According to results from the randomized, open-label, phase III ASCEND-4 trial, recently published in The Lancet, the tyrosine kinase inhibitor (TKI) ceritinib improves median progression-free survival (PFS) by 8.5 months compared to platinum-based chemotherapy in treatment-naïve patients with stage IIIB/IV anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). Patients (N = 376) received either oral ceritinib 750 mg/day or platinum-based chemotherapy every 3 weeks for 4 cycles, followed by maintenance pemetrexed.
Median PFS (assessed by the blinded independent review committee) was 16.6 months in patients receiving ceritinib, compared to 8.1 months in patients receiving chemotherapy (HR 0.55; P<.00001). The PFS benefit was observed regardless of baseline brain metastases. Patients with brain metastases treated with ceritinib had a median PFS of 10.7 months versus 6.7 months with chemotherapy (HR 0.70). Of note, median PFS of patients without brain metastases was 26.3 months with ceritinib versus 8.8 months with chemotherapy (HR 0.48). The overall response rate was 72.5% in the ceritinib arm and 26.7% in the chemotherapy arm. In patients with baseline brain metastases, the intracranial response rate was 46.3% with ceritinib and 21.2% with chemotherapy. Preliminary overall survival analysis showed a trend in favor of ceritinib, but these results are not mature (not reached vs 26.2 months; HR 0.73, P = .056).
Ceritinib was associated with a manageable adverse event (AE) profile consistent with previously published studies. The most common AEs of any grade associated with ceritinib were diarrhea (85%), nausea (69%), vomiting (66%), and increased alanine aminotransferase (60%).
In a commentary accompanying the article, Benjamin Solomon, MBBS, PhD (Peter MacCallum Cancer Center, Melbourne, Australia), called these results impressive and clinically meaningful, both in comparison to chemotherapy and compared to previously reported PROFILE 1014 results with first-line crizotinib. However, he noted that a potential limitation of this study is the comparison of ceritinib to chemotherapy instead of crizotinib, the current standard of care. Dr Soloman indicated that ceritinib should join crizotinib as a key option for treatment-naïve, ALK-positive NSCLC, particularly in patients with brain metastases.
Indeed, based on the findings from the ASCEND-4 trial, the US Food and Drug Administration and European Commission broadened the indication of ceritinib (Zykadia®, Novartis) to include previously untreated ALK-positive advanced NSCLC.
In addition to ceritinib, we may soon expect approval of alectinib in this setting. In the global phase III randomized ALEX trial, treatment with alectinib improved PFS by 15 months compared to crizotinib and yielded high and durable intracranial responses in patients with brain metastases.