Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

Considerations in the Care of Non-Small-Cell Lung Cancer: The Value Imperative.

Cancer costs in the United States continue to escalate at an alarming and unsustainable rate. These costs are not driven exclusively by a higher demand for services or by an aging population; rather, a number of systemic failures, highlighted by the Institute of Medicine (IOM), continue to plague our cancer care delivery systems and need to be rectified. Drug costs, plus expensive diagnostic tests, hospital admissions/readmissions, and unreasonable end-of-life care, combine to inflate the total cost of care. Cancer, particularly lung cancer, is one of the most expensive diseases in the United States. While individual oncologists are unlikely to influence costs in the short term, they can become more proficient at evaluating the value derived from new treatment options and maximizing the clinical benefit for their patients. Discussions of cost and patient values need not hinder patient-physician relationships, and, in fact, can strengthen them. This article discusses ways in which the oncologist can incorporate value into the management of patients with lung cancer and comply with the underlying principles of the Choose Wisely Campaign, as well as recent American Society of Clinical Oncology and European Society for Medical Oncology initiatives, to bend the cost curve downwards while maintaining efficacy.