New AACR 2026 Findings on TP53 Co-Mutations and RET Fusion Partners in RET+ NSCLC

New research from the 2026 AACR Annual Meeting shows that certain co-mutations and fusion partners can affect how well RET-positive lung cancer responds to targeted treatment.

Key Findings:

TP53 co-mutations are associated with poorer outcomes in RET+ advanced NSCLC and a more inflammatory tumor microenvironment.
RET fusion partners significantly influenced prognosis and therapeutic benefit. Patients with KIF5B-RET fusions experienced shorter progression-free survival (PFS) and overall survival (OS) compared to CCDC6-RET patients, whereas those with CCDC6-RET fusions demonstrated a more indolent disease and greater relative benefit from selective RET inhibitors.

At the 2026 AACR Annual Meeting, Dr. Daniela Miliziano from Dr. Mihaela Aldea’s group presented compelling new findings on the prognostic and predictive impact of TP53 co-mutations and RET fusion partners in RET advanced non-small cell lung cancer (NSCLC).

The study sought to better understand why some patients with RET-positive lung cancer respond differently to targeted therapies, with a particular focus on the role of co-mutations and RET fusion partners in shaping clinical outcomes.

Researchers conducted a large multicenter retrospective analysis involving 510 patients with RET-positive advanced NSCLC across 47 international cancer centers. The cohort had a median age of 63 years, included 59% women, 36% ever-smokers, and consisted predominantly of adenocarcinoma histology (92%).

The analysis revealed several important findings:

TP53 co-mutations are associated with poorer outcomes in RET cancer

Patients harboring TP53-mutant tumors experienced:

Shorter progression-free survival (PFS)
Inferior overall survival (OS)
More aggressive disease biology

Importantly, TP53 status did not significantly predict whether patients derived greater benefit from selective RET inhibitors compared with chemotherapy ± immunotherapy in the first-line setting.

These findings suggest that TP53 mutation functions primarily as a prognostic biomarker, rather than a predictive marker for treatment selection.

Distinct tumor biology in TP53-mutant RET disease

Comprehensive genomic and transcriptomic analyses demonstrated that TP53-mutant tumors exhibit distinct biological characteristics, including:

Increased RB1 co-mutations
Higher tumor mutational burden (TMB)
Elevated PD-L1 expression
Enhanced proliferative signaling pathways
Increased M1 macrophage infiltration
Reduced neutrophil presence

Together, these findings support the concept that TP53-mutant RET-positive lung cancers represent a biologically distinct subgroup characterized by a more inflammatory tumor microenvironment.

RET fusion partners influence treatment benefit

The study also highlighted clinically meaningful differences between two of the most common RET fusion partners: KIF5B and CCDC6.

KIF5B partner had inferior progression-free survival (PFS) and overall survival (OS) compared with CCDC6.

CCDC6-RET fusions were associated with a more indolent disease course and greater relative benefit from selective RET inhibitors

This suggests that RET fusion partners may have both prognostic significance and predictive value for therapeutic response.

Why These Findings Matter

A deeper understanding of co-mutational status and RET fusion partner biology could help clinicians:

Better stratify patient risk
Identify patients at higher risk of early progression
Optimize treatment sequencing strategies
Molecular subgroups within RET-driven lung cancer may require differentiated treatment approaches
Inform the design of future biomarker-driven clinical trials

These findings further advance the field toward more personalized treatment approaches for patients with RET-rearranged lung cancer.

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Find more information on the abstract.

For scientific correspondence:
daniela.miliziano@gustaveroussy.fr