Patients with non-small cell lung cancer (NSCLC) who have an ALK gene rearrangement and who were previously treated with the ALK inhibitor Xalkori (crizotinib) may strongly benefit from treatment with another ALK inhibitor, Zykadia (ceritinib), according to the results of a Phase 3 trial.

Recently presented data at the European Society for Medical Oncology (ESMO) Congress Oct. 7-11 in Denmark has shown that Zykadia more than triples patients’ progression-free survival rates compared to chemotherapy. However, Zykadia showed no survival benefit over chemotherapy in these patients.

“Patients with non-small cell lung cancer (NSCLC) should receive front line therapy with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib,” lead author and Prof. Giorgio Scagliotti, head of the Department of Oncology at the University of Turin, Italy, said in a press release. “Most patients develop resistance to crizotinib and currently second line treatment is represented by chemotherapy alone.”

“This was the first Phase 3 study to assess whether the second generation ALK inhibitor [Zykadia] was superior to chemotherapy upon progression on [Xalkori] therapy in NSCLC,” he added.

The randomized, multicenter, open-label Phase 3 ASCEND-5 study enrolled 231 patients with NSCLC who had been previously treated with chemotherapy and Xalkori.

Participants were randomized to receive Zykadia or one of two available chemotherapies: Alimta (pemetrexed) or Taxotere (docetaxel). Patients who discontinued chemotherapy due to disease progression were allowed to cross over to receive Zykadia.

The study’s primary endpoint was progression-free survival and secondary endpoints included overall survival, overall response rate, and duration of response.

Results revealed that Zykadia significantly improved the median progression-free survival compared to chemotherapy (5.4 months vs. 1.6 months). In addition, 39.1 percent of patients in the Zykadia group responded to the therapy compared to only 6.9 percent of patients in the chemotherapy arm.

However, Zykadia did not induce an increase in overall survival, which the researchers believe might be due to patient cross-over during the course of the study. Among the patients who progressed on chemotherapy, 75 crossed over to Zykadia.

“Progression-free survival was significantly lengthened with [Zykadia] compared to chemotherapy. We did not observe an improvement in overall survival with [Zykadia], probably because the patients who crossed over diluted the potential benefit,” Scagliotti said.

Zykadia toxicities were similar to those observed in prior Phase 1 and Phase 2 studies, with the most frequent grade 3-4 adverse events being nausea, vomiting and diarrhea in the Zykadia group.

The most common grade 3-4 adverse events in the chemotherapy group were a reduction in a subtype of white blood cells, fatigue, and nausea. Compared to the placebo, Zykadia was able to improve patient-reported outcomes, including overall health status and lung cancer-specific symptoms.

“This study opens up a new treatment paradigm after [Xalkori] failure,” said Scagliotti. “It would be logical now to give a sequence of active drugs, starting with [Xalkori] in first line and moving to [Zykadia] in second line.”

“The positive effect on progression-free survival in this Phase 3 study confirms that there is greater benefit using a second ALK inhibitor over standard chemotherapy,” said Dr. Alice Shaw, director of thoracic oncology at Massachusetts General Hospital Cancer Center in Boston. “This will establish sequential crizotinib followed by a second generation ALK inhibitor as the standard treatment for patients with metastatic ALK positive lung cancer.”

“We are now waiting on the results of trials testing the second generation ALK inhibitors ceritinib (vs. chemotherapy) and alectinib [Alecensa] (vs. crizotinib) in the first line setting,” Shaw added. “The latter trial addresses one of the most fundamental questions in the field, which is what should be the first ALK inhibitor that patients receive.”