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

3151 Background: The receptor tyrosine kinase (RTK)-RAS signaling axis comprises distinct membrane receptors and downstream effectors that regulate cell proliferation and survival. Alterations in this pathway drive carcinogenesis and are associated with poor prognosis. We analyzed the outcomes of patients with RTK-RAS pathway alterations enrolled 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. RTK-RAS pathway alterations were defined as those involving EGFR, ERBB2, ALK, MET, KRAS, NRAS, BRAF , and MAP2K1/2 genes. Cases were discussed at Molecular Tumor Board meetings. Patients were treated in clinical trials with investigational agents, including 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, 216 (44%) had RTK-RAS pathway alterations (median age, 62.3 years [range, 21-80]; female, 54.1%; ECOG performance status 1, 90.3%; median number of prior therapies, 3 [range, 0-10]; liver metastases, 46.3%; > 2 metastatic sites, 34.7%; high LDH, 37.0%; low albumin level, 11.1%). The most common cancers were gastrointestinal (40.3%), head/neck (10.2%), and lung (10.2%). Other tumor characteristics included PD-L1≥1%, 43.6% (58/133); MSI-H, 1.3% (2/153); and TMB-H, 10.7% (16/150). Concomitant pathway alterations were TP53 (62.5%), PI3K (26.9%), and cell cycle (34.3%) pathways. MTT targeted EGFR, n = 8; FGFR, n = 10; HER2, n = 6; BRAF+MEK, n = 3; ALK, n = 1; and MEK, n = 4 among others (n = 24). Clinical outcomes are shown in the Table. Conclusions: The ORR was 14.6% in IO-treated patients vs. 5% in the non-IO-treated group (p = 0.049), although the difference was not significant. No differences in PFS or OS were observed by therapy type in patients with RTK-RAS pathway alterations. Novel MTTs (i.e., KRAS inhibitors) that were unavailable during the study period may improve the outcomes of these patients. Identification of molecular subsets benefiting from MTT is needed. Clinical trial information: NCT02152254 . All patients MTT NTT P value IO Non-IO P value N=216 N=56 N=160 N=57 N=159 ORR (%) 14/189 (7.4) 5/50 (10) 9/139 (6.5) 0.53 7/48 (14.6) 7/141 (5) 0.049 CBR (%) 110/189 (58.2) 31/50 (62) 79/139 (56.8) 0.62 27/48 (56.3) 83/141 (58.9) 0.87 Median PFS, months(95% CI) 2.96(2.3, 3.81) 3.09(2.66, 8.02) 2.89(1.97, 4.08) 0.5 2.3(1.61, 5.42) 3.19(2.66, 4.08) 0.72 Median OS, months(95% CI) 7.36 (5.69, 9.21) 5.88(4.7, 18.28) 7.79(5.69, 9.44) 0.10 6.61(4.6, 12.76) 7.46(5.69, 9.21) 0.85