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SUMMARY The PI3K/AKT/mTOR pathway is commonly activated in non-small-cell lung cancer. It plays important roles in promoting oncogenesis in lung cancer and mediating resistance to EGF receptor tyrosine kinase inhibitors. Targeted agents against the components of this pathway are currently in development and their clinical benefits remain to be defined. This review provides an overview of the pathway dysregulation and novel agents targeting the pathway in lung cancer. In addition, potential predictive biomarkers guiding patient selection for targeted PI3K/AKT/mTOR inhibition is also discussed.

62 Background: Trastuzumab stimulates HER2-specific T cell responses and increases tumor PD-L1 expression, and anti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab. Oxaliplatin can further enhance T-cells by activating dendritic cells. We conducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab. Methods: Patients with previously untreated HER2 IHC 3+ or FISH+ tumors irrespective of PD-L1 status received intravenous P 200 mg flat dose, T 6 mg/kg (after 8 mg/kg load), O 130 mg/m2 every 3 weeks and oral C 850 mg/m2 2 weeks on/1 week off (or 5-FU continuous infusion). The primary endpoint was 6-months PFS; with target accrual of 37 patients. Secondary endpoints included safety, OS, ORR, exploratory biomarker analysis and 89Zr-trastuzumab PET. Results: 100% of the 24 evaluable pts had tumor regression (ranging from -22% to -100%). The RECIST 1.1 ORR was 83% [95%CI: 63%-95%] (17 PR , 3 CRs), median PFS 11.4 [95%CI: 6-15] months. In 31 pts evaluable for toxicity, common ( > 10%) adverse events included Gr 2 fatigue (35%), Gr 2/3 nausea (35%), Gr 2 diarrhea (26%), Gr2 AST/ALT elevation (16%), Gr2 neutropenia (16%). Immune related toxicities observed in 1 pt each: Gr 2 colitis, Gr 3 interstitial nephritis, Gr 3 AST/ALT elevation; and resolved with steroids. Of 21 patients with available material, 6 (29%) expressed PD-L1. Of these 6 patients, 5 had a PR while 1 had a CR. ERBB2 amplification was evident on NGS in 56% of pre-treatment tumors from 25 tested patients, while the remaining were ERBB2- by NGS likely due to tumor heterogeneity or low tumor content. Mutations in TP53 and alterations in KRAS occurred in 68% and 16%, respectively. To identify mechanisms of acquired resistance, patients are biopsied at progression. In 6 paired sample analysis, we identified two patients with loss of ERBB2 amp at progression. Conclusions: Updated survival, correlative studies and 89Zr-trastuzumab PET imaging will be presented. These promising preliminary safety and efficacy results led to initiation of a definitive phase III Keynote 811 trial. Clinical trial information: NCT02954536.