Clinical outcomes of patients with PI3K pathway alterations by treatment type: The MD Anderson Cancer Center IMPACT 2 study.

3150 Background: The phosphatidylinositol 3-kinase (PI3K) pathway regulates cell growth, metabolism, and survival and is involved in immune modulation. Alterations in PI3K signaling drive tumor progression and drug resistance in advanced cancers and are associated with poorer prognosis. Herein, we report the clinical outcomes of patients with PI3K pathway alterations treated in the IMPACT 2 study (2014-2023; NCT02152254). Methods: Patients with advanced cancer underwent tumor biopsy and molecular profiling (CLIA-certified lab). Pathway analysis was conducted using the maftools R package. PI3K pathway alterations were defined as those involving the PI3K, AKT1, AKT2, AKT3, MTOR, PIK3CA, PIK3CB, PIK3R1, PTEN, TSC1, and TSC2 genes. Cases were discussed at Molecular Tumor Board meetings. Patients were treated on clinical trials with investigational agents that included matched targeted therapies (MTTs) when available. We analyzed the following outcomes by treatment type (MTT vs. non-matched targeted therapy [NTT] and immunotherapy [IO] vs. non-IO): objective response rate (ORR; complete response + partial response), clinical benefit rate (CBR; ORR + stable disease ≥4 months), progression-free survival (PFS), and overall survival (OS). Results: Of 491 treated patients with targetable alterations, 133 (27.1%) had PI3K pathway alterations (median age, 60.3 years [range, 20.5-79.8]; female, 60.9%; ECOG performance status 1, 85.7%; median number of prior therapies, 3 [range, 0-14]; liver metastases, 42.9%; >2 metastatic sites, 44.3%; high lactate dehydrogenase levels, 42.1%; low albumin level, 9%). The most common tumor types were breast cancer (18%), colorectal cancer (15%), and sarcoma (12%). Concomitant pathway alterations were TP53 (49.6% of patients), RTK/RAS (43.6%), and cell cycle (35.3%). Other tumor characteristics included PD-L1≥1%, 40.5% (32/79); MSI-H, 2.2% (2/89); and TMB-H, 10.3% (9/87). MTT included mTOR inhibitors, n=17; AKT inhibitors, n=5, and PI3K inhibitors, n=4. Clinical outcomes are shown in the Table. Conclusions: Taking into consideration the relatively limited use of AKT and PI3K inhibitors compared with mTOR inhibitors, no differences were noted in tumor response, PFS, or OS, by type of treatment. Other contributing factors may include the biological complexity of targeting this pathway, the small number of patients and/or the limited availability and antitumor activity of MTTs. Clinical trial information: NCT02152254 . All patients MTT NTT P IO Non-IO P N = 133 N=26 N=107 N=35 N=98 ORR (%) 9/112 (8.0) 1/23 (4.3) 8/89 (9.0) 0.68 4/32 (12.5) 5/80 (6.3) 0.51 CBR (%) 63/112 (56.3) 15/23 (65.2) 48/89 (53.9) 0.36 18/32 (56.3) 45/80 (56.3) 1.00 Median PFS, months(95% CI) 2.96(2.27, 4.57) 4.08(2.17, NA) 2.66(2.1, 4.37) 0.36 4.14(1.84, 9.86) 2.96(2.24, 4.37) 0.31 Median OS, months(95% CI) 7.79(6.54, 10.92) 9.04 (6.64, 14.99) 7.3 (5.59, 11.21) 0.64 8.75(5.36, 25.55) 7.17(6.18, 0.78) 0.40