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The evolving landscape of tissue-agnostic therapies in precision oncology.
Literature Information
| DOI | 10.3322/caac.21844 |
|---|---|
| PMID | 38814103 |
| Journal | CA: a cancer journal for clinicians |
| Impact Factor | 232.4 |
| JCR Quartile | Q1 |
| Publication Year | 2024 |
| Times Cited | 27 |
| Keywords | immunotherapy, precision oncology, targeted therapy, tissue‐agnostic therapy, tumor‐agnostic drug development |
| Literature Type | Journal Article, Review, Research Support, N.I.H., Extramural |
| ISSN | 0007-9235 |
| Pages | 433-452 |
| Issue | 74(5) |
| Authors | Vivek Subbiah, Mohamed A Gouda, Bettina Ryll, Howard A Burris, Razelle Kurzrock |
TL;DR
This review discusses the emergence of tumor-agnostic therapies, which focus on specific genetic anomalies rather than tumor origin, highlighting key milestones such as the FDA's approval of pembrolizumab and NTRK inhibitors. By exploring the rationale, current therapies, and future prospects, the authors emphasize the potential of these treatments to offer personalized options for patients with advanced solid tumors, marking a significant advancement in oncology.
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immunotherapy · precision oncology · targeted therapy · tissue‐agnostic therapy · tumor‐agnostic drug development
Abstract
Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.
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Primary Questions Addressed
- How do tissue-agnostic therapies impact the treatment outcomes for patients with rare tumors that lack traditional treatment options?
- What are the challenges in identifying and validating new biomarkers for tissue-agnostic therapies in clinical practice?
- How do patient advocacy groups influence the development and approval of tissue-agnostic therapies?
- In what ways could the integration of artificial intelligence and machine learning enhance the discovery of new tissue-agnostic targets?
- What are the long-term implications of tumor-agnostic therapies on healthcare costs and resource allocation in oncology?
Key Findings
Research Background and Purpose
Tumor-agnostic therapies signify a transformative approach in oncology, shifting the focus from tumor origin or location to specific genetic abnormalities driving cancer. The primary purpose of this review is to explore the development, approval, and future potential of tumor-agnostic therapies, emphasizing their role in providing personalized treatment options based on genomic biomarkers.
Main Methods/Materials/Experimental Design
The review employs a comprehensive literature analysis to assess various tumor-agnostic therapies. It discusses the historical context, recent FDA approvals, and the underlying mechanisms of these therapies.
The following flowchart summarizes the technological approach to tumor-agnostic therapies:
Key Results and Findings
- Historical Milestones: The FDA's approval of pembrolizumab in 2017 marked a significant advancement in tumor-agnostic therapies, focusing on microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR).
- Approved Therapies: Subsequent approvals included NTRK inhibitors for NTRK gene fusions, BRAF V600E inhibitors, RET fusion therapies, and others based on specific genomic markers.
- Clinical Efficacy: These therapies demonstrate efficacy across various cancer types, including pediatric and adult solid tumors, offering new treatment avenues for patients with advanced cancers.
Main Conclusions/Significance/Innovation
Tumor-agnostic therapies represent a significant innovation in cancer treatment, allowing for a more personalized approach based on genetic makeup rather than tumor type. This paradigm shift has the potential to enhance treatment outcomes and improve patient quality of life by providing targeted therapies that align with specific biomarkers.
Research Limitations and Future Directions
- Limitations: The review highlights challenges such as the complexity of tumor genetics, the need for robust biomarker validation, and the accessibility of these therapies for diverse patient populations.
- Future Directions: There is a call for ongoing research to expand the understanding of tumor-agnostic therapies, including the exploration of additional biomarkers, enhancing patient access, and integrating patient advocacy into the development process.
| Aspect | Details |
|---|---|
| Historical Milestones | Pembrolizumab approval in 2017, NTRK inhibitors, and others. |
| Approved Therapies | Pembrolizumab, NTRK inhibitors, BRAF V600E, RET fusion therapies. |
| Clinical Efficacy | Effective across various tumor types, including pediatric cancers. |
| Challenges | Complexity of tumor genetics, biomarker validation, accessibility. |
| Future Research Opportunities | Explore additional biomarkers, enhance patient access, integrate advocacy. |
This review underscores the importance of tumor-agnostic therapies in modern oncology, offering hope for personalized cancer treatment strategies.
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