CME
Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™
Released: April 25, 2024
Expiration: April 24, 2025
Introduction
In this module, Narjust Florez, MD, discusses the evolution of treatment for advanced non-small-cell lung cancer (NSCLC) and rationale for targeting TROP‑2.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
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Molecular and PD-L1 Testing at Initial Diagnosis to Guide Treatment in NSCLC
Here, I will discuss the evolution of TROP-2 as a potential therapeutic target and where TROP-2‒targeting ADCs potentially may fit within the treatment paradigm of advanced NSCLC.
To provide an orientation to the current landscape of NSCLC, essential testing at diagnosis includes molecular and PD-L1 testing for all patients. I believe that the diagnosis of NSCLC is not final until all molecular and PD-L1 testing has been completed. NSCLC has evolved significantly over time, and treatments now are tailored to the patient’s genomic profile—to both the primary main mutation and comutations, if applicable. So, once we initially diagnose NSCLC, we now need to divide the disease into early and advanced stages. Again, biomarker testing is important at all stages of NSCLC. For patients with early-stage disease who are receiving neoadjuvant therapy, we need to ensure that they undergo testing to determine presence of EGFR and ALK mutations at a minimum. This is important because neoadjuvant chemoimmunotherapy is much less effective in patients with these genomic alterations,1,2 and potentially these patients may receive targeted therapy in a clinical trial or with recently approved treatments. PD-L1 also helps us understand the probability that the patient may respond to neoadjuvant therapy and the role of adjuvant immunotherapy.3
Ideally, biomarker testing should be completed at the time of diagnosis for early-stage NSCLC. If it has not been done in the neoadjuvant setting, then we should test for EGFR and ALK in the surgical specimen. In the adjuvant setting, EGFR-targeted therapy is approved, and ALK-targeted therapy was recently approved on April 18, 2024.3-5 Patients with PD-L1 >50% are most likely to benefit from single-agent immunotherapy.6-8
For advanced disease, molecular next-generation sequencing (NGS) is critical. It is important to understand not only the main driver mutation, but also the comutations, which will aid in understanding the risk for transformation to small-cell lung cancer, the potential target, and response to therapy. Broad molecular testing should be done in all patients with advanced NSCLC, particularly in those with nonsquamous histology. This includes EGFR, ALK, KRAS, ROS1, BRAF V600, NTRK, MET exon14 skipping mutation, RET, and HER2.9
It is very important that we have biomarker testing results prior to initiating any immune checkpoint inhibitor therapy because they can have no to very little efficacy for some mutations—EGFR and ALK, among others. In addition, because of the cross-toxicity, administering an immune checkpoint inhibitor prior to a tyrosine kinase inhibitor (TKI) can increase the risk of toxicity.3,10
Heterogeneity in NSCLC
This is important because we no longer talk simply about NSCLC or even adenocarcinoma vs squamous histology. We talk about NSCLC at the molecular level, and with emerging therapies, such as TROP-2‒targeting agents, we consider the molecular profile. Some TROP-2‒targeting therapies may be more effective in patients with EGFR and ALK genomic alterations compared with other mutations.11 Knowing the molecular background of the disease is extremely important not only for first-line treatment selection, but also for potential upcoming therapies, including TROP-2‒targeting ADCs.
Targeted Therapy in Advanced NSCLC With Actionable Driver Mutations (2024)
There is much to understand with targeted therapies in NSCLC because some are approved in the first-line setting, others are approved in the second-line setting, and some have indications for both early and advanced disease settings. First, I will distinguish between NGS and panel testing. Panel testing is when you individually order a test for every single gene. NGS is broader and allows for the identification of emerging biomarkers for which clinical trials may be available. In addition, NGS provides information on comutations, which enables greater classification of patients into high- or low-risk genomic profiles—and allows you to determine their next course of treatment.
Furthermore, it is crucial to understand that genomic testing is necessary at diagnosis and at any time of disease progression. Many patients with targetable mutations may have or develop resistance mechanisms, so obtaining a biopsy at the time of progression will inform the type of resistance mechanism that is present. In addition, patients may be eligible for another targeted therapy that will help with the resistance mechanism that was developed to the first or original targeted therapy.9
EGFR has expanded to include the classical and uncommon mutations. The classical mutations (exon 19 deletion or exon 21 L858R) typically are treated with osimertinib in the first-line setting, although other agents are approved.9,12 The uncommon mutations include exon 20 insertions, for which we have amivantamab, which originally was approved as monotherapy in the second-line setting and since has expanded to include the first-line setting in combination with platinum-based chemotherapy.13 Of note, the FDA indication for mobocertinib was voluntarily withdrawn in October 2023.14 Other uncommon EGFR mutations can be treated with afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib.9
ALK rearrangements have several targeted therapies approved for both the first- and second-line settings. This is the only alteration that has 2 lines of targeted therapy available. For ROS1 rearrangements, there are new and exciting data with repotrectinib in patients who previously had received a ROS1 TKI.15 Two targeted therapy combinations are approved for BRAF V600E mutations. NTRK gene fusions, which I refer to as the unicorn of NSCLC, are rarely identified. We have MET exon 14 skipping mutations and RET rearrangements, each with 2 preferred targeted therapy options approved in the first-line setting. For the KRAS G12C mutation, targeted therapy is approved only in the second-line setting, so patients need to progress on first-line chemoimmunotherapy before they are eligible for adagrasib or sotorasib.16,17 Patients with HER2 mutations will start with chemotherapy—I do not prefer immunotherapy in these patients—and upon progression they can proceed to trastuzumab deruxtecan,9,18 which is one of the latest therapies approved for this alteration.
TROP-2 as a Therapeutic Target
One of the emerging biomarkers that I am particularly excited about is TROP-2, which is a transmembrane glycoprotein overexpressed in solid tumors, including NSCLC. When transmembrane proteins such as TROP-2 are overexpressed, they affect subsequent pathways down the line. Here, this accelerated pathway can enhance cell activation and proliferation and, in some cases, cell migration.
TROP-2 is also an epithelial adhesion molecule that regulates the stem cell markers associated with cell regeneration. It can lead to uncontrolled cell proliferation when overexpressed and serve as a target for new therapeutic agents.19,20
TROP-2 Overexpression in NSCLC and Other Cancers
TROP-2 tends to be expressed in many cancers, and we still are trying to fully understand this biomarker. Even so, novel TROP-2‒targeting therapies are under investigation. Although TROP-2 is a new therapeutic target in NSCLC, is it not new for other malignancies, such as metastatic triple-negative breast cancer (TNBC), for which the TROP-2‒targeting ADC sacituzumab govitecan already is approved by the FDA.21
In NSCLC, TROP-2 overexpression is seen in 64% of all adenocarcinoma histology and 75% of all squamous cell carcinomas.22 Although there may be a higher incidence of overexpression in squamous NSCLC, there is some evidence that TROP-2 inhibitors are more beneficial in adenocarcinoma histology.23 This is one example of how we have yet to fully understand this biomarker.
In breast cancer, TROP-2 is overexpressed in 62% of tumors, with much higher overexpression in the TNBC subtype (78%).22 This makes more sense because the TROP-2 inhibitor sacituzumab govitecan shows good responses in TNBC, but in NSCLC we are not seeing the same correlation between TROP-2 overexpression and outcomes.
Association of Tumor TROP-2 Expression With Prognosis Varies Among Lung Cancer Subtypes
There are some limitations with TROP-2 as a predictive and prognostic biomarker. At this time, we have very limited data and have seen TROP-2 overexpression not be associated with response in some tumor types. So, there is more to learn about TROP-2 as a predictive biomarker of response to the new TROP-2‒targeting ADCs, as well as to understand how the disease behaves in tumors with TROP-2 overexpression. Is overexpression of TROP-2 associated with worse prognosis? There are data that suggest high TROP-2 expression is associated with higher lung cancer‒specific mortality in adenocarcinoma, but not squamous histology.24
TROP-2 Overexpression Associated With Shorter Overall Survival, Disease-Free Survival
Overall, numerous studies have demonstrated that overexpression of TROP-2 is associated with worse outcomes.
Summary
As the data continue to evolve, overall, I am very optimistic that with new therapies and effective biomarkers, we are going to have more available treatment options for patients with NSCLC. For patients with EGFR mutations, for example, after progression on a first-line EGFR TKI, chemotherapy is the next line of treatment. It is vital that we continue to develop therapies to improve treatment options for patients. Chemotherapy always will be available, but perhaps a new therapy could fit into the current treatment paradigm between targeted therapy and chemotherapy. In addition, in the future, we may see combinations of TROP-2 inhibitors with TKIs, similar to what we have seen with combinations of TKIs and chemotherapy.
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