Ceritinib Establishes PFS Advantage in Second-Line ALK+ NSCLC

Giorgio V. Scagliotti, MD

Progression-free survival (PFS) was more than 3 times longer with ceritinib (Zykadia) than with chemotherapy, the current second-line standard, in patients with advanced ALK-positive non—small cell lung cancer (NSCLC) who progressed after first-line crizotinib, according to findings presented at the 2016 ESMO Congress.

Results from the phase III ASCEND-5 trial help confirm earlier data that led to the FDA’s accelerated approval for ceritinib in a similar second-line NSCLC setting in April 2014.

The latest findings demonstrated that patients with ALK-positive NSCLC had significantly longer median PFS of 5.4 months with ceritinib compared with 1.6 months with chemotherapy (HR, 0.49; P <.001).

Giorgio V. Scagliotti, MD, head of the Department of Oncology, University of Turin, Italy, noted that the majority of patients treated with the current standard first-line treatment for ALK-positive NSCLC, crizotinib, develop resistance, making a more effective second-line approach a priority.

“Most patients develop resistance to crizotinib and currently second-line treatment is represented by chemotherapy alone,” Scagliotti said. “This was the first phase III study to assess whether the second-generation ALK inhibitor ceritinib was superior to chemotherapy upon progression on crizotinib therapy in NSCLC.”

Scagliotti and colleagues conducted ASCEND-5 in 231 patients with advanced ALK-positive NSCLC who had progressed following crizotinib and 1 or 2 prior regiments of chemotherapy.

Patients were randomized to daily ceritinib at 750 mg (n = 115) or investigator’s choice of chemotherapy, pemetrexed at 500 mg/m² (n = 40) or 75 mg/m² docetaxel (n = 73). Three patients were not treated.

Brain metastases at baseline were reported in 65 (56.5%) and 69 (59.5%) patients in the ceritinib and chemotherapy arms, respectively.

The primary endpoint was PFS, assessed by a blinded independent review committee (BIRC). Crossover to ceritinib was allowed upon disease progression; in all, 75 patients crossed over to ceritinib.

Overall survival (OS) was possibly confounded by crossover; similar median OS of 18.1 months with ceritinib versus 20.1 months with chemotherapy was seen. “We did not observe an improvement in overall survival with ceritinib, probably because the patients who crossed over diluted the potential benefit,” said Scagliotti.

The overall response rate by BIRC was 39.1% with ceritinib versus 6.9% with chemotherapy; complete or partial response was achieved by 45 patients who received ceritinib versus 8 participants who received chemotherapy. The disease control rates, consisting of complete and partial responses plus stable disease, were 76.5% with ceritinib versus 36.2% with chemotherapy, respectively.

Co-investigator Alice T. Shaw, MD, PhD, discussed the ASCEND-5 results in the context of prior research into ceritinib and alectinib (Alecensa), which also is an ALK inhibitor approved as a second-line NSCLC therapy for patients with the gene rearrangement.

“Single-arm studies have suggested that ceritinib and alectinib could be standard options in the second-line setting after crizotinib has failed,” Shaw, director of thoracic oncology at the Massachusetts General Hospital Cancer Center in Boston, said in a statement.

“But the positive effect on progression-free survival in this phase III study confirms that there is greater benefit using a second ALK inhibitor over standard chemotherapy,” she said. “This will establish sequential crizotinib followed by a second-generation ALK inhibitor as the standard treatment for patients with metastatic ALK-positive lung cancer.”

Toxicities were similar to previously reported studies. The most frequent grade 3 and 4 adverse events (AEs) with ceritinib were nausea (7.8%), vomiting (7.8%), and diarrhea (4.3%); with chemotherapy, these AEs were neutropenia (15.5%), fatigue (4.4%), and nausea (1.8%).

Scagliotti said patient-reported outcomes, including lung cancer—specific symptoms and overall health status, showed symptom improvement with ceritinib over placebo (P < .05), although he noted 2 scales for gastrointestinal symptoms showed deterioration.

He discussed how phase I studies had established a maximum tolerated dose but now it was time for re-evaluation. “It is now a learning process to decrease toxicity by reconsidering the dose,” said Scagliotti. “We need to find the optimal biological dose that maintains efficacy.”

Scagliotti G; Kim TM; Crinò L, et al. Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): results from the confirmatory phase 3 ASCEND-5 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. LBA42_PR.