Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer

Abstract

Recently, a firmer understanding of tumor immunology and tumor escape mechanisms has led to the development of immune checkpoint inhibitors, antibodies against programmed death-1 (PD-1) and its ligand (PD-L1). Nivolumab, pembrolizumab, and atezolizumab have dramatically altered the treatment paradigm in non-small cell lung cancer (NSCLC) and have each demonstrated improvements in outcomes and quality of life when compared to chemotherapy. Enrichment strategies to better select those patients more likely to respond have identified PD-L1 staining by immunohistochemistry (IHC) to be a predictive biomarker in both treatment naïve and refractory patients. Unfortunately, many challenges exist with this strategy and underscore the need for further exploration for more reliable biomarkers. Multiple tissue and plasma-based enrichment strategies have been identified in the hope of identifying patients more likely to benefit from checkpoint inhibitors. These include tumor mutational load; the "inflamed phenotype" including tumor infiltrating lymphocytes (TILS) and immunoscore; T-cell receptor clonality; gene signatures, and several plasma biomarkers. Several studies have revealed many of these biomarkers to be reliable predictors of response to immune checkpoint inhibitors across multiple tumor types. Given the small nature of these studies, additional prospective studies are warranted to formalize and validate each of these enrichment strategies.

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

“…46 Tumor mutational burden (TMB) is an additional, promising biomarker that appears to correlate better with responses and long-term benefit from checkpoint blockade in NSCLC. 46 Tumor mutational burden (TMB) is an additional, promising biomarker that appears to correlate better with responses and long-term benefit from checkpoint blockade in NSCLC.…”

“…For NSCLC patients treated with immune checkpoint inhibitors (ICI), PD-L1 expression of tumor cells as assessed by immunohistochemistry is widely used to predict benefit, but has limited reliability for individual patients. 46 Tumor mutational burden (TMB) is an additional, promising biomarker that appears to correlate better with responses and long-term benefit from checkpoint blockade in NSCLC. 47 Efforts that facilitate wide-scale implementation are currently underway.…”

Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD‐L1 expression in cancer patients

“…To calculate TMB, the number of somatic nonsilent protein-coding mutations with exclusion of copy number gene alterations and structural rearrangements were determined. 36 TMB-H was defined as greater than or equal to 17 mutations per megabase (Muts/Mb), TMB-intermediate was [6][7][8][9][10][11][12][13][14][15][16] Muts/Mb, and TMB-low <6 Muts/Mb. MSI instability by NGS microsatellite loci in the targeted genes of the panel was first identified using the multiobjective immune system algorithm (MISA; 8,921 locations identified).…”

“…9,10 It is unclear which cytotoxic chemotherapeutic agents will synergize best with immunotherapy. However, several biomarkers have been associated with responses to anti-PD-1/PD-L1 checkpoint inhibitors: microsatellite instability high status (MSI-H), 11 high tumor mutational burden (TMB-H), 12,13 programmed death-ligand 1 (PD-L1) amplification and increased expression of PD-L1 on immunohisochemistry. [14][15][16][17][18] Protein markers may aid in predicting response or resistance to specific cytotoxic chemotherapeutic agents (Supporting Information Table S1).…”

Molecular Testing in Lung Cancer: Where to Draw the Line?

“…3,4 It is in this context that we need to consider the updated College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) guideline 5 on the incorporation of testing for RET/ErbB2/MET aberrations in the diagnostic paradigm of optimal lung cancer management. Given the precedent on the above-mentioned molecularly defined tumor subsets, what is now the gold standard as to moving a biomarker up from investigational to clinically validated and deserving full partnership in the lineup of time-tested biomarkers?…”