1387P Phase Ib study of LXH254 + LTT462 in patients with KRAS- or BRAF-mutant NSCLC

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.

Oncogenic alterations in advanced NSCLC: a molecular super-highway

“…Some resistance mechanisms may be overcome by novel multi-RAF and downstream ERK1/2 inhibitors, like LXH254 and LTT462, which are in early phase trials for BRAF or KRAS mutant NSCLC [ 188 ]. VS-6766 is one such RAF/MEK clamp that is being studied in BRAF mutant NSCLC (RAMP 202 NCT).…”

Novel RAF‐directed approaches to overcome current clinical limits and block the RAS/RAF node

“…For example, trials for the combination of LXH254 with LTT462 or trametinib (Table 1 ) are currently active but not recruiting NSCLC and melanoma patients (NCT02974725 and NCT04417621). In the former, a good safety profile and preliminary efficacy were observed in BRAF mutants [ 142 ], while in the latter, the combination with LTT462 or trametinib appears to be promising in NRAS‐mutant melanoma patients [ 143 ]. These findings provide new hope for RAS mutant patients; however, it is unclear whether these approaches can be applied to all scenarios where the signaling is dependent on dimerization (e.g., class II or III BRAF mutants).…”

BRAF-Mutated Non-Small Cell Lung Cancer: Current Treatment Status and Future Perspective

“…This study further confirmed the survival advantage of dabrafenib plus trametinib combination compared to single agents. Furthermore, LXH254, a novel BRAF/CRAF inhibitor, plus LTT462, an ERK1/2 inhibitor, was explored to evaluate its activity in patients with advanced/metastatic K-ras- or BRAF -mutant NSCLC in a phase Ib dose escalation study; preliminary analysis showed signs of efficacy in patients with BRAF -mutant NSCLC ( 78 ). Dose expansion is ongoing, and further efficacy analysis remains to be seen.…”

“…These reports revealed that RAS gene might a critical gene modulator in resistance mechanisms to BRAF/MEK inhibitors. The last European Society For Medical Oncology (ESMO) congress reported a novel combination of LXH254 and LTT462 that might overcome RAS-related resistance to BRAF/MEK inhibitors ( 78 ). This regimen has shown antitumor activity in BRAF -mutant and K-ras -mutated patients.…”