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

3149 Background: Cell cycle pathway alterations are a hallmark of cancer. Disruption of cell cycle checkpoints results in genomic instability, uncontrolled proliferation and tumor progression to aggressive and treatment-resistant phenotypes. We report the clinical outcomes of patients with cell cycle 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. Cell cycle pathway alterations were defined as those involving the CCND1 , CCND2 , CCNE1 , CDK4 , CDK6 , CDKN2A , CDKN2B , and RB1 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 (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, 157 (32.0%) had cell cycle pathway alterations (median age, 61 years range, 21-82; female, 46.5%; ECOG performance status 1, 85.4%; median number of prior therapies, 3 range, 0-9; liver metastases, 40.8%; >2 metastatic sites, 36.3%; high LDH, 33.1%; low albumin, 10.8%). The most common cancers were sarcoma (19.7%), other gastrointestinal (17.2%), head and neck (14.0%), lung (9.6%), and breast (8.3%). Other tumor characteristics included PD-L1 ≥1%, 45.6% (41/90); MSI-H, 2.0% (2/102); and TMB-H, 13.0% (13/100). Concomitant pathway alterations were TP53 (67.5%), PI3K (29.9%), and RTK-RAS (47.1%). MTT targeted CDK4/6, n=9; BET, n=2; ATR, n=1; PKMYT1, n=1; and ACAT, n=1. Clinical outcomes are shown in the Table. Conclusions: Very few investigational therapies that target the cell cycle pathway were available. No differences were noted in tumor response, PFS, or OS by type of therapy, likely owing to the limited antitumor activity of the MTTs and the complexity of targeting this pathway. Novel and effective MTTs are needed for tumors with cell cycle dysregulation. Clinical trial information: NCT02152254 . All patients MTT NTT P IO Non-IO P N=157 N=14 N=143 N=40 N=117 ORR (%) 7/135 (5.2) 0/12 (0) 7/123 (5.7) 1.00 4/33 (12.1) 3/102 (2.9) 0.14 CBR (%) 76/135 (56.3) 6/12 (50.0) 70/123 (56.9) 0.76 19/33 (57.6) 57/102 (55.9) 1.00 Median PFS, months(95% CI) 3.75(2.66, 5.49) 3.75(1.81, NA) 3.58(2.66, 5.52) 0.81 2.96(1.81, 8.98) 3.75(2.66, 5.59) 0.98 Median OS, months(95% CI) 8.48(7.1, 11.21) 6.66(5.56, NA) 8.61(7.17, 11.57) 0.40 7.46(5.19, 17.42) 8.48(7.1, 11.57) 0.72