgroundEffective therapeutic options are limited for patients with advanced esophageal squamous cell carcinoma (ESCC). The incorporation of an immune checkpoint inhibitor and a molecular anti-angiogenic agent into the commonly adopted chemotherapy may produce synergistic effects. Therefore, we aimed to investigate the efficacy and safety of camrelizumab plus apatinib combined with chemotherapy as the first-line treatment of advanced ESCC.MethodsIn this single-arm prospective phase II trial, patients with unresectable locally advanced or recurrent/metastatic ESCC received camrelizumab 200 mg, liposomal paclitaxel 150 mg/m2 , and nedaplatin 50 mg/m2 on day 1, and apatinib 250 mg on days 1-14. The treatments were repeated every 14 days for up to 9 cycles, followed by maintenance therapy with camrelizumab and apatinib. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.ResultsWe enrolled 30 patients between August 7, 2018 and February 23, 2019. The median follow-up was 24.98 months (95% confidence interval [CI]: 23.05-26.16 months). The centrally assessed ORR was 80.0% (95% CI: 61.4%-92.3%), with a median duration of response of 9.77 months (range: 1.54 to 24.82+ months). The DCR reached 96.7% (95% CI: 82.8%-99.9%). The median PFS was 6.85 months (95% CI: 4.46-14.20 months), and the median OS was 19.43 months (95% CI: 9.93 months - not reached). The most common grade 3-4 treatment-related adverse events (AEs) were leukopenia (83.3%), neutropenia (60.0%), and increased aspartate aminotransferase level (26.7%). Treatment-related serious AEs included febrile neutropenia, leukopenia, and anorexia in one patient (3.3%), and single cases of increased blood bilirubin level (3.3%) and toxic epidermal necrolysis (3.3%). No treatment-related deaths occurred.ConclusionsCamrelizumab plus apatinib combined with liposomal paclitaxel and nedaplatin as first-line treatment demonstrated feasible anti-tumor activity and manageable safety in patients with advanced ESCC. Randomized trials to evaluate this new combination strategy are warranted.Trial registrationThis trial was registered on July 27, 2018, at ClinicalTrials.gov (identifier: NCT03603756).

Project description:BackgroundThe addition of bevacizumab or pembrolizumab to pemetrexed-platinum chemotherapy has produced significant clinical benefits to patients with untreated, advanced non-squamous non-small cell lung cancer (NSCLC) lacking targetable genetic aberrations. However, the direct comparison between these two first-line treatments needs to be investigated.MethodsWe retrospectively investigated the medical records of 102 patients with stage IIIB~IV non-squamous NSCLC, and without sensitizing EGFR/ALK/ROS1 alterations. All patients received pembrolizumab or bevacizumab plus pemetrexed-platinum chemotherapy as the first-line treatment between December 2018 to April 2021 at Fudan University Shanghai Cancer Center. Assessments included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). We also evaluated the prognostic biomarkers in the overall population and explored potential predictive biomarkers to aid the selection of optimal treatment regimens.ResultsThe median PFS was 10.0 months in the pembrolizumab group and 9.2 months in bevacizumab group (HR = 1.006; P = 0.982), while the median OS was not reached in either group (HR= 1.193; P =0.714). ORR was 36.7% versus 43.4% (P = 0.548) and DCR was 89.8% versus 92.5% (P = 0.735) in the pembrolizumab and bevacizumab groups, respectively. In the overall study population, baseline lymphocyte to monocyte ratio (LMR) >1.95 (HR = 0.312, P < 0.001) was an indicator of longer PFS. The presence of baseline bone metastasis (HR = 4.107, P = 0.009), baseline lactate dehydrogenase (LDH) >300 U/L (HR = 4.300, P = 0.025) and LMR ≤1.95 (HR = 5.291, P = 0.039) were associated with inferior OS. Baseline neutrophil-to-lymphocyte ratio (NLR) ≤3.10 was predictive of significantly favorable OS in the bevacizumab combination treatment (HR = 5.073, P = 0.039). The safety profiles were generally comparable between the two groups.ConclusionsIn patients with chemotherapy-naive, advanced, non-squamous NSCLC who lack driver mutations, the efficacy and safety of pembrolizumab and bevacizumab when combined with pemetrexed-platinum were comparable. For patients with baseline NLR ≤3.10, the bevacizumab combination therapy elicited significantly better OS benefits.

Dataset Information

Utilization of circulating cell-free DNA profiling to guide first-line chemotherapy in advanced lung squamous cell carcinoma.

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Utilization of circulating cell-free DNA profiling to guide first-line chemotherapy in advanced lung squamous cell carcinoma.

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