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H.A. Wakelee



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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-006 - Erlotinib (E) and Dovitinib (TKI258) (D) in Patients (pts) with Metastatic Non-Small Cell Lung Cancer (NSCLC): A Significant Pharmacokinetic (PK) Interaction (ID 878)

      09:30 - 09:30  |  Author(s): H.A. Wakelee

      • Abstract

      Background
      Dovitinib (TKI 258) is an oral antiangiogenic agent that targets PDGFR, KIT, FLT3, VEGF, RET, and FGFR. Dovitinib induces CYP1A1/A2, CYP2C19, CYP2C9, and it inhibits CYP3A4. Dovitinib is metabolized mainly by FMO, CYP3A4, and CYP1A1/A2. Erlotinib is metabolized mostly by CYP3A4 (70%) but also by CYP3A5, CYP1A1, and CYP1A2.

      Methods
      This is a phase I 3+3 trial of E+D in patients with EGFR wild-type or mutated metastatic NSCLC who could have previously received E. Four cohorts were planned with E given daily and D given 5 days on/2 days off, starting after a 2-week lead-in of E alone. Only two cohorts enrolled due to dose limiting toxicity (DLT): cohort 1 [150 mg E +300 mg D] and cohort -1 [150 mg E+200 mg D]. Plasma concentrations of E and its metabolite OSI-420 were measured on day 14+/-4 (E alone; pre-dose, 2, 4, 6, 8, and 24 hours) and day 29 +/- 4 (D+E, at same time points). Pharmacokinetic (PK) samples were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. PK parameters for E and OSI-420 were estimated from the plasma concentration data via noncompartmental analysis. Paired-t tests on log transformed PK parameters were used to detect a statistical difference (α < 0.05, 2-sided) between E alone versus E+D treatment days.

      Results
      Nine patients enrolled (3 in cohort 1 and 6 in cohort (-1)). The study was suspended due to excess of DLTs. Best response was evaluable in seven patients. Two unevaluable patients on follow-up scan were on E monotherapy for ~1 month. Four patients discontinued due to grade 3 AEs (syncope (n=1), fatigue (n=1), and pulmonary embolism (n=2)). Three patients had progressive disease and 4 had stable disease (duration: 6 cycles(C), 8 C, and 1-2 C for two patients who stopped due to AE). Two patients required a dose delay in D (one for grade 2 LFT elevation, the other for grade 3 fatigue) and one required dose reduction of E to 100 mg prior to initiation of D (dose-corrected for PK analysis). Six patients had data available for PK analysis. During E alone, erlotinib exposure (average C~max~ 2308 +/- 697 ng/ml and AUC~ 0-24 ~41.0 +/- 15.6 μg*h/ml) was similar to previous reports for multiple daily doses of 150 mg. During D co-administration, the concentrations of E were reduced. C~max~ on average decreased by 83% (p= 0.022) and AUC~0-24 ~by 94% (p= 0.0039). OSI-420 exposure was also reduced during D co-administration.

      Conclusion
      Our small study demonstrates a potential significant PK interaction with decrease of E and its metabolite in the presence of D. This decrease is higher than that reported in combination studies with other CYP1A1 or CYP3A4 inducers. Dovitinib PK data is pending. Given the toxicity and the potential PK interaction, further investigation with this drug combination will be challenging.

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    P3.22 - Poster Session 3 - Epidemiology, Etiology (ID 168)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.22-008 - Are there disparities in lung cancer incidence trends among Hispanics and African Americans? An analysis of the Surveillance Epidemiology and End Results Database 1992-2010 (ID 3049)

      09:30 - 09:30  |  Author(s): H.A. Wakelee

      • Abstract

      Background
      Previous studies demonstrate disparities in the incidence of lung cancer. Specifically, in the United States, in comparison to non-Hispanic Whites, African Americans have a higher incidence rate of lung cancer while a lower incidence rate is seen among Hispanics. Recent studies demonstrate significant progress in smoking-cessation programs for non-Hispanic Whites; however, there are still a lower number of smoking cessation programs directed towards African Americans and trends of increased smoking behavior among Hispanics. No studies have evaluated recent histologic-specific incidence trends of lung cancer that may reflect these changing smoking behavioral patterns.

      Methods
      Using the Surveillance, Epidemiology and End Results data from years 1992-2010, lung cancer incidence rates and average annual percentage change (APC) were computed overall and by histology for African Americans, Hispanics, and non-Hispanic Whites.

      Results
      Incidence rates of lung cancer steadily decreased for non-Hispanic Whites, African-Americans, and Hispanics males (APC = -2.0, -2.6, and -1.9, respectively) from 1992 to 2010. This was true for all histological subtypes. Overall incidence rates of lung cancer among females have been relatively stable, with evidence of recent declines since 2005 among African Americans and non-Hispanic Whites. These trends were seen for all histological subtypes among females, except for the notable exceptions of increases in adenocarcinoma among African Americans (APC = 2.9 from 2003-2010) and Hispanics (APC = 1.2 from 1992-2010).

      Conclusion
      For men, overall and histologic-specific incidence rates of lung cancer have decreased among Non-Hispanics Whites, African Americans, and Hispanics. For women, in recent years, non-Hispanic Whites demonstrate a similar pattern of decline in lung cancer incidence rates. However, the overall incidence rate of lung cancer among African American and Hispanic women while decreasing or remaining slightly stable, an increased incidence of adenocarcinoma has been observed that warrants further exploration.