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H. Tanaka
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.01 - A Phase II Study of Nivolumab: A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT) (ID 9111)
11:00 - 11:05 | Author(s): H. Tanaka
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and limited treatment options beyond progression after platinum-based combination with pemetrexed chemotherapy. Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a humanized monoclonal antibody, PD-1 immune-checkpoint inhibitor, has demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Here, we report the preliminary results of a phase II study to evaluate the efficacy and safety of Nivolumab in previously treated Japanese MPM patients (pts): ONO-4538-41/JapicCTI-No.163247.
Method:
This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including platinum-based combination therapy with pemetrexed. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable disease and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS).
Result:
From July to October 2016, 34 pts were enrolled in 15 centers. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6%. Median follow-up was 6.7 months. Independent review committee-assessed 6-month ORR was 29.4% (n=10, 95%CI: 16.8-46.2) and objective responses were observed across tissue types, epithelioid 7/27 (25.9%), sarcomatoid 2/3 (66.7%), biphasic 1/4 (25.0%). 13 pts (38.2%) had stable disease, resulting in a 6-month DCR of 67.6%. Median PFS was 6.1 months (95%IC: 2.9-NR). Median OS has not been reached. 6-month PFS and OS rates are 50.9% (95%CI: 32.7-66.5) and 85.3% (95%IC: 68.2-93.6). 23 (67.6%) pts experienced drug-related adverse event (DRAE), and 7 (20.6%) experienced grade 3/4 DRAEs. 2 pts required dose discontinuation because of pneumonitis (Grade2 and 3).
Conclusion:
Single-agent Nivolumab has significant activity in 2[nd]/3[rd] line MPM pts and met the primary endpoint, suggesting that Nivolumab has a potential to be a new therapeutic option for MPM.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-008 - Phase I/II Study of Intermitted Erlotinib in Combination with Docetaxel in Patients with Recurrent NSCLC with Wild-Type EGFR: WJOG 4708L (ID 7556)
09:30 - 09:30 | Author(s): H. Tanaka
- Abstract
Background:
Erlotinib (ERL) is modestly active to non-small cell lung cancer (NSCLC) with wild type epidermal growth factor receptor (EGFR). We hypothesized that an intermittent delivery of erlotinib and docetaxel (DOC) would increase efficacy.
Method:
This was a multi-center, single-arm phase I/II study in patients with wild type EGFR NSCLC who failed one prior chemotherapy. The phase I was designed a standard 3+3 dose escalation design to determine feasibility, the maximum tolerated dose (MTD) and phase II recommend dose (RD) of ERL on days 2 to 16, in combination with a fixed dose of 60mg/m[2] DOC on day 1. The phase II primary endpoint was objective response rate (ORR) by independent review committee. This study required 41 patients with expected ORR of 30% and threshold ORR of 10% (one-sided α= 0.025; β=0.1). The target number was 45 patients assuming the loss of follow-up cases. All eligible patients had ECOG performance status of 0/1 and adequate organ functions.
Result:
Between Mar 2009 and Dec 2010, 12 patients were enrolled in the phase I, and between May 2011 and Feb 2015, 46 patients in the phase II. Five patients were excluded from per protocol set, because of deviation of entry criteria. Planned dose escalation was completed without reaching a MTD. The RD was determined as 150 mg/dose of ERL. In the phase II, the ORR was 17.1% (95%CI, 7.2-32.1). The median progression free survival and median overall survival were 3.48 months (95%CI, 3.06-4.50) and 11.27 months (95%CI, 8.61-16.56), respectively. Gender, smoking status, or concomitant drugs which influence the ERL metabolism had no significant differences in ORR, or disease control rate. All 46 patients were evaluable for toxicity. The grade 3 non-hematological toxicities included 9 (19.6%) febrile neutropenia, 7 (15.2%) appetite loss, 3 (6.5%) oral mucositis and 3 (6.5%) infections. The grade 4 hematological toxicities were 31 (67.4%) neutropenia. Two treatment related deaths were observed; interstitial lung disease, and pleural infection.
Conclusion:
Intermittent dosing of ERL plus DOC is clinically feasible, but has no statistically significant improvement of ORR, in patients with recurrent NSCLC with wild type EGFR.
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P2.03-015 - Efficacy of EGFR-TKIs for EGFR Mutatnt NSCLC Patients with Central Nervous System Metastases: A Retrospective Analysis (ID 8297)
09:30 - 09:30 | Author(s): H. Tanaka
- Abstract
Background:
Central nervous system (CNS) is a common site of metastases of non-small cell lung cancer (NSCLC). The prognosis for patients with brain metastases and/or leptomeningeal metastases is extremely poor. NSCLC harboring epidermal growth factor receptor (EGFR) mutation generally shows good response to tyrosine kinase inhibitors (TKI). However, the efficacy of EGFR-TKI in patients with CNS metastases is unclear. And the data on the occurrence of leptomeningeal metastases in the patients with brain metastases after use or EGFR-TKI remain limited.
Method:
We retrospectively evaluated clinical outcome and background of EGFR mutant NSCLC patients with CNS metastases who received EGFR-TKI for the first line drug therapy between January 2008 and December 2014 in the facilities belong to Niigata lung cancer treatment group.
Result:
A total of 104 eligible patients were enrolled. The response rate was 62%. The median time to treatment failure was 7.8 months. The median survival time (MST) was 24.0 months. The response rate of CNS was 37%. The median CNS-progression free survival (PFS) was 13.2 months. There was no statistical significant difference in TTF, overall survival (OS) and CNS-PFS between patients with exon 19 deletion and those with exon 21 L858R point mutation (mTTF 8.3 vs. 7.8 months, MST 26.1 vs. 24.9 months, mCNS-PFS 14.4 vs. 12.4 months) or between patients treated by Gefitinib and those treated by Erlotinib (mTTF 8.4 vs. 6.3 months, MST 26.0 vs. 20.2 months, mCNS-PFS 13.8 vs. 13.2months). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months) and tended to prolong CNS-PFS (15.6 vs. 11.1 months), but was not significantly associated with OS (MST 26.1 vs. 24.0 months). There was no significant difference in treatment outcome between patients who received stereotactic irradiation and those who received whole brain irradiation as brain radiotherapy prior to EGFR-TKI. Leptomeningeal metastases (LM) were primarily found in 8 of 104 patients (8%), and those occurred subsequently during the clinical course in 19 patients (18%). Median time to occurrence of LM in the patients who had LM subsequently was 14.5 months. There was no significant difference in OS between patients who had LM subsequently and those without LM during the course (MST 28.1 vs. 24.9 months). MST from diagnosis of subsequent LM was 3.7 months.
Conclusion:
EGFR-TKI showed favorable effect for EGFR mutant NSCLC patients with CNS metastases. A longer TTF and CNS-PFS were observed with prior brain radiotherapy. Prognosis after occurrence of LM was poor.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-007 - Retrospective Analysis of Antitumor Effects and Biomarkers of Nivolumab in NSCLC Patients with EGFR Mutations (ID 7988)
09:30 - 09:30 | Author(s): H. Tanaka
- Abstract
Background:
Randomized phase III trials demonstrated that nivolumab was significantly more efficacious than docetaxel in previously treated NSCLC patients; however, subgroup analysis indicated that nivolumab had no superior antitumor effects in patients with EGFR mutations. Recent studies have shown that predictive biomarkers, such as PD-L1 expression on tumor cells and infiltration of CD8[+] T cells into tumor tissues, were associated with response to nivolumab. The present study was conducted to evaluate the antitumor effects and biomarkers of nivolumab in NSCLC patients with EGFR mutations.
Method:
We retrospectively assessed 8 EGFR-mutated NSCLC patients treated with nivolumab.
Result:
All patients had adenocarcinoma histology. Six patients had 19 deletion, 1 had L858R and 1 had S768I point mutations. During nivolumab treatment, no patients achieved partial response and stable disease. Seven patients had progressive disease and 1 was not evaluable. The median number of cycles was only 2. The median progression free survival and median overall survival from the beginning of nivolumab was 32 days (95% C.I. 7 to 51) and 370 days (95% C.I. 230 to 480). PD-L1 expression (28-8 pharmDx) was observed in 3/2/1 patients before the start of nivolumab using cutoffs of >1%, >5% and >50% tumor cell staining. Immunohistochemistry revealed that CD4[+] and CD8[+] tumor infiltrating lymphocytes were observed in all patients before nivolumab.
Conclusion:
The current study indicated that nivolumab was not effective in patients with EGFR mutations regardless of predictive biomarkers of nivolumab.
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-004 - Underrepresentation of Elderly Patients with ED-SCLC as Clinical Trial Candidates (JCOG1201/TORG1528) (ID 8837)
09:30 - 09:30 | Author(s): H. Tanaka
- Abstract
Background:
Since December 2013, we initiated a phase II/III trial [Japan Clinical Oncology Group (JCOG) 1201/Thoracic Oncology Research Group (TORG) 1528: UMIN000012605] for elderly patients with extensive-disease small-cell lung cancer (ED-SCLC). Aim of the study is to demonstrate that a carboplatin plus irinotecan regimen is superior to carboplatin plus etoposide in elderly patients with ED-SCLC. However, the patient accrual rate did not satisfactorily match our expectations a year from the time of initiation of our study. To define factors related to low accrual, we searched institutional records and analyzed.
Method:
We collected data of elderly patients with ED-SCLC from each institution and investigated the total number of elderly patients with ED-SCLC, number of patients eligible/ineligible for the study, numbers of patients registered for the study, and the reasons for non-registration of even eligible patients. Doctor-reported questionnaires concerning elderly (≥71 years old) ED-SCLC patients diagnosed in their institutions were sent to chief or coordinate doctors at each institution in December 2014.
Result:
We received a response from 32 (84%) of 38 institutions. Approximately 260 patients were diagnosed as elderly patients with ED-SCLC in the last year. Only 100 patients (38%) were eligible for the JCOG 1201/TORG1528 trial. Reasons for ineligibility primarily included poor performance status (PS) (25%), low organ functions (25%), interstitial pneumonitis (19%) and double cancer (18%). Only 23 patients among the 100 eligible candidates accrued to the study. The primary reasons for non-accrual were delayed approval from the Institutional Review Board (IRB) of the individual institution (24%), physician preferences (23%), patient refusal (18%), and registration for other trials (12%).
Conclusion:
Our data demonstrated that 62% of ED-SCLC patients were ineligible for the protocol due to frailty with the most frequent reason being comorbidities such as poor PS and low organ functions. However, inactive institutions need to increase their efforts to register a greater number of eligible patients in addition to obtaining quicker IRB approval of protocol. Based on responses to questionnaires sent out as part of our investigation, in January 2016, the protocol was revised in terms of eligibility criteria to enhance patient accrual. Eligibility criteria for participation of elderly patients with ED-SCLC need to be formulated prudently so that patients are benefitted in routine clinical practice.
