Moving Toward Newfound Diagnostic, Treatment Paradigms in Lung Cancer

Ignacio I. Wistuba, M.D.

Histological subtyping of lung cancer is still clinically important, said Ignacio I. Wistuba, MD. However, additional parameters such as driver alterations, alternative methods for molecular testing, and immunotherapy-related biomarkers have strengthened the diagnostic and treatment paradigms in lung cancer.

The diagnostic algorithm for lung cancer subtyping is broadly reliant on immunohistochemistry (IHC), said Wistuba, who is the chair in the Department of Translational Molecular Pathology and Division of Hematology/Pathology at The University of Texas MD Anderson Cancer Center.

“We can save tissue for molecular testing for EGFR and BRAF mutations, ALK, ROS1, and NTRK fusions, and MET exon14 splicing mutations,” said Wistuba in a presentation during the 21st Annual International Lung Cancer Congress, a program developed by Physicians’ Education Resource® (PER®), LLC.

In addition to tissue biopsy, cell-free DNA can be assessed by way of liquid biopsies when tissue biopsies are inaccessible or yield inconclusive results, said Wistuba. In the metastatic setting, liquid biopsy can be used to identify eligible patients for targeted therapy. Additionally, liquid biopsy can be easily repeated to monitor treatment efficacy and/or the detection of resistance mechanisms.

Although the method used depends on the quality of the tissue, the consensus for testing itself is a multiplex next-generation sequencing (NGS) panel that can identify an array of alterations, including mutations, deletions, insertions, fusions, and copy number variations, in a singular assay.

Notably, NGS can be performed in formalin-fixed paraffin-embedded tissue samples as well as liquid biopsy samples. Additionally, the turn-around time for NGS, averaging approximately 10 days, compares favorably to conventional sequencing technologies, said Wistuba. 

Clinically, NGS provides patients with more treatment options, both in clinical trial and commercial settings, as well as predictive information on genomic markers associated with response to immunotherapy.

“When you work with an NGS panel, it’s important to know the content and the limit of detections. Many of these panels don’t do well with fusions, so you may need to have another approach or highly sensitive method to detect fusions,” said Wistuba.

Regarding response to immunotherapy, PD-L1, tumor mutation burden (TMB), and microsatellite instability–high (MSI-H) have become the preeminent biomarkers of response to checkpoint inhibitors, evidenced by the FDA approvals of pembrolizumab (Keytruda) monotherapy in PD-L1–high non–small cell lung cancer (NSCLC), TMB–high solid tumors, and MSI-H solid tumors.

“We have [1] companion PD-L1 IHC assay which we need to be able to prescribe the drug according to the FDA approval, as well as [3] complementary assays which help inform how to treat the patient,” said Wistuba.

Although PD-L1 does enrich for response to immunotherapy, it is an imperfect biomarker, said Wistuba, who cited a recent study by investigators at Memorial Sloan Kettering Cancer Center showing that PD-L1 IHC expression and subsequent response to anti–PD(L)1 inhibition varied among primary and metastatic sites of disease.^1,2

In the study, patients who had PD-L1 expression greater than or equal to 50% in the lung experienced improved progression-free survival (PFS) and overall survival (OS) with the PD-(L)1 inhibitor. However, when PD-L1 was assessed in the lymph nodes, PFS and OS were no different in patients with PD-L1 expression greater than or equal to 50% or less than 50%.

Turning to TMB, Wistuba said there are 5 available NGS assays that can be used to determine TMB, defined as the total number of mutations per coding area of a tumor genome.

A number of clinical trials and retrospective analyses have shown a correlation between high TMB, in tissue and blood, and response rates and PFS with checkpoint inhibitors. However, many challenges remain before TMB can be effectively integrated into clinical practice.

“It’s important that we identify therapies whose response is best informed by TMB status, have a robust definition of a predictive TMB cut-point, have an acceptable NGS panel size and design, and [an assay that has the] robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories,” said Wistuba.

Although more work is needed to define the molecular underpinnings of lung cancer, the integration of molecular pathology into therapeutic decision making has never been more apparent than it is today, concluded Wistuba.

References

1. Schoenfeld AJ, Rizvi H, Bandlamudi C, et al. Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas. Ann Oncol. 2020;31(5):599-608. doi:10.1016/j.annonc.2020.01.065
2. Hong L, Negrao MV, Dibaj SS, et al. Programmed death-ligand 1 heterogeneity and its impact on benefit from immune checkpoint inhibitors in NSCLC. J Thor Oncol. 2020. doi:10.1016/j.jtho.2020.04.026