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Y. Fujita
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ORAL 10 - SCLC (ID 98)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:C. Faivre-Finn, P. Lara Jr.
- Coordinates: 9/07/2015, 10:45 - 12:15, 605+607
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ORAL10.07 - Clinical and Molecular Profiling of Surgically Resected Small Cell Lung Cancer (ID 2235)
12:10 - 12:21 | Author(s): Y. Fujita
- Abstract
- Presentation
Background:
NCCN, ACCP and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), while ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). In addition, the clinical impact of surgery with other variables on patients with early-stage SCLC has yet to be determined. Therefore, clarification of the clinical profile of surgically resected SCLC is required. Suppression of MED12, a subunit of the transcriptional MEDIATOR complex in conjunction with cell surface expression of TGF-βRII was reported to be correlated with the resistance mechanism of EGFR-TKIs, crizotinib, and chemotherapy. Few investigators examined the expression profile of MED12 as well as receptor tyrosine kinases in SCLC. A next-generation sequencing (NGS) system is a novel technology for sequencing genomes at high-throughput and with great accuracy using deep sequencing. It has been instrumental for translational study integrating the detection of genetic alteration analysis into the better understanding of tumor biology, as well as treatment of various types of cancers. Recently, SOX-2 amplification, histone modification, and genetic alterations in the PI3K/AKT/mTOR pathway were reported to be potential targets of SCLC using NGS through whole exon analysis. However, further investigation is needed for the personalized treatment of SCLC. We updated the molecular data using NGS, which had been presented at ESMO 2014 (abstract ID: 5724).
Methods:
We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 through January 2013. One hundred twenty-five formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using seven antibodies (MED12 and TGF-βRII, ALK, c-Met, EGFR, c-kit, and VEGFRII) and to NGS systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 cancer-specific genes. (UMIN registration No. 000010116 /10117).
Results:
Median relapse-free survival and overall survival (OS) were 15.6 (95%CI=6.8-24.5) and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without a history or presence of other types of cancer (HR: 0.545, 95%CI=0.335-0.887, p=0.014), with preoperative diagnosis (HR: 0.510, 95%CI=0.299-0.871, p=0.014), with c-stage II and under (HR: 0.288, 95%CI=0.154-0.541, p<0.001) and with prophylactic cranial irradiation (HR: 0.300, 95%CI=0.092-0.976, p=0.045). Of the 125 patients whose samples were available, MED12 and TGF-βRII were highly expressed in nucleus and cytoplasm, respectively in 92% and 55% of the samples. None of the tumors expressed ALK. There was no relationship between the expression of c-Met, EGFR, and VEGFRII and either of RFS or OS. Multivariate analysis demonstrated that high expression of c-kit in tumor is an independent factor for longer OS (HR=0.543, 95%CI: 0.310-0.953, p=0.033). Seventy-nine samples have been subjected to NGS. Three actionable gene mutations, EGFR (E746_A750del), KRAS (G12D), and AKT1 (E17K) were found.
Conclusion:
These results supported the ESMO guidelines for the management of early-stage SCLC, and indicated that presence or history of other types of cancer might be a major decisive factor for surgery. The results of immunohistochemistry using antibodies of selective molecules and NGS assist us in gaining a better understanding of the biology and treatment strategy of SCLC.
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P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.07-006 - Final Results of Randomized Phase II Study of Carboplatin plus Irinotecan vs. Carboplatin plus Amrubicin for ED-SCLC (ID 931)
09:30 - 09:30 | Author(s): Y. Fujita
- Abstract
Background:
Carboplatin-based regimens, such as carboplatin plus etoposide (CE), are among the standard regimens for the management of extended disease small-cell lung cancer (ED-SCLC). However, the efficacy of carboplatin-based regimens is unsatisfactory. Carboplatin plus irinotecan (CI) and carboplatin plus amrubicin (CA) are promising new carboplatin-based regimens identified in our previous studies. Accordingly, we conducted this randomized phase II study to identify the appropriate regimen for comparison with CE in future phase III trials.
Methods:
Chemotherapy-naïve patients with ED-SCLC were randomly assigned to receive 4–6 cycles of carboplatin (area under the curve [AUC] 5.0, day 1) plus irinotecan (70 mg/m[2], days 1 and 8) every 3 weeks (CI arm) or carboplatin (AUC 4.0, day 1) plus amrubicin (35 mg/m[2], days 1–3) every 3 weeks (CA arm). The primary endpoint was the overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.
Results:
Between December 2009 and March 2013, 71 patients were enrolled. One patient in each arm did not receive any protocol treatment owing to rapid disease progression. The characteristics of the treated patients were as follows: median age, 70 years (range 51–84 years) and proportion of males, 84%. Delivered mean dose intensities (mean actual dose/mean planned dose) were similar for both arms: carboplatin 98% and irinotecan 94% for CI arm, and carboplatin 97% and amrubicin 94% for CA arm. The ORRs were 79% and 89%, median PFS was 5.1 and 6.2 months (CA; hazard ratio [HR] = 0.59, 95% CI: 0.35–0.98, P = 0.042), and median OS was 12.2 and 15.9 months in the CI and CA arms, respectively (CA; HR, 0.77; 95% CI: 0.49–1.29; P =.318). Grade 3 or higher neutropenia (CI, 53% and CA, 89%), anemia (CI, 26% and CA, 20%), thrombocytopenia (CI, 18% and CA, 14%), and febrile neutropenia (CI, 12% and CA, 29%) were observed. No treatment-related deaths were observed. Overall, 25 patients (74%) in the CI arm and 28 patients (80%) in the CA arm received post-discontinuation therapies.
Conclusion:
CA was numerically effective than CI in chemotherapy-naïve patients with ED-SCLC, with acceptable toxicity. Therefore, CA could be selected for future phase III trials.
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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: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-056 - Phase II Study of Carboplatin plus Weekly Nab-Paclitaxel in Elderly Patients with NSCLC: North Japan Lung Cancer Study Group Trial 1301 (ID 576)
09:30 - 09:30 | Author(s): Y. Fujita
- Abstract
Background:
Recent IFCT-0501 trial demonstrated that carboplatin (CBDCA) combined with weekly paclitaxel (PTX) would be advantageous compared with monotherapy. Subsequently, CA031 trial suggested that weekly nab-paclitaxel (nab-PTX) was superior in efficacy and safety compared with 3-weekly PTX when combined with CBDCA. Since the subgroup analysis for elderly patients (pts) in CA031 showed very promising data (34% of overall response rate (ORR) and 8.0 months of progression-free survival (PFS)), we conducted this multicenter, non-randomized, open label, phase II trial to evaluate the efficacy and tolerability of CBDCA plus weekly nab-PTX regimen for elderly patients with advanced non-small cell lung cancer (NSCLC) prospectively.
Methods:
Eligible pts were aged 75 years or older with newly diagnosed clinical stage IIIB, IV, and postoperative recurrence NSCLC; ECOG performance status (PS) of 0-1; adequate organ function; written informed consent. Pts received CBDCA (AUC 6) on day 1 and nab-PTX (75mg/m[2]) on day1, 8, and 15, every 4 weeks. The primary endpoint was ORR and secondary endpoints were PFS, overall survival (OS), and toxicity profile. Assuming that ORR of 40% would be potential usefulness while ORR of 20% would be the lower limit of interest, 32 pts were required.
Results:
Between March 2013 and May 2014, 35 pts were enrolled and 32 pts were eligible. Median age was 78 years (range, 75-86), 84% (27/32) were male and 56% (18/32) were stage IV. 56% (18/32) had squamous cell carcinoma and 44% (14/32) had adenocarcinoma. Median treatment cycle was 4 (range, 1-6). ORR and DCR were 50% (95%CI: 33-67) and 94% (95%CI: 85-100), respectively. With a median follow-up of 9.1 months, median PFS was 6.4 months (95%CI: 4.8-8.0). Median OS had not been reached at the data cutoff point. Grade 3 or severer toxicities were as follows: neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). No febrile neutropenia and treatment-related deaths were observed.
Conclusion:
The combination of CBDCA and weekly nab-PTX demonstrated significant efficacy with acceptable toxicities in elderly patients with advanced NSCLC.
