Theresa Boyle, MD, PhD, molecular pathologist and assistant professor at Moffitt Cancer Center, discusses the current approach to biomarker testing in lung cancer.

Biomarker testing begins with staging to assess how comprehensive a test is needed, says Boyle. For example, a more targeted panel could be selected in a patient who requires rapid results, whereas a more comprehensive next-generation sequencing panel could be selected if the turnaround time can be longer, Boyle explains.

 G12C mutations have become druggable with investigational agents, such as sotorasib and adagrasib, in the clinical trial setting, says Boyle. Both agents have demonstrated efficacy in this subset of patients, explains Boyle. However, whether the presence of co-mutations, such as 

, limit the efficacy of immunotherapy in this patient population is yet to be determined, Boyle adds.

Notably, the field of targeted therapy for patients with lung cancer is rapidly evolving, so it is important to be in close communication with multidisciplinary experts to determine the optimal treatment for a patient, says Boyle. Additionally, biomarker testing should be supported so that tumor interrogation can be used to inform treatment selection, Boyle concludes.

Videos

Theresa Boyle, MD, PhD, discusses the current approach to biomarker testing in lung cancer.  



Dr. Boyle on Approaching Biomarker Testing in Lung Cancer 

John Longshore, PhD, FACMG, director, Molecular Pathology, Carolinas Pathology Group, Atrium Health, discusses selecting comprehensive vs single-gene molecular testing in lung cancer. 

Current guidelines support the use of comprehensive genomic profiling in patients with advanced or metastatic lung cancer where it is important to capture a wide range of biomarkers, says Longshore. However, in early-stage disease, single-gene testing for 

 mutations is likely preferred, Longshore explains. 

In the advanced setting, tissue biopsies are needed to confirm disease histology, says Longshore. As such, tissue-based testing is likely utilized first for molecular profiling. Liquid biopsy can be utilized in cases of extended turnaround time for tissue-based results, inconclusive tissue-based findings, or cases of insufficient tissue for tumor testing, Longshore says. 

The sensitivity of liquid biopsies depends on whether the technology uses DNA or RNA for testing, says Longshore. Ultimately, the sensitivity of the test depends on how much circulating tumor DNA (ctDNA) is shed. Because patients with metastatic lung cancer shed the most ctDNA, liquid biopsies have limited utility in the early-stage setting, Longshore explains. 

Additionally, multidisciplinary care for patients with lung cancer is critical, says Longshore. Medical oncologists, radiologists, pulmonologists, and pathologists should work collaboratively in diagnosing, staging, and molecularly testing patients to ensure that all eligible patients receive targeted therapy, Longshore explains. Finally, reflex testing for genomic profiling is important to eliminate human error and ensure that all patients receive testing, concludes Longshore.

John Longshore, PhD, FACMG, discusses selecting between comprehensive vs single-gene molecular testing in lung cancer.  



Dr. Longshore on Comprehensive Vs Single-Gene Molecular Testing in Lung Cancer 

Nasser H. Hanna, MD, Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research, professor of medicine, Indiana University School of Medicine, discusses his approach to biomarker testing in lung cancer. 

All patients with stage IV lung adenocarcinoma should undergo baseline molecular testing irrespective of smoking history, says Hanna. The selected molecular panel should test for 

 amplification, Hanna says. Additionally, emerging targets, such as 

 fusions, should be tested for, Hanna adds. 

Typically, newly diagnosed patients undergo immunohistochemistry (IHC) testing to confirm the disease histology, says Hanna. After IHC staining, if the patient has available tissue left, tissue-based biomarker testing should be performed. If the patient does not have available tissue, plasma-based molecular testing may suffice in identifying actionable alterations, Hanna says. Additionally, waiting for the molecular testing results to come back before initiating therapy should be standard practice, Hanna adds.

Specifically, immunotherapy should not be recommended before the results of molecular testing are returned because patients with 

 mutations, for example may not have an optimal response to immunotherapy even if their tumor is PD-L1 positive, says Hanna. In some instances, such as for patients with 

 V600E–mutant lung cancer, immunotherapy may be preferred despite the presence of an actionable alteration, Hanna explains. 

Generally, the commercially available sequencing platforms for tissue- and liquid-based testing are comparable, concludes Hanna. 

Nasser H. Hanna, MD, discusses his approach to biomarker testing in lung cancer.  



Dr. Hanna on Approaching Biomarker Testing in Lung Cancer 

Benjamin P. Levy, MD, associate professor of oncology and clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, discusses the importance of testing for 

 alterations have been included on molecular panels for years, only recently have KRAS inhibitors demonstrated efficacy in targeting 

However, because these inhibitors are not yet approved by the FDA, patients who harbor 

 G12C mutations are treated with immunotherapy alone or in combination with chemotherapy based on their PD-L1 expression, says Levy. 

 mutations have immunogenicity, so immunotherapy is a rationale treatment approach to pursue without FDA-approved KRAS inhibitors, Levy adds. 

To date, the oral KRAS G12C inhibitors sotorasib and adagrasib have demonstrated efficacy in treating patients with advanced stage, 

 G12C–mutant lung cancer, says Levy. The response rates observed with these agents appear to be lower compared with other targeted therapies in lung cancer, Levy explains. As such, novel strategies with these agents in combination with immunotherapy, other oral agents, SHP2 inhibitors, or chemotherapy may enhance the efficacy of sotorasib and adagrasib in the 

Additionally, data evaluating sotorasib and adagrasib in the frontline setting are needed for patients with treatment-naïve lung cancer, Levy says. From there, the field could assess whether combination approaches with KRAS G12C inhibitors could elicit durable responses with minimal toxicity in the newly diagnosed setting, concludes Levy.

Benjamin P. Levy, MD, discusses the importance of testing for KRAS mutations in lung cancer.  



Dr. Levy on the Importance of Testing for KRAS Mutations in Lung Cancer 

Alexander Spira, MD, PhD, FACP, a medical oncologist and director of the Virginia Cancer Specialists Research Institute and the Phase 1 Trial Program, discusses the role of broad molecular testing in lung cancer.

All patients with newly diagnosed lung cancer should undergo complete biomarker testing with a full next-generation sequencing panel, says Spira. The results of the test could inform which FDA-approved therapies or clinical trials the patient is eligible for, Spira explains. 

However, deciding whether to perform a liquid or tissue biopsy first, as well as whether concurrent liquid and tissue testing is indicated, can be challenging, Spira says. Notably, performing blood-based testing first could expedite treatment, but liquid biopsies are costly and may not provide 100% accuracy, adds Spira.

 G12C mutations, which were largely thought to be undruggable for many years, have pushed the biomarker field forward in lung cancer, Spira says. Currently, the KRAS inhibitors sotorasib (formerly AMG 510) and adagrasib (MRTX849) are in the late stages of clinical development, having demonstrated activity in treating patients with lung cancer who harbor 

 G12C mutations, Spira explains. Although subtle differences have been observed between the agents and they have not been compared directly, both appear to have a tolerable toxicity profile.

The response rates observed with sotorasib and adagrasib have been lower than those reported with other targeted therapies for patients with 

 mutations, Spira explains. However, the agents will likely receive FDA approval, and novel KRAS G12C inhibitors will emerge in the lung cancer pipeline to further the paradigm, concludes Spira. 

Alexander Spira, MD, PhD, FACP, discusses the role of broad molecular testing in lung cancer.  



Dr. Spira on the Role of Broad Molecular Testing in Lung Cancer 

John Longshore, PhD, FACMG, director, Molecular Pathology, Carolinas Pathology Group, Atrium Health, discusses key molecular markers in metastatic lung cancer.

The National Comprehensive Cancer Network guidelines recommend broad molecular testing. Genes that could harbor potentially actionable mutations and should be tested include 

 G12C. Additionally, tumor mutational burden should be profiled, says Longshore. 

Despite the wealth of actionable targets in the metastatic setting, 

 mutations are the only indicated molecular marker for early-stage disease based on the data from the phase 3 ADAURA trial, concludes Longshore. 

John Longshore, PhD, FACMG, discusses key molecular markers in metastatic lung cancer.  



Dr. Longshore on Key Molecular Markers in Metastatic Lung Cancer 

Theresa Boyle, MD, PhD, molecular pathologist and assistant professor at Moffitt Cancer Center, discusses the role of concurrent molecular testing in lung cancer.

The role of liquid biopsy has grown significantly in lung cancer and is often utilized before tissue-based testing, says Boyle. The results of plasma-based testing can be obtained quickly and inform targeted therapy options for patients, Boyle explains. Although similar molecular markers can be identified with liquid and tissue biopsies, tissue-based testing is often reserved for confirmation or to ensure a mutation was not missed with the liquid biopsy, Boyle says. 

For example, if a liquid biopsy does not reveal a driver mutation in a patient with lung adenocarcinoma who has never smoked, tissue testing is indicated to ensure nothing was missed, Boyle says. In some cases, patients may not have enough circulating tumor DNA for the liquid biopsy to identify an aberration, so tissue-based testing is often needed, concludes Boyle. 

Theresa Boyle, MD, PhD, discusses the role of concurrent molecular testing in lung cancer.  



Dr. Boyle on the Role of Concurrent Molecular Testing in Lung Cancer 

This Scientific Exchange workshop covers novel therapeutic targets in non–small cell lung cancer who harbor KRAS G12C mutations. 