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H. Kunitoh



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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O15.05 - Randomized Phase III Trial of S-1 plus Cisplatin versus Docetaxel plus Cisplatin for Advanced Non-Small-Cell Lung Cancer (TCOG0701): Subgroup Analysis. (ID 1895)

      11:15 - 11:25  |  Author(s): H. Kunitoh

      • Abstract
      • Presentation
      • Slides

      Background
      Docetaxel plus cisplatin (DP) is the only third-generation regimen that has demonstrated statistically significant improvements in overall survival and QOL by head-to-head comparison with a second-generation regimen (vindesine plus cisplatin) in patients with advanced non-small cell lung cancer (NSCLC). S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Molecularly targeted agents including bevacizumab (BEV) have shown activity and safety in non-squamous (non-Sq) NSCLC.

      Methods
      Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either oral S-1 80 mg/m[2]/day (40 mg/m[2] b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m[2] on day 8 every 5 weeks or docetaxel 60 mg/m[2 ]on day 1 plus cisplatin 80 mg/m[2] on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint was overall survival (OS). A non-inferiority study design was employed; the upper confidence interval (CI) limit of the hazard ratio (HR) was <1.322. Secondary endpoints included progression-free survival (PFS), response, safety, and QOL. Subgroup analysis by histology (non-Sq vs Sq) was conducted.

      Results
      From April 2007 through December 2008, 608 patients were randomly assigned to SP (n=303) or DP (n=305) at 66 sites in Japan. Patient demographics were well balanced between the two groups. Non-Sq and Sq patients in SP/DP arm was 251/247 and 50/48 respectively. Two interim analyses were preplanned. At the final analysis, a total of 480 deaths had occurred. The primary endpoint was met. OS in the SP arm was non-inferior to that in the DP arm (median survival, 16.1 vs. 17.1 months, respectively; HR=1.013; 96.4% confidence interval, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. The rates of febrile neutropenia (7.4% vs. 1.0%), grade 3/4 neutropenia (73.4% vs. 22.9%), grade 3/4 infection (14.5% vs. 5.3%), and grade 1/2 alopecia (59.3% vs. 12.3%) were significantly lower in the SP arm than in the DP arm. In terms of physical functioning and global functioning on the EORTC QLQ-C30 and lung cancer module (LC-13), QOL was better in the SP arm (repeated measures ANOVA: p<0.01). Subgroup analysis by histology revealed that the median OS of non-Sq and Sq patients in SP/DP group was 17.4/19.1 months and 12.3/11.7 months respectively, of which hazard ratio was 0.973 (95% CI, 0.797-1.187) and 1.239 (95% CI, 0.819-1.874). Interaction P value was 0.3004.

      Conclusion
      S-1 plus cisplatin is a standard first-line chemotherapeutic regimen for advanced NSCLC both non-Sq and Sq histology. Favorable toxicity profile of the SP regimen and encouraging outcome in patients with non-Sq prompted us to conduct a prospective study of SP plus BEV and maintenance S-1 BEV for non-SQ currently underway.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.11-011 - Observational study of treatment of epidermal growth factor receptor activating mutation positive (EGFRm+) advanced or recurrent non-small-cell lung cancer (NSCLC), after radiological progression to the first-line therapy with EGFR tyrosine kinase inhibitors (EGFR-TKI). (ID 1077)

      09:30 - 09:30  |  Author(s): H. Kunitoh

      • Abstract

      Background
      Although NSCLC with activating EGFR mutation is generally sensitive to EGFR-TKI, such as gefitinib or erlotinib, it eventually gets acquired resistance. However, the clinical course after radiological (RECIST-based) “progressive disease (PD) judgment" is highly variable. Some patients are reported to do well with continuation of TKI beyond PD, with or without local therapy. But, prior reports are only on small-numbered and selected cases. The objective of this study is to investigate the clinical course and the actual pattern of care after radiological "progressive disease" to the first-line therapy with EGFR-TKI in such cases.

      Methods
      Thirty-four institutions in Japan participate in the survey of the patterns of care and outcomes of the patients with EGFRm+ advanced or recurrent NSCLC, who received first-line gefitinib or erlotinib during the period from 2009 to 2011. The primary endpoint is the time from RECIST-based radiological PD to clinical PD in patients who were continuously received EGFR-TKI beyond “RECIST PD”. Clinical PD was defined as one or more of the following events: 1) symptomatic progression, 2) worsening of performance status due to progression, 3) threat to major vital organ(s), 4) multi-organ unequivocal progression. Durations of TKI administration and reasons of discontinuation (RECEIST PD vs. clinical PD vs. toxicity), concomitant administration of chemotherapy and/or local therapy with TKI, occurrence of “flare” phenomenon after TKI stoppage, and overall survival were also recorded.

      Results
      At the time of the abstract submission, 24 institutions reported the number of patients. There were 1,177 patients (395 in 2009, 397 in 2010 and 385 in 2011) with EGFRm+ advanced or recurrent NSCLC. Among them, 602 (51.1%) received first-line EGFR-TKI. The median number of EGFRm+ patients per institution was 32 (range: 9 to 151). The rates of those who received first-line TKI varied substantially among institutions, ranging from 30% to 88%, and tended to increase over time (41.0% in 2009, 56.9% in 2010 and 55.6% in 2011). In 2009, there were no institutions which administered TKI to every EGFRm+ patient, whereas there were 1 and 3 such institutions in 2010 and 2011, respectively.

      Conclusion
      In this large observational study, we will collect data on approximately 1,600 patients with EGFRm+ NSCLC, some 800 of them received first-line EGFR-TKI. Since the median progression-free survival of those patients with TKI has generally been reported to be 1 year or less, we will be able to see the pattern of care and outcome after PD in the majority of the cases. Clinical significance of continuation of EGFR-TKI “beyond PD” in the real world will be clarified. This research was conducted by Comprehensive Support Project for Oncology Research (CSPOR) of Public Health Research Foundation. The research fund was provided to CSPOR with support from an Investigator Sponsored Study Programme of AstraZeneca. Trial registry with UMIN#000010538.

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      P1.11-016 - A Prospective, Multi-center Phase II Trial on the Efficacy and Safety of Low-dose Erlotinib Monotherapy for Patients with EGFR Mutation-positive, Previously Treated Non-small Cell Lung Cancer: Results of Thoracic Oncology Research Group (TORG) Trial 0911. (ID 1385)

      09:30 - 09:30  |  Author(s): H. Kunitoh

      • Abstract

      Background
      Several studies of erlotinib and gefitinib have shown similar benefit in terms of response and progression-free survival (PFS) for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, the steady-state plasma trough concentration of erlotinib was approximately 3.5 times higher than that of gefitinib when administered at the respective approved dose. Hence, low-dose treatment of erlotinib may be as effective as gefitinib or erlotinib given at full dose, with reduced toxicity and treatment cost.

      Methods
      Eligible patients were adults (over 20 years), with advanced or recurrent EGFRm+ NSCLC who had received one to three prior chemotherapy regimens, ECOG PS of 0-2, measurable lesion, and adequate organ function. Erlotinib 50 mg was administered daily until disease progression or unacceptable toxicities. Dose was escalated to 150 mg/day in case of not achieving CR or PR classified by RECIST criteria (i.e., not responded, NR) at the first 4 weeks. The primary endpoint was objective response rate (ORR); SWOG two-stage design with an early stopping rule based on response rate was used. Response was initially judged by the investigators and confirmed by the independent review committee (IRC). Finally, 26 or more responses among 40 eligible patients were to be considered as evidence of sufficient efficacy of this treatment.

      Results
      Thirty-four patients were enrolled between April 2010 and November 2012: males/females 20/14; median age 67 (range 31-81); PS 0/1/2 16/18/0; Ad/Sq 33/1. EGFR mutation types were: exon 18 and 19/19/21/other 1/21/11/1. One patient was excluded for evaluation because of not having a measurable lesion, therefore, efficacy and safety were evaluated among 33 patients. The study was closed early according to the protocol definition at the time that NR was confirmed in 15 of 33 patients, because it was determined impossible to meet the primary endpoint even if the study was continued. The IRC-judged best responses to the 50 mg/day erlotinib were: PR 18 (54.5%), SD 10 (30.3%) and PD 5 (15.2%). ORR and disease control rate were 54.5% (95%CI: 36.4-71.9%) and 84.8 % (95%CI 68.1-94.9%), respectively. In addition, 4 out of the 10 patients with SD to the initial dose yielded PR after dose escalation to 150 mg/day. At data cut-off (April, 2013), median PFS was 8.6 months (95%CI: 6.7-15.0 months). Toxicities were generally mild, with a few grade 3 or more toxicities. The only grade 3 toxicities were 2 cases with neutropenia and 1 with AST/ALT elevation. No grade 4 toxicity or treatment-related death was observed. There was no treatment-related interstitial lung disease.

      Conclusion
      Although low-dose erlotinib appeared to have a certain efficacy in this population, this study could not meet the primary endpoint. Because of its relatively lower toxicity and cost, it may be worth further evaluation for elderly or frail patients.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P2.10-016 - Phase II study of gefitinib and inserted cisplatin plus docetaxel as a first-line treatment for advanced non-small-cell lung cancer harboring an epidermal growth factor receptor activating mutation (ID 1107)

      09:30 - 09:30  |  Author(s): H. Kunitoh

      • Abstract

      Background
      Gefitinib yields a longer progression-free survival (PFS) period than platinum-doublet chemotherapy as a first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) activating mutation, but most patients develop resistance against gefitinib after the initial response. We hypothesized that the insertion of platinum-doublet chemotherapy during the initial response could prevent the emergence of acquired resistance and prolong survival, compared with gefitinib monotherapy.

      Methods
      We performed a phase II study of the following first-line treatment for patients with advanced NSCLC with EGFR mutation. Gefitinib (250 mg) was administrated on days 1-56. After a two-week rest, three cycles of cisplatin (80 mg/m[2]) and docetaxel (60 mg/m[2]) were administered on days 71, 92, and 113. Gefitinib was re-started on day 134 and was continued until progression. The primary endpoint was the two-year PFS rate. The sample size was estimated at 33, and this treatment was considered worthy for further development if more than 11 of the 33 patients who started treatment had a 2-year PFS.

      Results
      Thirty-three Japanese patients were enrolled. Twenty-five patients could recieve the second gefitinib, 12 achieved a PFS period of over 2 years, and 7 continued to receive the protocol treatment without experiencing progression. The 1-, 2-, and 3-year estimated PFS rates were 67.0%, 40.2%, and 36.9%, respectively, and the median PFS time was 19.5 months. The 1-, 2-, and 3-year estimated survival rates were 90.6%, 71.9%, and 64.8%, respectively, and the median survival time had not been reached at the time of analysis. Treatment-related deaths and unexpected severe toxicities were not seen.

      Conclusion
      Our results indicated that first-line treatment consisting of gefitinib and inserted cisplatin plus docetaxel is promising in patients with advanced NSCLC with EGFR mutation. A phase III study of this treatment compared with gefitinib monotherapy is warranted.

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      P2.10-022 - Prospective observational cohort study of second-line chemotherapy administration after first-line platinum-based chemotherapy for patients with advanced NSCLC in Japan (SAPPHIRE study) (ID 1438)

      09:30 - 09:30  |  Author(s): H. Kunitoh

      • Abstract

      Background
      In advanced non- small cell lung cancer (NSCLC), second-line chemotherapy (second-CT) after the progression of the first-line platinum-based chemotherapy (first-CT) is the standard of care. More recently, maintenance therapy after the first-CT has been reported to be beneficial. However, its impact on overall survival appears to be marginal or negligible, when most patients could receive timely active second-CT after progression. The purposes of this study are to investigate the proportion of those who actually received the second-CT, and to elucidate factors associated with its administration in advanced NSCLC patients.

      Methods
      From April 2010 to September 2011, patients with advanced NSCLC who received platinum-based first-CT at 30 institutions in Japan were enrolled in this prospective observational study. Baseline characteristics, regimens and responses to the first-CT, presence or absense of the second-CT administration, and if not administered, its reasons were recorded. This is an interim report describing patients with at least 6 months of follow up. This study was supported by the Public Health Research Center Foundation CSPOR and registered at UMIN#000006393.

      Results
      A total of 865 eligible patients with advanced NSCLC provided patient characteristics and details of the first-CT. Median age was 65 (range: 24-86), proportion of patients with adenocarcinoma/squamous/NOS/others were 70/20/8/2%, and with EGFR mutant/wild/unknown were 10/60/30%. Platinum compound used in the first-CT were: cisplatin in 38.3% of the cases, carboplatin in 57.9%, and nedaplatin in 2.8%. Of the patients with non-squamous histology, 24% received bevacizumab. At the time of cut off, 797 patients were assessable for response of the first-CT. Among them, 225 patients had either disease progression or inadequate data (NE) to the first-CT and 572 patients were evaluated CR/PR/SD; 194 (22%) received maintenance therapy, including bevacizumab. Of the 572 patients, 51 have no disease progression after the first-CT, and data are not yet available in another 13. Therefore, 508 patients were further analyzed for the administaration of the second-CT. Among those, 132 patients (26%) failed to receive the second-CT. The reasons for not receiving were as follows: declined PS, 79 (60%); patient refusal, 28 (21%); death of any cause, 6 (5%); loss of follow-up and others, 19 (14%). Explorative analysis of association between characterisics and administration of the second-CT revealed age (<65 vs ≥65, odds ratio [OR], 0.59; 95% CI, 0.39-0.90, p=0.01), PS (0 vs 1-4, OR 0.33, 95% CI 0.22-0.53, p<0.0001), and smoking status (never vs ever, OR 0.47, 95% CI 0.26-0.85, p=0.01) as possible factors.

      Conclusion
      Preliminary results of this large observational study in Japan suggested that around one-fourth of the patients missed an opportunity to receive appropriate the second-CT. Further investigation is needed to clarify optimal management of the patients after the first-CT, particularly on how to identify the patients that would be less likely to receive the second-CT after disease progression and thus would be more likely to receive benefit from maintenance therapy strategy.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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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): H. Kunitoh

      • 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.