RNA-Based NGS Offers the Potential to Identify More Patients With Rare Alterations in NSCLC

Joel Neal, MD, PhD

The field of non–small cell lung cancer (NSCLC) has exploded with continuous advances in targeted therapies directed toward key molecular alterations, including rare mutations like MET exon 14 (METex14) skipping mutations, RET rearrangements, and ROS1 mutations, said Joel Neal, MD, PhD, who added that utilizing RNA-based next-generation sequencing (NGS) may show improved sensitivity compared with current testing methods.

“We’ve done a fantastic job in not only identifying targets that are driver oncogenes in lung cancer but also finding targeted therapies that work in those subsets of lung cancer,” said Neal, an associate professor of medicine (oncology) in the University Medical Line of the Department of Medicine-Oncology at Stanford University and a member of Stanford Cancer Institute.

“We also have had a lot of advances in testing technology, but we may identify more genetic targets through things like RNA[-based] NGS. In addition to DNA[-based] NGS, RNA[-based] NGS could be more sensitive in identifying rare targets, especially for gene rearrangements,” Neal added.

In an interview with OncLive^® during the 19th Annual Winter Lung Cancer Conference®, a program hosted by the Physicians’ Education Resource®, LLC, Neal discussed the state of molecular testing in NSCLC, the incidence of common and rare actionable targets, recently approved targeted therapies, and emerging treatment strategies like antibody-drug conjugates (ADCs) that are on the horizon.

OncLive^®: What is the importance of testing patients with NSCLC for common and rare molecular alterations?

Neal: If we don’t test patients’ tumors to see whether they have an actionable target, we will miss a potentially effective therapy. Some of these new targeted therapies that we have can work well for years and control brain metastases. Additionally, when patients receive chemotherapy and immunotherapy as first-line therapy instead of a targeted treatment for common or uncommon genetic alterations, there are sometimes interactions with the immunotherapy and the targeted therapy that they receive later. It is important to test everyone’s tumors up front with a comprehensive panel to make sure patients don’t miss the opportunity to receive one of these exciting new therapies.

How may RNA-based NGS testing improve upon DNA-based NGS?

In addition to testing for targets, how to test is important. There were some sessions [at Winter Lung] on that. DNA testing can cover some of these [targets], but RNA-based tissue testing will be important in identifying more targets. Liquid biopsy is useful when it is positive but can’t be used to rule out the presence of a driver oncogene in a tumor.

What is the incidence of some of the common and rare alterations that should be tested for in NSCLC?

There are now 9 targetable alterations in NSCLC of adenocarcinoma histology. A few of these [targets] were covered by other talks during the 19th Annual Winter Lung Cancer Conference, such as EGFR, including EGFR exon 20, and KRAS G12C. The [incidence of the] remaining targets is relatively infrequent. EGFRmutations are common and seen in around 10% to 15% [of patients], and KRAS G12C mutations are seen in about 10% to 15% of patients. EGFR exon 20 insertions are less frequent at around 3%. From there, the target frequency goes down. METex14 skipping mutations are probably the next most common at around 3%. HER2mutations, also known at ERBB2 alterations, [are found in] around 2% [of patients]. RET gene rearrangements are found in around 2% of patients. ROS1 mutations are found in around 3% of patients. NRG1 and NTRKmutations are much less frequent at less than 1% with NTRK being more common in other solid tumor types. The relative frequency of NRG1 [fusions] because they have only recently been identified hasn’t been well described yet. 

What recent FDA approvals have reshaped the field of targeted therapy and what agents are in development that could further affect treatment for patients with rare mutations?

There are many FDA-approved targeted therapies for rare [mutations] in NSCLC. Some of the more exciting recent approvals include capmatinib [Tabrecta] and tepotinib [Tepmetko] in METex14-positive lung cancer, selpercatinib [Retevmo] and pralsetinib [Gavreto] in RET-rearranged NSCLC, and entrectinib [Rozlytrek] in ROS1-mutated NSCLC, in addition to the drug that was previously used: crizotinib [Xalkori]. Many of these new therapies work longer than the previous options and have better brain penetration with generally tolerable safety profiles.

We are still looking at emerging therapies for HER2/ERBB2-altered NSCLC. The ADC fam-trastuzumab deruxtecan-nxki [Enhertu] is an emerging new therapy in HER2-positive NSCLC.

For NRG1-mutated disease, there are anti-HER3 antibodies in clinical development that we will keep an eye on.

What is the potential to move beyond traditional small molecule inhibitors to targeting proteins in NSCLC?

Beyond genomic drivers for lung cancer, I’m excited about the ADCs. There are new, emerging targets of proteins on the outside of lung cancer cells, such as CEACAM5, TROP2, HER2 amplifications, and METamplifications.

We are moving away from just identifying genetic targets to identifying protein targets. Over the next few years, I’m excited to see how the research with ADCs goes to battle these lung cancers with protein overexpression for some of these targets.