Phase III Trial Finds First-Line Ceritinib Improves PFS vs Platinum-Based Chemotherapy in ALK-Rearranged NSCLC


Key Points

  • First-line ceritinib was associated with a marked improvement in progression-free survival vs platinum-containing therapy in patients with advanced ALK-rearranged NSCLC.
  • The progression-free survival benefit was greater among patients without brain metastases at baseline.

In a phase III trial (ASCEND-4) reported in The Lancet, Soria et al found that ceritinib (Zykadia) improved progression-free survival vs platinum-based chemotherapy in first-line treatment of advanced ALK-rearranged non–small cell lung cancer (NSCLC). Ceritinib is a next-generation selective ALK inhibitor reported to have greater potency in vitro than crizotinib (Xalkori). Ceritinib is currently approved for use in patients with ALK-positive metastatic NSCLC who have had disease progression on or are intolerant of crizotinib.

Study Details

In the open-label trial, 376 patients with stage IIIB/IV ALK-rearranged nonsquamous NSCLC from 134 sites in 28 countries (in Europe and Asia, Brazil, Mexico, Australia, New Zealand) were randomized between August 2013 and May 2015 to receive ceritinib (n = 189) or chemotherapy (n = 187). Oral ceritinib was given at 750 mg/d. Platinum-based chemotherapy was given as cisplatin at 75 mg/m² or carboplatin at AUC 5–6 plus pemetrexed at 500 mg/m² every 3 weeks for 4 cycles followed by maintenance pemetrexed (Alimta).

Randomization was stratified by World Health Organization (WHO) performance status, previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases. The primary endpoint was progression-free survival assessed by a blinded independent review committee in all randomized patients. Safety analysis was performed in all patients receiving at least one dose of study drug.

For the ceritinib vs chemotherapy groups: median age was 55 vs 54 years; 54% vs 61% were female, 55% vs 52% were white, and 40% vs 44% were Asian; WHO performance status was 0 in 37% in both, 1 in 57% vs 56%, and 2 in 7% vs 6%; 57% vs 65% were never smokers; 95% vs 98% had adenocarcinoma; 95% vs 97% had stage IV disease; metastatic sites were bone in 41% vs 43%, brain in 31% vs 33%, and liver in 18% vs 21%; and previous treatments included surgery in 23% in both, radiotherapy in 20% vs 21%, radiotherapy to the brain in 13% vs 14% (≤ 3 months to randomization in 92% vs 89%), and adjuvant chemotherapy in 5% vs 4% and neoadjuvant chemotherapy in 0% vs 1% (all receiving 1 regimen).

Improved Progression-Free Survival

Median follow-up for progression-free survival was 19.7 months. Median progression-free survival on independent review was 16.6 months (95% confidence interval [CI] = 12.6–27.2 months) in the ceritinib group vs 8.1 months (95% CI = 5.8–11.1 months) in the chemotherapy group (hazard ratio [HR] = 0.55, P < .00001). On investigator assessment, median progression-free survival was 16.8 vs 7.2 months (HR = 0·49, P < .00001). Hazard ratios consistently favored ceritinib across predefined subgroups and were statistically significant for most.

On blinded independent review, improvement in median progression-free survival with ceritinib among patients with brain metastases did not achieve significance (10.7 months [95% CI = 8.1–16.4 months] vs 6.7 months [95% CI = 4.1–10.6 months] in the chemotherapy group, HR = 0.70, 95% CI = 0.44–1.12). Among patients without brain metastases, median progression-free survival was 26.3 months (95% CI = 15.4–27.7 months) in the ceritinib group vs 8.3 months (95% CI = 6.0–13.7 months) in the chemotherapy group (HR = 0.48, 95% CI = 0.33–0.69).

Overall Survival, Response Rates

At the time of analysis, overall survival data were not mature (at 42% of required events for final analysis). Median overall survival was not reached in the ceritinib group (95% CI = 29.3 months to not estimable) and 26.2 months (95% CI = 22.8 months to not estimable) in the chemotherapy group (HR = 0.73, P = .056). Estimated 24-month overall survival was 70.6% vs 58.2%. The study did not cross the stopping boundary for overall survival at this analysis. A total of 105 of 145 patients (72%) in the chemotherapy group received an ALK inhibitor after discontinuation of chemotherapy, including ceritinib in 80 patients.

Overall response rates on blinded independent review were 72.5% vs 26.7%. Median time to response was 6.1 vs 13.4 weeks, and median duration of response was 23.9 vs 11.1 months.

Adverse Events

The most common adverse events of any grade in the ceritinib group were diarrhea (85% vs 11% in chemotherapy group), nausea (69% vs 55%), vomiting (66% vs 36%), increased alanine transaminase (ALT; 60% vs 32%), increased aspartate transaminase (AST; 53% vs 19%), increased gamma-glutamyltransferase (37% vs 10%), and decreased appetite (34% vs 31%). Any-grade anemia (15% vs 35%), neutropenia (5% vs 22%), and leukopenia (18% vs 4%) were more common in the chemotherapy group. The most common grade 3 or 4 adverse events in the ceritinib group were increased ALT (31% vs 3%), increased gamma-glutamyltransferase (29% vs 2%), and increased AST (17% vs 2%).

No grade 4 QT prolongation or torsade de pointes, Hy’s law cases, or pancreatitis was reported. Interstitial lung disease or pneumonitis occurred in 2% vs 1% of patients.

Adverse events led to dose adjustment or interruption in 80% vs 45% of patients and were most commonly due to gastrointestinal toxicity and liver function abnormalities in the ceritinib group. Adverse events considered related to study treatment led to discontinuation of treatment in 5% vs 11% of patients. Death occurred during treatment (up to 30 days after the last dose) in 6% vs 3% of patients, with none of the deaths considered related to study treatment.

The investigators concluded: “First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC.”

The study was funded by Novartis Pharmaceuticals Corporation.

Jean-Charles Soria, MD, of Institut Gustave Roussy, is the corresponding author of The Lancet article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.