Alessandro Riva, MD
Ceritinib (Zykadia) improved progression-free survival (PFS) compared with standard chemotherapy as a first-line treatment for patients with ALK
-positive non–small cell lung cancer (NSCLC), according to results from the phase III ASCEND-4 trial.
Beyond reaching the study’s primary PFS endpoint, ceritinib also met key secondary outcome measures, including objective response rate (ORR) and duration of response, according to Novartis, the manufacturer of the second-generation ALK inhibitor. The safety profile was consistent with previous adverse event (AE) data reported for ceritinib. Novartis plans to present the data from the trial at an upcoming medical meeting.
"Zykadia has proven to be an important treatment option for ALK+ NSCLC patients who have progressed following treatment with crizotinib," Alessandro Riva, MD, global head, Oncology Development and Medical Affairs, Novartis Oncology, said in a statement. "We are pleased to see these topline results show promise in untreated patients with advanced disease, and look forward to sharing these data with regulatory authorities in the coming months."
The open-label phase III ASCEND-4 trial randomized 376 treatment-naive patients with stage IIIB or IV ALK+ NSCLC to either 750 mg of oral ceritinib daily or standard chemotherapy (500 mg/m2
of pemetrexed plus 75 mg/m2
of cisplatin or carboplatin AUC 5-6), including pemetrexed maintenance. Patients were enrolled at 203 locations cross 31 countries.
In April 2014, the FDA approved ceritinib for patients with ALK
-positive NSCLC following treatment with the ALK inhibitor crizotinib (Xalkori). The subsequent phase II ASCEND-3 trial examined the use of ceritinib prior to treatment with another ALK inhibitor.
Data from ASCEND-3 presented at the 2015 ASCO Annual Meeting included 124 ALK treatment–naive patients with ALK
Patients could receive up to 3 lines of prior chemotherapy. The median patient age was 56 (range, 27-82), 40.3% were male, 59.7% were Asian, and 38.7% were white. The median follow-up was 8.3 months (range, 0.6-16.3).
In the overall population, the whole body (WB) ORR (complete response [CR] + partial response [PR]) was 63.7% (n = 79), including 29 of 50 (58%) patients with brain metastases and 50 of 74 (67.6%) patients without brain metastases.
The WB disease control rate (CR + PR + stable disease) was 89.5% (n = 111), including 43 of 50 (86%) patients with brain metastases and 68 of 74 (91.0%) patients without brain metastases.
Across the entire study, the median duration of response was 9.3 months and the median PFS was 11.1 months. The median PFS was 10.8 and 11.1 months in patients with and without brain metastases, respectively.
Adverse events were mostly grade 1/2 and included diarrhea (82.3%), nausea (74.2%), and vomiting (66.9%). There were AE-related discontinuations in 7.3% of patients.
Crizotinib was established as a frontline therapy in advanced ALK
-positive NSCLC based on the phase III PROFILE 1014 trial, which compared the ALK inhibitor with pemetrexed–platinum (cisplatin or carboplatin) chemotherapy.2
In 343 evenly randomized patients, frontline crizotinib significantly improved PFS versus chemotherapy (median, 10.9 vs 7 months; HR, 0.454; 95% CI, 0.346-0.596; P
<.0001). The ORR was also significantly improved with crizotinib at 74% versus 45% with chemotherapy (P
The open-label phase III J-ALEX Japanese study presented at the 2016 ASCO Annual Meeting showed that the second-generation ALK inhibitor alectinib (Alecensa) improved PFS by 66% compared with crizotinib as a frontline treatment for advanced ALK+ NSCLC.3
Among 207 evenly randomized patients, the median PFS was not yet reached in the alectinib arm, compared with 10.2 months in the crizotinib arm (HR, 0.34; P
- Felip E, Orlov S, Park K, et al. ASCEND-3: A single-arm, open-label, multicenter phase II study of ceritinib in ALKi-naïve adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol 33, 2015 (suppl; abstr 8060).
- Mok T, Kim D-W, Wu Y-L, et al. First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol 32:5s, 2014 (suppl; abstr 8002).
- Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. J Clin Oncol 34, 2016 (suppl; abstr 9008).