Specificity in NSCLC Treatment Grows With Acceptance of NGS and cfDNA

Benjamin P. Levy, MD

The introduction of next-generation sequencing (NGS) platforms and cell-free DNA (cfDNA) have provided the opportunity for clinicians to be more specific in targeting mutations in patients with non—small cell lung cancer (NSCLC), according to Benjamin P. Levy, MD.

In a presentation during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Levy, assistant professor of Oncology, clinical director of Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins Medicine, discussed optimal strategies for molecular interrogation of NSCLC.

"Adenocarcinoma now can be parsed out into molecular subsets, and based on the molecular subsets identified, they can be wed to a targeted therapy," Levy said. "The story of molecular profiling began with EGFR and ALK, but that is the tip of the iceberg. We now have other actionable mutations, like ROS1 and BRAF, that have approved therapies."

Questions on Implementing Sequencing

In addition, there are patients with NSCLC who express MET exon 14 alterations, as well as those who express HER2, RET, and NTRK abnormalities. This list of targets answers the question of why genomic testing should be done in patients with NSCLC, according to Levy. This goes beyond lung cancer, he added, as basket trials such as ASCO’s TAPUR study and the NCI-MATCH trial include patients from multiple tumor types.A recently published study in JAMA on advanced NSCLC sought to determine the association of broad-based genomic sequencing and survival in the community oncology setting.¹ This study looked at the difference between patients who had comprehensive genomic profiling of their lung cancer versus those who had only had EGFR and ALK panel testing. This retrospective analysis of over 5000 patients showed no difference in outcomes, and broad-based genomic sequencing only directly informed treatment in a minority of patients. This was a surprising result, Levy explained.

Levy advised that clinicians read the study and decipher the meaning for themselves, but consider that this is not necessarily real-world data. He added that there is a deeper clinical value in getting information from a broad-based genomic sequencing assay than just survival.

Community practices are often worried about the cost of doing these broad-based genomic sequencing assays. In a study presented at the 2018 ASCO Annual Meeting, the economic impact of NGS compared with sequential single-gene testing modalities to detect genomic alterations in patients with metastatic NSCLC was analyzed using a decision analytic model.² This model included 1 million hypothetical newly diagnosed patients with Medicare and commercial health plans.

Findings showed that that NGS could save Center for Medicare and Medicaid Services (CMS) payers $1.4 million to $2.1 million, and commercial insurance providers more than $250,000.

Liquid Biopsies

"NGS was cost effective when compared with sequential, exclusionary, and a hotspot panel, both for a CMS and Medicare perspective, and for commercial payers. This is a hypothetical patient population, but there is a lot more work we need to do to understand whether this is cost effective or not," summarized Levy.Although NGS is a beneficial option, Levy noted that the turnaround time is often long. There are also issues with tissue procurement. Traditional tissue biopsies are invasive, and there are questions regarding tissue stewardship. Additionally, every institution has a different way of reporting results from the tissue biopsy, Levy said.

"Where does the tissue go? You do the biopsy, it is sent to the pathology lab, then it goes to a whole different bunch of labs," Levy explained. "How do we find the tissue? Where is it? Once it is pinned down, how do you report it? There are challenges with tissue, even in the best of circumstances."

cfDNA is captured by a simple noninvasive blood test, often referred to as a liquid biopsy. Shedding of cfDNA is a product of apoptosis and necrosis, and now more sensitive diagnostic platforms have the capability to genetically interrogate isolate DNA from the blood, explained Levy. This method may circumvent the need for tissue biopsies, he added.

The FLAURA trial of osimertinib (Tagrisso) established the agent as the new standard of care for patients with NSCLC who have EGFR sensitizing mutations. Investigators on this trial showed that there was a concordance between plasma and tumor tissue testing by EGFR mutation status. High sensitivity was observed for those with exon 19 deletions and exon 21 L858R substitution mutations, noted Levy.

In a study of osimertinib resistance presented at the 2018 ESMO Congress, investigators used cfDNA to determine common resistance mechanisms. Findings from the liquid biopsy showed that the most common resistance mechanisms were MET amplification and EGFR C797S mutations. Additionally, HER2 amplification, PIK3CA mutations, and RAS mutations were observed.³

According to Levy, several studies have shown that plasma uncovers mutations not shown in the tissue sample of the same patient.

"This may be from tumor heterogeneity, or this may be that the tissue NGS was not as deep a sequencer as the plasma was. Nevertheless, we are finding additional mutations," Levy said.

In a recent study published in JAMA Oncology, the additive value of incorporating plasma into a tissue diagnosis was evaluated.⁴ Most patients included on the study were treatment-naïve, and some were refractory to treatment. Of 323 patients enrolled, 94 received only plasma NGS due to patient or physician preference, 101 received only plasma NGS due to insufficient tissue, and 128 received concurrent plasma and tissue NGS.

"At least in the 128 [population], if you layered in plasma with the tissue, you were able to identify additional mutations or uncover mutations in the blood that were not found in the tissue," Levy said. "This is may be due to tissue heterogeneity, and where you stuck that needle wasn't where the mutation was. This may be dependent on the NGS platform used in the tissue versus plasma."

The important takeaway, Levy said, is that there were targetable mutations uncovered with the plasma.

Considering the available data, Levy advises that clinicians begin with a tissue biopsy, and if there is not enough tissue, default to plasma. He also noted that plasma negativity “means nothing.” If nothing is seen in plasma, another biopsy should be done.

"Genetic interrogation is paramount in optimizing frontline decision-making and helping to select genotype-driven therapies in the resistant setting. It is important that we do comprehensive genomic profiling or NGS on our patients," concluded Levy.

Additionally, Levy noted that studies evaluating cfDNA platforms in monitoring residual disease following curative intent therapy—as well as identification of early-stage disease—are promising.

References

1. Presley CJ, Tang D, Soulos PR, et al. Association of broad-based genomic sequencing with survival among patients with advanced non—small cell lung cancer in the community oncology setting. JAMA. 2018;320(5):469-477. doi: 10.1001/jama.2018.9824.
2. Pennell NA, Mutebi A, Zhou Z, et al. Economic impact of next generation sequencing vs sequential single- gene testing modalities to detect genomic alterations in metastatic non-small cell lung cancer using a decision analytic model. J Clin Oncol. 2018;36 (suppl; abstr 9031).
3. Ramalingam SS, Cheng Y, Zhou C, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA50. doi: 10.1093/annonc/mdy424.063.
4. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non—small cell lung cancer [published online ahead of print October 11, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.4305.