Transcriptomic Analyses Of Molecular Subsets And Correlations With Clinical Outcomes From The phase 3 IMforte Study Of LURBINECTEDIN ( lurbi ) + ATEZOLIZUMAB ( atezo ) MAINTENANCE TREATMENT (Tx) In EXTENSIVE-STAGE SMALL CELL LUNG CANCER (ES-SCLC) .
Luis Paz-Ares
Hospital Universitario 12 de Octubre, Universidad Complutense and Ciberonc, Madrid, Spain .
Abstract
Transcriptomic analyses of pre-Tx tumor samples from the Phase 3 IMpower133 study identified 4 molecular subtypes with distinct clinical outcomes to first-line (1L) Tx with atezo and chemotherapy (chemo). Neuroendocrine (NE) tumors with low tumor-associated macrophage (TAM)/high T-effector (T-eff) signal demonstrated longer overall survival (OS) vs non-NE tumors with high TAM/high T-eff, suggesting that TAM contributes to resistance to atezo. Lurbi, an alkylating agent that modifies the tumor microenvironment and synergizes with immune checkpoint inhibitors, could enhance atezo activity. Lurbi + atezo as 1L maintenance Tx significantly improved progression-free survival (PFS) and OS vs atezo in patients (pts) with ES-SCLC in the Phase 3 IMforte study (NCT05091567). We report exploratory biomarker analyses from IMforte .
Methods :
Adults with Tx-naïve ES-SCLC, without disease progression after induction with atezo + chemo, received maintenance Tx of either 3.2 mg/m² lurbi + 1200 mg atezo or 1200 mg atezo q3w until unacceptable toxicity or disease progression. Transcriptomic analyses were conducted on pre-induction Tx tumor samples to identify subgroups with concordance to previously reported SCLC subtypes (SCLC-A, -N, -I-NE and -I-non-NE), immune gene expression signatures (TAM, T-eff) and SLFN11. Post-hoc exploratory analyses were conducted for correlation with IRF-assessed PFS and OS .
Of 483 randomized pts, 303 had samples for RNA sequencing. Of 303 tissue samples analyzed, 104 (34.3%) were classified as SCLC-A, 89 (29.4%) as SCLC-N, 46 (15.2%) as SCLC-I-NE and 64 (21.1%) as SCLC-I-non-NE. Clinical outcomes in the 303 pts (median [m] PFS: 5.5 vs 2.4 months [mo], hazard ratio [HR] 0.61; mOS: 13.5 vs 11.7 mo, HR 0.72, for lurbi + atezo [n = 150] vs atezo [n = 153], respectively) were consistent with the full analysis set. PFS and OS benefit from lurbi + atezo were comparable between NE (mPFS: 5.5 vs 2.1 mo, HR 0.58; mOS: 13.5 vs 11.7 mo, HR 0.74, for lurbi + atezo [n = 115] vs atezo [n = 124], respectively) and non-NE subtypes (mPFS: 4.6 vs 2.8 mo, HR 0.73; mOS: not reached vs 12.0 mo, HR 0.68, for lurbi + atezo [n = 35] vs atezo [n = 29], respectively). Pts with high TAM/high T-eff in the atezo arm had shorter OS vs those with low TAM/high T-eff. The addition of lurbi improved OS in the high TAM/high T-eff subgroup vs atezo alone (HR 0.56). SLFN11 expression was high at baseline across subtypes and had no predictive value for lurbi + atezo clinical benefit .
Conclusions :
The prevalence of the 4 SCLC subtypes and the TAM/T-eff pre-Tx data for IMforte are consistent with findings from IMpower133. PFS and OS were longer for lurbi + atezo vs atezo irrespective of molecular subset, though numerical trends suggest that lurbi may overcome TAM-mediated resistance to atezo.
