Molecular Profiling Plays a Key Role in Optimizing NSCLC Therapy

Treating patients with chronic myeloid leukemia, melanomas, and non–small-cell lung cancer (NSCLC) with targeted therapy improves objective response rates and progression-free survival (PFS) compared with standard-of-care cytotoxic chemotherapy regimens.¹ This demonstrates the benefit of targeted therapy and highlights the importance of identifying the underlying molecular mechanism (and the specific biomarker) to optimize treatment.^2,3

Lung cancer has a significant rate of genetic alterations compared with other cancers.⁴ There are several oncogenic driver mutations in NSCLC that are actionable for treatment. For example, patients with NSCLC who have a somatic activating mutation in EGFR (approximately 20% of patients) can be treated with EGFR tyrosine kinase inhibitors, resulting in longer PFS compared with platinum-based chemotherapy treatment.² Approximately 5% of patients with metastatic NSCLC have gene rearrangements that result in fusions and overexpression of the protein anaplastic lymphoma kinase (ALK).² Chromosomal rearrangements in the gene encoding ROS1 are present in approximately 1% of patients with NSCLC, and 1% to 2% of patients with lung adenocarcinoma have somatic activating BRAF mutations.²

Molecularly targeted approaches have produced positive outcomes for patients with NSCLC with these oncogenic drivers (responses vary).² Researchers have identified several other molecular alterations, including MET exon 14 skipping mutations (approximately 4% of patients with NSCLC), HER2 mutations (approximately 2% of patients with lung cancer), NTRK gene alterations (approximately 1% of NSCLC tumors), and rearrangements in the RET gene (1%-2% of patients with NSCLC).^2,5

Employing medications approved for other diseases or molecular alterations to treat targets for which specific inhibitors are not available (such as MET, RET, and HER2) has produced limited success.² Multikinase inhibitors have been found to have limited efficacy in patients with RET-driven tumors, possibly because the therapy also inhibits non-RET kinases.¹ Researchers continue to evaluate specific therapies to target these oncogenic drivers.²

In 2013, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) jointly issued guidelines recommending molecular testing of patients with lung cancer for EGFR mutations and ALK gene fusions.⁶ In 2018, these guidelines were updated to include a recommendation for molecular identification of ROS1 gene rearrangements.⁷ The American Society of Clinical Oncology concurred with the 2018 CAP/IASLC/AMP guidelines for the treatment of patients with lung cancer with targeted tyrosine kinase inhibitors, but added a recommendation to screen for BRAF mutations.⁸

Uptake of biomarker testing and molecular profiling in clinical practice has been uneven.⁹ In 2018, it was estimated that approximately 72% of newly diagnosed patients with NSCLC received EGFR testing, and roughly 69% of patients received ALK testing. Another study found relatively low rates of screening for ROS1 rearrangements (38%), HER2 mutations (16%), and RET rearrangements (14%).¹⁰

Some barriers to molecular testing can be overcome with the introduction of next-generation sequencing–based assays that will be able to produce a complete molecular profile, evaluating all proven and emerging biomarkers in one test with a single sample.⁹ Expanded uptake and more widespread use of molecular profiling in clinical practice, especially in the community, can optimize NSCLC treatment and lead to better outcomes for patients.⁷

References

1. Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15:151-167.
2. Arbour KC, Riely GJ. Systemic therapy for locally advanced and metastatic non–small-cell lung cancer: a review. JAMA. 2019;322:764-774.
3. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311:1998-2006.
4. Barlesi F, Mazieres J, Merlio JP, et al; for the Biomarkers France contributors. Routine molecular profiling of patients with advanced non–small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387:1415-1426.
5. Mayekar MK, Bivona TG. Current landscape of targeted therapy in lung cancer. Clin Pharmacol Ther. 2017;102:757-764.
6. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association of the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2013;137:828-860. Erratum in: Arch Pathol Lab Med. 2013;137:1174.
7. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142:321-346.
8. Kalmkerian GP, Narula N, Kennedy EB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology clinical practice guideline update. J Clin Oncol. 2018;36:911-919.
9. Pennell NA, Arcila ME, Gandara DR, West H. Biomarker testing for patients with advanced non–small-cell lung cancer: real-world issues and tough choices. Am Soc Clin Oncol Educ Book. 2019;39:531-542.
10. Audibert CM, Shea MB, Glass DJ, et al. Trends in the molecular diagnosis of lung cancer: results from an online market research survey. July 20, 2017. www.focr.org/sites/default/files/pdf/FINAL%202017%20Friends%20NSCLC%20White%20Paper.pdf. Accessed September 11, 2020.