A New Molecularly Targeted Therapy for Lung Cancer

The U.S. Food and Drug Administration approval provides a new treatment option for patients whose cancer is not responding to crizotinib

The U.S. Food and Drug Administration (FDA) has approved the molecularly targeted therapeutic alectinib (Alecensa) for treating certain patients with advanced non-small cell lung cancer (NSCLC).

Alectinib is intended for treating patients who have tumors driven by mutations in the ALK gene and whose disease is not responding to treatment with the ALK inhibitor crizotinib (Xalkori). The new therapeutic was shown to shrink tumors in patients participating in two early-stage clinical trials.

Alectinib was the seventh new anticancer therapeutic approved by the FDA for treating patients with NSCLC in 2015. Most of the new therapeutics work in different ways to fight the cancer, highlighting the fact that researchers are building broadly on our growing knowledge of the biology of cancer to spur progress against the most common form of lung cancer.

Alectinib works by targeting the signaling protein ALK, which is abnormally active in up to 5 percent of NSCLC cases as a result of mutations in the ALK gene.

The FDA changed the face of treatment for patients with ALK-positive NSCLC in August 2011, when it approved the first ALK-targeted therapeutic, crizotinib. However, most patients whose disease responds to crizotinib go on to have disease progression within a year of starting the treatment because the tumors develop resistance to the medication. In many cases, crizotinib resistance emerges because NSCLC cells acquire additional ALK mutations.

Preclinical studies showed that alectinib was a more potent ALK inhibitor than crizotinib and that it could inhibit most of the clinically observed ALK mutations that drive resistance to crizotinib. These data provided rationale for testing whether alectinib might benefit patients with crizotinib-refractory NSCLC; that is, patients whose disease either progressed after treatment with crizotinib or failed to respond to crizotinib in the first place.

Results from two phase I/II clinical trials showed that alectinib did indeed benefit patients with ALK-positive NSCLC, and these data provided the basis for the FDA approval. According to the FDA announcement, 44 percent of patients in the first clinical trial (NP28673) and 38 percent of those in the second clinical trial (NP28761) had shrinkage of their NSCLC tumors (an objective response). These responses lasted for an average of 11.2 months and 7.5 months for patients in the two clinical trials, respectively.

Because ALK-positive NSCLC frequently metastasizes to the brain, researchers involved in the two clinical trials looked closely at the effect of alectinib on brain metastases. Promisingly, the FDA reported that 61 percent of patients in the two trials who had measurable brain metastases had shrinkage of their brain tumors and these responses lasted an average of 9.1 months.

These data are encouraging, especially for patients whose NSCLC has spread to the brain. However, because the FDA approval was based on objective response rate data, rather than overall survival, alectinib’s manufacturer – Roche – is required to conduct a study to confirm that the new ALK inhibitor provides meaningful clinical benefit. Among the clinical trials designed to show this is ALEX, a randomized phase III trial that is comparing alectinib with crizotinib as a treatment for patients who have not previously received medication to treat ALK-positive NSCLC. Early results for this clinical trial are not expected until 2018, but it is clear that many patients with ALK-positive NSCLC will be treated with alectinib in the interim.

The FDA approval was rendered on Dec.11, 2015.