The Role of Biomarkers in the Treatment of Metastatic NSCLC

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This article was sponsored by AstraZeneca.

This article includes expert insights from Kristen A. Marrone, MD, program director of the Hematology/Medical Oncology Fellowship Program and assistant professor of Oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland.

Importance of Biomarker Testing in Metastatic NSCLC

Although there have been recent gains in survival for patients diagnosed with lung cancer, the disease remains the leading cause of cancer-related deaths in the United States.1,2 Non–small cell lung cancer (NSCLC) is the most common major type of lung cancer, accounting for 80-85% of all cases.3 The majority—approximately 70%—of NSCLC diagnoses occur when the disease is advanced and more difficult-to-treat, and, therefore, when the prognosis is worse.4 Prognosis is particularly poor for patients with metastatic NSCLC (mNSCLC), as only 9% will live beyond 5 years after diagnosis.5

mNSCLC is a complex heterogeneous disease with various biomarkers that may influence outcomes.6 More than half of patients with mNSCLC of adenocarcinoma histology may have an actionable mutation.7-10 The FDA has approved a number of therapy options, and others are being studied, in combination or alone, for mNSCLC, highlighting the importance of accurate testing for these biomarkers.11,12 This critical biomarker information not only aids in diagnosis at the onset of cancer treatment, but it can be used throughout treatment to help guide decisions.11,12

“As precision medicine expands in oncology, biomarker testing becomes more essential to tailor treatment plans based on a patient’s unique genetic profile,” said Kristen A. Marrone, MD. “We need to continue to push the field of biomarker-directed care forward for our patients, by educating them and involving them in clinical trials, so that patients understand their therapeutic options and the potential of precision-based medicine, and we learn how best to individualize care for each patient at their time of diagnosis.”

Actionable Biomarkers in mNSCLC
The National Comprehensive Cancer Network® (NCCN®) recommends broad molecular profiling to help inform disease management plans for patients with mNSCLC.13 NCCN actionable biomarkers include: EGFR, KRAS G12C, ALK rearrangement, ROS1 rearrangement, BRAF, NTRK1/2/3 gene fusion, MET exon 14 skipping, RET rearrangement, HER2 (ERBB2), and PD-L1 expression status.13 Actionable biomarkers are defined as genetic alterations that are functional in driving malignancy and may be targeted by an FDA-approved treatment regimen.13 Additionally, high-level MET amplification is an emerging biomarker.13

“The use of targeted therapies and immunotherapies, and an expanding understanding of actionable molecular alterations in lung cancer, have led to an exciting, yet complicated, approach to 1st-line therapy treatment decisions in mNSCLC,”13 Dr Marrone noted. “There are a multitude of barriers to obtaining biomarker testing that is needed—including quantity of tissue needed, ordering and identifying appropriate testing, and payer cost—but doing this consistently and appropriately will ultimately be what is most important so that we can use the treatments at our disposal.”14

If the appropriate biomarker testing is completed but no actionable alterations are found, Dr Marrone said she considers tumor (tissue histology and PD-L1 and HER2 immunohistochemistry [IHC] testing), disease (overall burden and location of metastases), and patient factors (relevant medical history, physical fitness, and preferences) to help determine the appropriate treatment regimen, which may include an immune checkpoint inhibitor (ICI) alone, ICI combination therapy plus chemotherapy or chemotherapy alone.

She added that ensuring comprehensive next-generation sequencing (NGS) testing, which also evaluates for rare molecular changes, such as translocations and fusions, is a critical part of the diagnosis process as potential novel biomarkers for mNSCLC emerge.14

The Role of Immunotherapy in the Management of mNSCLC
Several therapeutic agents, such as ICIs, targeting PD-1 and PD-L1 are currently approved as 1st-line treatment options for patients with mNSCLC without known EGFR mutations or ALK alterations.15-18 Testing for the PD-L1 biomarker at time of diagnosis can be used as a decision-making tool to help determine whether a patient may benefit from immunotherapy to treat their lung cancer.19 Tumors that express high amounts of PD-L1 (50% or greater) may respond particularly well to ICI therapies.20

Despite its widespread use, PD-L1 has limitations as a predictive biomarker.21 Exploratory subgroup analyses of Phase III trials suggest that patients with tumors expressing <1% PD-L1 may see suboptimal outcomes from combined first-line PD-(L)1 inhibition and chemotherapy, compared with patients with higher PD-L1 expression.22-27

Dr Marrone concurs that the PD-L1 negative tumor space remains an area of unmet need for patients. “We are looking to determine if we can identify novel biomarkers to help us inform disease management plans.”

Biomarkers of Interest in mNSCLC
To help better inform treatment planning for difficult-to-treat patient populations in newly diagnosed mNSCLC, novel prognostic and predictive biomarkers of interest are an evolving area of research.29

The majority of patients with metastatic adenocarcinoma NSCLC may have genetic alterations that are actionable across various lines of therapy.6-8 However, about two-thirds of patients with mNSCLC do not have actionable alterations for 1st-line targeted therapy and may be eligible for 1st-line immunotherapy regimens, as supported by PD-L1 testing.6,8

Several possible biomarkers of interest are being investigated in this mNSCLC setting, including STK11, KEAP1, and SMARCA4:

  • STK11: A tumor-suppressor gene. STK11m may be associated with rapid tumor progression and poor prognosis, according to exploratory studies30-32
    • STK11 is among the more often mutated genes in NSCLC and may be associated with a lack of PD-L1 expression33-35
  • KEAP1: A tumor-suppressor gene. KEAP1m may be associated with poor prognosis36-38
    • Mutations of KEAP1 in NSCLC may impact tumor growth and may be associated with resistance to various anticancer therapies36-38
  • SMARCA4: A tumor-suppressor gene. Although individual SMARCA4 mutations may predict positive response, SMARCA4 mutations co-occurring with KRAS (≈36% co-occurrence) may be associated with poorer response to immunotherapy regimens compared with KRAS mutations alone.39,40
  • KRAS: The most common oncogene. KRAS mutations frequently co-occur with STK11, KEAP1 and/or SMARCA4, and these co-mutated subgroups may be associated with suboptimal outcomes to immunotherapy regimens.29,30,36,38,39,41,42
    • KRASm NSCLC represents a large and highly heterogeneous patient subgroup (≈30% of NSCLC) with a poorer prognosis and a high co-mutation rate that can complicate treatment planning.40,43-45

Small, retrospective, exploratory subgroup analyses in NSCLC suggest that inactivation of these genes may negatively impact disease outcomes in patients with NSCLC.37-39,41 One study found that more than 95% of samples from NSCLC patients with high-risk tumors and 10.2% of samples from patients with mNSCLC had mutations in both STK11 and KEAP1.46 Additionally, several genotypes were found to be common among the high-risk group including KRAS/STK11/KEAP1 (28%), TP53/STK11/KEAP1 (25%), and KRAS/STK11/KEAP1/SMARC4 (16%).46

Additional investigation is needed to further characterize how certain biomarkers of interest, such as STK11 and KEAP1, can aid in patient selection for 1st-line immunotherapy regimens in those with NSCLC. Until more research becomes available, there is a need to focus on realizing the promise of immunotherapy as a potential treatment option for certain patients with mNSCLC.

Abbreviations
ALK: anaplastic lymphoma kinase; BRAF V600E: v-rag murine sarcoma viral oncogene homolog B1; EGFR: epidermal growth factor receptor; FDA: Food and Drug Administration; HER2: human epidermal growth factor receptor 2 (also known as ERBB2); ICI: immune checkpoint inhibitor; IHC: immunohistochemistry;KEAP1: Kelch-like ECH-associated protein 1; KRAS G12C: Kirsten rat sarcoma viral oncogene homologue gene glycine-to-cysteine substitution at codon 12; MET: mesenchymal epithelial transition factor receptor; mNSCLC: metastatic non-small cell lung cancer; NCCN: National Comprehensive Cancer Network®; NGS: next-generation sequencing; NSCLC: non-small cell lung cancer; NTRK: neurotrophic tyrosine receptor kinase; PD-L1: programmed death-1 ligand 1; ROS1: ROS proto-oncogene 1; SMARCA4: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; STK11: serine/threonine kinase 11; TP53: tumor protein p53

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