PFS Three Times Longer With Ceritinib Than With Chemotherapy in 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 advancedALK-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 withALK-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 forALK-positive NSCLC, crizotinib, develop resistance, making a more effective second-line approach a priority.

&ldquo;Most patients develop resistance to crizotinib and currently second-line treatment is represented by chemotherapy alone,&rdquo; Scagliotti said. &ldquo;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.&rdquo;

Scagliotti and colleagues conducted ASCEND-5 in 231 patients with advancedALK-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&rsquo;s choice of chemotherapy, pemetrexed at 500 mg/m²(n = 40) or 75 mg/m²docetaxel (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. &ldquo;We did not observe an improvement in overall survival with ceritinib, probably because the patients who crossed over diluted the potential benefit,&rdquo; 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.

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

&ldquo;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,&rdquo; she said. &ldquo;This will establish sequential crizotinib followed by a second-generation ALK inhibitor as the standard treatment for patients with metastatic ALK-positive lung cancer.&rdquo;

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. &ldquo;It is now a learning process to decrease toxicity by reconsidering the dose,&rdquo; said Scagliotti. &ldquo;We need to find the optimal biological dose that maintains efficacy.&rdquo;

Reference:

Scagliotti G; Kim TM; Crin&ograve; 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.