Clinical profile of ceritinib

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Ceritinib has demonstrated significant activity in crizotinib-naïve ALK+-NSCLC models. In vitro enzymatic assays reveal that ceritinib is more potent than crizotinib at inhibiting the oncogenic ALK fusion protein.32 Ceritinib also inhibits the phosphorylation of both the ALK fusion protein and the downstream signaling pathways ERK and PI3K/AKT at much lower doses than crizotinib.32 In vivo H2228 xenograft models demonstrated the long-lasting antitumor properties of ceritinib. Tumor-bearing animals harboring ALK+ tumors were treated with either crizotinib (100 mg/kg) or ceritinib (25–50 mg/kg) daily for 2 weeks, with the latter experiencing both stronger antitumor suppression and longer durations of responses than the former.32 Additional assays demonstrated that ceritinib potently inhibited cell proliferation in cell lines with one of four resistance mutations in EML4–ALKamino acid sequencing (L1196M, G1269A, I1171T, and S1206Y), yet the five EML4–ALK resistance mutants exhibiting one of five amino acid sequence mutations (C1156Y, L1152R, F1174C, G1202R, and 1151T) demonstrated insignificant suppression of growth (albeit with stronger antitumor activity than the same mutant lines treated with crizotinib). From a structural basis of ligand-kinase domain docking, variation in ceritinib efficacy can be explained by the structural change in the kinase’s active site via point mutation. As previously mentioned, the mutations L1196M and G1269A confer resistance to crizotinib but remain sensitive to ceritinib – changes that result in steric interference of crizotinib with the EML4–ALK catalytic domain but do not affect ceritinib binding.32 However, the G1202R mutation results in significant steric hindrance in the active site, which disallows binding of both ceritinib and crizotinib. While currently unknown in their effects on TKI inhibition, the resistance mutations C1156Y, L1152R, F1174C, and 1151T have been predicted to either alter that conformation of the entire kinase or decrease the Km of ceritinib and crizotinib – both possibilities significantly impacting the TKI ability to act as an ATP-competitive agent.32 Thus, ceritinib shows efficacy in tumor cells harboring the common crizotinib-induced resistance mutations, with less impressive results in treating tumors harboring the rarer crizotinib-induced resistance mutations.

In ASCEND-1, a Phase I study investigating ceritinib’s safety and efficacy in ALK+-NSCLC patients, a total of 246 ALK+-NSCLC patients were treated with ceritinib at the established maximal tolerated dose of 750 mg/daily.8,34 A total of 163 (66%) patients had received prior crizotinib and 83 (34%) patients were ALK inhibitor-naïve. The ORR was 58.5%. Among 163 patients previously treated with crizotinib, an ORR of 54.6% as well as a PFS of 6.9 months was achieved. Among the remaining 83 patients naïve to crizotinib treatment, an ORR of 66.3% was achieved. At the time of data cutoff, a median PFS could not be estimated for crizotinib-naïve patients.34 This study concluded that ceritinib at 750 mg/day demonstrated potent antitumor activity in ALK+-NSCLC regardless of previous therapy status.

A subgroup analysis between Asian and Caucasian patients (82 and 156 patients, respectively) in the ASCEND-1 sought to determine differences in efficacy and adverse reactions among the two distinct populations.35 Data from 173 patients demonstrated ORRs of 69% in Asian patients and 57% in Caucasian patients. Median durations of responses in the Asian and Caucasian patients were 10.1 months and 6.9 months, respectively.35 Observable variances in ceritinib treatment for these two populations could not be explained by previous ALK inhibitor therapies.

Adverse reaction data (Table 1) collected from 255 ALK+-NSCLC patients treated with 750 mg daily ceritinib were mainly gastrointestinal, manifested by diarrhea, vomiting, constipation, nausea, and abdominal pain.8 Additional serious side effects include hypophosphatemia, hyperglycemia, anemia, elevated liver and pancreatic enzymes, interstitial lung disease, and QT interval prolongation.8,33These adverse events are often reversible after discontinuation of ceritinib treatment.

Table 1. The most common adverse reactions observed in 255 ALK+-NSCLC patients treated with ≥400 mg daily ceritinib

Adverse reactions Any grade (%) Grades 3/4 (%)
Diarrhea 86 6
Anemia 84 5
Nausia 80 4
Increased alanine aminotransferase 80 27
Increased aspartate aminotransferase 75 13
Vomiting 60 4
Increased serum creatine 58 2
Abdominal pain 54 2
Fatigue 52 5
Hyperglycemia 49 13
Decreased phosphate 36 7
Anorexia 34 1
Constipation 29 0
GERD 16 1
Note: Data from Shaw et al,8 Novartis,33 and Kim et al.36 Abbreviations: ALK, anaplastic lymphoma kinase; GERD, gastroesophageal reflux disease; NSCLC, non-small-cell lung cancer.

A total of 19 crizotinib-resistant NSCLC patients underwent tumor biopsy prior to beginning ceritinib treatment. Biopsies from all 19 patients tested positive for ALK rearrangement through FISH: two of the 19 patients exhibited ALK amplification, five patients exhibited secondary resistance mutations in the tyrosine kinase domain of the EML4–ALK fusion protein, and the remaining 12 patients solely exhibited the original oncogenic rearrangement of ALK.8 Treatment of these cases with the daily maximum dosage of ceritinib resulted in notable antitumor activity in all 19 patients. Significant responses were observed in six of the seven patients harboring either ALK amplification or resistance mutations as well as in seven of the 12 patients harboring no other genetic anomalies besides the original oncogenic alteration. These results demonstrate the efficacy of ceritinib in the tumor regression of crizotinib-resistant ALK+-NSCLC patients, regardless of the various genetic mechanisms leading to crizotinib resistance.8

As with crizotinib, patients treated with ceritinib also develop progression of disease. While ceritinib has been observed to overcome the resistance mutations L1196M, G1269A, S1206Y, and L1171T induced through crizotinib treatment, secondary mutations remain that are unable to be overcome by ceritinib. In a small study of 11 biopsied ceritinib-resistant tumors (two of the 11 obtained from different tumors in the same patient), five samples were found to harbor either F1174C or G1202R, two mutations that were also observed in crizotinib-resistant tumor samples. The patient who underwent biopsies at two different sites harbored two distinct resistance mutations, highlighting the inter-tumoral heterogeneity of resistance mechanisms.32 Better understanding of mechanisms of acquired ceritinib resistance is necessary to maximize the clinical efficacy of ceritinib in targetingALK+-NSCLCs.