Results of these trials are summarized in Table 2. More recently, clinical trials have established a role for ICI and ICI-based combinations in multiple settings for the treatment of clear cell and non-clear cell RCC. High-dose IL-2 maintains a category 2B recommendation for treatment of metastatic disease in certain circumstances by the National Comprehensive Cancer Network (NCCN). In addition, clear cell RCC was one of the first cancers to be treated with cytokine-based immunotherapy such as recombinant IFN-⍺ and high-dose IL-2. Targeted therapies with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs), mammalian target rapamycin (mTOR) inhibitors are widely used in first and second-line treatment in both metastatic clear cell and non-clear cell RCC. RCC is subclassified into two groups: clear cell histology which makes up 75–80% of cases and non-clear cell histology which includes papillary, sarcomatoid, chromophobe subtypes. Renal cell carcinomas (RCC) are the eighth most common cancer diagnosis with an estimated 74,000 new cases diagnosed in 2019. Elucidating a mechanistic basis for these associations are areas of active research. Patient demographic and clinical parameters such as the commensal microbiome and body-mass index have also been shown to associate with responses to ICI. In addition, high non-synonymous somatic tumor mutational burden (TMB) and genomic insertions and deletions correlate with benefit to ICI. Biomarkers which act as surrogates of T cell infiltration, also described as the T cell-inflamed tumor microenvironment (TME), have been observed to associate with improved outcomes to ICI across multiple cancer types.
Patients without threshold PD-L1 expression achieve responses, however, suggesting PD-L1 assessment alone is insufficient to identify patients for whom ICI should be withheld. For example, increased PD-L1 expression on tumor cells correlates with clinical benefit to anti-PD-1/PD-L1 ICI in patients with NSCLC, a trend that is observed in some but not all ICI-responsive malignancies. Features of tumor-immune biology have been found to associate with response and resistance to ICI and are being evaluated in the clinical setting for use as predictive biomarkers. Unfortunately, practice-changing efficacy of ICI has been limited to a subset of tumor types, such as melanoma, kidney, bladder and non-small cell lung cancer (NSCLC), and many tumors fail to derive benefit, such as tumors of the gastrointestinal tract.
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