Frontline Ceritinib Improves PFS Over Platinum-Based Chemo in ALK+ NSCLC

Gilberto de Castro Jr MD, PhD

Frontline treatment with ceritinib (Zykadia) improved progression-free survival (PFS) over standard chemotherapy in patients with ALK-rearranged non—small cell lung cancer (NSCLC), according to results from the phase III ASCEND-4 trial that were presented at the IASLC 17th World Conference on Lung Cancer in Vienna.

Patients with advanced ALK-positive NSCLC who received first-line ceritinib experienced a 45% risk reduction compared with patients receiving standard chemotherapy.

In addition to reaching the study’s primary endpoint of PFS, ceritinib also improved key secondary outcome measures, including objective response rate (ORR) and duration of response. Median PFS by RECIST v1.1 criteria was 16.6 months (95% CI, 12.6-27.2) compared with 8.1 months (95% CI, 5.8-11.1) with chemotherapy (HR, 0.55; P < .001).

The ORR with ceritinib was higher at 72.5% compared with 26.7% in the chemotherapy group. The median duration of response (DOR) was 23.9 months versus 11.1 months, respectively.

“Ceritinib demonstrated a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy,” said lead study author Gilberto de Castro Jr MD, PhD, of the Instituto do Câncer do Estado de São Paulo ICESP, in Brazil.

ASCEND-4 enrolled 376 patients with untreated ALK positive, advanced, nonsquamous NSCLC. Following stratification by WHO performance status (0 versus 1-2), the presence of brain metastases at screening, and prior neoadjuvant chemotherapy, 189 patients were randomized to ceritinib 750 mg/day and 187 patients to pemetrexed at 500 mg/m² plus cisplatin 75 mg/m² or to carboplatin area under the curve of 5 to 6 for 4 cycles followed by maintenance pemetrexed. Brain metastases were present in 59 patients in the ceritinib arm versus 62 patients in the chemotherapy arm.

The median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy.

Among patients with measurable baseline brain metastases and 1 or more post-baseline assessment, the intracranial ORR by modified RECIST v1.1 was also higher with ceritinib at 72.7% (95% CI, 49.8-89.3) compared with 27.3% (95% CI, 10.7-50.2) with chemotherapy.

“Patients without brain metastases at diagnosis experienced median progression-free survival of 26.3 months, the longest seen in a global phase III study in ALK-positive NSCLC,” de Castro noted. In this subgroup of patients without baseline brain metastases, the median PFS was 26.3 months (95% CI, 15.4-27.7) with ceritinib compared with 8.3 months (95% CI, 6.0-13.7) with standard chemotherapy.

Crossover from chemotherapy to ceritinib was allowed at disease progression; 80 patients crossed over, which could possibly impact overall survival (OS). OS data were immature at the interim analysis.

“There was a high incidence of adverse events (AEs) with ceritinib, but most were grade 1 and manageable,” said de Castro.

Fewer patients in the ceritinib arm (5.3%) discontinued treatment due to AEs compared with 11.4% of chemotherapy-treated patients. The most commonly reported AEs occurring in >50% of patients with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%).

"In addition to the risk reduction of disease progression, ceritinib patients achieved high and durable systemic responses overall, and high overall intracranial responses in patients with measurable brain metastases,” said de Castro.

In 2014, the FDA approved ceritinib for patients with ALK-positive NSCLC following treatment with the ALK inhibitor crizotinib (Xalkori); however, de Castro called for ceritinib to move to frontline following these findings.

UPDATE 5/26/2017: FDA Approves Ceritinib for Frontline ALK+ NSCLC

“Ceritinib should be considered as a new first-line therapeutic option in patients with ALK-rearranged advanced NSCLC,” he said.

de Castro G, Tan DS, Crinò L, et al. First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4). Presented at: Presented at: 17th World Lung Cancer Conference, the Annual Meeting of the International Association for the Study of Lung Cancer (IASLC); December 4-7, 2016; Vienna, Austria.

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