Fine-Tuning Molecularly Targeted Therapy for Lung Cancer

Results from two clinical trials highlight the benefits of the molecularly targeted therapeutics ceritinib and osimertinib

fine tuning molecularly targeted therapy lung cancer

There has been an explosion in the number of treatments approved by the U.S. Food and Drug Administration (FDA) for patients with advanced non-small cell lung cancer (NSCLC) in the past few years. These treatments include immunotherapeutics such as atezolizumab (Tecentriq), nivolumab (Opdivo), and pembrolizumab (Keytruda) and molecularly targeted therapeutics such as ceritinib (Zykadia) and osimertinib (Tagrisso).

NSCLC accounts for about 80 to 85 percent of the more than 200,000 cases of lung cancer diagnosed each year in the United States. About 57 percent of lung cancers are diagnosed at the advanced stage.

Given the growing array of treatment options for advanced NSCLC, many researchers working in the field are focused on determining the most appropriate treatment for a given patient at a given time.

Recent results from two clinical trials confirm the benefit of and may help fine-tune the use of two molecularly targeted therapeutics, ceritinib and osimertinib.

A Question of Timing

Most of the new treatments for advanced NSCLC are approved only for second-line use, meaning only for use after a patient’s disease has worsened while receiving another treatment. For example, ceritinib is approved only for treating patients whose disease worsened during treatment with crizotinib (Xalkori) or who could not tolerate crizotinib.

Ceritinib and crizotinib both target the molecule ALK, which is mutated in about 3 to 7 percent of NSCLCs. They are both used only to treat patients whose NSCLC tests positive for an ALK mutation, like James “Rocky” Lagno’s cancer did in 2012.

New clinical trial results, which were presented recently at a scientific conference, show that ceritinib benefited patients with advanced, ALK-positive NSCLC who had not received any prior treatment for their metastatic disease. That is, first-line treatment with ceritinib benefited patients.

In fact, ceritinib more than doubled the time before disease worsened compared with chemotherapy. The median progression-free survival was 16.6 months among those receiving ceritinib compared with 8.1 months among those receiving chemotherapy.

These results will not immediately change clinical practice, meaning that patients newly diagnosed with advanced, ALK-positive NSCLC should not currently expect to be offered treatment with ceritinib. However, the company that makes ceritinib, Novartis, said in a news release, “Based on these results, Novartis is initiating discussions with regulatory authorities worldwide regarding this potential use of Zykadia to further improve outcomes for patients with ALK+ advanced NSCLC.”

Confirming Benefit

The second set of clinical trial results announced recently are initial results from the AURA3 phase III trial testing the molecularly targeted therapeutic osimertinib as a treatment for certain patients with advanced NSCLC.

Osimertinib specifically targets the mutant forms of EGFR that fuel the growth of about 10 to 15 percent of NSCLCs. It even targets the EGFR T790M mutant that is the most frequent cause of resistance to other EGFR-targeted therapeutics such as afatinib (Gilotrif), erlotinib (Tarceva), and gefitinib (Iressa).

Osimertinib was approved by the FDA in December 2015 for treating patients with advanced NSCLC that has an EGFR T790M mutation and that has progressed despite treatment with other EGFR-targeted therapeutics. This approval was based on objective response rate data, rather than overall survival data. As a result, osimertinib’s manufacturer, AstraZeneca, was required by the FDA to conduct a clinical trial to confirm that the drug improves survival for patients.

The recent results are the first from that trial and they showed that osimertinib significantly increased the time before disease worsened compared with standard chemotherapy. Median progression-free survival was 10.1 months for those receiving osimertinib compared with 4.4 months for those receiving standard chemotherapy.

Patients receiving osimertinib through the clinical trial also experienced fewer severe adverse events compared with those receiving standard chemotherapy.

This mirrors the positive experience of Ginger Tam, a 54-year-old single mom with metastatic NSCLC. Ginger received osimertinib through a clinical trial and says about her experience, “Within two months of starting a clinical trial testing a drug called osimertinib (Tagrisso), I had my voice back, along with my breath. Although my lung cancer progressed after two years of receiving osimertinib, my experience with the drug was so awesome that I always said if my lung cancer progressed again, I would look to enroll in a clinical trial testing osimertinib in combination with other treatments.”

Although more time is needed before we can discover whether osimertinib improves overall survival, the new AURA3 data provide more hope for patients with NSCLC, like Ginger.