Virtual Library
Start Your Search
Y. Hasegawa
Author of
-
+
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
-
+
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): Y. Hasegawa
- 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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)
-
+
P2.01-080 - Pemetrexed, Carboplatin and Bevacizumab in Patients with Non-Squamous NSCLC without or with Activating EGFR Mutation (CJLSG0909/0910) (ID 615)
09:30 - 17:00 | Author(s): Y. Hasegawa
- Abstract
Background:
Treatment strategies for advanced non-squamous (sq) non-small cell lung cancer (NSCLC) are divided by EGFR mutations. However, there has been no previous report about efficacy of cytotoxic agents separated by EGFR mutations. In addition, the influence of the EGFR mutations on the maintenance therapy with pemetrexed (Pem) or bevacizumab (Bev) has not been elucidated. We planned two studies designed to evaluate the efficacy and safety of combination therapy with Pem, carboplatin (Cb) and Bev followed by Pem and Bev maintenance therapy for non-sq NSCLC patients without or with activating EGFR mutation.
Methods:
We undertook two multicenter, open-label, single-arm, phase II studies. Patients with wild type EGFR or with EGFR mutation (exon 19 deletions or exon 21 point mutation) entered CJLSG0909 or 0910, respectively. Patients received Pem 500mg/m[2], Cb AUC 6, and Bev 15mg/kg day1, every 3 weeks, 4 to 6 cycles (induction therapy). Patients who had achieved disease control received Pem+Bev maintenance therapy until progressive disease or unacceptable adverse event. Key inclusion criteria were stage IIIB, IV, or recurrent disease after surgery, no prior chemotherapy, age 20 to 74. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were the disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. (Unique trial Number; UMIN000003736/UMIN000003737)
Results:
In CJLSG0909, 50 patients received induction treatment. They had a median age of 64 years and were predominantly men (40 [80%]) with adenocarcinoma (47 [94%]), stage IV (40 [80%]), and a performance status (PS) of 1 (40 [80%]). The median of induction therapy was 5 cycles. Thirty-five (70%) patients received maintenance therapy, and the median of maintenance therapy was 5 cycles. Partial response was observed in 25 patients with a ORR of 50.0% (95% confidence interval, 33.7–62.6%). Stable disease was observed in 21 patients and the DCR was 92%. Median PFS was 6.8 months and median OS was 19.4 months. Grade 3/4 toxicities during induction therapy included neutropenia (40 [80%]), thrombocytopenia (12 [24%]), anemia (8 [16%]), nausea (4 [8%]), anorexia (3 [6%]), ALT elevation (3 [6%]), AST elevation (2 [4%]), vomiting, periodontal, hemoptysis, thrombosis and proteinuria (1 [2%]) respectively. In CJLSG0910, 30 patients received induction treatment. They had a median age of 65.5 years and were predominantly women (17 [57%]) with adenocarcinoma (29 [97%]), stage IV (27 [90%]), and a PS of 0 (23 [77%]). The median of induction therapy was 6 cycles. Twenty-five (83%) patients received maintenance therapy, and the median of maintenance therapy was 8.5 cycles. Partial response was observed in 15 patients with a ORR of 50.0% (95% confidence interval, 33.9–66.1%). Stable disease was observed in 15 patients and the DCR was 100%. Median PFS was 10.0 months and median OS was 41.4 months. Grade 3/4 toxicities during induction therapy included neutropenia (14 [47%]), thrombocytopenia (6 [20%]), anemia (6 [20%]), diarrhea (2 [7%]), nausea, anorexia, amylase elevation (1 [3%]) respectively.
Conclusion:
These studies suggested that chemotherapy with Pem+Cb+Bev, including Pem+Bev maintenance therapy is candidate for first line therapy in non-sq NSCLC patients regardless of the activating EGFR mutations.
-
+
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)
-
+
P2.04-022 - Development of Microfluidic Devices for Rapid, Low-Cost Detection of EGFR Mutations in Cytological Samples from Patients with Lung Cancer (ID 999)
09:30 - 17:00 | Author(s): Y. Hasegawa
- Abstract
Background:
Epidermal Growth Factor Receptor (EGFR) mutation testing plays an important role in selecting patients for targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs). However, a currently available PCR-based sequencing is time-consuming and expensive. In order to overcome these problems, we have developed microfluidic devices which enable rapid and specific detection of mutant EGFR proteins at low-cost in cytological samples from patients with non-small cell lung cancer (NSCLC).
Methods:
The diagnostic device consisted of the capture antibody against EGFR and photo-reactive polymer. The antibody-immobilized photo-reactive polymer wall (40 μm width, 40 μm height and 4 mm length) was constructed at the center of a microchannel (1 mm width, 40 μm height and 8.5 mm length) by ultraviolet light irradiation. The substrate was made of cyclic olefin polymer by using injection molding. The inner wall of the microchannel was blocked with bovine serum albumin. By using the diagnosis devices, the sandwich-type fluorescence immunoassay procedure was conducted. The sample, detection antibody reagent (mutation specific monoclonal antibody against EGFR with the E746_A750 deletion in exon 19 or the L858R point mutation and control EGFR antibody), and fluorescence-labeled anti-IgG antibody reagent were injected in turn. Between each injection, we performed a washing procedure, in which the microchannel was filled with the washing buffer for 1 minute followed by flushing with 5 μL of the same washing buffer. The amount of the sample and reagents to fill the microchannel was 1 μL. Incubation times were 15 minutes, 30 seconds, and 30 seconds for capture antibody-antigen reaction, antigen-detection antibody reaction, and detection antibody-fluorescence-labeled antibody reaction, respectively. After the immunoassay, fluorescence images were captured by using a digital CCD camera. Malignant pleural effusions (MPEs) were obtained from patients with NSCLC with written informed consent. After centrifugation, the cell pellets of MPEs were lysed in 200μl of lysis buffer.
Results:
First, we performed a pilot study by using cell lysates of 3 lung cancer lines expressing wild-type (H358) or E746_A750del mutant (HCC827) or L858R mutant (H3255) EGFR. Using our newly developed diagnostic device, we were able to specifically distinguish EGFR mutant proteins from that of wild-type EGFR in all of these cell lines. Next, we tested the device for detecting EGFR mutations in cytological samples of MPEs. Results of the mutation testing of the lysates using this device were consistent with those obtained by commercially available techniques in Japan although the number of samples assessed in this experiment was limited. The cost was less than a few dollars per assay.
Conclusion:
These results suggest that our device may be possible candidates for the next generation companion diagnostics devices for EGFR-TKI. Further investigation will be needed to elucidate the most appropriate detection method of EGFR mutation as a companion diagnostics.
