# Evaluating Tissue-Agnostic Approvals in Thoracic and Head and Neck Malignancies

## TL;DR

This paper reviews how cancer drug approvals are shifting to target molecular markers instead of tumor location, but thoracic and head and neck cancers are underrepresented in these studies.

## Contribution

The paper systematically evaluates the representation and applicability of tissue-agnostic therapies in thoracic and head and neck cancers, highlighting gaps in clinical trial data.

## Key findings

- Thoracic and head and neck cancers accounted for fewer than 8% of patients in pivotal tissue-agnostic trials.
- Most approvals rely on single-arm basket studies with small, heterogeneous subsets.
- RNA-based fusion testing was used in less than 40% of trials, limiting diagnostic consistency.

## Abstract

This review examines how recent cancer drug approvals have shifted from organ-specific indications to biomarker-defined, or “tissue-agnostic,” approaches. These therapies target molecular alterations that drive tumorigenesis across histologies, including NTRK fusions treated with larotrectinib, entrectinib, and repotrectinib; RET fusions responsive to selpercatinib; BRAF V600E mutations targeted with the combination of dabrafenib and trametinib; HER2 overexpression (IHC 3+) treated with fam-trastuzumab deruxtecan-nxki; microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) tumors treated with pembrolizumab or dostarlimab; and high-tumor-mutational-burden (TMB-H) tumors eligible for pembrolizumab. Despite these advances, thoracic and head and neck cancers have been inconsistently represented in the pivotal trials supporting such approvals. This review synthesizes evidence from all nine U.S. Food and Drug Administration tissue-agnostic approvals, critically evaluates their applicability to thoracic and head and neck malignancies, and highlights emerging biomarkers and ongoing challenges related to molecular testing, therapeutic resistance, and equitable access. These insights aim to inform trial design and enhance the implementation of precision oncology in underrepresented tumor types.

Background/Objectives: Tissue-agnostic therapy has transformed oncology by enabling treatment selection based on molecular alterations rather than tumor origin. Since 2017, nine U.S. Food and Drug Administration approvals across six biomarker classes have defined this paradigm. Thoracic and head and neck (H&N) cancers have been underrepresented in the registrational evidence supporting these approvals. This review systematically evaluated biomarker representation, histologic distribution, and clinical applicability of tissue-agnostic therapies in thoracic and H&N malignancies. Methods: A narrative systematic review was conducted using PubMed, ClinicalTrials.gov, and regulatory documents for all tissue-agnostic approvals between January 2017 and October 2025. Data were extracted from pivotal trials, including total enrollment, objective response rate (ORR), histologic distribution, and thoracic/H&N representation. Emerging biomarkers and resistance mechanisms were assessed from phase I–III studies and basket trials. Results: Nine tissue-agnostic approvals encompassing six biomarkers were identified: MSI-H/dMMR, TMB-High, NTRK, RET, BRAF V600E, and HER2 (IHC 3+). Across pivotal datasets (3800 patients), thoracic and H&N cancers accounted for fewer than 8% (n = 290) of enrolled patients. Thoracic representation was dominated by non-small-cell lung cancer (NSCLC) in RET, NTRK, and HER2 programs (150 patients, 4%), while small-cell lung, mesothelioma, and thymic carcinomas contributed <1% combined. H&N cancers comprised 140 patients (3–4%), primarily secretory salivary carcinoma in NTRK trials (n = 12–20), thyroid carcinoma in BRAF (n = 36) and RET (n = 45) programs, and rare HER2-positive salivary duct carcinomas. Conventional HNSCC and sinonasal cancers were limited to 1–2 cases per trial. Only two of nine trials (22%) reported prespecified CNS endpoints, and RNA-based fusion testing was employed in <40%, underscoring diagnostic variability and limited applicability. Conclusions: Although tissue-agnostic therapy has expanded the reach of precision oncology, thoracic and H&N cancers remain underrepresented in registrational evidence. Most approvals rely on single-arm basket studies with small, heterogeneous subsets that preclude histology-specific conclusions. Future research should prioritize histology-enriched trial designs, standardized molecular diagnostics, and real-world validation to establish reliable, equitable standards of care for these underrepresented malignancies.