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T. Yoshida
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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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MINI31.09 - Association of Crizotinib Toxicity with Pharmacokinetics and Pharmacogenomics in Non-Small Cell Lung Cancer Harboring ALK Fusion Gene (ID 464)
18:30 - 20:00 | Author(s): T. Yoshida
- Abstract
- Presentation
Background:
Crizotinib, a standard care for advanced ALK-positive NSCLC, is a substrate for ABCB1-encoded P-glycoprotein, and is primarily metabolized by CYP3A4/5. The most common adverse events (AEs) are visual disorder, gastrointestinal disorders, and elevated transaminase levels. Serious AEs such as grade (Gr) ≥ 3 elevated transaminase levels and interstitial lung disease (ILD) occasionally develop.
Methods:
ALK-positive NSCLC patients were enrolled in cohort A (enrollment before starting crizotinib therapy) or cohort B (enrollment during crizotinib therapy). Trough concentrations of crizotinib at steady state were measured using LC/MS/MS and ABCB1 polymorphisms were analyzed. We evaluated clinically significant AEs, defined as Gr 4 hematological toxicity, Gr ≥ 3 non-hematological toxicity, or any ILD. AEs during 8 weeks were also evaluated prospectively on the patients enrolled in cohort A.
Results:
A total of 78 patients at 17 institutions were enrolled. In cohort A (n = 47), AEs which occurred in more than 40% of patients during 8 weeks were ALT increased (75.0%), visual disorder (47.2%), anorexia (45.5%), nausea (45.5%), and AST increased (43.2%). In both cohorts (n = 75), 26 clinically significant AEs (n = 25) were observed: Gr ≥ 3 elevated transaminase level (14.7%), ILD (4.0%), Gr 4 neutropenia (4.0%), Gr 3 thromboembolic event (4.0%), Gr 3 esophagitis (2.6%), and Gr 3 QTc prolongation (2.6%). There was one treatment-related death (1.3%) due to ILD. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance (38.4% vs. 19.2%, respectively; p = 0.09). Blood samples for trough concentrations of crizotinib at steady state were collected from 63 patients. The geometric mean of trough concentrations were 396 (95% CI, 325-483) ng/ml in male and 395 (95% CI, 329-474) ng/ml in female, respectively (p=0.569, Mann-Whitney U test). No clinical factors including gender, weight, body surface area, and age which influenced trough concentrations or AEs of crizotinib were identified. Moreover, the trough concentration of crizotinib was not significantly different between patient with clinically significant and without (429 [95% CI, 361-509] ng/ml vs. 378 [95% CI, 313-456] ng/ml, respectively [p=0.365]).
Conclusion:
In this multicenter study, we observed crizotinib AEs as previously reported. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance. Furthermore, we will present the association of clinically significant AEs and trough concentration with ABCB1 polymorphism.
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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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P2.01-059 - Does Pemetrexed/Platinum Fit All Patients with Non-Squamous Non-Small Cell Lung Cancer? A Retrospective Study of Clinical Factors and Outcomes (ID 2308)
09:30 - 17:00 | Author(s): T. Yoshida
- Abstract
Background:
Pemetrexed/platinum is one of the standard treatment regimens for patients with advanced non-squamous non-small cell lung cancer(NSCLC). The aim of this study was to examine the association between survival of lung cancer patients treated with pemetrexed/platinum and clinical factors.
Methods:
The medical records of advanced or relapsed non-squamous NSCLC patients treated with pemetrexed/platinum at our hospital between January 2010 and December 2013 were reviewed. Basic characteristics, histological subtypes of NSCLC, driver mutation status, TTF1 staining status and status of treatment with taxane were evaluated for association with the survival from pemetrexed/platinum started day to deaths.
Results:
Two hundreds nine records were reviewed. The median age was 62 (28-79), 60% were male, 40% were never smoker, 89% had an ECOG PS0-1 and 11% had a PS 2-3. The median value of CEA and CYFRA were 10.5 ng/ml and 3.0 ng/ml, respectively. 93% were diagnosed as adenocarcinoma and 7% were diagnosed as other subtypes (large, adenosquamous, sarcomatoid and not otherwise specified). 79% (81/102) had a positive TTF1 staining. 26% had EGFR mutation, 7% had ALK fusion and 11% had KRAS mutation. 36% of patients were received bevacizumab with pemetrexed/platinum. 35% of patients were treated with cisplatin. The response rate of pemetrexed/platinum was 34.8%. Median overall survival was 537days. 65% of patients were treated with taxane and the response rate was 15.0%. In multivariate analysis, poor PS(HR 1.33; p=0.027), others in histological subtypes (HR2.00; p=0.047) and K-RAS mutation(HR 2.74; p=0.021) correlated significantly with a shorter overall survival and low CYFRA(≤3.0ng/ml, HR 0.55; p=0.002) correlated significantly with a longer overall survival.
Conclusion:
High CYFRA, KRAS mutation and others in histological subtypes may be associated with shorter overall survival treated with pemetrexed/platinum in non-squamous NSCLC. The development of effective treatment regimens for such patients is needed to improve their outcomes.
