Caris Life Sciences has published a landmark study in Nature Communications that provides unprecedented insights into the real-world effectiveness of tissue-agnostic cancer therapies. The research, analyzing over 295,000 patient samples, represents the largest real-world cohort of tissue-agnostic indications reported to date and reveals critical findings about these powerful "pan-cancer" treatments.
One in Five Cancer Patients Eligible for Tissue-Agnostic Therapies
The comprehensive analysis found that 21.5% of all cancer patients harbor molecular alterations making them candidates for tissue-agnostic drugs such as pembrolizumab and larotrectinib. These therapies target specific genetic or molecular features of tumors rather than their anatomical location or tissue type.
"By harnessing the power of Caris' large clinico-genomic dataset, we have shown that tissue-agnostic drugs produce different outcomes in different tissues," said George W. Sledge, Jr., MD, EVP and Chief Medical Officer of Caris and study author. "We additionally found evidence of clinical benefit beyond approved indications, illustrating the enormous potential of real-world data to inform the clinical use of tissue-agnostic drug approvals, potentially improving patient outcomes."
Importantly, approximately 5% of patients who lacked any tumor-specific indication were found to carry a tissue-agnostic indication, making them eligible for these treatments when they might otherwise have had limited therapeutic options.
Variable Efficacy Across Cancer Types
The study revealed significant differences in treatment outcomes across tumor types for patients receiving tissue-agnostic therapies. For TMB-High (tumor mutational burden-high) cancers treated with pembrolizumab, median time on treatment ranged from 4.9 months for non-small cell lung cancer to just 2.4 months for small cell lung cancer.
Similar variations were observed for MSI-High/MMRd (microsatellite instability-high/mismatch repair deficient) cancers, with time on treatment ranging from 3.0 months for prostate cancer to 6.3 months for colorectal adenocarcinoma.
These findings challenge the notion that tissue-agnostic therapies work equally well across all cancer types, suggesting that while the molecular target may be the same, the underlying biology of different tumor types significantly influences treatment response.
Underutilization of Effective Therapies
Despite the proven efficacy of tissue-agnostic therapies, the study uncovered poor clinical uptake for rare indications. For example, only about one-third of patients with NTRK gene fusions received the highly effective NTRK inhibitors larotrectinib or entrectinib in any given year.
This finding highlights a critical gap in clinical practice and underscores the need for enhanced physician education about rare molecular alterations and their associated targeted therapies.
Expanding Treatment Options
The research also demonstrated that clinical benefits extended beyond the tumor types and drugs investigated in the original clinical trials, suggesting potential for expanding therapeutic avenues for tissue-agnostic indications.
"Caris has generated one of the most extensive clinico-genomic datasets in oncology through years of comprehensive molecular profiling," said Caris President and study author David Spetzler, MS, PhD, MBA. "Our advanced analyses of real-world data now enable us to uncover findings of clinical value for large patient populations. One in five patients in our study were eligible for a tissue-agnostic drug, which demonstrates the widespread impact of our findings."
Comprehensive Molecular Profiling Approach
The study utilized Caris' proprietary platform, which provides Whole Exome Sequencing (WES) and Whole Transcriptome Sequencing (WTS) as standard practice. The platform sequences at sector-leading depth of coverage, which directly correlates to increased accuracy and detection of low-frequency biomarkers of relevance.
The comprehensive approach reveals an individualized molecular blueprint of a patient's disease, providing actionable, personalized treatment pathways and driving superior clinical outcomes.
Implications for Precision Oncology
This landmark study has significant implications for the field of precision oncology. By demonstrating the widespread applicability of tissue-agnostic therapies and identifying patterns of response across different tumor types, the research provides valuable guidance for clinicians in treatment selection.
The findings also suggest that real-world evidence can support the extension of tissue-agnostic indications to other members of the same drug class, potentially expanding treatment options for patients with limited alternatives.
As molecular profiling becomes increasingly integrated into routine cancer care, understanding the nuances of tissue-agnostic therapies will be crucial for optimizing patient outcomes and advancing the promise of precision medicine in oncology.
