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

Our plain-English summary of Evaluating Tissue-Agnostic Approvals in Thoracic and Head and Neck Malignancies, by D.T. Jones, R.K. Nanda, A.A. Hussain, et al (Cancers, 2026).

The study

• Authors: D.T. Jones, R.K. Nanda, A.A. Hussain, R. Hattin, Y.M. Myat, R. Thawani, J. Cetnar, M. Shanshal, K.Z. Thein, S. Kummar
• Journal: Cancers
• Published: 2026;18(5)
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This article was a review, not a new study of patients, and it did not discuss asbestos. The authors looked at the evidence behind nine U.S. Food and Drug Administration approvals, made from 2017 to 2024, of cancer drugs chosen by a tumor's molecular marker rather than by the organ where the cancer started. They took data from the main trials behind each approval and counted how many patients had chest (thoracic) or head and neck cancers. The article's abstract reported that these cancers made up fewer than 8% (n = 290) of about 3800 enrolled patients. Small-cell lung cancer, mesothelioma and thymic carcinomas together made up less than 1%. In the pembrolizumab data for MSI-H tumors, 4 patients had mesothelioma. In the pembrolizumab group with high tumor mutational burden, the single mesothelioma patient did not respond. Only two of nine trials reported prespecified brain (CNS) endpoints. The authors concluded that these cancers remain underrepresented and that small, mixed subgroups preclude conclusions for specific cancer types. They noted that they did not perform a pooled meta-analysis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review (described as a narrative systematic review) of the pivotal trials and FDA documents behind the nine FDA tissue-agnostic approvals; no new patient data
• Who was studied: Pivotal trial datasets supporting nine FDA tissue-agnostic approvals (2017 to 2024) across six biomarker classes, about 3800 patients in total, with a focus on thoracic and head and neck cancers
• Exposure: No asbestos exposure was studied. The 'exposures' were biomarker-selected cancer drugs: pembrolizumab, dostarlimab, larotrectinib, entrectinib, repotrectinib, dabrafenib plus trametinib, selpercatinib and fam-trastuzumab deruxtecan
• Main results:
  • Across the pivotal datasets (3800 patients), thoracic and head and neck cancers accounted for fewer than 8% (n = 290) of enrolled patients
  • Small-cell lung cancer, mesothelioma and thymic carcinomas together contributed less than 1% of enrolled patients
  • Head and neck cancers made up 140 patients (3 to 4%), mostly secretory salivary carcinoma in NTRK trials
  • In the KEYNOTE-158 data supporting pembrolizumab for MSI-H/dMMR tumors, the thoracic cancers included small-cell lung cancer (n = 4) and mesothelioma (n = 4)
  • In the KEYNOTE-158 TMB-High group (102 patients, overall response rate 29%), 10 of 34 small-cell lung cancer patients responded, and the single mesothelioma patient did not respond
  • Only two of the nine trials (22%) reported prespecified CNS (brain) endpoints, and RNA-based fusion testing was used in fewer than 40%
• The authors' conclusion: The authors concluded that thoracic and head and neck cancers remain underrepresented in the evidence behind these approvals. In their view, most approvals rely on single-arm basket studies whose small, mixed subgroups preclude conclusions for specific cancer types.
• Limitations the authors state:
  • The review summarized approvals and trial characteristics rather than performing a pooled meta-analysis, and no formal PRISMA flow diagram was used
  • Small thoracic and head and neck subgroups in the underlying trials limited statistical power for conclusions about specific cancer types
  • For the TMB-High subgroups, including the one mesothelioma patient, the numbers were so small that the results are descriptive only

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Systematic Review, Microsatellite Instability (MSI-H), BRAF V600E, HER2, Lung Cancer, Mesothelioma, Carcinoma.

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