• Author
    Olga Tsvetkova
  • Discovery PI

    Aaron Lisberg, MD

  • Project Co-Author

    Sofi Castanon

  • Abstract Title

    PIK3CA and PTEN alterations may be associated with shorter progression-free survival in patients with advanced lung cancer treated with a novel antibody–drug conjugate: an exploratory analysis.

  • Discovery AOC Petal or Dual Degree Program

    Basic, Clinical, & Translational Research

  • Abstract

    Keywords: Lung cancer, novel therapy, PIK3CA, PTEN, biomarker

    Background: Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody–drug conjugate carrying a topoisomerase I cytotoxic payload. Although Dato-DXd demonstrated superior efficacy compared with historical standard options in advanced EGFR-mutated NSCLC after progression on EGFR-directed therapy and platinum chemotherapy, it failed to reach efficacy objectives in the broader NSCLC population and showed inferior outcomes in squamous cell carcinoma. The mechanisms behind the differential efficacy observed with Dato-DXd are under investigation. Preclinical studies have shown that the dynamics of TROP2 expression can play a role in efficacy. However, emerging evidence suggests that TROP2 alone is insufficient to explain the variability in clinical activity of Dato-DXd, as cytotoxic payload-related factors may also be implicated. Additional studies are needed to assess whether the presence of driver mutations affecting intracellular signaling can contribute to the differential efficacy of Dato-DXd in lung cancer. Activating mutations in PIK3CA and loss-of-function alterations in PTEN play a significant role in resistance to systemic therapy and may also modulate the response to the cytotoxic payload of Dato-DXd.

    Objective: To evaluate whether the presence of alteration in PIKCA/PTEN is associated with differential response to Dato-DXd in lung cancer.

    Methods: In this retrospective exploratory analysis, genomic testing results from 35 patients with lung cancer previously enrolled in the TROPION-PanTumor01, TROPION-Lung01, and TROPION-Lung05 trials at UCLA were reviewed for PIK3CA and PTEN alterations. Eight patients with canonical activating PIK3CA mutations and/or PTEN loss were classified as PI3K/PTEN-altered.Twenty-seven patients without PIK3CA or PTEN alterations were included in the control group. Progression-free survival (PFS) was evaluated using Kaplan-Meier methods and multivariable Cox proportional hazards models adjusted for dose at cycle 1, prior lines of therapy, and histology. Statistical analyses were performed in R. 

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