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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 144-147
 

Ceritinib in anaplastic lymphoma kinase-positive nonsmall cell lung cancer among patients who were previously exposed to crizotinib: Experience from the Indian subcontinent


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Molecular Biology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Prof. K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_186_17

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 » Abstract 

Ceritinib is a novel ALK inhibitor approved for advanced stage NSCLC with ALK gene rearrangement, progressed and/or intolerant to crizotinib. 13 patients were included in our study who received ceritinib. Majority of them were women and never smokers with a median age of 47 yrs. Nearly half of them had a compromised performance status and received ceritinib in third line and beyond. Ceritinib showed nearly 50% response rates. With a median follow up of 9 months for the entire cohort, median PFS and OS were not reached. However, the mean values for PFS and OS were 10.9 and 14.8 months,with an estimated 1 year PFS and OS being 56% and 78% respectively.1/3 of the patients had gastrointestinal and liver toxicities. Metabolic abnormalities were seen in 1/4 th of them. ceritinib was permanently discontinued in one patient due to pneumonitis. In conclusion, ceritinib has a favorable efficacy and side effect profile in our patient population., similar to that reported in large clinical trials. It has shown promising efficacy even in patients with compromised performance status; presence of brain metastases and heavily pre-treated disease.


Keywords: Adverse effects, anaplastic lymphoma kinase-positive nonsmall cell lung cancer, ceritinib exposed, ceritinib, response rates, survival


How to cite this article:
Joshi A P, Chandrakanth M V, Noronha V, Patil V, Chougule A, Mahajan A, Janu A K, Chanana R, Prabhash K. Ceritinib in anaplastic lymphoma kinase-positive nonsmall cell lung cancer among patients who were previously exposed to crizotinib: Experience from the Indian subcontinent. Indian J Cancer 2017;54:144-7

How to cite this URL:
Joshi A P, Chandrakanth M V, Noronha V, Patil V, Chougule A, Mahajan A, Janu A K, Chanana R, Prabhash K. Ceritinib in anaplastic lymphoma kinase-positive nonsmall cell lung cancer among patients who were previously exposed to crizotinib: Experience from the Indian subcontinent. Indian J Cancer [serial online] 2017 [cited 2019 Nov 18];54:144-7. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/144/219559



 » Introduction Top


Crizotinib is the treatment of choice in first line for anaplastic lymphoma kinase (ALK)-positive advanced nonsmall cell lung cancer (NSCLC).[1] Unfortunately, majority of patients on crizotinib develop disease progression within a year, with central nervous system (CNS) being the common site.[2] In contrast to crizotinib, ceritinib is a more potent and specific inhibitor of ALK.[3],[4] It has 20 times greater potency than crizotinib in enzymatic assays. It crosses the blood–brain barrier with a brain-to-blood exposure ratio of about 15% in a rat model. It also inhibits insulin-like growth factor-1 but not MET.[5] Ceritinib is approved for the treatment of ALK-positive NSCLC who progress on or are intolerant to crizotinib. This is based on an expanded Phase 1 trial which demonstrated an objective response rate of 56% and a progression-free survival (PFS) of 7 months in patients who were prior treated with crizotinib.[6] There are limited real world data on the usage of ceritinib from India. Here, we report our experience with ceritinib in terms of its efficacy and safety among ALK-positive NSCLC patients who were previously exposed to crizotinib.


 » Materials and Methods Top


Patient selection

Patients from January 2016 to September 2016 were selected for this analysis subject to the following criteria (all criteria to be fulfilled).

  • Advanced NSCLC
  • Planned for treatment with a palliative intent
  • Presence of ALK fusion reported as positive, either by immunohistochemistry or break-apart fluorescence in situ hybridization
  • Patients who have received ceritinib as a result of documented disease progression and/or who have intolerable side effects to crizotinib.


The details of these patients were obtained from the prospective lung cancer audit database that is maintained in the department of medical oncology. Details of patients' demographic data (age, gender, comorbidities, smoking status, and performance status [PS]), tumor characteristics (histology, stage, number, and sites of metastases), treatment details (ceritinib dose, sequence of treatment, dose interruptions, and treatment used before and after ceritinib), efficacy, and side effects were retrieved. Response evaluation was done by RECIST 1.1 criteria. Side effects were classified according to Common Terminology Criteria for Adverse Events version 4.02 (CTCAE v 4.02) CTCAE is devised by National Cancer Institute, SPSS by: IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.

Statistical analysis

SPSS version 16 was used for analysis. Descriptive statistics were performed as required. Median value with interquartile range was provided for continuous variables. PFS was calculated in months from the date of start of ceritinib till the date of progression on ceritinib. Patients who had not progressed at the time of the last follow-up were censored. Overall survival (OS) was calculated in months from the date of start of ceritinib till the date of death. Patients who had not died at the time of the last follow-up were censored. Kaplan–Meier curve was plotted for time-to-event analysis.


 » Results Top


Demographic details and tumor characteristics

Details on demographic characteristics are shown in [Table 1]. A total of 13 patients satisfied the predefined selection criteria and received ceritinib. A higher proportion was women with only one patient had a history of tobacco exposure. Almost half of our patients had an Eastern Cooperative Oncology Group PS of ≥2. Nearly three-fourth of patients had extrathoracic disease spread and half of them had brain metastases.
Table 1: Demographic and baseline tumor characteristics (n=13)

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Treatment sequence at which ceritinib was used

Ceritinib was given as second-line therapy in six (46%) patients, third line in five (38%) patients, and as fourth in two (16%) patients.

Therapeutic agents used before ceritinib

All the patients were exposed to crizotinib at first or subsequent lines. In the first line, patients were treated with crizotinib in six patients (46%), platinum-based doublet in five patients (38%), and erlotinib in two patients (16%) (due to compromised PS). However, among those seven patients not exposed to crizotinib in first line and were exposed to the same at subsequent lines.

Therapeutic agents used postceritinib

Four patients received therapy after progression on ceritinib. Two of them received pemetrexed platinum and two received taxanes. Both the patients who received pemetrexed-based regimen had stable disease as their best response. Among those who received taxanes, one had progressive disease and the other had stable disease as their best response.

Safety and adverse events with ceritinib

[Table 2] depicts the side effects of ceritinib. Salient points to note are that more than one-third had vomiting, diarrhea, and transaminitis and more than one-fourth had metabolic abnormalities. Grade 3/4 adverse events along with other significant toxicities were reported. One-third of patients required temporary cessation (due to diarrhea/transaminitis), and in one patient, ceritinib was permanently discontinued due to pneumonitis.
Table 2: Adverse events and safety (n=13)

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Response rates and outcomes

Response rates and outcomes are shown in [Table 3] and [Graph 1] and [Graph 2]. Nearly half of our patients showed a partial response. With a median follow-up of 9 months for the entire cohort, median PFS and OS were not reached. However, the mean values for PFS and OS were 10.9 and 14.8 months, with an estimated 1-year PFS and OS being 56% and 78%, respectively.
Table 3: Response rates, survival, and pattern of progression on ceritinib (n=13)

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 » Discussion Top


In the era of targeted therapy and immunotherapy, drugs are gaining accelerated approval based on their impressive results in Phase I and II studies. In such a scenario, it is necessary to evaluate whether such an efficacy and safety are reproduced in the real world setting, especially in regions where these drugs are not developed but marketed for use. We have also observed the differences in outcome when used in a population of different ethnic groups. Hence, the need for reporting the outcomes of a drug in a population with different ethnicities.[7]

Analyzing the demographics, our patients were of a slightly younger age group, all were nonsmokers and a female preponderance was seen comparable to those reported in larger trials. A higher proportion, i.e., nearly 45% of our patients were PS 2 and 3, which highlights the utility of this drug in clinical practice as seen with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in poor PS patients with EGFR mutations.[8]

Assessing the response rates, nearly half of our patients had responses with a clinical benefit in three-fourth of patients. These results are in par with those reported in larger studies. In our study, median PFS and OS were not reached. However, mean PFS and OS of the entire population were 10.9 and 14.9 months, respectively. An estimated 1-year PFS and OS was 56% and 78%, respectively. When compared to larger studies, our study population had a longer PFS and OS. This may be due to a smaller sample size, shorter duration of follow-up, and occurrence of few events. None of our patients had disease progression in brain despite the fact that approximately 50% of our patients had brain metastases. This highlights that the drug is active in the CNS.

Analyzing the profile of adverse events in our patients, about three-fourth of patients had vomiting, diarrhea, and fatigue of all grades. However, Grade 3/4 vomiting, diarrhea, and fatigue were seen in 7%, 15%, and 15%, respectively. Liver toxicity of all grades was seen in 60% of our patients, with Grade 3/4 toxicity in 15% of them. These findings are in par with that reported in larger studies. Nearly three-fourth of our patients had metabolic abnormalities such as hypophosphatemia and hyperglycemia. In comparison to larger studies, a significantly larger proportion of our population had metabolic abnormalities. This needs to be investigated in the future. Other toxicities such as visual disturbances, ECG abnormalities, and pneumonitis were seen in around 10% of our patients.

About 30% of our patients required dose interruptions, the median duration of cessation was for 1 week. Twenty-two percent of them were started at reduced doses which they tolerated well. The frequency of temporary/permanent cessation and dose reduction was relatively lower than that reported in standard trials. This may be because of a smaller sample size and shorter duration of ceritinib exposure.

This data have certain limitations including the retrospective nature of the study, smaller sample size, and shorter duration of median follow-up.


 » Conclusion Top


Ceritinib has a favorable efficacy and side effect profile in our patient population, similar to that reported in large clinical trials. It has shown promising efficacy even in patients with compromised PS; presence of brain metastases and heavily pretreated disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: Results from PROFILE 1014. J Clin Oncol 2016;34:2858-65.  Back to cited text no. 1
[PUBMED]    
2.
Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 2014;4:662-73.  Back to cited text no. 2
    
3.
Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 2012;4:120ra17.  Back to cited text no. 3
[PUBMED]    
4.
Otterson GA, Riely GJ, Shaw AT, Lucio Crinò, Dong-Wan Kim, Renato Martins, et al. Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): Potential implications for management. J Clin Oncol;2012;30 Suppl. [Abstract 7600].  Back to cited text no. 4
    
5.
Zykadia Prescribing Information. Basel: Novartis AG; 2014. Available from: https://www.pharma.us.novartis.com/product/pi/pdf/zykadia.pdf. [Last accessed on 2016 Jun 23].  Back to cited text no. 5
    
6.
Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 2016;17:452-63.  Back to cited text no. 6
[PUBMED]    
7.
Soo RA, Kawaguchi T, Loh M, Ou SH, Shieh MP, Cho BC, et al. Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy. Future Oncol 2012;8:451-62.  Back to cited text no. 7
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8.
Goss G, Ferry D, Wierzbicki R, Laurie SA, Thompson J, Biesma B, et al. Randomized phase II study of gefitinib compared with placebo in chemotherapy-naive patients with advanced non-small-cell lung cancer and poor performance status. J Clin Oncol 2009;27:2253-60.  Back to cited text no. 8
[PUBMED]    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]

This article has been cited by
1 Ceritinib
Reactions Weekly. 2018; 1684(1): 66
[Pubmed] | [DOI]



 

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