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E. Juhasz
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.03 - Smoking Predicts Sensitivity to PARP Inhibitor, Veliparib, in Advanced NSCLC Patients (ID 1279)
18:40 - 18:45 | Author(s): E. Juhasz
- Abstract
- Presentation
Background:
Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-induced DNA damage in preclinical studies, and a recent Phase 2 trial of advanced NSCLC trended to improved survival (HR 0.80; CI 0.54–1.18) when V was added to carboplatin (C) and paclitaxel (P). Here we report outcomes based on smoking status from this randomized Phase 2 study of CP with either V or placebo in advanced NSCLC.
Methods:
Patients with previously untreated advanced/metastatic NSCLC were randomized 2:1 to CP with either V at 120mg BID or placebo (randomization stratified by histology and smoking history). Cotinine was measured in patients’ plasma samples as an index of recent tobacco use.
Results:
Of 158 patients, 68% were male, and 49% had squamous NSCLC. At study entry, 60% pts were self-reported current smokers, 27% former smokers, and 13% never smoked. There were no significant differences in veliparib pharmacokinetic parameters between cotinine-high and low. Grade 3/4 AEs were elevated in current-smokers treated with VCP vs CP (66% vs. 40%, p=0.026); all-grade AEs and SAEs were similar between the two groups. The most common AEs in current-smokers were neutropenia (41% VCP; 27% CP), alopecia (36%; 33%), and anemia (31%; 40%). Figure 1 A sensitivity analysis of heavy vs light-smokers (≥ vs <39 pack-years, current or former smokers) showed advantage of veliparib in heavy-smokers: median PFS [HR(95% CI)] for VCP/CP was 7.0 vs 3.5 [0.43(0.20–0.94)] for heavy-smokers and 4.4 vs 4.2 [0.97(0.49–1.92)] for light-smokers; median OS was 12.6 vs 8.8 [0.52 (0.27–1.02)] for heavy-smokers and 9.9 vs 8.8 [0.92(0.53–1.61)] for light-smokers. A cotinine sensitivity analysis found that outcomes in cotinine-high were similar to current-smokers: PFS, cotinine-high HR was 0.38 (0.19–0.73) and cotinine-low was 0.97 (0.51–1.87); OS, cotinine-high HR was 0.52 (0.29–0.92) and cotinine-low was 1.07 (0.63–1.81). In univariate analyses assessing the influence of baseline characteristics and treatment on outcomes, smoking status and treatment had a significant interaction (p=0.0301 PFS, p=0.0118 OS). Additionally, multivariate analysis including all factors also identified current smoking as predictive of improved outcomes with VCP.
Conclusion:
Smoking status was a strong predictor of efficacy for veliparib-chemotherapy combination in advanced NSCLC. No differences in pharmacokinetics of V were seen based on plasma cotinine; toxicity of VCP was acceptable regardless of smoking history. A Phase 3 study has been initiated in patients with smoking history (M14-359).
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P2.07 - Poster Session/ Small Cell Lung Cancer (ID 222)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.07-010 - Alisertib (MLN8237)+Paclitaxel versus Placebo+Paclitaxel for Relapsed SCLC (ID 1158)
09:30 - 09:30 | Author(s): E. Juhasz
- Abstract
Background:
Small cell lung cancer (SCLC) is an aggressive malignant disease comprising approximately 14% of all lung cancers, with approximately 31,000 new diagnoses each year in the USA. SCLC has a very poor prognosis, particularly in patients presenting with extensive stage disease. Platinum-based combinations are standard first-line therapy for SCLC; however, relapse is almost universal (≥85%) and patients require further treatment in subsequent lines. Effective new targeted therapies are needed to improve the poor outcomes observed in SCLC. Alisertib is an investigational, orally available, selective inhibitor of Aurora A kinase. Alisertib has shown single-agent antitumor activity in preclinical in vivo models of SCLC and has demonstrated synergism with paclitaxel in this setting. Single-agent alisertib has demonstrated promising efficacy in patients with relapsed/refractory SCLC (Melichar B, et al. Lancet Oncol 2015;16[4]:395–405). Further, phase 1 and 2 evaluation of alisertib+paclitaxel in patients with relapsed ovarian cancer and breast cancer has suggested the antitumor activity of this combination (Falchook G, et al. Int J Gynecol Cancer 2013;23[8] Suppl_1:abstract; Coleman R, et al. Ann Oncol 2014;25[Suppl_4]:abstract 876O). Here we describe the design and objectives of an ongoing phase 2, randomized, double-blind, placebo-controlled study of alisertib+paclitaxel versus placebo+paclitaxel in patients with relapsed SCLC and previously treated with only one line of platinum-based therapy (NCT02038647).
Methods:
Approximately 166 adult patients with relapsed SCLC after standard first-line platinum-based therapy, measurable disease by RECIST v1.1, and Eastern Cooperative Oncology Group performance status 0 or 1 will be enrolled at approximately 80 sites in the USA and Europe. Patients will be randomized 1:1 (stratified by type of relapse [sensitive vs resistant/refractory] and presence of brain metastases) to receive 28-day cycles of either alisertib 40 mg or matched placebo PO twice daily on days 1−3, 8−10, and 15−17, plus paclitaxel 60 or 80 mg/m[2 ]IV, respectively, on days 1, 8, and 15, until disease progression or unacceptable toxicity. The primary endpoint of the trial is progression-free survival (PFS). Assuming a hazard ratio of 0.6 for PFS, a total of 138 progression/death events will be required to provide 85% power (two-sided alpha=0.05). Secondary endpoints include: overall and complete response rates; disease control rate; duration of response; overall survival; safety (NCI-CTCAE v4.03); alisertib pharmacokinetics; and symptom-related endpoints (symptom score, time to symptom relief, time to symptom progression). Evaluation of candidate biomarkers in tumor tissue specimens and in circulating tumor cells (CTC)/circulating tumor DNA, change from baseline in CTC numbers, and health-related quality of life (EORTC QLQ-C30/QLQ-LC13 instruments) are exploratory endpoints. As of 10 April 2015, there are 60 sites open in 6 countries with 90 patients randomized. The study continues to enroll patients.
Results:
not applicable
Conclusion:
not applicable
