Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib

Abstract

Purpose: Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents.

Experimental design: We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib.

Results: Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4-10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1-694). The mPFS on ceritinib was 7.8 months (6.5-9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4-9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5-19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5-63.1).

Conclusions: Ceritinib has significant antitumor activity in ALK-positive NSCLC-even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib.

Figure 1

Progression-free survival (PFS) of anaplastic lymphoma kinase (ALK)-positive patients treated with ALK inhibitors. (A) PFS on crizotinib. The median number of lines of therapy prior to treatment with crizotinib was 1 (range 0–8). (B) PFS on ceritinib. All patients received crizotinib prior to treatment with ceritinib. (C) PFS on ceritinib among patients who had no intervening therapies between discontinuation of crizotinib and initiation of treatment with ceritinib. (D) PFS on ceritinib among patients with or without ALK resistance mutations identified in post-crizotinib/pre-ceritinib biopsies.

Figure 2

Individual swimmer plots for each patient in the overall study population, depicting progression-free survival (PFS) on crizotinib (blue), duration of crizotinib use post-progression (red), interval between crizotinib discontinuation and initiation of ceritinib (green), and PFS on ceritinib (purple). Arrows indicate patients who remain on ceritinib at the time of data cut-off. Patients who discontinued crizotinib due to toxicity are depicted with a (#), while patients who discontinued ceritinib due to toxicity are depicted with a (*).

Figure 3

Individual ceritinib progression-free survival (PFS) data in patients with post-crizotinib/pre-ceritinib biopsies. ALK-positive patients with ALK resistance mutations are represented in gray, while those without ALK resistance mutations are presented in black. All samples analyzed by ALK FISH (n=19) were positive for the original ALK rearrangement. ALK amp refers to patients with amplification of the ALK fusion gene identified via ALK FISH. NM refers to patients without ALK resistance mutations or ALK gene amplification. Arrows indicate patients who remain on ceritinib at the time of data cut-off.

Figure 4

Overall survival (OS) for anaplastic lymphoma kinase (ALK)-positive patients. (A) OS from the time of metastatic diagnosis for overall study population. (B) OS of ALK-positive patients treated with second-line crizotinib. OS is measured from the start of crizotinib.