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Q. Chu



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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-037 - Phase II activity of the HSP90 inhibitor AUY922 in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) (ID 2730)

      09:30 - 09:30  |  Author(s): Q. Chu

      • Abstract

      Background
      AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a molecular chaperone of oncogenic client proteins relevant in NSCLC pathogenesis, including epidermal growth factor receptor (EGFR), which is mutated in 10% of NSCLC cases in the Western population, and in 30% of NSCLC cases in the Asian population. We report here a subgroup analysis of data from the 2 EGFR mutation strata of a Phase II study of AUY922 in patients with previously treated, advanced NSCLC stratified by molecular status.

      Methods
      Patients with advanced NSCLC who progressed following ≥1 prior line of therapy, received AUY922 (70 mg/m[2]) as a once-weekly, 1-hour infusion. Patients with EGFR-mutant NSCLC were divided into 2 strata: pretreated EGFR-mutant (>2 prior regimens), or less-heavily treated EGFR-mutant (≤2 prior regimens and documented response to an EGFR tyrosine kinase inhibitor [TKI]). The primary endpoint was confirmed response, stable disease at 18 weeks, or no clinical benefit. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety/tolerability.

      Results
      At the cut-off date of 14 March 2013, 66 patients with EGFR-mutant NSCLC had been treated (median age 58 years; 67% female; 94% adenocarcinoma; EGFR-initial stratum n=35; less-heavily pretreated EGFR-mutant stratum n=31); all patients had been pretreated with an EGFR TKI. Clinical activity of AUY922 was seen, with any responses (investigator assessed), in 12/66 (18.2%) patients. A total of 34/66 (51.5%) patients had a best overall response of stable disease or non-confirmed partial response; of these patients, 11 (32%) had stable disease for ≥18 weeks. The 18-week PFS rate was 39% in all patients with ≤2 prior lines of therapy (n=43), and 28% in all patients (n=21) who had received >2 lines of therapy. The most frequent adverse events (AEs; any grade, regardless of study drug relationship) were diarrhea (73%), nausea (47%), decreased appetite (38%), fatigue (35%), and headache and night blindness (both 29%). Most AEs were Grade 1 or 2; Grade 3 or 4 AEs included diarrhea (9%), and fatigue, decreased appetite, and hyponatremia (all 6%).

      Conclusion
      AUY922 had an acceptable safety profile. Strong evidence of clinical activity was demonstrated in EGFR TKI-pretreated patients with EGFR-mutant NSCLC. Median PFS, OS and biomarker data for the EGFR-mutant stratum will be presented.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-042 - Acid suppression therapy impairs Erlotinib efficacy in Non-Small Cell Lung Cancer (ID 2930)

      09:30 - 09:30  |  Author(s): Q. Chu

      • Abstract

      Background
      Erlotinib is a key treatment option in all advanced or metastatic non-small cell lung cancer (mNSCLC) subtypes regardless of epidermal growth factor receptor (EGFR) status. Despite side effect advantages over cytotoxic chemotherapy, a shortcoming of erlotinib is pH-dependent absorption. Recent evidence highlights this inconsistency further by showing reduced plasma levels of various oral tyrosine kinase inhibitors (TKIs) in the presence of acid suppression therapy. Given the prevalence of gastroesophageal reflux disease (GERD) and diseases that use acid suppression, goals of this study are to determine if coadministration of acid suppressants and erlotinib affected clinical outcomes in advanced NSCLC patients.

      Methods
      A cohort of patients with mNSCLC from 2007-2012 who received erlotinib through our institution was retrospectively reviewed. In addition to stage, age, gender, performance status, and NSCLC subtype, patients were then identified as receiving acid suppression (AS) if their pharmacy records included either proton pump inhibitors (PPIs) or histamine blockers (anti-H2). Patients were considered taking these medications concomitantly if dates for acid suppressants overlapped their erlotinib prescription by ≥ 20% of the treatment duration. Patients who received erlotinib for ≥ 1 week were analyzed for progression free survival (PFS) and overall survival (OS).

      Results
      544 stage IIIB/IV NSCLC patients were identified. Of those, 507 were eligible for review. Median age was 64 years, gender 235 male, and 272 female. By subtype, 318 were adenocarcinoma, 106 squamous, 43 poorly differentiated, 11 large cell, and 29 not otherwise specified (NOS). 124 patients received concomitant AS therapy with the most common type being PPIs. Analysis unselected for EGFR mutational status yielded median PFS and OS in the AS versus no-AS group as 1.4 v 2.3 months (p<0.001) and 12.9 v 16.8 months (p=0.003), respectively. In multivariate analysis with gender, NSCLC subtype, and performance status, Cox proportional hazards ratios for PFS and OS for AS and non-AS groups were 1.83 (95% CI 1.48-2.25) and 1.37 (95% CI 1.11-1.69) respectively. Subgroup analysis by subtype in the AS and non-AS groups was significant in the following types (p<0.05): adenocarcinoma, PFS 1.8 v 2.7 months, OS 13.2 v 17.5 months; squamous PFS 1.5 v 2.3 months, OS 13.4 v 15.9 months; poorly differentiated PFS 0.8 v 2.0 months, OS 7.6 v 15.5 months, and NOS PFS 1.2 v 1.7 months, OS 10.8 v 14.5 months. Effects of AS in EGFR mutated patients are being studied.

      Conclusion
      Despite limitations of retrospective analyses, this large population based study demonstrates erlotinib efficacy is dependent on gastric acidity and OS can be adversely affected. This is the first study the authors are aware of that demonstrates an impact on clinical outcomes by co-administration of acid suppression and TKI therapy. Caution should be taken with co-administration of other TKIs and acid suppressive therapy.

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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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      P3.11-027 - A randomised, open-label phase II trial of volasertib as monotherapy and in combination with standard dose pemetrexed compared with pemetrexed monotherapy in second-line non-small cell lung cancer (NSCLC) (ID 2307)

      09:30 - 09:30  |  Author(s): Q. Chu

      • Abstract

      Background
      Polo-like kinases (Plks) are overexpressed in many cancers including NSCLC. Volasertib (BI 6727; an investigational drug) is a selective and potent Plk inhibitor, which induces mitotic arrest and apoptosis. This 3-arm trial compared the efficacy, safety and pharmacokinetics of volasertib monotherapy, volasertib combined with pemetrexed and single-agent pemetrexed as second-line therapy in patients with advanced/metastatic NSCLC (NCT00824408).

      Methods
      An initial run-in phase was conducted to determine the tolerability and dose of volasertib combined with pemetrexed 500mg/m[2]. Subsequent patients were randomised to one of three arms: (A) volasertib 300mg, (B) volasertib 300mg plus pemetrexed 500mg/m[2], or (C) pemetrexed 500mg/m[2]. Both drugs were administered on Day 1 every 21 days. Eligible patients had advanced/metastatic NSCLC, ECOG PS 0–2, adequate organ function and prior platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS) evaluated using a stratified one-sided log-rank test (Arms B versus C); an exploratory analysis was performed for Arms A versus C. Secondary endpoints included objective response rate (ORR), overall survival (OS), safety and pharmacokinetics.

      Results
      Twelve patients were included in the run-in phase; the volasertib dose selected for the randomised phase was 300mg. 131 patients were then randomised to the three arms (A: n=37, B: n=47, C: n=47). Arm A recruitment was stopped early due to an increased rate of early progression. Demographic data were balanced between the arms. One patient per arm did not receive treatment. The median number (range) of treatment cycles in Arms A, B and C was 2 (1–49), 4 (1–36) and 5.5 (1–38), respectively. Median PFS (Arms A/B/C) was 1.4/3.3/5.3 months (HR B versus C =1.141 [95% CI: 0.735–1.771; p=0.2804]; HR A versus C =2.045 [95% CI: 1.271–3.292; two-sided p=0.0030]). ORR (Arms A/B/C) was 8%/21%/9%; no complete responses were observed. Disease control rates (Arms A/B/C) were 27%/66%/68%. Median OS (Arms A/B/C) was 22.9/17.1/17.4 months. Median relative dose intensity was 100% for both volasertib and pemetrexed in all arms with a range of 80.6–111.1% in Arm A and 83.3–100.0% in Arm B for volasertib, and 87.5–100% in Arm B and 81.3–100% in Arm C for pemetrexed. The most common all-grade adverse events (AEs) were (Arms A/B/C): fatigue (56%/74%/70%), nausea (14%/48%/54%), decreased appetite (8%/44%/41%), constipation (17%/37%/22%), dyspnoea (17%/28%/30%) and vomiting (19%/33%/24%). Most common grade 3/4 AEs (>5%) were (Arms A/B/C): fatigue (8%/13%/17%), neutropenia (14%/11%/4%) and dyspnoea (3%/9% /13%). Grade 3/4 febrile neutropenia was seen in 2 (4%) patients in Arm B and 1 (2%) patient in Arm C. One fatal AE of septic shock (Arm B) was considered drug-related; 22%/22%/26% of patients experienced a serious AE. Pharmacokinetic analysis of volasertib in Arms A and B, together with historical pharmacokinetic data for pemetrexed, did not reveal any evidence of pharmacokinetic interactions between volasertib and pemetrexed.

      Conclusion
      Volasertib and pemetrexed could be combined at full single-agent doses, with generally acceptable toxicities, and demonstrated modest antitumour activity. However, the addition of volasertib did not improve PFS compared to single-agent pemetrexed in patients with relapsed or refractory NSCLC after platinum-based first-line therapy.