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M. Shibuya



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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-012 - Activity of S-1 for non-small cell lung cancer pretreated with or without pemetrexed. (ID 882)

      09:30 - 09:30  |  Author(s): M. Shibuya

      • Abstract

      Background
      S-1, a 5-fluorouracil derivative, and pemetrexed (PEM) are antimetabolites that both mainly target thymidylate synthase. S-1 received approval as a therapeutic drug for treating non-small cell lung cancer (NSCLC) in Japan in December 2004, and has been primarily used as a single agent for salvage chemotherapy. To our knowledge, there has been no clinical evidence whether the activity of S-1 is influenced by PEM resistance.

      Methods
      Patients with pretreated NSCLC who underwent S-1 monotherapy were identified from an institutional database. This study was approved by the institutional review board. Eligible patients were classified into three groups; patients with non-squamous NSCLC pretreated with PEM (PEM+) or not (PEM−), or those with squamous cell lung cancer (SQ). Progression-free survival (PFS) and overall survival (OS) from S-1 administration were estimated using the Kaplan-Meier method and the log-rank test was used for inter-group comparisons. Impacts of prior PEM therapy on PFS and OS were examined using Cox proportional hazards modeling with variables including number of prior chemotherapy regimens, histological subtype of NSCLC, sex and age (<70 vs. ≥70 years).

      Results
      We identified 125 patients who underwent S-1 monotherapy for pretreated NSCLC. Median age was 69 years (range, 39-86 years), with 31% female. Histological subtype was 82 (66%) adenocarcinoma, 33 (26%) squamous cell carcinoma and 10 (8%) NSCLC not otherwise specified. Number of prior chemotherapy regimens was one in 32 (26%), two in 54 (43%), three in 26 (21%) and four or more in 13 (10%) patients. Among 108 patients with measurable disease, response rate was 12% and disease control rate was 45%. Response rates for S-1 monotherapy as second-, third- and fourth-line chemotherapy were 19% (5/27), 13% (6/45) and 9% (2/23), respectively. Forty-eight patients had received PEM-based chemotherapy prior to S-1 administration. Median PFS were 2.0 months for the PEM− group (reference), 2.1 months for the PEM+ group (crude hazard ratio (HR) 1.11, 95%CI 0.73-1.69, p = 0.6), and 2.2 months for SQ group (crude HR 0.72, 95%CI 0.44-1.15, p = 0.2). Median OS were 4.5 months for the PEM− group (reference), 5.9 months for the PEM+ group (crude HR 0.65, 95%CI 0.41-1.03, p = 0.07), and 8.4 months for SQ group (crude HR 0.76, 95%CI 0.47-1.23, p = 0.3). Multivariate analyses revealed that only female sex was associated with longer PFS (HR 0.59, 95%CI 0.38-0.91, p = 0.02) and OS (HR 0.58, 95%CI 0.36-0.91, p = 0.01), with history of PEM therapy or histological subtype exerting no influence.

      Conclusion
      Activity of S-1 is unaffected by prior PEM therapy. These results are compatible with recent preclinical findings. Further study is warranted.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-003 - A multicenter, proof-of-concept study of short-term supplementation of folic acid and vitamin B<sub>12</sub> prior to cisplatin-pemetrexed therapy for non-small cell lung cancer. (ID 186)

      09:30 - 09:30  |  Author(s): M. Shibuya

      • Abstract

      Background
      Pemetrexed, a multi-targeted antifolate, requires supplementation with folic acid and vitamin B~12~ prior to its first administration in order to reduce toxicity. The lead-in time for this vitamin supplementation is advised to be at least seven days on the drug package insert. Previous studies suggested that parenteral vitamin B~12~ pervades the major organs in 24 hours, while oral folic acid supplementation usually takes much longer than seven days to correct folic acid deficiency. We hypothesized that the lead-in time for vitamin supplementation can be shortened to 24 hours, enabling earlier administration of standard chemotherapy and potential avoidance of treatment alterations due to rapid disease progression before starting chemotherapy. Since only a few retrospective analyses related to early initiation of pemetrexed have been conducted, the first prospective study evaluating shortened vitamin supplementation for pemetrexed-based chemotherapy was planned.

      Methods
      A multicenter, single-arm phase 2 study was conducted. Patients with advanced non-squamous non-small cell lung cancer were enrolled. Major eligibility criteria were adequate organ function, performance status 0-1, no symptomatic brain metastasis, and no prior cytotoxic chemotherapy. Patients who had provided written informed consent were administered 1000 μg of vitamin B~12~ by intramuscular injection and started taking 350-500 μg of folic acid per day. Cisplatin (75 mg/m[2]) plus pemetrexed (500 mg/m[2]) therapy was commenced 24-48 hours after vitamin B~12~ injection and repeated for four cycles unless disease progression or unacceptable toxicity was observed. The primary endpoint was the proportion of patients experiencing neutropenia ≥grade 3. Thirty patients were to be accrued to detect the difference between the expected 30% of patients with neutropenia ≥grade 3 and the null hypothesis of 50%, using a two-stage design with 70% power and 5% alpha. Clinical trial registry number UMIN000006546.

      Results
      From November 2011 to March 2013, 31 patients were enrolled. Their median age was 66 years (range, 34-74 years), with 32% female. Most patients had adenocarcinoma (87%) and stage IV disease (90%). Performance status was 0 in 16 (52%) and 1 in 15 (48%) patients. Of the 30 patients who started chemotherapy within 48 hours from vitamin administration, 21 (70%) patients completed four cycles of cisplatin/pemetrexed therapy. Six (20%) patients discontinued chemotherapy due to disease progression, and the treatment of three (10%) patients was stopped due to adverse events. No treatment-related deaths or grade 4 toxicity occurred. Grade 3 neutropenia was observed in 7% (95%CI, 2-21%) of patients. Other grade 3 toxicities were anemia (two patients), decreased white blood cell count, diarrhea, thromboembolic event, hypertension, and myocardial infarction (one patient, respectively). The plasma homocysteine level before vitamin administration, a marker for vitamin B~12~ and/or folate deficiency, was elevated in four patients, but none of the patients experienced grade 3 toxicities. The response rate and the disease control rate of chemotherapy were 43% (95%CI, 27-61%) and 77% (95%CI, 59-88%), respectively.

      Conclusion
      This study met its primary endpoint. Absence of relationship between baseline homocysteine levels and toxicities of chemotherapy suggests the efficacy of short-term vitamin supplementation. A pragmatic study with a larger cohort that can detect uncommon toxicities is being conducted.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.10-012 - Feasibility study of docetaxel and bevacizumab in elderly patients with advanced nonsquamous non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 1014. (ID 1148)

      09:30 - 09:30  |  Author(s): M. Shibuya

      • Abstract

      Background
      A series of Japanese trials indicate docetaxel (DTX) monotherapy is a standard of care in elderly patients with advanced non-small cell lung cancer (NSCLC), and that the addition of platinum does not significantly improve the outcomes. Bevacizumab (BEV) has been shown to be beneficial when added to standard platinum-doublet chemotherapy in good-risk NSCLC patients. BEV toxicity is a major concern for elderly patients.

      Methods
      Patients with chemotherapy-naïve advanced non-squamous NSCLC who were >70 year old with performance status (PS) 0/1 and adequate organ function were enrolled. Eligible patients received DTX 60 (Level 0) or 50 (Level -1) mg/m2 and BEV 15 mg/kg on day 1, every 3 weeks. Toxicity was the primary endpoint and secondary endpoints were response rate, progression free survival (PFS), overall survival (OS), and completion rate of the 3 cycles of treatment. The planned sample size was 12 to 24, with at least 6 subjects treated at each level.

      Results
      Between December 2010 and September 2012, 21 elderly patients (9 in level 0 and 12 in level -1) were enrolled in the study (median age, 75 years; 43% male; 90% adenocarcinoma; 67% PS 1). Two of the 9 patients in level 0 had a dose limiting toxicities (DLTs). After 9 patients enrolled on level 0, two severe adverse events were reported. One patient had grade 4 sepsis in cycle 4 and another patient had grade 4 sepsis in cycle 5. We decided to stop enrollment to level 0 and reduce dose to level -1. Two of 12 patients in dose level -1 experienced DLTs. Grade 3 or 4 of toxicities among all patients were neutropenia (86%), anemia (5%), hypertension (19%), anorexia (10%), and increased aminotransferase levels (10%). Three out of 9 patients in level 0 achieved partial response (PR) and 3 out of 11 assessable patients in level -1 obtained PR. Completion rates of the 3 cycles of treatment were 78% (7/9) in level 0 and 67 % (8/12) in level -1. The median PFS and OS were 5.4 and 11.1 months, respectively.

      Conclusion
      The recommended dose for this combination in future study is docetaxel 50 mg/m2 and bevacizumab 15mg/kg.

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      P3.10-016 - A phase I/II study of combination chemotherapy with erlotinib and S-1 in pretreated Non-Small Cell Lung Cancer (NSCLC): Thoracic Oncology Research Group (TORG) 0808/0913 (ID 1351)

      09:30 - 09:30  |  Author(s): M. Shibuya

      • Abstract

      Background
      In BR.21 Study, erlotinib was shown to significantly prolong OS, PFS and the time to progression of NSCLC-associated symptoms. The study reported that the RR was 7% for EGFR-wt cases but the MST was longer than placebo. S-1 is a fourth-generation oral fluoropyrimidine that contains tegafur, a prodrug of 5-fluorouracil (5-FU). The consecutive administration of S-1 at 80 mg/m[2]/day was well tolerated. The objective RR and MST were 22.0% and 10.2 months. Regarding the EGFR-TKI and 5-FU-based chemotherapy, EGFR-TKI has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported in basic study. Thus, we conducted a phase I study to find the maximum tolerated doses of erlotinib/ S-1 combination therapy, and a phase II study to evaluate the efficacy and toxicity of this combination strategy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC in the absence of EGFR gene mutations.

      Methods
      Eligibility criterias were as follows: 1) patients with histologically or cytologically diagnosed NSCLC, 2) patients at clinical stage IIIB or IV not indicated for radical radiotherapy/radical surgery or those with postoperative recurrence, 3) patients having received 2 or fewer prior regimens of chemotherapy (at least one regimen being platinum-based), 4) patients with no history of treatment with EGFR-TKI and drugs of the fluoropyridimine family. This combination chemotherapy consisted of two 3-week cycles of S-1 treatment and once daily erlotinib at a dose of 150 mg/body. In phase I study, the initial dose of S-1 was 60 mg/m[2]/day, and 3 patients were registered for each level of S-1 treatment. In phase II study, S-1 at recommended dose and erlotinib were administered similarly to the phase I study.

      Results
      In phase I study, seven patients (one man and 6 women) with a median age of 66 years (range: 52-70 years) were enrolled. All patients had ECOG PS of 0-1, six patients had adenocarcinomas, and one had large cell carcinoma. All patients were at clinical stage IV. No patient had grade 2 or more neutropenia, and each 1 had grade 2 leukocytepenia, anemia, mucositis, general fatigue, skin rash, and diarrhea; however, none experienced DLT. The RD for the phase II study was determined as 80 mg/m[2] S-1 and 150 mg/m[2] erlotinib. The phase II study was conducted in 10 patients, 9 men and 1 woman, with a median age of 60.5 years (range 42–75). PS was 0 in 2, 1 in 6, and 2 in 2 patients. The histological subtype was adenocarcinoma in 5 patients, squamous-cell carcinoma in 4, and others in 1. One patient had grade 3 diarrhea, grade 4 colitis, and grade 4 septic shock, and the other had grade 4 dehydration and acute respiratory failure which resulted in two treatment-related deaths. With these findings, the trial was closed to additional enrollment.

      Conclusion
      Erlotinib(150mg) and S-1(80 mg/m[2] for 14 days every 21 days) therapy seemed to be toxic for pretreated patients with EGFR-wt NSCLC patients.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-014 - Multicenter study of zoledronic acid in lung cancer patients with bone metastasis. Thoracic Oncology Research Group (TORG) 1017. (ID 1043)

      09:30 - 09:30  |  Author(s): M. Shibuya

      • Abstract

      Background
      Bone is the most frequent site of metastasis for lung cancer, and metastatic bone disease causes pain. Furthermore, bone metastasis may produce skeletal-related events (SREs) that greatly reduce quality of life and may even lead to death. Several guidelines have recommended use of bone-modifying agents (BMA) such as zoledronic acid (ZA) at the first diagnosis of bone metastases in patients with solid tumors, continued every 3-4 weeks as long as the patient is able to tolerate therapy or until evidence of a substantial decline in performance status. However, due to the risk of osteonecrosis of the jaw (ONJ) and a perceived lack of evidence for reduced SRE in lung cancer, some physicians have hesitated to administer ZA in lung cancer patients with bone metastasis. Therefore, the main objective of the present study was both to describe real world data of ZA and to compare SREs among previous reports.

      Methods
      All patients with non-small cell lung cancer (NSCLC) accompanied by metastatic bone disease (MBD) who were administered ZA at least twice from 12 hospitals in the TORG in Japan between January 2008 and December 2009 were eligible for inclusion in the study.

      Results
      A total of 198 consecutive patients (126 men, 72 women; median age, 64 years; range, 44-89 years) were identified. Histological type was as follows: adenocarcinoma (n=131, 66%); squamous cell carcinoma (n=30, 15%); and others (n=37, 19%). About two-thirds of patients experienced SRE before starting anti-cancer therapy. Median duration of ZA administration was 106 days (range, 28-1126 days), and median number of ZA administrations was four (range, 2-41). Median time to first SRE in patients who experienced SRE after treatment was 202 days (range, 156-264 days). No ONJ was reported from the 198 patients.

      Conclusion
      We found that ZA was not used sufficiently in clinical practice in Japan. Our data suggest that ONJ during the treatment of lung cancer patients is very rare, and ZA is potentially useful in lung patients with bone metastasis.