Prognostic and Predictive Biomarkers in the Era of Immunotherapy for Lung Cancer

Abstract

The therapeutic algorithm of lung cancer has recently been revolutionized by the emergence of immune checkpoint inhibitors. However, an objective and durable response rate remains low with those recent therapies and some patients even experience severe adverse events. Prognostic and predictive biomarkers are therefore needed in order to select patients who will respond. Nowadays, the only validated biomarker is the PD-L1 expression, but its predictive value remains imperfect, and it does not offer any certainty of a sustained response to treatment. With recent progresses in molecular biology, genome sequencing techniques, and the understanding of the immune microenvironment of the tumor and its host, new molecular features have been highlighted. There are evidence in favor of the positive predictive value of the tumor mutational burden, as an example. From the expression of molecular interactions within tumor cells to biomarkers circulating in peripheral blood, many markers have been identified as associated with the response to immunotherapy. In this review, we would like to summarize the latest knowledge about predictive and prognostic biomarkers of immune checkpoint inhibitors efficacy in order to go further in the field of precision immuno-oncology.

Predictive Impact of Diffuse Positivity for TTF-1 Expression in Patients Treated With Platinum-Doublet Chemotherapy Plus Immune Checkpoint Inhibitors for Advanced Nonsquamous NSCLC

“…Specifically, the PFS and OS were better in patients with high PD-L1 TPS (≥50%) than in those with low (1%–49%) or negative (<1%) PD-L1 TPS. 3 , 5 , 7 , 31 Although current efforts are intensely exploring potential predictive factors for chemoimmunotherapy, no definitive marker other than the PD-L1 TPS has been validated as predictors of chemoimmunotherapy response in advanced NSCLC without driver mutations. Several studies exploring TTF-1 expression status as a treatment response marker reported that the PFS and OS were significantly better in patients with TTF-1–positive tumors than in those with TTF-1–negative tumors.…”

Vitiligo-like Lesions as a Predictor of Response to Immunotherapy in Non-Small Cell Lung Cancer: Comprehensive Review and Case Series from a University Center

“…In the rapidly evolving landscape of cancer treatment, ICIs have emerged as a transformative approach, particularly in NSCLC [1,52,53,[59][60][61][62][63][64]. Nevertheless, the success of ICI treatment is closely intertwined with the identification of predictive biomarkers [65,66]. These biomarkers play a pivotal role in stratifying patients, guiding treatment decisions, and optimizing therapeutic outcomes.…”

“…Among the main identified predictive markers, PD-L1 expression, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), neutrophil/lymphocyte ratio (NLR), and specific genetic mutations emerged as established or potential tools to tailor ICIbased strategies for NSCLC patients [65,66]. The prognostic value of these biomarkers is summarized in Table 3.…”

“…Despite its inaccurate and insufficient value, PD-L1 expression is still consensually referred to as the most current clinically impactful biomarker predictive of ICI response in NSCLC [65,66]. Trials like IMpower010, PACIFIC, KEYNOTE-024, KEYNOTE-042, IMpower110, CheckMate-026 and EMPOWER-Lung 1 are some of the most relevant studies that allowed understanding of that, for different defined cut-offs, with different drugs in different settings, higher values of PD-L1 expression tend to translate into greater benefit from ICI use or, eventually, differentiate from those without any clinical outcome advantage from ICI use [1,52,53,[59][60][61][62][63][64].…”

Exploring histological predictive biomarkers for immune checkpoint inhibitor therapy response in non–small cell lung cancer

“…PD-L1 expression, along with tumor mutational burden and mismatch gene repair deficiency, has been validated as a predictive marker for ICI response and has received U.S. Food and Drug Administration (FDA) approval for companion diagnostics [ 11 ]. Other markers, such as tumor mutational burden and microsatellite instability, have also been recognized as predictive markers of ICI response [ 11 - 13 ]. However, the search for a perfect and reliable biomarker for ICI response is ongoing, and advanced molecular techniques are not readily available in many clinical situations.…”