29P - PTEN/CREBBP/NOTCH1 co-alterations with TP53/RB1 define molecular subtypes associated with primary therapy resistance in small cell lung cancer (SCLC)

Background

Comprehensive genomic testing is not considered standard of care for patients with small cell lung cancer (SCLC), as no molecular targeted therapies have been approved. Currently there is limited data on the clinical impact of molecular co-alterations in SCLC.

Methods

Patients with extensive-stage SCLC undergoing panel sequencing at initial diagnosis were enrolled in the study between December 1st, 2022, and December 1st, 2024. The panel sequencing was based on the examination of 324 genes and the introns of 34 genes known to be involved in rearrangements. Clinical data, including overall survival (OS) and real-world progression-free survival (rwPFS) to different treatment lines, were retrospectively assessed. Multivariate Cox regression models included patient characteristics, specific two-way interactions, OS, TMB, PD-L1 status, and molecular co-alterations detected by next-generation sequencing.

Results

A total of 29 patients with SCLC were analyzed, 18 (62%) males with a median age of 62 years (range: 41-78). Further molecular subgroups were classified based on their genomic co-alteration profile: 5 (17%) patients with NOTCH1/RB1/TP53 co-mutations, 4 (14%) patients with CREBBP/RB1/TP53 and 4 (14%) patients with PTEN/RB1/TP53 co-mutations. Median overall survival (mOS) was shortest in patients with CREBBP/RB1/TP53 at 3 months (ms) followed by patients with PTEN/RB1/TP53 with an mOS of 9 ms. The mOS across all enrolled patients was 14ms. The rwPFS to first-line treatment (rwPFS-1) was shortest in the PTEN/RB1/TP53 subgroup at 5.5 ms followed by 6 ms in both the NOTCH1/RB1/TP53 and CREBBP/RB1/TP53 subgroups. rwPFS-2 was 4.5 ms across all three subgroups.

Conclusions

Patients with co-alterations in any of the three genes PTEN, NOTCH1, or CREBBP to RB1 or TP53 showed inferior median overall survival (mOS), underlining that these co-alterations are poor risk factors associated with a dismal prognosis. Our findings based on real-world data indicate that the use of panel sequencing in extensive-stage SCLC patients identifies co-mutated subgroups associated with therapy resistance to current standard treatments and highlights the unmet need for targeted therapeutic strategies.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.