P1.14-23 Resistance Mechanisms to Osimertinib Treatment in EGFR-Mutated Lung Cancer in a Real Life Cohort

Abstract

Background: Genomic instability is a universal hallmark of all cancers. Many of the most commonly used chemotherapeutic agents target this genomic instability by directly damaging the DNA, which results in tumour cell death. Our previous work has revealed that loss of SASH1 is associated with impaired apoptosis and increased cellular proliferation. A new generation of drugs have been developed that target the DNA repair enzyme PARP to induce DNA damage and cell death. SASH1 (SAM and SH3 domain containing protein 1) has been described as a tumour suppressor and in support of this SASH1 mRNA levels are decreased in lung, breast, thyroid and colorectal cancers. Our data demonstrates that SASH1 functions in the repair of DNA damage and loss of SASH1 protein expression could be used as a companion diagnostic for PARP inhibitors. Method: SASH1 IHC staining of lung cancer was correlated with patient survival. DNA damage repair was assessed following the depleted of SASH1 (siRNA). SASH1 protein levels in cell lines were correlated to PARP inhibitor sensitivity. Result: A lung cancer tissue microarray (TMA) of 225 patients was assessed for SASH1 protein level. Low SASH1 levels were associated with an improved patient prognosis in adenocarcinoma on univariate analysis (p ¼ 0.03). Analysis of DNA repair pathways demonstrated that SASH1 plays a role in homologous recombination (HR). Based on this observation, the impact of SASH1 expression on sensitivity to PARP inhibitors was explored. An inverse correlation between SASH1 levels and sensitivity to Olaparib was identified in lung cancer cell lines Figure 1 (R 2 ¼ 0.882). We subsequently analysed Olaparib sensitivity in a panel of SASH1 depleted lung cancer cells that demonstrated increased Olaparib sensitivity. Conclusion: Our results indicate that SASH1 protein expression is a prognostic factor in lung cancer, high levels being associated with a worse prognosis in adenocarcinoma. Low SASH1 expression

Reduced frequency dosing of osimertinib in EGFR-mutant non-small cell lung carcinoma: Real world data

“…The corresponding e cacy parameters noted in the patients who received chemotherapy in the AURA3 trial were an ORR of 31%, median PFS of 4.4 months (95% CI, 4.2-5.6) and median OS of 22.5 months (95% CI, 20.2, 28.8). A recent retrospective European study in 135 patients reported that chemotherapy after progression on rst line TKI resulted in a median PFS of 5.4 months (95% CI, 4.7-6.1), and median OS of 15.3 months (95% CI, 116 − 18.9) [40]. In an earlier real world study report, we found that osimertinib at 80 mg a day in the second line and beyond setting for 17 patients with EGFR T790M mutation led to an ORR of 55% and DCR of 90.9%; survival data were immature at the time of this report [41].…”