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Y. Hosomi
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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.03 - Biomarkers for Efficacy in JO25567 Study Evaluating Erlotinib plus Bevacizumab versus Erlotinib in Advanced NSCLC with EGFR Mutation (ID 306)
11:07 - 11:18 | Author(s): Y. Hosomi
- Abstract
- Presentation
Background:
Bevacizumab (B), an anti-vascular endothelial growth factor (VEGF) monoclonal antibody has been proven to provide additional efficacy benefit in combination with platinum-based chemotherapy for 1[st] line therapy of non-squamous non-small cell lung cancer (NSCLC). In JO25567 study, we observed that bevacizumab in combination with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib (E) also provided additional 6.3 months median progression free survival (PFS) in advanced EGFR mutation-positive non-squamous NSCLC. To try to understand this additional effect of bevacizumab, we investigated the predictive biomarkers related to angiogenesis comprehensively in JO25567 study. Clnical trials registry number: JapicCTI-111390
Methods:
We evaluated the biomarkers in blood and tissue samples. All samples were collected before E+B or E treatment in JO25567 study. Angiogenesis related ligands and soluble receptors in serum were analyzed by multiplex, bead-based suspension array. Single nucleotide polymorphisms (SNPs) or variable number of tandem repeats (VNTR) of angiogenesis related genes were analyzed by direct sequencing or electrophoresis after PCR for blood sample. VEGF-A concentration in plasma were analyzed by Immunological Multi-Parametric Chip Technique (IMPACT) assay. Messenger RNA of genes related to angiogenesis in tumor tissue were quantitated by multiplex TOF-mass spectrometry (MassARRAY). Immunohistochemistry of neuropilin and exploratory proteomics analysis were planned for surgically resected tumor tissues. PFS were used as an efficacy variable of prediction. Multivariate Fractional Polynomial (MFP) and Subpopulation Treatment Effect Pattern Plot (STEPP) were used for biomarker screening.
Results:
One hundred fifty-two patients were treated with E+B or E in JO25567 study. We analyzed 26 ligands or soluble receptors in 134 serum samples. Follistatin and leptin were identified as potential biomarkers by MFP. The interaction p-value with adjustment of covariates for biomarker and efficacy was 0.0168 for follistatin and 0.0049 for leptin. STEPP suggested that high follistatin related to limited bevacizumab efficacy and low leptin related to higher bevacizumab efficacy. SNPs could be analyzed in 135 blood samples. In 12 SNPs and 1 VNTR of 8 genes, no gene related to bevacizumab efficacy. Plasma samples were collected from 105 patients. Median VEGF-A concentration of E+B group and E group were 18.0 pg/mL and 18.8 pg/mL respectively and was one sixth or more lower than previously reported breast and gastric cancers. Hazard ratio of E+B comparing with E for was 0.23 (95% CI: 0.09-0.60) for low plasma VEGF and was 0.56 (95% CI: 0.26-1.25) for high plasma VEGF. This trend was not consistent with previously reported studies. We analyzed mRNA expression from 24 surgical resected tumors and no predictive value was observed. Because of limited number of surgically resected tumors obtained, we couldn’t proceed exploratory proteomics analysis nor evaluate predictive value of neuropilin expression.
Conclusion:
In this comprehensive predictive biomarker analysis, follistatin and leptin in blood were identified as potential biomarker candidates for E+B therapy.
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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: 2
- 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 - 09:30 | Author(s): Y. Hosomi
- 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.
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P3.07-015 - Final Report of Phase I/II Study of Induction Carboplatin and Irinotecan Followed by TRT for Elderly Patients with LD-SCLC: TORG 0604 (ID 3232)
09:30 - 09:30 | Author(s): Y. Hosomi
- Abstract
Background:
In elderly patients with LD-SCLC, the role of irinotecan has been unclear and the timing of TRT combined with chemo-therapy has not been fully evaluated. Furthermore, no standard treatment has been established for them. We report a phase I/II trial of induction chemotherapy of carboplatin and irinotecan followed by sequential TRT in this population.
Methods:
Patients with untreated, measurable LD-SCLC >70 years with performance status (PS) 0 to 2 and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8 every 21 days for four cycles. TRT of 54Gy in 27 fractions was then administered sequentially. Carboplatin dose was escalated from AUC of 4 to 5 (Levels 1 and 2, respectively) with a fixed dose of irinotecan at 50 mg/m[2]. The primary objective of the phase II portion was evaluation of efficacy.
Results:
A total of 41 patients were enrolled [median age 75 years, range 70-86 years; 31 male, 10 female; PS 0/1/2: 22/18/1]. At Level 1 (n=6), one patient experienced dose-limiting toxicity (DLT) as Grade 3 hypertension. At Level 2 (n=6), two patients experienced DLT as Grade 4 thrombocytopenia. Therefore, level 1 was chosen as the recommended dose. The phase II trial was then expanded by 35 patients in the level 1 based on the Simon minimax design. In all cohorts, the median chemotherapy cycle was 4 (1/2/3/4 courses administered as 4/2/2/33); median radiation dose was 54Gy (range 36-60). Toxicities were generally mild, as expected. Gr 3/4 leukopenia and thrombocytopenia were both observed in six (15%) patients. No Gr 3/4 diarrhea or esophagitis was noted. Although Gr 3 febrile neutropenia and Gr 3 pneumonitis were seen in two patients each, no treatment-related deaths occurred. There were five complete responses and 32 partial responses, for a response rate of 90%. With median follow-up of 80.4 months (n=41), median progression-free and overall survival times were 11.2 and 27.1 months, respectively.
Conclusion:
Induction chemotherapy with carboplatin plus irinotecan followed by sequential TRT was well tolerated and highly effective in elderly patients with LD-SCLC. Further confirmatory studies are warranted.
