Emerging biomarkers may better guide NSCLC immunotherapy


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Emerging biomarkers hold promise for better selecting patients with non–small cell lung cancer (NSCLC) who are good candidates for immune checkpoint inhibitors, according to a review published in the journal Cancer.

Oncologists now have available three immune checkpoint inhibitors – the programmed death 1 (PD-1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda), and the programmed death ligand 1 (PD-L1) inhibitor atezolizumab (Tecentriq)– shown to improve outcomes of NSCLC, note the authors, who were led by J. Nicholas Bodor, MD, PhD, a fellow in the department of hematology/oncology, Fox Chase Cancer Center, Philadelphia.

“The emergence of immunotherapy has dramatically changed how non–small cell lung cancer is treated, and longer survival is now possible for some patients, even those with advanced disease,” they maintain. “Although some patients achieve durable responses to checkpoint blockade, not all experience such benefits, and some suffer from significant immunotoxicities. Given this, biomarkers that predict response to therapy are essential … ”

PD-L1 expression

Assessment of PD-L1 expression by immunohistochemistry (IHC) is the standard of care for identifying patients with advanced NSCLC more likely to benefit from immunotherapy, according to Dr. Bodor and colleagues. Patients with a higher percentage of tumor cells positive for PD-L1 have had better outcomes with immune checkpoint inhibitors as compared with chemotherapy in both first- and second-line trials.

However, “PD-L1 remains a controversial biomarker of immunotherapy response, and several issues limit its utility,” they add. Those issues include differences in testing platforms, use of varied expression cutoffs across agents, and heterogeneous ligand expression within tumors. In addition, some patients with high expression do not have a response or obtain durable benefit, while others with little to no expression do.

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“Although PD-L1 expression on the surface of tumor cells detected by IHC remains the recommended approach for predicting a tumor’s responsiveness to immunotherapy, and testing is the current standard of care for any newly diagnosed NSCLC, it is a less than perfect predictor of response,” the authors wrote.

Tumor mutational burden

An alternate biomarker being investigated is tumor mutational burden (TMB), the number of somatic mutations per coding area of a tumor genome as assessed with whole-exome sequencing or with next-generation sequencing using the FoundationOne CDx assay.

“A high number of somatic mutations is thought to result in a greater number of neoantigens presented on the surface of tumor cells, which, in turn, increases immunogenicity and results in tumors becoming more sensitive to treatment with immune-checkpoint agents,” Dr. Bodor and coauthors explain.

Among patients with advanced NSCLC, those having higher TMB (10 or more mutations per megabase [Mb]) have achieved better progression-free survival with the first-line combination of nivolumab and ipilimumab (Yervoy), an immune checkpoint inhibitor that inhibits of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), versus chemotherapy, regardless of PD-L1 expression. However, higher TMB as defined did not predict better overall survival.

“In addition, TMB as a biomarker has other limitations, including lack of standardization between the testing plat-forms used and lack of an identified, fixed TMB threshold defining a tumor as having ‘high’ TMB,” the authors note.

“Although PD-L1 expression on the surface of tumor cells detected by IHC remains the recommended approach for predicting a tumor’s responsiveness to immunotherapy, and testing is the current standard of care for any newly diagnosed NSCLC, it is a less than perfect predictor of response,” the authors wrote.

Tumor-infiltrating lymphocytes

There is similarly a sound biological rationale for assessing tumor-infiltrating lymphocytes (TILs) as a predictor of immunotherapy benefit. “A high density of TILs is considered to reflect greater immune recognition of tumor cells in a patient and represents a T cell–inflamed tumor microenvironment,” Dr. Bodor and colleagues explain.

TILs have been found to be prognostic in NSCLC, with patients whose tumors have a higher density of TILs achieving better survival. In addition, higher PD-L1 expression on TILs has been shown to predict a better response to atezolizumab.

“The increase in the intratumoral presence of infiltrative immune cells, both before and during treatment, may be predictive of clinical and radiographic response,” the authors propose. “Continued research to confirm this is needed as well as determining clinically meaningful thresholds of increased TIL density.”

Tumor-specific genotypes

Thus far, tumor-specific genotypes – ascertained by use of fluorescence in situ hybridization or next-generation sequencing to identify alterations in genes such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) – have had limited utility for immunotherapy, as negative predictors of benefit.

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“Unfortunately, EGFR-positive and ALK-positive tumors have not demonstrated the same responsiveness to checkpoint blockade as other genotypes, and the second-line trials with single-agent immunotherapy have not demonstrated a survival benefit in this subgroup,” Dr. Bodor and coauthors said. In addition, some data have raised concern that immunotherapy may accelerate progression of EGFR-positive tumors.

“While underlying factors that explain why certain tumor genotypes do not respond to checkpoint inhibition continue to be elucidated, recent trials using combinations with immunochemotherapy and vascular endothelial growth factor (VEGF) inhibition suggest that such therapies may overcome the resistance seen in EGFR-positive and ALK-positive tumors,” they note.

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Gene expression signatures

Multigene profiling now is being used to identify immunogenic gene expression signatures correlating with immunotherapy benefit, in particular, those associated with interferon-gamma (IFN-gamma) signaling and activation of T-cells, according to Dr. Bodor and coauthors.

Among patients with advanced NSCLC, high expression of the T effector–related and INF-gamma–related gene signature has been found to confer better overall survival with second-line atezolizumab therapy versus chemotherapy. Also, chemokine and immunosuppressive molecule expression profiles have been found to improve prediction of response to pembrolizumab.

“Multigene profiling holds promise for identifying immunogenic tumors that are more likely to benefit from immunotherapy agents, although further clinical study and prospective validation are needed,” the authors contend.

Serum-based biomarkers

Serum-based biomarkers such as the neutrophil to lymphocyte ratio (NLR) also have garnered interest as predictors of immunotherapy benefit, according to Dr. Bodor and coauthors. In advanced NSCLC treated with immunotherapy or chemotherapy, higher NLR is a poor prognostic indicator. Furthermore, higher NLR early in the course of second-line nivolumab therapy has been correlated with poorer progression-free survival.

“The NLR and other such peripheral blood markers may have utility in patients treated with checkpoint blockade, although studies to date have been small and retrospective, and prospective validation is needed,” they maintain.

Another serum-based biomarker under investigation in NSCLC is the blood tumor mutational burden (bTMB). Higher bTMB (16 or more mutations per Mb) has been associated with longer progression-free survival in patients given second-line atezolizumab, and with better overall survival in patients given first-line combination immunotherapy with tremelimumab, an investigational CTLA-4 inhibitor, and durvalumab (Imfinzi), a PD-L1 inhibitor.

TILs have been found to be prognostic in NSCLC, with patients whose tumors have a higher density of TILs achieving better survival.

Going forward

“Chemoimmunotherapy combinations will likely increase the number of patients who will be treated with a checkpoint inhibitor, although a proportion still will not benefit from a response. Moreover, treatment with checkpoint blockade is not without side effects or potential life-threatening immunotoxicities,” Dr. Bodor and coauthors said.

“This makes it all the more essential to continue the study and development of improved biomarkers that are predictors of toxicity and sensitive and specific indicators of immunotherapy response,” they wrote.

Dr. Bodor reported having no relevant disclosures. The authors were supported in part by a National Cancer Institute Core Grant to Fox Chase Cancer Center.

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