1386P Anlotinib combined with whole brain radiation therapy (WBRT) for advanced non-small cell lung cancer with multiple brain metastases: An open-label, single-arm phase II trial

Abstract

Background: Tumor tissue has a complex structure, which includes different cellular and matrix components. Ex vivo tissue explants retain individual features of original neoplasms and may be used for personalized testing of the drug sensitivity. The existing morphological methods for evaluation of drug response in alive tissue sections are extraordinarily time-consuming and have poor interlaboratory reproducibility. We attempted to establish RNA-based expression assays, which may supplement or replace the existing pathology-based analyses.Methods: Fresh tumor tissues were obtained from patients with non-small cell lung cancer (NSCLC) undergoing surgery. Tumor 0.4-mm-thick slices were generated with a tissue chopper. NSCLC explants were cultured for 24 hours in a standard media containing either cisplatin (30 mkg/ml) or gefitinib (4 mkg/ml) or no drug (control). Samples from the same tumor sections were analyzed in parallel both with RNAexpression tests (PCR, RNAseq) and immunohistochemistry (IHC).Results: 234 individual explants from 16 NSCLCs were obtained. The expression level of Ki-67 determined by PCR showed only limited correlation with percentage of Ki-67 positive cells identified by IHC (R 2 ¼0.27). MKI-67 (Ki-67 encoding gene) and TPX2 were chosen as proliferation markers for RNA expression tests. They showed nearly identical changes in expression upon drug exposure. As expected, EGFR-mutated tumors demonstrated more pronounced decline of expression of RNA proliferation markers in response to gefitinib as compared to EGFR wild-type NSCLCs. Interestingly, EGFR-mutated cancers appeared to be more sensitive to cisplatin as well. Selected tumor sets were further subjected to transcriptome RNAseq analysis. EGFR-mutated explants had significantly higher expression level of MAGEA3 than the wild-type samples. Furthermore, MAGEA3 expression in EGFR-mutated tumors was decreasing during incubation with gefitinib but not with cisplatin. Several genes were responsive to cisplatin exposure. HEXIM1, NXF1, POLG2 and CCL7 appeared to be the most promising markers of cisplatin sensitivity.Conclusions: RNA expression markers are promising reporters of individual tumor drug responsiveness.Legal entity responsible for the study: The authors.

Whole-Brain Radiotherapy Combined With Anlotinib for Multiple Brain Metastases From Non-small Cell Lung Cancer Without Targetable Driver Mutation: A Single-Arm, Phase II Study

“…29 Recently, a phase II study of anlotinib combined with WBRT reported significant therapeutic efficacy of this regimen and manageable AEs in patients with advanced NSCLC with multiple BMs. 28 Among the 10 patients, 6 achieved PR and 3 had SD during the intracranial evaluation. The 6-month iPFS rate was 87.5%.…”

“… 24 Cranial radiotherapy can increase the permeability of the BBB, which may increase anlotinib content in brain tissue; thus, the curative effect of cranial radiotherapy combined with anlotinib may be superior to that of cranial radiotherapy alone for NSCLC patients with no specific gene mutation. 25 A previous retrospective study 26 and 2 prospective studies 27 , 28 suggested that anlotinib combined with radiotherapy for BM has satisfactory efficacy with tolerable toxicity. A phase III trial, ALTER 0303, showed that anlotinib improved the PFS and OS as a second- or third-line therapy for advanced NSCLC.…”