Extensive-disease small-cell lung cancer (ED-SCLC) is highly responsive to first-line therapy, but early relapses commonly occur, and prognosis is poor. To date, no biomarker-driven therapies have been established. Based on the involvement of the immune system in the pathophysiology of SCLC and the high mutational burden of this disease, immunotherapy has potential as a novel treatment option.
Standard treatment for patients with ALK-positive, advanced NSCLC includes the first-generation ALK inhibitor crizotinib and, more recently, second-generation ALK TKIs such as ceritinib and alectinib. The global, phase III ALEX trial tested the highly selective, CNS-active ALK inhibitor alectinib as first-line agent compared to crizotinib in patients with stage IIIB/IV ALK-positive NSCLC. Asymptomatic brain metastases were allowed in this study.
Afatinib has been licensed for the second-line treatment of patients with squamous-cell carcinoma of the lung. A combination trial is ongoing that is testing afatinib plus pembrolizumab. What can we expect from this regimen?
EGFR TKI treatment has become a standard first-line strategy for patients with advanced, EGFR-mutation–positive NSCLC. Established agents include the first-generation drugs gefitinib and erlotinib, the second-generation agents afatinib and dacomitinib, and the third-generation TKI osimertinib. Combinations of EGFR TKIs with other drug classes might lead to outcome optimisation, for instance the additional administration of anti-angiogenic drugs, such as bevacizumab and ramucirumab.
Various clinical factors beyond PD-L1 expression have been explored as predictors of response to immune checkpoint inhibition. Specifically, analyses have associated lack of tobacco exposure with diminished responsiveness to PD-1 pathway blockade in NSCLC. One possible explanation for this is that lung cancers arising in never or minimal smokers generally show low TMB.
Monotherapy with the anti-PD-1 monoclonal antibody pembrolizumab has significantly improved clinical endpoints compared to chemotherapy in patients with metastatic non–small-cell lung cancer (NSCLC). KEYNOTE-024 showed overall survival (OS) improvement in addition to a progression-free survival (PFS) benefit; moreover, patients treated with pembrolizumab had a better safety profile than those receiving chemotherapy.
As physicians and researchers, we are fortunate to be part of the dramatic innovation in cancer research and treatment brought about by precision medicine. Although the success of precision medicine may seem like an overnight success, it has actually been a thoughtful, strategic approach based upon decades of hard, disciplined work by dedicated scientists from around the world.
