Lung cancer has emerged as a prime example of both the promise and pitfalls of precision medicine. Significant progress has been made in the treatment of patients whose tumors have specific molecular drivers, such as epidermal growth factor receptor (EGFR
) mutations and anaplastic lymphoma kinase (ALK
) gene fusions. Drugs designed to target these drivers have dramatically improved outcomes for patients with the most common type of lung cancer, adenocarcinoma.
Yet despite these successes, driver mutations have been identified in only a minority of cases and patients with other types of lung cancer, such as squamous cell carcinoma (SCC) and small-cell lung cancer (SCLC), do not currently benefit from targeted therapies. As the leading cause of cancer- related mortality worldwide, better treatment options for patients with lung cancer have been and continue to be a pressing need.
Efforts to expand the pool of therapeutically actionable targets have turned to comprehensive molecular profiling studies. Technological advancements in our ability to detect these genetic variants in smaller samples and in minimally invasive techniques could help to bring the promise of precision medicine to a greater number of patients with lung cancer.
Poster Child for Precision Medicine
Non–small cell (NSCLC) and SCLC histologies comprise the 2 major types of lung cancer, with the former making up 85% of cases. Among patients with NSCLC, nearly two-thirds have adenocarcinomas.
The prevalence of EGFR
mutations in NSCLC is between 10% and 35%, depending on the patient population. Most commonly, the mutation occurs in exon 19 or 21 of the EGFR
gene, activating the tyrosine kinase activity of the EGFR protein and promoting lung cancer growth and progression. The small-molecule EGFR inhibitors erlotinib (Tarceva) and gefitinib (Iressa) are accepted firstline therapies, demonstrating response rates up to 75% and improving progression-free survival (PFS), compared with standard chemotherapy regimens.
The more potent second-generation inhibitor afatinib (Gilotrif) is also approved as front-line therapy in EGFR-mutant metastatic NSCLC and demonstrated improved ORR and PFS compared with chemotherapy, but also improved overall survival (OS) in patients with exon 19 deletions.
The long-term benefit these drugs provide is hampered by the ability of cancer cells to evolve numerous different mechanisms of resistance. Approximately half of resistance cases involve a secondary mutation in the EGFR
, the so-called gatekeeper mutation that restores ATP binding. A third generation of EGFR inhibitors with specificity for this EGFR mutant has been developed and osimertinib (Tagrisso) was very recently approved in this setting.
The discovery of gene fusions involving ALK, which result in constitutive activation of its tyrosine kinase activity, opened up another therapeutic avenue for patients with NSCLC. This abnormality is seen in 2% to 7% of patients and renders tumors sensitive to small-molecule inhibitors of the ALK protein. Crizotinib (Xalkori), although originally developed as a MET inhibitor, was subsequently found to have potent inhibitory activity against the ALK and ROS1 proteins and received regulatory approval following demonstration of improved response rates and PFS.
A similar narrative of acquired resistance has played out for ALK inhibitors, including an analogous gatekeeper mutation, L1196M, as the most common cause. The second-generation inhibitors ceritinib (Zykadia) and alectinib (Alecensa) have also been approved by the FDA, with alectinib showing a unique ability to benefit patients with central nervous system metastases.
The identification of gene fusions involving the ROS1 gene has further expanded the list of targetable oncogenic drivers in NSCLC, with the approved indications of crizotinib expanded to include patients with this rarer alteration in the past year.
Screening patients for these specific alterations and matching them to targeted therapy demonstrates the power of precision medicine in oncology. Yet, only a small proportion of patients with NSCLC are eligible for this kind of treatment; in the vast majority of cases, the molecular driver of the tumor remains unknown and 5-year survival rates are about 19%.
Sequencing Studies Define Subtype Differences
Stand-alone studies have identified many potentially targetable mutations in NSCLC beyond EGFR
, including other tyrosine kinase receptors such as MET and HER2 and downstream components of these signaling pathways such as BRAF, AKT, and PIK3CA, but none are currently actionable.