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Y. Ohe
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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): Y. Ohe
- 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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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:D. Ettinger, G.R. Simon
- Coordinates: 9/09/2015, 18:30 - 20:00, 605+607
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MINI37.06 - Randomized Phase II Trial of CODE or Amrubicin Plus Cisplatin Chemotherapy after Chemoradiotherapy for Limited-Disease Small Cell Lung Cancer (ID 1033)
18:30 - 20:00 | Author(s): Y. Ohe
- Abstract
- Presentation
Background:
Four cycles of etoposide plus cisplatin (EP) concurrently with accelerated hyperfractionation thoracic radiotherapy (AHTRT) is the standard treatment for limited-disease small cell lung cancer (LD-SCLC). The objectives of this study were to evaluate efficacy and toxicities of CODE or amrubicin plus cisplatin (AP) chemotherapy following one cycle of EP and AHTRT in patients with LD-SCLC, and to select the promising arm for subsequent phase III trials.
Methods:
Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, and 20-70 years of age. Eligible patients received one cycle of EP (etoposide 100 mg/m[2] on days 1-3 and cisplatin 80mg/m[2] on day 1) plus AHTRT (45Gy/ 30 fractions in 3 weeks). Patients who achieved CR, PR or SD were secondarily registered and randomized to receive either 3 cycles of CODE (cisplatin 25 mg/m[2] on days 1 and 8, doxorubicin 40 mg/m[2] on day 1, etoposide 80 mg/m[2] on days 1-3, and vincristine 1 mg/m[2] on 8 every 2 weeks) or 3 cycles of AP (amrubicin 40 mg/m[2] on days 1-3 and cisplatin 60 mg/m[2] on day 1 every 3 weeks). G-CSF was administered on the days when chemotherapy was not administered in CODE, or on day 5 to the day when a neutrophil count exceeded 5,000/µL in AP. Patients with CR after CODE or AP received prophylactic cranial irradiation. The primary endpoint was the one-year progression-free survival (PFS) after the second registration. Tumor responses were assessed with RECIST version 1.1 by the central review committee. A better regimen for phase III trial is determined with a randomized phase II selection design. The sample size was 72 randomized patients to detect >= 10% difference in one-year PFS with a probability of 80%.
Results:
From May 2011 to Jan 2014, 85 patients from 28 institutions were registered. After the induction EP plus AHTRT, 75 patients were randomized to CODE (n=39) or AP (n=36). Patient demographics were well balanced between the arms. One patient did not receive CODE and 34 (89%) of the 38 patients received 3 cycles of CODE, whereas 33 (92%) of the 36 patients received 3 cycles of AP. Grade 4 neutropenia, anemia and thrombocytopenia were observed in 47%, 21% and 16% of patients in CODE, and in 78%, 6% and 17% of patients in AP, respectively. Grade 3 non-hematological toxicities with the incidence of 5% or higher included febrile neutropenia (16%), hyponatremia (8%), hypokalemia (5%), fatigue (5%), and anorexia (5%) in CODE, and febrile neutropenia (42%), nausea (11%), anorexia (11%), fatigue (8%), esophagitis (6%) in AP. CR and PR were noted in 13 and 25 patients in CODE, and in 10 and 24 patients in AP, respectively. The median overall survival in the 74 patients was 42.8 months. The one-year PFS (95% CI) was 41.0 (25.7 - 55.8) % in CODE and 54.3 (36.6 - 69.0) % in AP.
Conclusion:
The one-year PFS seemed better in AP than in CODE. AP arm is considered to be the test regimen for the subsequent phase III trial.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-026 - First Case of SMARCB1(INI1)- Deficient Squamous Cell Carcinoma of the Pleura (ID 978)
09:30 - 17:00 | Author(s): Y. Ohe
- Abstract
Background:
SMARCB1(INI1) is a tumor-suppressor gene located at 22q11.2. It is considered an integral component of the chromatin remodeling complex SW1/SNF. Loss of SMARCB1 expression has been reported to be associated with atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues. In addition, sinonasal basaloid carcinomas and neoplasms arising from the gastrointestinal tract, pancreas and uterus with SMARCB1 deficiency have been reported.To date, however, SMARCB1-deficient carcinoma of the pleura has not been reported.
Methods:
We report the first case of SMARCB1-deficient squamous cell carcinoma of the pleura in a patient, and describe the clinical course from initial presentation to diagnosis with pathological findings.
Results:
The case was a 33-year-old female never smoker with no previous medical or family history of malignant disease. She visited a previous hospital with a one-month history of worsening cough and dyspnea. Chest X-ray and computed tomography (CT) showed left pleural tumors with a large amount of pleural effusion. She underwent the diagnostic thoracoscopy to obtain sufficient tumor tissue from the parietal pleura. Systemic work-up including CT identified no other lesions apart from those in the left thoracic cavity. Pathological diagnosis in the previous hospital was squamous cell carcinoma of the pleura. She received six cycles of cisplatin plus gemcitabine therapy and achieved stable disease an overall best response. After progression, she transferred to our institution for expected further treatment. Although she received TS-1 therapy as second-line treatment, her disease progressed rapidly with worsening chest pain and dyspnea, and she died at 10 months after diagnosis. On pathological review of formalin-fixed, paraffin-embedded tissues of parietal pleura obtained in the previous hospital, primary tumors were composed of morphologically poorly differentiated cancer cells with characteristics of squamous cell carcinoma. Tumor cells were completely negative for INI1 protein expression by immunohistochemistry. Malignant pleural mesothelioma, thymic carcinoma and NUT midline carcinoma were ruled out. Claudin4 and MOC31 were positive, and C-kit and NUT were negative by immunohistochemistry suggesting that the tumor was primary squamous cell carcinoma of the pleura with SMARCB1 deficiency. Genome analysis using next-generation sequence data revealed no oncogene mutations, such as EGFR mutation, ALK, RET or ROS1 rearrangement.
Conclusion:
To our knowledge, this is the first report of SMARCB1-deficient squamous cell carcinoma of pleura. The tumor was highly aggressive and carried a poor prognosis with short survival. The existence of other SMARCB1- deficient tumors is likely, such as atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues. The clinical features and treatments of this tumor are not clear, and additional cases wiii assist the establishment of treatments and improve the poor prognosis.
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P1.08-028 - PD-L1 Expression in Neuroendocrine Tumors of the Lung (ID 2217)
09:30 - 17:00 | Author(s): Y. Ohe
- Abstract
Background:
The World Health Organization (WHO) classification recognizes four major types of neuroendocrine tumors of the lung: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large-cell neuroendocrine carcinoma (LCNEC). These diagnostic categories have different prognostic implications and require distinct treatment strategies. The PD-1/PD-L1 pathway is a major target of anti-tumor immunotherapy. PD-L1 expression has been reported to cause local immune suppression and is considered as a predictive marker of immune checkpoint therapeutics. In order to clarify any differences in the expression of PD-L1 according to the type of neuroendocrine tumor in the lung, we investigated the expression levels of PD-L1 by immunohistochemistry in neuroendocrine tumors of the lung.
Methods:
The subjects of this study were patients who were diagnosed as having lung neuroendocrine tumors and were treated at the National Cancer Center Hospital from 1982 to 2010. A tissue microarray (TMA) made from the surgical specimens was analyzed. After the rabbit monoclonal PD-L1 antibody was validated (clone E1L3N, Cell Signaling Technology, Danvers, MA), the TMA was stained and the tumor PD-L1 expression score was calculated by a semiquantitative method (by multiplying the intensity [0–3] by the staining area [0–100%]). To determine the PD-L1 expression, 3 (1%) was used as the cutoff score.
Results:
A total of 227 patients were included in this study. The characteristics of the entire patient population were as follows; median age, 65 years (range: 19-84 years); gender, male 168 (74.0%) / female 59 (26.0%); smoking status, smokers 191 (84.1%)/non-smokers 36 (15.9%); pStage: IA 79 (34.8%)/IB 36 (15.9%)/IIA 25 (11.0%)/IIB 29 (12.8%)/IIIA 47 (20.7%)/IIIB 6 (2.6%)/IV 5 (2.2%); histology, typical carcinoid 46 (20.3%)/atypical carcinoid 6 (2.6%)/SCLC 69 (30.4%)/LCNEC 106 (46.7%). Of the 227, samples from 15 (6.6%) showed positive staining for PD-L1. The characteristics of the patients showing positive staining for PD-L1 were as follows; median age, 71 years (range: 37-84 years); gender, males 12 (7.1%)/females 3 (5.1%); smoking status, smokers 13 (6.8%)/non-smokers 2 (5.6%); pStage, IA 3 (3.8%)/IB 2 (5.6%)/IIA 2 (8.0%)/IIB 5 (17.2%)/IIIA 2 (4.3%)/IIIB 0 (0%)/IV 1 (20.0%); histology, typical carcinoid 0 (0%)/atypical carcinoid 0 (0%)/SCLC 4 (5.8%)/LCNEC 11 (10.4%). In 31 of the 69 cases of SCLC who were treated by surgery, the disease recurred; of these 31 patients who developed disease recurrence, positive expression for PD-L1 was noted in 2 patients (6.5%). Furthermore, the disease recurred in 33 of the 106 cases of LCNEC treated by surgery; of the 33, 2 (6.1%) showed expression of PD-L1.
Conclusion:
None of the tumors in the patients with typical or atypical carcinoid in our study showed expression of PD-L1. Only the tumors in 4 of the 69 patients (5.8%) with SCLC and 11 of the 106 patients (10.4%) with LCNEC showed positive staining results for PD-L1. The data suggest that drugs directed against PD-1/PD-L1 might be potentially useful in the immunotherapy of SCLC and LCNEC.
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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: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-020 - Updated Data from JP28927 Study of Alectinib in ALK+ NSCLC Patients with or without History of ALK Inhibitor Treatment (ID 346)
09:30 - 17:00 | Author(s): Y. Ohe
- Abstract
Background:
Alectinib, a next generation ALK inhibitor, was granted approval in Japan 2014, since it showed good efficacy and tolerability in ALK+ NSCLC patients without previous ALK inhibitor treatment in Phase I/II study (AF-001JP). We also reported its promising response and good tolerability for crizotinib pre-treated patients in JP28927 study (ESMO 2014). This report describes the update of efficacy and safety result in JP28927 study.
Methods:
Patients (with/without prior ALK inhibitor treatment) who had ALK+ NSCLC were enrolled in JP28927. Patients received alectinib (300mg) twice daily; treatment was continued until the investigator determined lack of clinical benefit.
Results:
Thirty-five patients were enrolled into JP28927 study. Median follow-up duration was 400 days (35-457 days). The median progression free survival (PFS) of 35 patients was 13.9 months (95%CI: 11.1- NR). Among 30 patients with the target lesions at base line, the overall response rate (ORR) was 70% (95%CI: 50.6-85.3) with rapid response (the median time to response was 1.2 months [95%CI: 1.1-2.1]). Twenty-three out of 35 patients had been confirmed the progressive disease with crizotinib treatment. Their median PFS was 12.9 months (95%CI: 3.9-NR). Twenty out of 23 patients had the target lesions at base line. ORR was 65% (95%CI: 40.8-84.6) and the median time to response was 1.2 months (95%CI: 1.1-1.3). The treatment-related adverse events (AEs) observed in more than 10% of the patients were constipation (31.4%), dysgeusia (25.7%), WBC count decreased (22.9%), neutrophil count decreased (22.9%), vomiting (14.3%), rash (14.3%), blood bilirubin increased (14.3%) and AST increase (14.3%). Treatment-related Grade 3 AEs, i.e. pulmonary thrombosis, lymphocyte count decrease, hypophosphatemia, were observed in 3 patients. No treatment-related Grade 4 or 5 AEs were observed.
Conclusion:
The updated results in JP28927 study once again endorsed our previous reports which had indicated alectinib’s promising response even for ALK+NSCLC patients who failed to crizotinib treatment.
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P3.01-080 - An Open-Label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC) (ID 184)
09:30 - 17:00 | Author(s): Y. Ohe
- Abstract
Background:
Necitumumab (N) is a human IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Squamous (SQ) histology accounts for 25-30% of non-small cell lung cancer (NSCLC) and gemcitabine combined with cisplatin (GC) is a standard of care for advanced or metastatic SQ-NSCLC. In the previous global randomized, open-label, Phase 3 trial (SQUIRE), compared with GC, the addition of N to GC (GC+N) significantly improved overall survival (OS) (HR=0.84, p=0.012; median 11.5 vs 9.9 months) and progression-free survival (PFS) (HR=0.85, p=0.020; median 5.7 vs 5.5 months). The objective response rate (ORR) was 31% vs 29% (p=0.400), and the disease control rate (DCR) was 82% vs 77% (p=0.043), respectively. The SQUIRE results were an important advance in the search for a new treatment for patients with metastatic SQ-NSCLC, where limited progress has been made over the last two decades. However, only 8% of patients in SQUIRE Trial were Asian and no Japanese institutions participated. We have therefore conducted this Phase 1b/2 trial to evaluate the efficacy and safety of GC+N in Japanese patients with advanced SQ-NSCLC.
Methods:
This trial consists of a Phase 1b and Phase 2 part. Patients with advanced (Stage IV) SQ-NSCLC are eligible for enrollment if they are aged³20 years with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1; measurable or nonmeasurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0; adequate organ function. GC+N or GC may continue for a maximum of 4 cycles; patients with at least stable disease in GC+N may continue to receive N until disease progression or emerging non-acceptable toxicity. The purpose of Phase 1b part is to determine the recommended dose of the combination of GC (G=1000 or 1250 mg/m[2] iv, Days 1 and 8; C=75 mg/m[2] iv, Day 1; 3-week cycle) and N (800 mg iv, Days 1 and 8; 3-week cycle). Patients are enrolled in 2 cohorts using a conventional 3+3 study design, with dose-escalation of gemcitabine permitted according to the incidence of dose-limiting toxicity (DLT). The Phase 2 part is an open-label, randomized trial to evaluate the efficacy and safety of addition of N to GC. Patients are randomly assigned on a 1:1 basis (Stratification factors: ECOG PS and gender) to GC+N (Arm A) or GC (Arm B). The primary endpoint is OS for which the final analysis will be performed when at least 137 events are observed. The sample size of 180 patients (137 events) has 68% power for a log-rank test at 0.2 one-sided alpha. The secondary endpoints include PFS, ORR, time to treatment failure, Pharmacokinetics, safety and patient-reported outcomes. The relationship between EGFR protein expression level by immunohistochemistry (IHC) and each of several efficacy measures will also be assessed. Translational research analyses will be performed to analyze relevant biomarkers for clinical outcomes. ClinicalTrial.gov Identifier: NCT01763788.
Results:
Not applicable
Conclusion:
Not applicable
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P3.07 - Poster Session/ Small Cell Lung Cancer (ID 223)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.07-005 - Maintenance Irinotecan Therapy in Extensive Disease Small Cell Lung Cancer: A Feasibility Study (ID 607)
09:30 - 17:00 | Author(s): Y. Ohe
- Abstract
Background:
We performed a feasibility study of maintenance irinotecan therapy in patients with extensive disease small cell lung cancer (ED-SCLC) who responded to the induction irinotecan plus cisplatin (IP) therapy.
Methods:
The eligibility criteria included pts with ED-SCLC who responded to four cycles of induction IP therapy, ECOG performance status (PS) of 0 to 1, age of 20 to 70 years and adequate organ functions. Pts received irinotecan monotherapy at 60 mg/m2 on days 1, 8 and 15 of a 28-day cycles until disease progression. The primary endpoint was the proportion of treatment success (TS) at 6 months. Using a binomial design, a lower activity level (p0) of 0.25 and a target activity level (p1) of 0.50, the preplanned accrual of 28 patients was sufficient (alpha, 0.10 and power, 0.90).
Results:
Between August 2012 and August 2013, 22 pts were enrolled. However, accrual was discontinued because of the three grade 3 pneumonitis events (3 of 22 patients, 13.6%). Patient characteristics of the 22 eligible pts were as follows; the median age was 65 (54-70) years; 12 pts had a PS of 0, and 16 pts were male. The median number of cycles delivered was four (range, 1–31). Four of 22 (18.2%) patients achieved TS at 6 months. Median progression free survival and overall survival from the start of the maintenance irinotecan therapy were 3.2 months and 15.9 months, respectively. Grade ≥3 toxicities included neutropenia (4.5%), hyponatremia (4.5%), pneumonitis (13.6%) and cholangitis (4.5%). No treatment-related deaths occurred. Figure 1
Conclusion:
This trial was early terminated due to the unexpected toxicity, but maintenance irinotecan therapy was still active for a subset of ED-SCLC.
