|Year : 2017 | Volume
| Issue : 2 | Page : 436-438
ROS1 rearranged nonsmall cell lung cancer and crizotinib: An Indian experience
V Noronha1, MV Chandrakanth1, AP Joshi1, V Patil1, A Chougule1, A Mahajan2, AK Janu1, R Chanana1, K Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||21-Feb-2018|
Dr. K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
ROS1 rearrangement acts as a driver mutation in 1-2% of NSCLC. Crizotinib is approved in this situation both in treatment naïve and pre-treated patients. Here we report our experience with crizotinib in patients with advanced NSCLC harbouring ROS1 rearrangement. Eleven patients were included in our study. More than half of our patients had associated comorbidities and one fourth of them had a compromised performance status. Out of 11 patients, 5 of them were exposed to crizotinib .The response rates among crizotinib treated patients was 80%. With a median follow up of 9 months, median PFS and OS were 5.4 months and 8.5 months respectively for the entire population. Analyzing the outcomes separately , median PFS and OS was not reached for those who received crizotinib compared to median PFS of 2.5 months and median OS of 4.2 months in those who were not exposed to crizotinib. The difference was statistically significant. Estimated 1 year OS was 80% for those who received crizotinib compared to 18% for who did not receive crizotinib. In conclusion, crizotinib is effective with acceptable side effect profile in patients with ROS1 rearranged NSCLC in our population.
Keywords: Crizotinib, nonsmall cell lung cancer, ROS1
|How to cite this article:|
Noronha V, Chandrakanth M V, Joshi A P, Patil V, Chougule A, Mahajan A, Janu A K, Chanana R, Prabhash K. ROS1 rearranged nonsmall cell lung cancer and crizotinib: An Indian experience. Indian J Cancer 2017;54:436-8
|How to cite this URL:|
Noronha V, Chandrakanth M V, Joshi A P, Patil V, Chougule A, Mahajan A, Janu A K, Chanana R, Prabhash K. ROS1 rearranged nonsmall cell lung cancer and crizotinib: An Indian experience. Indian J Cancer [serial online] 2017 [cited 2020 May 30];54:436-8. Available from: http://www.indianjcancer.com/text.asp?2017/54/2/436/225803
| » Introduction|| |
ROS1 is a receptor tyrosine kinase that belongs to insulin receptor family. It acts as a driver oncogene in 1%–2% of nonsmall cell lung cancer (NSCLC) patients. ROS1 fusion partners include SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, and CCDC6, most common being CD74. The kinase domain is always fully retained on the ROS1 fusion protein. A homology exists between ALK and ROS1 kinase domains. They share 77% amino acid identity within the ATP-binding sites. Crizotinib binds with high affinity to both ALK and ROS1, which is consistent with this homology. Crizotinib is approved for patients with the ROS1 translocation including those who have received chemotherapy and those who are treatment naive. This is based on a Phase 1 expansion study which enrolled fifty patients with ROS1 rearrangement. Over 80% of patients had received one or more prior chemotherapy treatment regimens. The objective response rate was 72%. The median duration of response was 17.6 months, and the median progression-free survival was 19.2 months. A retrospective series from Europe which included 32 patients reported 80% response rates and progression-free survival (PFS) of 9.1 months. In this paper, we report our experience with ROS1 rearranged NSCLC from India.
| » Materials and Methods|| |
Patients fulfilling all the following criteria were selected:
- Advanced NSCLC with treatment planned with palliative intent
- Presence of ROS1 fusion reported as positive by break-apart fluorescence in situ hybridization.
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 (crizotinib dose, sequence of treatment, dose interruptions, and treatment used before and after crizotinib,) efficacy, and side effects were retrieved. Response evaluation done by RECIST 1.1 criteria, side effects were classified according to the Common Terminology Criteria for Adverse Events version 4.02.
SPSS version 16 was used for analysis. Descriptive statistics was performed as required. Median value with interquartile range was provided for continuous variables. PFS was calculated in months from the date of start of crizotinib till the date of progression or death if death happened before progression on crizotinib. Patients who had not progressed at the time of last follow-up were censored. Overall survival (OS) was calculated in months from the date of start of crizotinib till the date of death. Patients who had not died at the time of last follow-up were censored. Kaplan–Meier curve was plotted for time to event analysis. The log-rank test was used to compare survival curve.
| » Results|| |
Demographic details and tumor characteristics
A total of 11 patients satisfied the predefined selection criteria. Details on demographic characteristics are shown in [Table 1]. There was no gender predilection. More than 1/4th of patients had an ECOG PS of ≥2. Nearly 1/2 of patients had comorbidities, and half of them had extrathoracic disease spread with none having brain or adrenal metastases.
Eight patients received platinum-based doublet chemotherapy in the first-line setting, two of them received oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and one patient received up front crizotinib. Four patients among those who received platinum doublet were subsequently exposed to crizotinib (none had disease progression on the first line). Hence, total of five patients (46%) were ultimately exposed to crizotinib. Among the four patients treated with platinum-based doublet, two had a partial response and two had stable disease. In the patients treated with EGFR TKI initially, crizotinib was started before to the formal response evaluation was performed.
Safety and adverse events
Out of five patients who received crizotinib, three patients experienced Grade ½ fatigue and Grade ½ Vomiting. Grade ½ transaminitis, visual symptoms, Grade ½ diarrhea, Grade ½ neutropenia, and asymptomatic bradycardia were seen in one patient each. Out of eight patients who received chemotherapy three patients had Grade ½ anemia, Grade ½ vomiting. One patient had Grade ½ neutropenia and thrombocytopenia each. There was one mortality during the course of treatment in the noncrizotinib group.
Response rates and outcomes
The response rates and outcomes are summarized in [Table 2]. Out of five patients who received crizotinib, four patients had partial response (80%). With a median follow-up of 9 months, median PFS and OS were 5.4 and 8.5 months, respectively, for the entire cohort. Analyzing the outcomes separately, median PFS, and OS was not reached for those who received crizotinib compared to median PFS of 2.5 months and median OS of 4.2 months in those who were not exposed to crizotinib. The difference was statistically significant. Estimated 1-year OS was 80% for those who received crizotinib and 18% for those who did not [Graphs 1] and [Graphs 2].
| » Discussion|| |
Targeting ROS1 is an excellent example that illustrates the efficiency of targeted therapy. ROS1 inhibition appears to confer a greater benefit than ALK and EGFR inhibition in terms of response rates and PFS. There are very few reports in literature regarding ROS1 rearranged NSCLC among Indian population.
The demographic profile is similar to that of large studies in terms of age, gender, and tobacco exposure, but a higher proportion of patients had a compromised PS and associated comorbidities. This is because such patients are excluded from clinical trials.
The tumor characteristics in our patient population were similar to large studies. About 50% of our patients had extrathoracic spread with none having brain metastases. Larger studies have reported 3%–5% of patients having brain metastases in ROS1 rearranged patients. This is in contrast to ALK-positive patients where nearly 40%–50% of them develop brain metastases. Enrolling larger number of patients and a longer duration of follow-up would further clarify our findings.
We were able to expose 5 out of 11 patients to crizotinib. This highlights the limitation of access to treatment in our setting due to logistic issues. The PFS and OS among those who were not exposed to crizotinib are far inferior when compared to the outcomes of advanced NSCLC when treated with standard agents. These short survival rates among patients who were not exposed to crizotinib are because a substantial proportion of patients had compromised PS (50%), comorbidities such as a preexisting renal disease (12%) and one patient expired during chemotherapy. Such marked difference in the survival between the crizotinib and the noncrizotinib groups is partly due to the efficacy of crizotinib and also due to the difference in the demographic profile between the two groups. This also highlights that exposure to crizotinib is important in improving outcome. Out of our five patients, two patients were of lower socioeconomic status, and they could procure crizotinib through extramural support.
The side effect profile of crizotinib is similar to that reported in larger studies. However, a greater toxicity was seen in the noncrizotinib group due to compromised PS and associated comorbidities.
| » Conclusion|| |
Crizotinib is effective with acceptable side effect profile in patients with ROS1 rearranged NSCLC in our population.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Acquaviva J, Wong R, Charest A. The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta 2009;1795:37-52.
Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, et al.
ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70.
Rimkunas VM, Crosby KE, Li D, Hu Y, Kelly ME, Gu TL, et al.
Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: Identification of a FIG-ROS1 fusion. Clin Cancer Res 2012;18:4449-57.
Mazières J, Zalcman G, Crinò L, Biondani P, Barlesi F, Filleron T, et al
. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J Clin Oncol 2015;33:992-9.
Shaw AT, Ou SH, Bang YJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N
Engl J Med 2014;371:1963-71.
Song Z, Su H, Zhang Y. Patients with ROS1 rearrangement-positive non-small-cell lung cancer benefit from pemetrexed-based chemotherapy. Cancer Med 2016;5:2688-93.
[Table 1], [Table 2]
|This article has been cited by|
||CNS metastasis in ROS1+ NSCLC: An urgent call to action, to understand, and to overcome
| ||Sai-Hong Ignatius Ou,Viola W. Zhu |
| ||Lung Cancer. 2019; 130: 201 |
|[Pubmed] | [DOI]|
||Biomarkers in Non-Small Cell Lung Cancers: Indian Consensus Guidelines for Molecular Testing
| ||Kumar Prabhash,Suresh H. Advani,Ullas Batra,Bivas Biswas,Anuradha Chougule,Mithua Ghosh,Vamshi Krishna Muddu,T. P. Sahoo,Ashok K. Vaid |
| ||Advances in Therapy. 2019; 36(4): 766 |
|[Pubmed] | [DOI]|