Novartis announced updated results from a phase II study (ASCEND-3), which demonstrated that anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) patients taking Zykadia (ceritinib) as their first ALK inhibitor (post-chemotherapy) had a median progression-free survival (PFS) of 18.4 months [95% CI: 10.9-26.3; median follow-up time of 25.9 months, as measured by blinded independent review committee (BIRC)]. Results were presented during an oral session at the Annual European Society for Medical Oncology Congress (ESMO) in Copenhagen.

These results are consistent with findings from the phase I ASCEND-1 study, which demonstrated a median PFS of 18.4 months (95% CI: 15.2-not reached) as per BIRC assessment with a median follow-up of 11.1 months. The previous analysis by BIRC in ASCEND-3 indicated that the median PFS had not been reached after a median follow-up time of 8.3 months.

Further, in a sub-analysis of these data, patients who entered the study with brain metastases at baseline experienced an overall response rate (ORR) of 63.3% (95% CI: 48.3-76.6) and a disease control rate (DCR) of 83.7% (95% CI: 70.3-92.7), both as measured by BIRC. These results were similar to those in patients without brain metastases, who demonstrated an ORR of 64.0% (95% CI: 52.1-74.8) and DCR of 88.0% (95% CI: 78.4-94.4), based on BIRC assessment.

"The unfortunate reality of ALK+ NSCLC is that advancement is needed to delay disease progression in these patients," said lead investigator Dr. Enriqueta Felip, Head of the Thoracic Tumors Group, Vall d'Hebron University Hospital. "These data, coupled with a compelling response in the sub-analysis of patients with baseline brain metastases, provide greater evidence of Zykadia's potential efficacy in the ALKi-naïve population."

At the time of analysis, the estimated 18-month overall survival (OS) rate was 73.4% (95% CI: 64.6-80.4). This population also demonstrated an ORR of 63.7% (95% CI: 54.6-72.2) and median duration of response of 23.9 months (95% CI: 16.6-not estimable), according to BIRC assessment. A decrease in tumor burden from baseline was shown in 94.7% patients (investigator assessment only, no BIRC assessment available).

"Novartis is committed to extending lives of patients with difficult-to-treat forms of cancer, and these data presented at ESMO affirm our desire to improve outcomes for those with metastatic NSCLC, specifically," said Alessandro Riva, MD, global head, oncology development and medical affairs, Novartis Oncology. "With our first-line phase III results forthcoming as well as ongoing brain metastases studies, we look forward to sharing further evidence of Zykadia's full potential."

Results from the randomized phase III ASCEND-5 study were also presented for the first time, and were included as part of a late-breaking oral session as well as in the ESMO press program. The ASCEND-5 study assessed median PFS in patients previously treated with crizotinib and one or two prior regimens of cytotoxic chemotherapy (including platinum doublet), who then received either Zykadia or standard chemotherapy. Results demonstrated a statistically significant and clinically meaningful improvement in median PFS by BIRC for patients taking Zykadia versus chemotherapy (HR 0.49, 95% CI 0.36-0.67; p<0.001 one sided). Median PFS by BIRC for Zykadia and chemotherapy were 5.4 months (95% CI: 4.1-6.9) vs. 1.6 months (95% CI: 1.4-2.8), respectively.

The ALK gene arrangement, one of the three most common biomarkers - or genetic drivers -of NSCLC, affects approximately 2-7% of cases each year. More than half of these patients are either former smokers or have never smoked. These patients are candidates for treatment with a targeted ALK inhibitor.

ASCEND-3 is a phase II single-arm, open-label, multicenter study which included 124 patients with ALK+ NSCLC who had received up to three lines of chemotherapy and had no prior experience with an ALK inhibitor. Brain metastases at baseline were seen in 39.5% of patients. The most frequent adverse events were diarrhea [85.5% (3.2% grade 3/4)], nausea [77.4% (6.5% grade 3/4)] and vomiting [71.8% (6.5% grade 3/4)].

ASCEND-5 is an open-label, randomized, active-controlled, multicenter phase III study to compare the efficacy and safety of Zykadia to standard second-line chemotherapy (pemetrexed or docetaxel) in patients with advanced ALK+ NSCLC who progressed on prior crizotinib and one or two prior regimens of chemotherapy. Of 231 patients, 115 were randomized to ceritinib and 116 to chemotherapy. Of patients discontinuing chemotherapy due to disease progression, 75 crossed over to Zykadia. The most frequent adverse events were diarrhea [72.2% (4.3% grade 3/4)], nausea [66.1% (7.8% grade 3/4)] and vomiting [52.2% (7.8% grade 3/4)] with ceritinib; fatigue [28.3% (4.4% grade 3/4)], nausea [23.0% (1.8% grade 3/4)], alopecia [21.2% (0% grade 3/4)] and neutropenia [20.4% (15.0% grade 3/4)] with chemotherapy.

Zykadia is an oral, selective inhibitor of anaplastic lymphoma kinase (ALK), a gene that can fuse with others to form an abnormal "fusion protein" that promotes the development and growth of certain tumors in cancers including non-small cell lung cancer (NSCLC). Zykadia was granted conditional approval in the EU for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib. In the US, Zykadia was granted accelerated approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Zykadia is currently approved in over 55 countries worldwide.