Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with nonsmall cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy.Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR-driven and ALK-driven diseases. K E Y W O R D Sdriver mutations, genomic aberrations, nonsmall cell lung cancer (NSCLC), targeted therapy, tyrosine kinase inhibitors (TKI) 18.9 months with osimertinib versus 10.2 months with firstgeneration EGFR inhibitors (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.37-0.57) 6 in patients with EGFR-mutant NSCLC and 37.8 months with alectinib versus 23.0 months with crizotinib, respectively (HR, 0.43; 95% CI, 0.32-0.58), 7 in those with ALK-driven NSCLC. This has guided a consecutive generation of TKIs to regulatory approval and has established them as the standard of care for patients with EGFR-mutant and ALK-rearranged tumors in the first-line context for advanced NSCLC.

8562 Background: Malignant Pleural Mesothelioma (MPM) has been characterized by an immune suppressive microenvironment. The immune checkpoint (IC) VISTA is notably expressed in MPM, in contrast to other IC proteins such us PD-L1. Recently, CD47 has been described as a possible diagnostic biomarker for MPM, although its impact in prognosis has not been established yet. Methods: This is a retrospective observational study of immunotherapy naïve MPM patients. Immunochemistry (IHC) assessment of PD-L1, VISTA and CD47 protein expression was performed on tissue microarray of 46 surgical samples. Means were compared using Mann-Whitney U test. Correlation was estimated using Pearson’s coefficients. Overall survival (OS) was assessed using Kaplan–Meier curves and Cox proportional hazard models. A two-sided alpha error of 0.05 was used to assess statistical significance. Statistical analysis was conducted with Stata/SE version 16.1. Results: A total of 46 patients, 71.7% (33/46) male, were included in our study. Among them, 77.8% (35/45) had stage IIIB-IV, 84.8% (39/46) had received systemic therapy and 16.7% (7/42) had undergone radical-intent surgery. Asbestos exposure was confirmed in 65,7% (23/35) patients. Regarding the histological subtype, 71.7% (33/46) were epithelioid (Ep) and 13.0% (6/46) non-epithelioid (NEp), including 5 sarcomatoid and 1 biphasic. In IHC analysis, VISTA and CD47 were expressed in 63.0% (29/46) and 58.7% (27/46), respectively, whereas only 28.3% (13/46) patients had positive PD-L1 expression (≥1%). Median expression of VISTA, CD47 and PD-L1 in tumor samples was 41.8 (95% IC 0.5 - 50.7), 26.3 (95% IC 0 - 45.8) and 0 (95% IC 0-0.5), respectively. VISTA and CD47 expression were significantly higher in the Ep subgroup vs. the NEp subgroup (VISTA 39.4% vs 7.2% p = 0.028; CD47 37.3 vs. 0.8 p = 0.01). Additionally, we found a significant positive correlation between VISTA and CD47 protein expression (Pearson's r = 0.55, p < 0.001), which was consistent with the results we found in an independent MPM patient series from TCGA PanCancer Atlas (N = 87) based on RNA expression (r = 0.46; p < 0.001). Median OS, available in 40/46 cases, was 16.6 months (95% CI 12.03-20.43). On multivariate analysis, CD47 ≥1% expression was significantly associated with longer OS (29.7 vs 10.53 months, HR 0.35, [IC 95% 0.14-0.86]; p = 0.02) after adjusting for histological subtype, PDL1 and VISTA expression. In contrast, PD-L1 ≥1% showed a trend towards worse prognosis (10.3 vs 19.3 months), without reaching statistical significance (HR 2.23 [95% IC 0.95-5.23]; p = 0.065). No OS differences were found regarding VISTA expression. Conclusions: To our knowledge, this is the first study to describe VISTA and CD47 correlation in MPM. Moreover, we demonstrate CD47 expression to be an independent prognostic marker in MPM, suggesting C47 may play a key role in tumor biology of MPM, for which further validation and functional studies are necessary.