Paramountcy of Molecular Testing Is Increasing in Early-Stage NSCLC

Fred R. Hirsch, MD, PhD

The molecular characterization of tumors has helped drive treatment decisions for patients with advanced non–small cell lung cancer (NSCLC), and the continued emergence of data for targeted therapies in the early-stage setting is underscoring the need to identify genetic subtypes in all patients with NSCLC, according to Fred R. Hirsch, MD, PhD.

Hirsch pointed to data that have led to the FDA approvals of adjuvant targeted therapies for select patients with early-stage NSCLC, including findings from the phase 3 ADAURA trial (NCT02511106) of adjuvant osimertinib (Tagrisso) in patients with EGFR-mutated NSCLC and the phase 3 ALINA trial (NCT03456076) of adjuvant alectinib (Alecensa) in patients with ALK-positive NSCLC.^1,2

“Today, it is crucial to [conduct] molecular testing for patients with early-stage disease,” Hirsch said in an interview with OncLive^® during the 26th Annual International Lung Cancer Congress^®.

In the interview, Hirsch discussed the role of molecular testing in the early-stage setting for patients with NSCLC; noted the growing understanding of co-mutations and their clinical implications; and detailed the benefits and drawbacks of tissue vs liquid biopsies.

Hirsch is the executive director of the Center for Thoracic Oncology, co-director of the Center of Excellence for Thoracic Oncology, and associate director of Biomarker Discovery at The Tisch Cancer Institute at Mount Sinai, as well as the Joe Lowe and Louis Price Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai in New York, New York.

OncLive: What is the importance of conducting molecular testing for patients with NSCLC, particularly in the early-stage setting?

Hirsch: We have learned a lot from patients with advanced disease, and it is clear that molecular characterization of the tumor is crucial for determining the most optimal therapy in [patients with] advanced disease.

Now, we are moving our attention to early-stage disease, and we have more and more clinical data there indicating the crucial role of molecular testing in early-stage disease. We have results with the [adjuvant use of the] EGFR inhibitor [osimertinib] from the ADAURA trial. We [also have results] with the ALK inhibitor alectinib [from] the ALINA study. We will [continue to] see more and more [data for targeted therapies in the early-stage setting].

What questions remain regarding the role of molecular testing during treatment, particularly given the potential for co-mutations to develop at disease progression?

The whole scenario around co-mutations is relatively new. We learned very early that EGFR [mutations] in combination with p53 [mutations] indicate a poorer outcome [for patients] with advanced [NSCLC]. However, today we are learning much more about co-mutations and [how they] potentially reduce the effect of the primary targeted therapy. We don't have all the answers [for how to address co-mutations] yet; learning more about the clinical role of co-mutations is important.

Regarding current biopsy strategies, what are some of the benefits and drawbacks of tissue vs liquid biopsies?

I'm still in favor of the tissue [biopsy, which] is easier. Is [tissue biopsy] still relevant? In my opinion, yes. We need a solid tissue [sample] to determine molecular characterization; however, liquid biopsy [technology is improving]. We have [seen] a continuous improvement of the liquid biopsy assays, and we are learning more and more about the capability of liquid biopsy.

We are still struggling with the sensitivity of liquid biopsy assays. What does a negative result on liquid biopsy mean? Can we trust it? We are getting better and better in [improving the] sensitivity [of liquid biopsy assays]. [For a] positive liquid biopsy result, the specificity—for practical purposes—is almost 100%. We trust a positive result. The question is: can we trust a negative result? In many cases, yes; the sensitivity today might be around 80%. However, we [need to keep] doing better and better.

In my institution, we are [conducting] parallel examination [using both] tissue and liquid [biopsies at] primary diagnosis. There are cases where [a patient is] positive on a liquid biopsy and negative on the tissue biopsy. This could [be attributed to] insufficient tissue or the heterogeneity [of a tumor]. There can be several factors [for a negative tissue biopsy and a positive liquid biopsy]. Sufficient tissue is not always [available]; therefore, that is the reason we initially [conduct] parallel [biopsies].

References

1. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed August 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations
2. FDA approves Genentech's Alecensa as first adjuvant treatment for people with ALK-positive early-stage lung cancer. News release. Genentech. April 18, 2024. Accessed August 6, 2024. https://www.gene.com/media/press-releases/15023/2024-04-18/fda-approves-genentechs-alecensa-as-firs