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S. Umemura
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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)
19:15 - 19:20 | Author(s): S. Umemura
- 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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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-022 - Radiologic Features of Advanced ALK-Rearranged Lung Cancer (ID 995)
09:30 - 09:30 | Author(s): S. Umemura
- Abstract
Background:
Reportedly, the radiologic features of most primary resectable lung cancers harboring an anaplastic lymphoma kinase (ALK)-fusion do not exhibit a ground-glass opacity (GGO) component when viewed using CT. However, little is known about the features of advanced ALK-rearranged lung cancer.
Methods:
The radiologic features of 21 advanced ALK-positive lung cancers treated at the National Cancer Center Hospital East between January 2012 and June 2014 were retrospectively investigated. ALK-fusion was confirmed using IHC and FISH or RT-PCR methods. The primary tumor’s diameter and characteristics (i.e., presence of a GGO component, notch, spiculation, and pleural indentation) as viewed using CT and the SUVmax observed using PET before treatment were evaluated. The radiologic features of 181 EGFR/ALK-negative non-sq NSCLCs treated during the same period were also evaluated as a control group. In addition, sites of distant metastases were evaluated.
Results:
The median age of patients with ALK-positive lung cancer was 58 years (range, 25-83 years). Of the 21 patients, 8 (39%) were female and 11 (52%) were never-smokers. The proportion of primary tumors smaller than 3 cm was significantly higher among the ALK-positive tumors than among the EGFR/ALK-negative tumors (48% vs. 21%, P = 0.01). Notches (71% vs. 41%, P = 0.01) and pleural indentations (81% vs. 55%, P = 0.03) were significantly more common among the ALK-positive tumors than among the EGFR/ALK-negative tumors. No significant differences in peripheral GGO (4.8% vs. 6.1%, P = 1.00) and spiculation (71.4% vs. 54.7%, P = 0.17) were observed. The median SUVmax values of the primary tumors were not significantly different (9.33 [range 4.56-28.81] vs. 10.54 [range 1.20-38.18], P = 0.91). Regarding the sites of distant metastases, liver (33% vs. 8%, P < 0.03) and pleural dissemination (48% vs. 24%, P = 0.03) were more frequent among patients with ALK-positive tumors than among patients with EGFR/ALK-negative tumors.
Conclusion:
We identified the radiologic features of advanced ALK-positive lung cancer, which include smaller-sized primary tumors and higher frequencies of notch and pleural indentation, compared with EGFR/ALK-negative tumors. These findings might be useful for the selection of patients with advanced ALK-positive lung cancer.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-064 - Microenvironmental Factor of Primary Lung Adenocarcinoma Which Predicts the Effectiveness of Chemotherapy in Patients with Recurrences (ID 815)
09:30 - 09:30 | Author(s): S. Umemura
- Abstract
Background:
The influence of microenvironmental factors on the effectiveness of chemotherapy is being increasingly recognized. Stromal cells in cancer tissue, such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), have been shown to influence tumor progression. The associations of CD204-positive cells, which represent an M2 phenotype of TAMs, and podoplanin-positive CAFs, which represent a subpopulation of CAFs with a tumor-promoting phenotype, with a poor prognosis have been identified in patients with lung adenocarcinoma, but whether these associations are involved in the response to chemotherapy remains unknown. The purpose of this study was to investigate the relationships between cancer cell and stromal cell phenotypes in primary tumors and the progression-free survival (PFS) of recurrent lung cancer patients who received platinum-based chemotherapy.
Methods:
We retrospectively analyzed 87 postoperative recurrent lung adenocarcinoma patients treated with platinum-based chemotherapy. The expressions of drug resistance-related proteins including BCRP, Ezrin and ALDH1 in cancer cells, the number of CD204-positive TAMs, and the presence of podoplanin-positive CAFs in the primary tumor were examined. The relationships between the immunohistochemical staining results of primary tumors and the PFS after receiving chemotherapy were also analyzed.
Results:
Among the clinicopathological factors of primary tumors, only an advanced pathological stage was significantly associated with a shorter PFS. As for immunohistochemical staining, no significant relationships were found between the PFS and the expression of BCRP, Ezrin, or ALDH1. The number of CD204-positive TAMs was not associated with the PFS. The presence of podoplanin-positive CAFs, identified in thirty (34%) of 87 samples, was significantly associated with a shorter PFS (median PFS: 5.1 vs. 7.8 months, P=0.028), but was not significantly associated with a shorter overall survival (median survival time: 18.1 vs. 23.7 months, P=0.156). A multivariate analysis revealed a tendency of podoplanin-positive CAFs to be correlated with a shorter PFS (P=0.087).
Conclusion:
The presence of podoplanin-positive CAFs in the primary tumor could be a predictor of a shorter PFS in recurrent lung adenocarcinoma patients who received chemotherapy. These findings suggest that stromal-cell derived factors should be incorporated into predictions of the effectiveness of chemotherapy.
