What Must Be Tested in NSCLC Today and Likely Tomorrow

Key Takeaways:

• Approximately 50% of patients with advanced nonsquamous non-small-cell lung cancer harbor a targetable driver alteration.
• Overall survival is significantly improved for patients who receive targeted therapy compared with those who do not receive targeted therapy.
• Broad next-generation sequencing–based biomarker testing is critical to identify as many actionable driver alterations as possible.

At the time of diagnosis, pathologists must classify non-small-cell lung cancer (NSCLC) according to histologic subtypes: squamous cell, large cell, and adenocarcinoma. This is critical because certain therapies—such as the combination of pemetrexed with bevacizumab—are more effective in patients with adenocarcinoma of the lung compared with those with squamous cell histology. Over time, this paradigm evolved with the development of new technologies and the knowledge that certain genetic alterations drive and fuel the growth and progression of NSCLC. The discovery of novel therapeutics that specifically target these “driver genetic variants” opened the door and ushered in the exciting era of precision medicine in NSCLC. With the more recent advent of immune checkpoint inhibitors, especially those targeting PD-L1, immune checkpoint inhibitors have dramatically changed the way NSCLC is treated today.

In nonsquamous NSCLC, activating genetic alterations involving EGFR, ALK, ROS1, and BRAF have been established therapeutic targets for a while, and patients with advanced NSCLC harboring variants in these genes have received treatment with FDA-approved agents targeting these alterations for more than a decade. Other genetic alterations and targeted therapies, however, are “fresh off the press,” with FDA approval of the targeted agents granted within the past 2 years. In advanced nonsquamous NSCLC, the most common genetic driver alterations are KRAS (25%, with 14% of patients harboring the KRAS G12C mutation), EGFR sensitizing mutations (17%), and ALK rearrangements (7%). Uncommon EGFR alterations occur in 4% of patients; of these, EGFR exon 20 insertion mutations are found in 0.1% to 4% of patients. Among patients with advanced NSCLC, the incidence of MET exon 14 skipping mutations is 3%; alterations such as BRAF mutations, HER2 mutations, ROS1 fusions/rearrangements, and RET fusions each occur in 2% of patients. Each of the abnormalities in genes such as NTRK, PIK3CA, NRG1, and FGFR occurs in ≤1% of patients with advanced NSCLC.

Altogether, approximately 50% of patients with advanced nonsquamous NSCLC harbor a targetable driver mutation, gene fusion, or rearrangement for which FDA-approved agents are available or for which investigational agents can be used in a protocol setting. The treatment landscape for NSCLC continues to evolve with the addition of newer generations of drugs for existing targets, as well as new and emerging targets. To provide optimal care for patients, comprehensive next-generation sequencing (NGS)-based biomarker testing that identifies variants across hundreds of genes in 1 seamless workflow is the most effective method for identifying as many actionable driver gene alterations as possible. Furthermore, NGS-based testing facilitates enrollment on clinical trials of investigational agents that target specific gene variants because this may be the best treatment approach for some patients with newly diagnosed NSCLC. Of note, current testing guidelines recommend broad NGS-based biomarker testing, as well as the measurement of PD-L1 expression by immunohistochemistry for all patients who are newly diagnosed with advanced NSCLC. With the new FDA approvals of targeted therapy and immunotherapy in the early-stage, adjuvant setting, testing limited to EGFR status and PD-L1 expression is essential for patients with completely resected NSCLC. However, for patients with early-stage NSCLC undergoing neoadjuvant therapy, molecular testing or PD‑L1 status determinations are not required. 

Of importance, patients who receive targeted therapy have significantly better overall survival compared with patients who do not receive targeted therapy, regardless of the driver mutation identified in their tumors. Medical oncologists are strongly encouraged to wait for NGS-based biomarker test results before initiating treatment with an immune checkpoint inhibitor–based therapy. This is necessary to make the optimal frontline treatment choice and to avoid unnecessary and heightened toxicities associated with switching from upfront chemoimmunotherapy to an EGFR tyrosine kinase inhibitor, for example.

The well-established genetic alterations and corresponding targeted treatments approved by the FDA in the first-line treatment of advanced NSCLC are EGFR mutations (osimertinib, afatinib, dacomitinib, erlotinib, gefitinib), ALK rearrangements (alectinib, brigatinib, lorlatinib, crizotinib, ceritinib), ROS1 fusions (crizotinib, entrectinib), and BRAF V600E mutations (dabrafenib plus trametinib). In the past few years, there has been a rush of new FDA approvals for various new targeted therapies in NSCLC. The targeted agents entrectinib and larotrectinib are approved by the FDA for patients with advanced NSCLC harboring NTRK fusions. Capmatinib and tepotinib are approved by the FDA for patients with advanced NSCLC harboring MET exon 14 skipping mutations. Selpercatinib and pralsetinib have received approval for RET fusion–positive advanced NSCLC.

Recently, sotorasib received FDA approval for the treatment of patients with KRAS G12C mutation–positive advanced NSCLC after 1 or more prior lines of systemic therapy. Although adagrasib is not yet approved by the FDA, it is currently under FDA review for use in the second-line setting for patients with KRAS G12C mutation–positive advanced NSCLC. For patients with EGFR exon 20 insertion mutations, amivantamab and mobocertinib were both recently approved for use after disease progression on or after platinum-containing chemotherapy. Some of the emerging treatment-directed targets include HER2 exon 20 insertion mutations. In fact, treatment for HER2 mutations in advanced NSCLC already appears in the National Comprehensive Cancer Network guidelines. Other emerging biomarkers on the horizon in NSCLC include NRG1 gene fusions, FGFR gene alterations, and TROP2 overexpression. For these emerging alterations, ongoing clinical trials are evaluating investigational targeted therapies for eligible patients.

Patients with advanced NSCLC and high PD-L1 expression (≥50%) whose disease does not harbor any actionable alteration should be considered for a single-agent immune checkpoint inhibitor (pembrolizumab, atezolizumab, or cemiplimab), an immune checkpoint inhibitor in combination with chemotherapy, or dual immune checkpoint inhibitor therapy. On the other hand, patients with low or negative PD-L1 expression levels (<1% to 49%) should generally receive chemotherapy in combination with either an immune checkpoint inhibitor or dual immune checkpoint inhibitor therapy. Irrespective of the PD-L1 expression level, there is a role for PD‑1 inhibition in combination with CTLA-4 inhibition with or without chemotherapy. The optimal choice of first-line treatment combination is yet to be settled in comparative trials. To reiterate, it is important to have the PD-L1 status in hand to be able to make the best first-line treatment decision, especially if the disease does not harbor any actionable alteration.

Conclusions
This is an exciting time in thoracic oncology, and NSCLC is an excellent model for personalized patient care. Quite simply, you cannot treat a target that you have not identified! Some of the most common reasons broad NGS-based biomarker testing is not performed include the lack of sufficient amount of tissue sample, the lack of high-quality and/or quantity of isolated DNA/RNA from the available sample, and a delayed turnaround time that exceeds 14 days. In the case of a patient with newly diagnosed advanced-stage NSCLC in need of immediate upfront therapy and for whom only a small tissue sample is available for testing, it is recommended that initial biomarker tests include PD-L1 expression and genetic analysis of EGFR status including EGFR exon 20 insertion mutations, BRAF V600E mutations, KRAS G12C mutations, MET exon 14 skipping mutations, and ALK/ROS1/NTRK/RET gene fusions or rearrangements. Fortunately, recently introduced testing platforms make it feasible and reliable to perform targeted testing when only small tissue samples are available. In the past 10 years or so, thoracic oncology has moved to the forefront of the 2 most important trends in medical oncology—namely, targeted therapy and immunotherapy. In conclusion, ensuring that our patients with NSCLC have access to high-quality standard-of-care molecular testing and appropriate targeted treatments requires an effective and efficient communication among medical oncologists, pathologists, and all other stakeholders in the multidisciplinary care team.

Join us for a live webinar titled, “Testing Before Treating: Molecular Determinants of Optimal Therapy for NSCLC” on Friday, July 29, 2022, at 12:00 PM Eastern time and Thursday, August 11, 2022, at 7:00 PM Eastern time, where we will discuss the latest guidance and answer your questions.

Your Thoughts?
What are the challenges you experience in your practice when it comes to requesting NGS testing for your patients with NSCLC or interpreting the associated results? Answer the polling question and join the conversation in the discussion box below.