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  • UNC1999 br Material and methods Clinical trial NCT

    2019-08-26


    Material and methods Clinical trial NCT00729612 (NCCN A-08) was a phase II trial of carboplatin and nab-paclitaxel in 63 patients with advanced or metastatic NSCLC conducted at The Ohio State University with the support of the National Comprehensive Cancer Network (NCCN) Oncology Research Program. The methods and results of the clinical study have been reported previously [17]. Briefly, treatment consisted of nab-paclitaxel (300 mg/m2 for the first 40 patients; dose reduced to 260 mg/m2 in the remaining 23 patients) and carboplatin area under the curve (AUC) 6 administered as an intravenous infusion on day 1 of a 21-day cycle. The study was conducted between September 2008 and December 2011. Eligible patients included previously untreated patients with contraindications to bevacizumab therapy, including squamous histology, hemoptysis, thromboembolic disease, requirement for therapeutic anticoagulation, or cavitary lung lesions. Major inclusion criteria included measurable disease, ECOG performance status of 0–2, and adequate organ function. Relevant exclusion criteria included recent major surgery, baseline peripheral neuropathy, or previous chemotherapy. All patients were consented as part of the trial to have their initial diagnostic specimen (i.e pretreatment specimen) evaluated for research purposes. The study was approved by the Institutional Review Board and conducted in accordance with Good Clinical Practice Guidelines.
    Results A total of 63 patients (mean age: 63 yrs) were accrued to the study, with 54 patients evaluable for response. The majority of patients (n = 48) had squamous cell NSCLC, 42 were male (66.7%), and 57 (90%) were current or former smokers (Supplemental Table 1). As reported previously, the overall response rate was 38% (24 partial responses and no complete responses), with median PFS of 5 months and median OS of 9.7 months [17].
    Discussion Chemotherapy remains a cornerstone of the treatment for patients with advanced NSCLC. For patients with LSCC, treatment with carboplatin and nab-paclitaxel has been shown to have increase rate of response compared to carboplatin and paclitaxel, and improvement in survival has been reported in some patient populations [24]. Recently, the addition of immune-checkpoint inhibitors (ICI) to chemotherapy in the first line treatment demonstrated improvement in survival for patients with NSCLC of all histologies compared to chemotherapy alone [1]. Platinum based chemotherapy in combination with ICI UNC1999 now an approved first line treatment for patients with metastatic NSCLC regardless of histology [1,4]. There remains an urgent need for reliable predictive biomarkers for both chemotherapy and immune-directed therapies. Tumor expression of PD-L1 and TMB have emerged as potential biomarkers for ICI treatment [2,13,25,26]. However, both are imperfect biomarkers due to inter-assay variability and tumor heterogeneity for PD-L1 [27,28] and the lack of standardization for TMB calculation and reporting [13,25]. The role of these biomarkers for patients treated with combination chemotherapy and ICI remains unclear. In this study, we retrospectively evaluated tumor samples from patients treated with carboplatin and nab-paclitaxel in a phase 2 trial to evaluate possible predictive biomarkers. We found that patients whose tumors have mutations in homologous recombination DNA repair pathways had shorter PFS and OS than those without homologous recombination mutations, as well as a trend toward lower response rate. Mutations in other pathways including JAK-STAT, MAPK-ERK, and IGF-1 were not associated with survival or response to treatment. Aberrations in the genes involved in DNA repair can lead to the development of cancer, and ineffective or defective DNA repair has long been evaluated as a biomarker or target for anti-neoplastic therapy [29]. Mutations leading to UNC1999 defective mismatch repair enzymes results in microsatellite instability which is associated with a response to ICI [30]. In NSCLC, DNA repair pathways have been evaluated as a predictor of clinical benefit from platinum-based chemotherapy. The DNA repair gene excision repair cross-complementation group-1 (ERCC1), a component of the nucleotide excision repair (NER) pathway, has been studied as a predictive biomarker for platinum-based chemotherapy in NSCLC [15,16]. However, encouraging findings of the predictive utility of ERCC1 protein expression were not replicated in subsequent studies, possibly due to differing isoforms of ERCC1 and limitations of the antibodies used for testing [31,32]. DNA repair pathway mutations have been shown to play a role in response to platinum-based chemotherapy in NSCLC including RAD50 [33,34]. Mutations in DNA repair pathways have also been associated with increased neo-antigen load and T-cell infiltration [21], as well as with overall tumor mutational burden in several cancers [35], including NSCLC [36]. These studies support further investigation of DNA repair pathways as a predictor of response to treatment.