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G. Ostoros
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-003 - Metastatic Site-Specific Variation of KRAS Status in Lung Adenocarcinoma (ID 2704)
09:30 - 09:30 | Author(s): G. Ostoros
- Abstract
Background:
While KRAS mutation is a negative predictive marker for EGFR tyrosine kinase inhibitor therapy, there is limited data available regarding the influence of KRAS mutation on the organ specificity of lung adenocarcinoma metastases.
Methods:
In our retrospective, single center study, 820 lung adenocarcinoma patients with KRAS mutation analyses were included. At the time of diagnosis, 462 patients had metastatic disease. These cases were analyzed for the potential association between KRAS status and metastatic site and clinical outcome. Patients with known EGFR mutations were excluded from the study.
Results:
534 (65.3%) KRAS wild-type and 284 (34.7%) KRAS-mutant cases were identified. There was no difference in the KRAS mutation prevalence between the metastatic (35.7%) and non-metastatic cases (33.4%). The most frequent metastatic sites included bone (29%), contralateral lung (24.8%), ipsilateral lung (19.7%), brain (17.3%), adrenal gland (15.6%), pleura (12.8%) and liver (11.7%). Patients with multiple metastases tended to have inferior median overall survival (OS) compared to those with single-organ metastasis (6.3 vs. 8.2 months, respectively; p=0.09) and, moreover, showed a slight but non-significant increase in the prevalence of KRAS mutations (38.5%, p=0.35). Importantly, patients with brain (35.8%), bone (33.1%) or adrenal gland (35.2%) metastases demonstrated similar KRAS mutation frequencies. However, both ipsilateral and contralateral intrapulmonary metastatic cases demonstrated increased KRAS mutation frequency when compared to those with extrapulmonary metastases (42.2% and 42.5%, p=0.014). In contrast, pleural dissemination and liver metastasis were associated with decreased KRAS mutation prevalence (25.4% and 24.1%, respectively; p=0.007). We found no difference in the median OS between KRAS-mutant and WT cases in any metastatic site-specific analysis.
Conclusion:
Lung adenocarcinoma patients with KRAS-mutant tumors more often present with intrapulmonary metastases. KRAS mutation prevalence, however, lacks to provide prognostic information. Further studies are required to determine if KRAS status can be used to risk stratify patients for the onset of pulmonary metastasis.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-096 - Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide (TH-302) in Combination with Pemetrexed in Advanced ns-NSCLC (ID 659)
09:30 - 09:30 | Author(s): G. Ostoros
- Abstract
Background:
Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea.
Methods:
An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m[2]) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m[2]) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing.
Results:
not applicable
Conclusion:
not applicable
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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: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.07-003 - Attempt to Validate Drug Repositioning for Metastatic Small Cell Lung Cancer (SCLC) Therapy Identifies Statins Associated with Survival Benefit (ID 2277)
09:30 - 09:30 | Author(s): G. Ostoros
- Abstract
Background:
SCLC is an aggressive malignancy with limited treatment options. Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. Drug dose levels that demonstrated anti-cancer activity were similar to those used in the clinics. The aim of our study is to confirm whether use of these medications is associated with survival benefit in a large cohort of SCLC patients from a single institution.
Methods:
Consecutive patients with cytologically or histologically confirmed, metastatic SCLC evaluated between 2000-2013 at the National Koranyi Institute of Pulmonology were analyzed in this retrospective analysis. Patients that were prescribed statins, aspirin, clomipramine (a tricyclic antidepressant [TCA]), selective serotonin re-uptake inhibitors (SSRIs), doxazosin, and prazosin were identified. Next, we evaluated the associations amongst these various medications, clinicopathological characteristics (including gender, age, and Eastern Cooperative Oncology Group performance status [ECOG PS]), and overall survival (OS) in univariate and multivariate analyses with Bonferroni correction applied.
Results:
There were a total of 876 patients (508 men and 368 women) with a median age of 61 years (range, 33-86). 75% of the chemotherapy administered in the first line setting was platinum-based. Aspirin, statin, SSRIs, doxazosin, prazosin, and TCA were administered in 138, 72, 20, 14, 14, and 5 cases; respectively. Univariate analysis identified age, ECOG PS, and statin treatment as significant prognostic factors (p<0.001; p<0.001; and p=0.002; respectively). A statistically significant increase in OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (median OS, 8.4 vs. 6.1 months; respectively). The administration of SSRIs, TCA, aspirin, prazosin, or doxazosin did not result in a statistically significant OS benefit (median OS, 8.5, 7.2, 6.8, 6.8, and 4.6 months; respectively). The multivariate Cox model showed that besides age and ECOG PS, statin treatment was an independent survival predictor (Hazard Ratio, 1.41; 95% confidence interval, 1.1–1.8; p=0.007).
Conclusion:
Statins appear to provide a statistically significant survival benefit in metastatic SCLC. Other classes of medications analyzed in this study did not validate the preclinical drug repositioning studies previously reported. Drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic.
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P2.07-010 - Alisertib (MLN8237)+Paclitaxel versus Placebo+Paclitaxel for Relapsed SCLC (ID 1158)
09:30 - 09:30 | Author(s): G. Ostoros
- 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
