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K. Azuma
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.03 - Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) (ID 5597)
11:00 - 12:30 | Author(s): K. Azuma
- Abstract
- Presentation
Background:
ALK inhibitors are the standard treatment for ALK+ NSCLC and the comparison between 2 ALK inhibitors will be valuable in determining therapeutic strategy for ALK+ NSCLC patients (pts). We conducted the randomized open-label Phase III trial designed to prove the superior PFS of ALC to CRZ in ALK-inhibitor naïve ALK+ NSCLC.
Methods:
ALK+ NSCLC pts were randomized 1:1 either to receive ALC (300 mg b.i.d.) or CRZ (250 mg b.i.d.) and stratified by ECOG PS (0/1 vs 2), treatment line (1[st] vs 2[nd]), and clinical stage (IIIB/IV vs recurrence). Primary endpoint was PFS according to the blinded independent review board. Secondary endpoints included overall survival, objective response rate, and safety. Under an assumption of expected hazard ratio (HR) of 0.643, 164 events were required to have 80% power with 2-sided alpha of 0.05. Three interim analyses (IA) for early stopping due to efficacy were planned after 33%, 50%, and 75% of required PFS events occurred.
Results:
207 pts were enrolled at 41 centers in Japan between November 2013 and August 2015. Independent data monitoring committee recommended the release of study data because the superiority in PFS had been demonstrated for ALC based on second IA. The PFS HR of ALC arm to CRZ arm was 0.34 (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not Reached (NR)) in ALC arm while it was 10.2 months (95%CI: 8.2-12.0) in CRZ arm. ALC demonstrated favorable result of PFS in each sub-group for instance, treatment line (1[st] line: HR = 0.30, ALC: NR vs CRZ: 10.2 months, 2[nd] line: HR = 0.39, ALC: 20.3 months vs CRZ: 8.2 months), brain metastases at baseline (yes: HR = 0.08, ALC: NR vs CRZ: 10.2 months, no: HR = 0.39, ALC: 20.3 moths vs CRZ: 10.0 months) and clinical stage (stage IIIb/IV: HR = 0.31 ALC: 20.3 months vs CRZ: 8.3 months, recurrence: HR = 0.49, ALC: NR vs CRZ: 11.6 months). Grade 3-4 AEs (ALC: 26% vs CRZ: 52%), discontinuation of study drug due to AEs (ALC: 9% vs CRZ: 20%) and dose interruptions due to AEs (ALC: 29% vs CRZ: 74%) occurred with lower rate in the ALC arm. There were no treatment-related deaths in either arm.
Conclusion:
ALC demonstrated prolonged PFS compared with CRZ in all sub-groups with a favorable AE profile representing a potential new standard treatment for 1[st] line ALK+ NSCLC pts.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-015 - The NICE Salvage Study: A Phase II Trial of Weekly Nab-Paclitaxel in the Salvage Setting for Advanced Non-Small Cell Lung Cancer (ID 4566)
14:30 - 15:45 | Author(s): K. Azuma
- Abstract
Background:
The standard chemotherapy for advanced NSCLC after the failing of second or third line chemotherapy has yet to be established. In these salvage setting patients the acceptable safety and efficacy of solvent-based paclitaxel (sb-P) monotherapy have been previously reported as one possible treatment option (Anticancer Res 2005). Compared with sb-P, nab-paclitaxel(nab-P) yielded a higher mean maximal circulating concentration of free paclitaxel and delivered higher drug concentration to tumors in preclinical xenograft models (Clin. Cancer Res. 2006). Moreover, a large multicenter international phase III study (CA031) of nab-P + carboplatin (C) vs sb-P + C, nab-P + C produced a significantly higher overall response rate (ORR) compared with sb-P + C, and had an acceptable safety profile as a first line chemotherapy (J. Clin. Oncol. 2012) .These results suggest that nab-P monotherapy have possibility to be more efficacious and tolerable compared to sb-P monotherapy. KTOSG trial 1301 has recently revealed weekly nab-P as a second line chemotherapy is associated with acceptable toxicity and a favorable ORR in patients with advanced NSCLC (Lung Cancer 2016). However, there are no reports of nab-P monotherapy after the failing of second or third line chemotherapy. We therefore planned this study aiming to assess the efficacy and safety of nab-P monotherapy for patients in the salvage setting.
Methods:
This multicenter single arm phase II study assesses the efficacy of nab-P in pts with PS 0-2 and aged < 75 years with advanced non-small cell lung cancer. Pts must have failed two or three prior lines of therapy including at least a platinum- containing chemotherapy. Pts pretreated with sb-P or nab-P, or tumors harboring EGFR mutation or ALK fusion gene are excluded. Pts receive nab-P 80 mg/m2 on days 1,8 and 15 of a 28-days cycle. The primary endpoint of the trial is progression-free survival in an intent-to-treat analysis using the Kaplan-Meier method and log-rank test. Secondary endpoints include overall survival, ORR, disease control rate, efficacy according to prior docetaxel, quality of life, and safety. The study is powered to detect a 1.5-month improvement in median PFS in this investigational arm beyond the 2.0-month median PFS estimated from historical data. Assuming a one-sided 0.10 level of Type I error and 80% power, the sample size was calculated to be 35 pts based on the Brookmeyer-Crowley method. The target sample size is established as 38 pts. As of June 2016, 14 pts were registered and recruitment is ongoing (UMIN000016173).
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-120 - EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib (ID 4818)
14:30 - 15:45 | Author(s): K. Azuma
- Abstract
Background:
Afatinib is effective for lung cancers harboring common EGFR mutations, Del19 and L858R. We reported that tumors with exon 18 mutations are especially sensitive to afatinib compared with first generation (1G) EGFR- tyrosine kinase inhibitors (TKIs). However, data on the mechanisms of acquired resistance to afatinib are limited
Methods:
We established afatinib-resistant cells from Ba/F3 cells transfected with common or exon 18 (G719A and Del18) mutations and PC9 (del E746_A750), HCC4006 (del E746_A750), and 11_18 (L858R) cell lines by chronic exposure to increasing concentrations of afatinib. Separately, afatinib-resistant clones were established from above Ba/F3 cells by exposure to fixed concentrations of afatinib using N-ethyl-N-nitrosurea (ENU) mutagenesis. Re-biopsy samples from patients whose tumors acquired resistance to afatinib were collected. EGFR secondary mutations and bypass tracks were analyzed by Sanger sequence, western blot, and real time PCR.
Results:
Afatinib-resistant cells transfected with Del19, L858R, or G719A developed T790M, whereas those with Del18 acquired novel L792F mutation. ENU mutagenesis screening established 84 afatinib-resistant clones. All Del19 clones and most of the other clones acquired only T790M. However, C797S occurred in subsets of L858R, G719A, and Del18 clones. Additionally, subsets of Del18 clones acquired L792F. C797S-acquired cells were sensitive to erlotinib. L792F demonstrated intermediate resistance between T790M and C797S to both 1G and 3G-TKIs, whereas L792F was the least resistant to 2G-TKIs, particularly dacomitinib. Chronic exposure of Del18+L792F cells to dacomitinib induced additional T790M acquisition. T790M was detected in 1 of 4 clinical samples, whereas no EGFR secondary mutations were detected in afatinib-resistant PC9, HCC4006, or 11_18 cell lines. Regarding bypass tracks, IGF1R was over expressed in all of the three afatinib-resistant cell lines compared with parental cells, whereas expression of AXL and PTEN were not changed. Neither mutations in PIK3CA and BRAF nor amplification of MET and FGFR1 were detected in clinical samples and resistant cell lines.
Conclusion:
L792F and C797S, in addition to major T790M, can develop in afatinib-resistant cells, and these minor mutations appear to exhibit sensitivity to dacomitinib and erlotinib, respectively. These secondary mutations should be tested in clinical practice. Bypass track through IGF1R may be associated with acquired resistance to afatinib.
