Ceritinib: a new first-line therapy against ALK-rearranged lung cancer?

About 20% of Caucasian non-small-cell lung cancer (NSCLC) patients (1), and 50% of Eastern Asian ones (2), are diagnosed with an oncogene-addicted disease, due to the presence of epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) rearrangements. These gene alterations identify patients who benefit from the use of correspondent inhibitors. On the other hand, in this era of personalized medicine, most NSCLC patients do not harbor such genetic alterations, thus chemotherapy represents the standard-of-care for first-line therapy (3,4).

ALK-rearrangements occur in 3–7% of NSCLC patients and seem to be associated with specific clinical characteristics including never or light smoking history, young age and adenocarcinoma histology with signet rings (1,2). Crizotinib, an oral small-molecule tyrosine kinase inhibitor (TKI) of ALK, MET, and ROS1 kinases, is the standard-of-care for this subgroup of patients (3,4). However, most patients treated with crizotinib ultimately progress (5), with the central nervous system (CNS) being the common site of progression (6). To date, several small molecules are being developed as next-generation ALK-TKIs, such as ceritinib (LDK-378), alectinib (CH-5424802), brigatinib (AP26113), lorlatinib (PF-06463922), and ensartinib (X-396), showing significant activity in crizotinib-naive patients, as well as in patients experiencing progression on crizotinib (7). Most of these ALK-TKIs are able to cross the blood-brain barrier (BBB) with the potential increase of brain metastases control, too (7). Among these new inhibitors, ceritinib is in late stage of clinical development. Based on the first results coming from early phase trials (8-10), on April 29, 2014, and on June 04, 2015, the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), respectively granted ceritinib accelerated approval for the treatment of patients with ALK-positive metastatic NSCLC who experience disease progression or who are intolerant to crizotinib.

Recently, the final results of the ASCEND-4 (11), open-label, phase III study, were published. In this trial, 376 untreated patients with advanced ALK-rearranged nonsquamous NSCLC were randomized to receive oral ceritinib, at the dose of 750 mg/day, or cisplatin 75 mg/m² or carboplatin at the area under the curve (AUC) 5–6 plus pemetrexed 500 mg/m², every 3 weeks, for four cycles followed by maintenance pemetrexed. Also patients with the presence of brain metastases were allowed to be enrolled. The primary endpoint was blinded independent review committee assessed progression-free survival (PFS). The median PFS was 16.6 months in the ceritinib group and 8.1 months in the chemotherapy group [hazard ratio (HR) 0.55; 95% confidence interval (CI): 0.42–0.73; P<0.00001]. The median PFS in patients without brain metastases (n=255) was 26.3 months in the ceritinib group versus 8.8 months in the chemotherapy group (HR 0.48; 95% CI: 0.33–0.69) while the median PFS in patients with brain metastases (n=121) was 10.7 months in the ceritinib group versus 6.7 months in the chemotherapy group (HR 0.70; 95% CI: 0.44–1.12). An overall response rate (ORR) as assessed by the blinded independent review committee was 72.5% in the ceritinib group and 26.7% in the chemotherapy group. In patients with measurable brain metastases at baseline, the overall intracranial response was 72.7% in the ceritinib group and 27.3% in the chemotherapy group. The overall survival (OS) data were not mature with a median not reached in the ceritinib group and 26.2 months in the chemotherapy group (HR 0.73; 95% CI: 0.50–1.08; P=0.056). The median relative dose intensity was 78.4% for patients receiving ceritinib and 93.8–99.2% for each individual component in patients treated with chemotherapy. Drug-related toxicities were reported in 97% of patients treated with ceritinib and 89% of patients receiving chemotherapy. Grade ≥3 toxicities were reported in 65% and 40%, respectively, and the most common were an increase in alanine aminotransferase (30% versus 3%), aspartate aminotransferase (17% versus 2%) and gamma-glutamyltransferase (29% versus 2%) in the ceritinib group. In the chemotherapy group grade ≥3 hematologic toxicities, such as anemia (7% versus 2%) and neutropenia (11% versus 1%), were more frequent than in the ceritinib group. Patients discontinuing treatment due to adverse events were 5% in the ceritinib group and 11% in the chemotherapy group. Overall, general quality of life was in favor of ceritinib (11).

Based on these findings, ceritinib could be considered a further first-line therapeutic option in patients with ALK-rearranged NSCLC. The PROFILE 1014 study compared crizotinib, at the oral standard dose of 250 mg twice daily, to chemotherapy with cisplatin 75 mg/m² or carboplatin AUC 5–6 plus pemetrexed 500 mg/m², every 3 weeks, for six cycles. The primary endpoint was PFS assessed by independent radiologic review, which was 10.9 months for the crizotinib group versus 7.0 months for the chemotherapy group (HR 0.45; 95% CI: 0.35–0.60; P<0.001) (12).

Of course, the comparison between the ASCEND-4 (11) and PROFILE 1014 (12) trials is due (Table 1). The comparator of ceritinib and crizotinib, in both trials (11,12), was platinum/pemetrexed regimen (11,12). In the ASCEND-4 trial (11), platinum/pemetrexed was followed by pemetrexed maintenance. At the moment, this regimen is the standard-of-care for non-squamous NSCLC patients (3,4). This means that the chemotherapy regimen used in the ASCEND-4 trial was a robust comparator. In the PROFILE 1014 trial (12), the platinum/pemetrexed therapy was administered for a maximum of six cycles and then patients were followed-up until progression. At the time of the beginning of the PROFILE 1014 study, this chemotherapy regimen was the standard-of-care. Of interest is that the chemotherapy regimen administered in the ASCEND-4 trial showed a better PFS than the one used in the PROFILE 1014 study (11,12), while ceritinib showed a median PFS higher than the one reported with the crizotinib therapy. Surprisingly, ORR was higher for the chemotherapy regimen used in the PROFILE 1014 study than the one reported by the chemotherapy regimen employed in the ASCEND-4 study (11,12). Probably, the ORR of the chemotherapy regimen in the ASCEND-4 trial may be affected by the higher number of enrolled patients with brain metastases (32%). In the PROFILE 1014 study, of the 343 patients in the intent-to-treat population, 23% were affected by previously treated brain metastases. Median PFS was 9.0 months with crizotinib versus 4.0 months with chemotherapy (HR 0.40; 95% CI: 0.23–0.69). The global ORR was statistically significantly higher with crizotinib (77%) than with chemotherapy (28%; P<0.001) (6). In this subgroup of patients, the results were similar between the two trials but in the ASCEND-4 study (11), 16.7% of the enrolled patients did not receive any treatment for brain metastases and 8.2% with measurable baseline untreated brain metastases showed an intracranial ORR of 69.2% with ceritinib and 27.8% with chemotherapy (11). A preclinical rat model showed that ceritinib penetrates the BBB with a brain-to-blood exposure ratio of approximately 15%. This ceritinib efficacy was observed in patients previously treated with or without crizotinib (13). Overall, median PFS of patients with brain metastases and treated with ceritinib was 10.7 months, which is shorter than what reported in patients without brain metastases, which was 26.3 months. Moreover, brain was a common site of first progression on ceritinib both in patients with baseline brain metastases (48% of cases) and without brain metastases (30% of patients). Thus, brain metastases remained a big problem, especially in oncogene-addicted NSCLC due to the longer natural history of the disease, emphasizing the need for more effective strategies to manage CNS involvement.

Ceritinib, given at a starting dose of 750 mg/day, led to frequent toxicity, predominantly gastrointestinal (nausea, vomiting, and diarrhea) and raised liver function tests, necessitating dose interruptions or reductions in 80% of patients. These toxicities were more frequent than those reported with crizotinib in the PROFILE 1014 study (12), in which the most grade ≥3 toxicity were the aminotransferase levels elevations occurred in 14% of patients. Despite grade ≥3 toxicities occurred in 65% of patients treated with ceritinib, only 5% of cases led to its discontinuation (11). In fact, the ceritinib dose modifications and use of supportive medications led to the optimal management of these toxicities. In this view, a phase I study to assess the systemic exposure, efficacy, and safety of ceritinib at the dose of 450 or 600 mg taken with a low-fat meal as compared with ceritinib at the standard dose of 750 mg taken in the fasted state is ongoing. The primary outcome of this study is to evaluate the plasma concentration of the different doses of ceritinib with the main secondary endpoints being safety profile and ORR (14).

It is important to stress that all the comparisons made between the ASCEND-4 and PROFILE 1014 trials should be considered with the caveats of cross-trial comparisons due to the lack of head-to-head trials involving crizotinib and ceritinib. Unfortunately, ceritinib was compared with chemotherapy and not with crizotinib which is the standard-of-care for ALK-rearranged lung cancer patients. However, the ASCEND-4 trial started when crizotinib was not considered the first-line choice yet. The ASCEND-4 trial gives us a new weapon for first-line therapy in this subgroup of patients, and drug choice for each patient should be based on the balance between efficacy and toxicity. To date, the J-ALEX trial is the only study comparing head-to-head two ALK-TKIs, specifically crizotinib versus alectinib, suggesting that efficacy with new generation ALK-TKIs might be superior to crizotinib, particularly in patients with brain metastases (15). There are further ongoing or planned phase III first-line trials comparing head-to-head new generation ALK-TKIs which can produce new important information for the treatment of this subgroup of NSCLC patients. Considering the results reported by the ASCEND-4 trial showing a very impressive median PFS, ceritinib is most probably the best comparator for future head-to-head trials. The availability of several ALK-TKIs arises the question of which might be the optimal sequential approach to these patients, many of whom have diseases which are still ALK-dependent even beyond progression on first-line ALK-TKIs. In the next future, for ALK-addicted NSCLC patients, trials investigating different sequential strategic approaches with different ALK-TKIs are warranted.

Acknowledgements

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Qing-Yuan Huangi (Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/amj.2017.04.04). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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