Dr Hirsch on the Benefits of Tissue vs Liquid Biopsy in NSCLC

Fred R. Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, The Tisch Cancer Institute at Mount Sinai; Joe Lowe and Louis Price Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, discusses the pros and cons of completing a tissue biopsy compared with a liquid biopsy in non–small cell lung cancer (NSCLC).

Tissue biopsy remains an essential method for determining molecular characterization, despite the advancements in liquid biopsy technology, Hirsch begins. Solid tissue samples provide crucial insights into tumor biology that are not yet fully replicated by liquid biopsy methods, he says. The primary advantage of tissue biopsy lies in its ability to offer a comprehensive and detailed analysis of the tumor's molecular profile, which is critical for accurate diagnosis and guiding treatment decisions, Hirsch explains. Tissue biopsies allow for the examination of the tumor's histology, architecture, and cellular environment, providing information that is vital for identifying specific mutations and understanding the tumor's behavior, he adds.

However, liquid biopsy technology has made significant strides and provides a less invasive alternative to tissue biopsy, Hirsch states. Liquid biopsies involve the analysis of circulating tumor DNA (ctDNA) and other biomarkers found in the blood, providing a snapshot of the tumor's genetic landscape. The main challenge with liquid biopsies lies in their sensitivity, Hirsch says. Although a positive liquid biopsy result is highly reliable, with specificity approaching 100%, the interpretation of a negative result is more complex. The current sensitivity of liquid biopsy assays is around 80%, meaning that some mutations may not be detected, potentially leading to incomplete or inaccurate assessments of the tumor, he details.

To overcome these limitations, many institutions, including Mount Sinai, are adopting a parallel approach, Hirsch says. This involves conducting both tissue and liquid biopsies simultaneously at the primary diagnosis stage. This dual approach helps to mitigate the shortcomings of each method, he explains. For instance, there are cases where a liquid biopsy detects a mutation that a tissue biopsy misses, which can occur due to tumor heterogeneity or insufficient tissue samples, he notes. By using both methods in conjunction, the likelihood of accurately identifying mutation increases, leading to better-informed treatment decisions, Hirsch concludes.

Videos

 Fred R. Hirsch, MD, PhD, discusses the pros and cons of completing a tissue biopsy compared with a liquid biopsy in non–small cell lung cancer.
 

Dr Hirsch on the Treatment of NRG1 Fusion+ NSCLC

Fred R. Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, The Tisch Cancer Institute at Mount Sinai; Joe Lowe and Louis Price Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, discusses the activity of HER3-directed agents in patients with non–small cell lung cancer (NSCLC) harboring 

NRG1 is implicated in the interaction and dimerization of HER2 and HER3 receptors, as well as the activation of these receptors, Hirsch begins. Thus, blocking NRG1 disrupts this interaction, he notes. Zenocutuzumab (MCLA-128), a bispecific antibody targeting HER2/HER3, has showcased encouraging results in clinical trials in patients with 

-positive NSCLC, according to Hirsch. For instance, in the phase 1/2 eNRGy trial (NCT04100694), the agent yielded an ORR of 37.2% (95% CI, 26.5%-48.9%). In 2023, 

zenocutuzumab received FDA breakthrough therapy designation

 for this indication, and the agent is currently 

 for this population. Another agent, afatinib (Gilotrif), has also exhibited some efficacy in this patient population and is under further clinical investigation, as are several other NRG1-targeted therapies, Hirsch notes. However, optimal treatment strategies for patients with 

 fusions, including the ideal line of therapy in which to use these agents, remain undetermined, Hirsch emphasizes.

Furthermore, the relationship between NRG1-targeted therapies and immunotherapy is unclear, Hirsch adds. Although anecdotal evidence varies, a global registry of patients with 

 fusion–positive NSCLC indicates that these tumors typically have low PD-L1 expression and low tumor mutational burden, indicating potentially limited responsiveness to immunotherapy, Hirsch says. Nonetheless, there is currently a lack of comprehensive clinical data to draw definitive conclusions, Hirsch reports. Thus, the integration of NRG1-targeted treatments with immunotherapy and the optimal sequencing of these agents in 

 fusion–positive disease requires further investigation, Hirsch concludes.

Fred R. Hirsch, MD, PhD, discusses the activity of HER3-directed agents in patients with non–small cell lung cancer harboring NRG1 mutations.

Fred R. Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, The Tisch Cancer Institute at Mount Sinai; Joe Lowe and Louis Price Professor of Medicine, Icahn School of Medicine at Mount Sinai, discusses the rarity of diagnosing patients with small cell lung cancer (SCLC) early in the disease course, unmet needs in SCLC screening, the importance of ECOG performance score (PS) when considering patients for clinical trials, and factors influencing hospice care decisions in patients with SCLC.

Dr. Hirsch on Early SCLC Diagnosis and Management

In rare cases, SCLC can be diagnosed in early, localized stages, including T1, T2, node-negative, or nonmetastatic stages, Hirsch says. For these patients, lobectomy is a potentially effective option for managing the disease, Hirsch notes. However, most cases of SCLC present at locoregional or extensive disease stages at diagnosis, at which point surgery is no longer an option, Hirsch says. More research is necessary to discover more sensitive SCLC screening methods and determine best practices for diagnosing this disease, so more patients can be diagnosed earlier in their disease course and receive surgery, Hirsch concludes.

Hospice care should be considered the last stage of treatment for patients with SCLC and is often an option for patients who have exhausted all recommended therapies, such as topotecan and lurbinectedin (Zepzelca), and have a poor ECOG PS, Hirsch says. Fortunately, many ongoing clinical trials in SCLC could provide therapeutic alternatives to hospice for patients who enroll. However, a low PS is often a key eligibility requirement for participation in these trials, Hirsch emphasizes. If patients have a PS of 2 or higher and have progressed on the standards of care in the first and second lines, hospice care, after communication with the patients and their families, can be an option, Hirsch explains.

Fred R. Hirsch, MD, PhD, discusses the rarity of diagnosing small cell lung cancer early in the disease course, unmet needs in SCLC screening, the importance of ECOG performance score when considering patients for clinical trials, and factors influencing hospice care decisions in patients with SCLC.

Dr. Hirsch on Diagnosing and Managing Metastatic SCLC

Fred R. Hirsch, MD, PhD, executive director in the Center for Thoracic Oncology at The Tisch Cancer Institute and the Joe Lowe and Louis Price professor of medicine (hematology and medical oncology) at the Icahn School of Medicine at Mount Sinai Hospital, discusses the expansion of molecular testing in lung cancer.

Genetic and genomic testing has expanded quickly over the past few years, Hirsch explains. There are emerging technologies to test for biomarkers and an increasing number of actionable targets in lung cancer. It is crucial that all patients with adenocarcinoma and not otherwise specified lung cancer receive testing for molecular characteristics, according to Hirsch, who has been involved in creating the molecular testing guidelines for The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Small cell lung cancers and squamous cell carcinomas, on the other hand, are not routinely tested in clinical practice but are usually tested in academic centers, says Hirsch. However, an exception to this practice is younger patients who have no smoking history and those with squamous histology; these subgroups should undergo molecular testing, concludes Hirsch.

View more from the 2019 New York Lung Cancers Symposium

Fred R. Hirsch, MD, PhD, discusses the expansion of molecular testing in lung cancer.

Dr. Hirsch on the Expansion of Molecular Testing in Lung Cancer

Fred R. Hirsch, MD, PhD, professor of Medicine, University of Colorado Denver, CEO, the International Association for the Study of Lung Cancer (IASLC), discusses the value of PD-L1 assays for patients with non—small cell lung cancer (NSCLC). Hirsch shared his during an interview at the 2016 IASLC Multidisciplinary Symposium on Thoracic Oncology.

Some studies clearly indicate a significant role for PD-L1 assays in predicting outcome for patients with NSCLC, Hirsch adds, while others do not disclose such importance with such tests. He adds that there are not significant differences between the PD-1 and PD-L1 antibodies, and evidence suggests that the efficacy and safety are relatively similar.

The challenge is, however, is that each of the PD-1/PD-L1 drugs are associated with their own predictive PD-L1 assay. This is because there are differences in cut-off values, Hirsch explains.

Fred R. Hirsch, MD, PhD, professor of Medicine, University of Colorado Denver, CEO, the International Association for the Study of Lung Cancer (IASLC), discusses the value of PD-L1 assays for patients with non–small cell lung cancer. Hirsch shared his during an interview at the 2016 IASLC Multidisciplinary Symposium on Thoracic Oncology.

Dr. Hirsch on Value of PD-L1 Testing in Patients With Lung Cancer

Fred R. Hirsch, MD, PhD, professor of Medicine, University of Colorado Denver, CEO, the International Association for the Study of Lung Cancer, discusses the importance of molecular testing for patients with lung cancer.

Molecular testing in lung cancer is crucial, Hirsch explains. With the development of personalized medicine, it is important to map a tumor's molecular characteristics, as this has significant clinical implications for many patients. This continues to be an evolving field, he adds.

Over recent years, a collaboration between three organizations has led to the development of a set of evidence-based guidelines for molecular testing. 

View more from the 2016 International Lung Cancer Congress

Dr. Hirsch on Importance of Molecular Testing in Lung Cancer

Fred R. Hirsch, MD, PhD, professor of medicine and pathology, University of Colorado Cancer Center, CEO, International Association for the Study of Lung Cancer (IASLC), discusses necitumumab for first-line treatment of advanced squamous non-small cell lung cancer (NSCLC).

The phase III SQUIRE trial, which investigated novel EGFR-antibody necitumumab plus chemotherapy in advanced NSCLC, demonstrated that the combination had superior survival compared to chemotherapy alone. In the combination arm, there was with a median overall survival rate of 11.5 months versus 9.9 months in the chemotherapy alone group.

Necitumumab is approved in the U.S for NSCLC without any biomarker, while it Europe it is only approved for patients with EGFR-expressing tumors.

Necitumumab is now being investigated in other combinations, including with immunotherapy, says Hirsch. A better way to select patients that will benefit from necitumumab is also being investigated. Protein expression or gene copy number by FISH are potential ways patients could be selected to receive or not receive the drug, he says.

Fred R. Hirsch, MD, PhD, professor of medicine and pathology, University of Colorado Cancer Center, CEO, International Association for the Study of Lung Cancer (IASLC), discusses necitumumab for first-line treatment of advanced squamous non-small cell lung cancer (NSCLC). 


Dr. Fred Hirsch on Next Steps for Necitumumab in NSCLC

Fred R. Hirsch, MD, PhD Professor of Medicine and Pathology, Associate Director for International Programs, University of Colorado Cancer Center, discusses the role of next-generation EGFR inhibitors for patients with non-small cell lung cancer.

Many patients develop resistance to first-generation EGFR inhibitors through the acquisition of a 

 mutation. However, the next-generation EGFR TKIs seem to overcome this specific mutation, Hirsch says. This gives physicians new hope to treat patients after they have become resistant to first-generation EGFR TKIs.

In addition to the continued efficacy in resistant patients, the new generation of EGFR TKIs are also better tolerated compared to the first generation of EGFR TKIs. Further research is needed to determine if these next-generation EGFR inhibitors can be combined with other agents in order get closer to a cure, Hirsch states.

View more from the 15th Annual International Lung Cancer Congress

Fred R. Hirsch, MD, PhD Professor of Medicine and Pathology, Associate Director for International Programs, University of Colorado Cancer Center, discusses the role of next-generation EGFR inhibitors.

Fred R. Hirsch, MD, PhD

Articles