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K. Kiura
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.02 - TAE226, a Bis-Anilino Pyrimidine Compound, Shows Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells including T790M Mutant (ID 1646)
10:50 - 10:55 | Author(s): K. Kiura
- Abstract
- Presentation
Background:
TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). These tyrosine kinases are known to be overexpressed in many malignant tumors including some NSCLCs and to play an oncogenic role in cancer cells.
Methods:
We investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. Drug sensitivity of TAE226 to various NSCLC cell lines was determined by MTS assay. Interaction of TAE226 and variant EGFR proteins was evaluated by in vitro binding assay, and kinetic interaction analysis to calculate K~d~ value. Finally, the effect of TAE226 on NSCLC was investigated using a xenograft mouse model.
Results:
TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity.
Conclusion:
We showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation. Our results showed that the EGFR L858R/T790M (or delE746_A750/T790M) mutant retains the binding affinity to TAE226 comparable to that of the L858R (or delE746_A750) mutant, suggesting that TAE226, or its relatives, is promising to overcome acquired TKI resistance mediated by EGFR T790M mutation.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-010 - Development of Skin Rash within the First Week Is a Potential Surrogate Marker of Effect in Afatinib for EGFR Mutant NSCLC (ID 1184)
09:30 - 09:30 | Author(s): K. Kiura
- Abstract
Background:
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now key agents in EGFR-mutant non-small-cell lung cancer (NSCLC). In gefitinib or erlotinib monotherapy, its efficacy could be predicted by development of skin rash, however, it has not been fully evaluated if this is similarly the case with afatinib monotherapy.
Methods:
We retrospectively studied consecutive 49 patients with EGFR-mutant NSCLC who received afatinib therapy between 2009 and 2015. Relationship with several toxicities and tumor response was examined.
Results:
Figure 1Figure 2The Grade 2 or worse common adverse events (AEs) included skin rash in 17 patients (35%), diarrhea in 19 (39%) and mucositis in 15 (31%). Of these, number of patients who developed ≥ Grade 2 AEs within the first week was 5 (10%; skin rash), 12 (25%; diarrhea) and 4 (8%; mucositis). As for objective response, 21 (43%) of the 49 had partial response. In association with AEs and antitumor effect, those who had Grade 2 or worse skin rash within the first week tended to have better tumor response as compared with those who did not have (80% vs. 39%; p = 0.077).
Conclusion:
Our small study demonstrated that early development of skin rash might predict the response to afatinib monotherapy.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-013 - A Phase II Study of S-1 and Thoracic Irradiation for Elderly Pts with Locally Advanced Non-Small Cell Lung Cancer: Okayama Lung Cancer Study Group (ID 224)
09:30 - 09:30 | Author(s): K. Kiura
- Abstract
Background:
Although thoracic irradiation (TRT) is one of the standarad therapies in elderly pts with locally advanced non-small cell lung cancer (LA-NSCLC), its treatment outcome is still poor. We previously reported safety profiles of S-1, an oral fluoropyrimidine possesing a radio-sensitizing effect, and concurrent TRT in such population [Lung Cancer 2011]. Here, we investigated the efficacy and safety of S-1 with concurrent TRT for elderly pts with LA-NSCLC.
Methods:
Pts with stage III, aged >75 years and PS 0-1, and without any prior chemotherapy were eligible for this study. Pts were treated with S-1 (40 mg/m2/dose b.i.d on days 1-14 and 29-42) and TRT (60 Gy/30 fr over 6 weeks starting on day 1). Primary endpoint was response rate (RR), and required sample siza was 30 pts.
Results:
Between 2007 and 2012, 30 pts were enrolled (24 men; median age, 79 years; PS 1, 15; IIIa, 20; Sq, 12). Median Charlson score was 1 (range; 0-3). The proportion of actual dose schedule relative to the planned one of S-1 and TRT was 95 and 98%, respectively. Partial response was observed in 19 pts (63%; 95% confidence interval: 45-82%), which did not meet the endpoint. At the time of the analysis, 24 (80%) of the 30 had experienced recurrences; 13 (43%) were locoregional, 6(20%) distant, and 5 (17%) both locoregional and distant. At a median follow-up of 23.7 months, median progression-free survival and MST were 13.0 months and 27.9 months, respectively. Toxicities were generally mild, including G3/4 neutropenia (17%), G3 febrile neutropenia (7%) and G3 pneumonitis (10%). No toxic deaths occurred.
Conclusion:
This study did not meet the primary endpoint. However, concurrent S-1 and TRT yielded favorable survival data. Also, it was well-tolerated in elderly pts with LA-NSCLC
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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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P3.01-014 - Interleukin-6 Is a Valuable Predictive Marker for Therapeutic Effect of Gefitinib in Patients with Advanced NSCLC Harboring EGFR Mutations (ID 1187)
09:30 - 09:30 | Author(s): K. Kiura
- Abstract
Background:
Although epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) are the key drug in patients with EGFR-mutant Non-small-cell Lung Cancer (NSCLC), some of them can not respond well to its therapy. An overexpression of Interleukin (IL)-6 in tumor cells is postulated as a potential mechanism for such resistance or low sensitivity to EGFR-TKI in the preclinical models (PNAS 2010). Here, we evaluated clinically if tumor IL-6 level can be predictive for the effect of EGFR-TKI therapy.
Methods:
A total of 52 patients with advanced EGFR-mutation NSCLC who had received gefitinib were retrospectively assessed. The protein expression of IL-6 in the tumor cells was immunostained. Each specimen was assessed independently by 2 physicians (YK and TT) and 2 pathologists (KI and TT), and judged as positive if ≥ 50% of 100 tumor cells were stained positively (BJC 1999). Serum IL-6 level was measured by CLEIA in 11 (21%) of 52 patients.
Results:
Patients demographics were as follows: 24 men; median age, 66 yrs; PS 0-1, 48; stage IV, 22; Ad, 49; exon19, 29). Of these, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse PFS (75% v 92% at 6m; p < 0.05), which was retained in the multivariate analysis (HR: 2.38; 95%CI: 1.00-5.68; p=0.05) (Fig1). In contrast, PFS in the platinum-based chemotherapy did not differ in groups P and N (p=0.47). The serum IL-6 level ranged from 0.75 to 23.80 pg/ml (median: 2.90 pg/ml), which correlated neither to that in the tumor cells (regression coefficient: 1.69, p = 0.29) nor PFS in gefitinib therapy (p = 0.44). Figure 1 Figure 2
Conclusion:
Patients in group P benefited less from gefitinib therapy. This might suggest the inhibition of IL-6 expression can improve the low sensitivity to EGFR-TKI especially in EGFR-mutation tumors with high IL-6 expression.
