Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial

Abstract

ObjectiveRobust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients.MethodsA total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mg/m2, day 3, every 3 weeks) for 4–6 cycles, followed by maintenance therapy with sintilimab (200 mg, day 1, every 3 weeks) until disease progression or unacceptable toxic effects. Blood samples were prospectively collected at baseline, and after 2 cycles of treatment (6 weeks post-treatment). All samples were subjected to targeted next-generation sequencing with a panel of 448 cancer-related genes. The landscape of high-frequency genomic profile of baseline and 6th week was described. Major molecular characteristics in preselected genes of interest associated with response to second-line chemoimmunotherapy were analyzed. The curative effects and prognosis of patients were evaluated.ResultsPatients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days; p<0.0001) and overall survival (47 vs 467 days; p =0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p =0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR=100 (95% CI 4.10 to 2503.00), p=0.005).ConclusionctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.

Sintilimab with two cycles of chemotherapy for the treatment of advanced squamous non-small cell lung cancer: a phase 2 clinical trial

“…Song et al monitored ctDNA dynamics in a longitudinal cohort of advanced NSCLC patients and found that the ctDNA clearance at any timepoint during treatment was associated with a longer PFS 38 . Han et al evaluated the predictive value of ctDNA clearance (C2) in second-line chemotherapy (6 weeks post-treatment), and found it to be an independent risk factor for PD or death 39 . The Camel-Sq trial revealed that the mean variant allele frequencies of variants at C2 had a strong association with ORR.…”

Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review

“…The Clopper-Pearson method for the estimation of objective response rates and disease control, and the use of two-sided tests at the 0.05 significance level, as in the study of docetaxel plus sintilimab, highlight the rigor in comparing treatments' efficacy [63]. Furthermore, advanced techniques like cross-validation for the determination of the optimal cut-off for the bTMB and the minimum p-value approach reflect the ongoing evolution of statistical methods in oncological research [54].…”

Clinical application of liquid biopsy based on circulating tumor DNA in non-small cell lung cancer

“…Currently, numerous studies have provided evidence that ctDNA-based biomarkers are essential for guiding immunotherapy and predicting its subsequent efficacy ( Wang et al, 2022c ; Peters et al, 2022 ; Sun et al, 2022 ). One such study by Han et al employed ctDNA to forecast the effectiveness of sintilimab plus docetaxel in the second-line treatment of advanced NSCLC ( Han et al, 2022 ). Blood samples were prospectively collected at baseline and after 2 cycles of treatment (6 weeks after treatment) to describe the landscape of high-frequency genomic profiles at baseline and week 6 ( Han et al, 2022 ).…”

“…One such study by Han et al employed ctDNA to forecast the effectiveness of sintilimab plus docetaxel in the second-line treatment of advanced NSCLC ( Han et al, 2022 ). Blood samples were prospectively collected at baseline and after 2 cycles of treatment (6 weeks after treatment) to describe the landscape of high-frequency genomic profiles at baseline and week 6 ( Han et al, 2022 ). Major molecular features of preselected genes associated with response to second-line chemoimmunotherapy were analyzed.…”

“…Results indicated that patients exhibiting ctDNA clearance at the sixth week demonstrated decreased tumor volume, while those with ctDNA positive at the sixth week recorded an increase in tumor volume. Notably, patients with a positive sixth-week ctDNA had significantly shorter PFS (91 vs. NR days; p < 0.0001) and OS (47 vs. 467 days; p = 0.0039) compared to those with ctDNA clearance at week 6, leading to the conclusion that ctDNA clearance at the sixth week independently served as a risk factor for progression or death (HR = 100 (95%CI = 4.10–2503.00), p = 0.005) ( Han et al, 2022 ). These findings indicate that ctDNA status and ctDNA mutation clearance could potentially serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.…”