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D. Ma
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.07 - Cardiac Toxicity of Crizotinib Therapy in Advanced ALK-Rearranged Non-Small Cell Lung Cancer (ID 2626)
19:05 - 19:10 | Author(s): D. Ma
- Abstract
- Presentation
Background:
Crizotinib (XALKORI [TM], Pfizer) , a tyrosine kinase inhibitor targeting ALK, ROS1 and MET, is used for the therapy of advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Cardiac toxicity is one of its adverse events which may interrupt the administration of crizotinib. Elevation of CK-MB has been reported but it remains to be determined whether the level of CK-MB can reflect cardiac toxicity of crizotinib therapy. We investigated the clinical manifestations and relevant frequency of heart-related side effects in 94 advanced ALK-rearranged NSCLC patients with treatment of crizotinib to share experiences of management of cardiac toxicity of crizotinib.
Methods:
A retrospective analysis was conducted to demonstrate the clinical manifestations as well as the corresponding frequency of cardiac toxicity in advanced ALK-rearranged NSCLC patients with treatment of crizotinib enrolled in our hospital in the past 4 years.
Results:
In the past 4 years, 95 advanced ALK-rearranged NSCLC patients were treated with crizotinib in our hospital, among which one patient dropped the treatment in 3 days due to grade 4 vomiting. In 94 eligible patients who continue the therapy more than one month, the heart-related side effects include QT interval prolongation (2/94), bradycardia (12/94), hypotension (3/94), aggravation of atrial fibrillation (1/94) and elevation of creatine kinase-MB(CK-MB) (59/94). Consequently, one of 2 patients with QT interval prolongation reduced dosage from 250 mg to 200mg twice daily for QT interval >500 ms on two electrocardiograms and then well tolerated. 12 patients with bradycardia presented asymptomatic and one patient with profound sinus bradycardia (heart rate [HR]≦45) continued crizotinib without dose reduction as she was asymptomatic and benefiting from continuous crizotinib treatment against the deadly disease. Patients with hypotension and aggravation of atrial fibrillation are tolerated and under close follow-up without dose reduction. Remarkably, we observed that majority of our patients (62.77%) experienced elevation of CK-MB and no correlation between age and CK-MB elevation (Pearson Correlation =-0.153，p=0.137).
Conclusion:
Cardiac toxicity is common during crizotinib treatment so that heart-related examinations, such as ECG as well as CK-MB, should be performed regularly especially for those with prior heart disease.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-027 - Responses to Crizotinib in Six Lung Adenocarcinoma Patients of ALK IHC-Positive and FISH-Negative (ID 2152)
09:30 - 09:30 | Author(s): D. Ma
- Abstract
Background:
The anaplastic large cell kinase gene (ALK)-positive is a special type of non-small cell lung carcinomas (NSCLC). Although Ventana IHC (D5F3) and FISH showed high coincidence for detecting ALK rearrangement, discordant results exist in some cases. Treatment strategy as well as efficacy of crizotinib in these cases is such an issue. We studied and reported the efficacy of crizotinib in six lung adenocarcinomas patients with ALK IHC positive and FISH negative.
Methods:
All histologic and cytologic specimens were stained by IHC with an anti-ALK monoclonal antibody (D5F3, Roche) with the OptiView DAB IHC Detection Kit (Roche) and OptiView Amplification kit (Ventana Medical Systems, Inc., Tucson, AZ). All histologic and cytologic samples were also tested by FISH, which was carried out using the Vysis ALK Break Apart FISH probe kit. Three samples [one histologic (patient 1) and two cytologic samples (patients 2 and 6), patients’ numbers were listed in Table 1] were still enough to further perform for EML4-ALK fusion by qRT-PCR. Two samples [one histologic(patient 1) and one cytologic sample(patient 6)] were still enough to further perform for next generation sequencing (NGS) analysis (using modified circulating single molecule amplification and resequencing technology, cSMART). The follow up data from 6 lung adenocarcinoma patients with ALK IHC-positive and FISH-negative who received crizotinib treatment were collected.
Results:
Table 1 showed the clinicopathological characteristics and the therapeutic efficacy of crozitinib for 6 patients in the study. The patients have achieved a response rate of 66.7% (4/6). Pathologically, for patient 1, the 3 unique DNA templates with EML4->EXOC6B->ALK fusion were identified in 710 DNA copies in tumor tissue. The fusion ratio is only 0.42%. For patient 6, we detected 75 unique DNA templates in total 495 DNA copies with 15.15% fusion ration in cytologic specimen. The fusion types of patient 1 and 6 were confirmed by sanger sequencing. Some unknown mechanisms caused the 3 gene fragments fusion of patient 1, the complex fusion type and low fusion ratio cause FISH negative.Table 1：Patient Characteristics, pathologic characteristics and molecular tests in 6 cases
ALK FISH: % of split signals by FISH; NGS: Next generation sequencing; +: No progressive disease was observed at the time of analyse.Patient NO. Gender Age Smoking history ALK IHC ALK FISH NGS-ALK PFS (month) Assessment P1 Female 31 Never smoked + 6% E13:EXOC6B :A20 7.46+ Partial response P2 Male 48 Ever smoker + 10% - 11.96+ Stable disease P3 Female 49 Never smoked + 6% - 19.94+ Partial response P4 Male 59 Ever smoker + 6% - 6.60+ Partial response P5 Male 69 Ever smoker + 10% - 15.08+ Partial response P6 Female 65 Never smoked + 12% E13:A2 3.58 Stable disease
Conclusion:
Lung adenocarcinoma patients with ALK IHC-positive and FISH-negative may also response to crizotinib. Ventana IHC is another candidate method for detecting ALK. One new fusion type EML4->EXOC6B->ALK fusion was verified and the patient with this fusion type showed partial response to crozitinib.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-024 - The Effect of Pemetrexed as First Line Chemotherapy in Advanced Non-Small-Cell Lung Cancer with Anaplastic Lymphoma Kinase Gene Rearrangements (ID 1179)
09:30 - 09:30 | Author(s): D. Ma
- Abstract
Background:
The efficacy of pemetrexed-based first-line chemotherapy in ALK-positive NSCLC has been documented in several studies. More data for Chinese population are still needed.
Methods:
We retrospectively reviewed the chart of 34 patients with ALK-positive advanced NSCLC. All of them had received pemetrexed as the first-line chemotherapy in our hospital from May 2011 to October 2014. We analyzed the clinical characteristics and treatment outcomes of these patients.The primary end points were response rate and progression-free survival.
Results:
The median age was 52 years (range from 34 to 76) and 58.8% (20/34) of the patients were never smokers. All tumors were adenocarcinoma. There were two cases harboring ALK translocation and EGFR mutation. Pemetrexed combined with platinum was administered in the first-line setting and the median treatment cycle was 4.5. The median progression-free survival (PFS) of ALK-positive patients was 8.8 months (95%CI 7.397-10.213). At the time of analysis, 7 with PR (20.6%)，23 with SD (67.6%)，4 with PD (11.8%) and no CR achieved. The objective response rate was 20.6% (7/34)，and the disease control rate was 88.2% (30/34). Common adverse events with pemetrexed were neutropenia (52.9%)，nausea (58.8%)，transaminase elevation (29.4%) and fatigue (9.3%)，mainly in grade 1 or 2.
Conclusion:
Pemetrexed is efficient and well tolerated as first-line treatment for ALK-positive NSCLC in Chinese population. Thus, pemetrexed might provide an alternative option for the treatment of ALK-positive lung adenocarcinoma.
