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D. Clemett



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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.02 - Efficacy of standard care for second-line advanced non-small cell lung cancer (NSCLC) by <em>KRAS</em> mutation status: observations on MEK inhibitor enhancement of chemotherapy (ID 3329)

      10:40 - 10:50  |  Author(s): D. Clemett

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS mutations that activate the MEK/ERK pathway are found in 20–30% of NSCLC. Response to second-line therapies for advanced NSCLC may be different in the presence or absence of a KRAS mutation. MEK inhibitors are being developed in combination with cytotoxic chemotherapy for NSCLC, based on preclinical findings that MEK inhibition increases pro-apoptotic BIM levels, enhancing cytotoxic therapy, and that MEK inhibition reduces KRAS mutation-induced oncogenic drive. We reviewed available information from KRAS mutation-positive (KRAS+) and KRAS wild-type subsets in AstraZeneca clinical studies in second-line NSCLC and published data on MEK inhibitors. Our objective was to determine whether differential therapeutic activity is present in KRAS+ and KRAS wild-type populations and whether preclinical findings translate into enhanced tumour response.

      Methods
      We reviewed data on objective clinical response in second-line NSCLC according to KRAS status in five randomised double-blind Phase II or III studies of gefitinib, vandetanib or selumetinib and three published studies of trametinib. Ninety-five percent confidence intervals (CI) around point estimates of objective response were calculated using exact (Clopper-Pearson) methods for a single proportion.

      Results
      The studies involved 4466 patients receiving second- or later line treatment for advanced NSCLC. In total, 1286 patients received singlet chemotherapy (docetaxel or pemetrexed), including 429 with known tumour KRAS mutation status: 138 had KRAS+ and 291 had KRAS wild-type NSCLC. Additionally, 132 patients with known KRAS status received singlet chemotherapy plus a MEK inhibitor (selumetinib or trametinib): 91 with KRAS+ and 41 with KRAS wild-type NSCLC. Figure 1

      Conclusion
      Our retrospective comparison suggests that second-line singlet chemotherapy response rates may be greater in KRAS wild-type than in KRAS+ NSCLC, and that MEK inhibition may enhance second-line chemotherapy activity in both KRAS+ and KRAS wild-type NSCLC. These observations support prospective validation of these results and further evaluation of MEK inhibitors plus chemotherapy in second-line KRAS unselected NSCLC.

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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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      P3.11-028 - Exploration of the relationship between neutrophil count and clinical consequences in patients with advanced non-small cell lung cancer (NSCLC) receiving selumetinib plus docetaxel: predicted effect of primary prophylactic GCSF (ID 2320)

      09:30 - 09:30  |  Author(s): D. Clemett

      • Abstract

      Background
      Selumetinib (AZD6244, ARRY-142886) is an orally available, potent and selective, non-ATP-competitive MEK1/2 inhibitor being investigated with docetaxel for treatment of KRAS mutation-positive advanced NSCLC. A randomised Phase II study of selumetinib 75 mg twice daily (bid) plus docetaxel 75 mg/m[2] q21d (SEL-DOC 75/75), with secondary granulocyte colony-stimulating factor (GCSF) prophylaxis if indicated, has shown promising efficacy in this setting but with more diarrhoea, neutropenic events, infections, hospitalisations and dose modifications than docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47; NCT00890825). Data from a small number of patients with advanced solid tumours in an open-label, Phase I study (NCT00600496) suggested that primary prophylactic (pp) GCSF reduces the incidence of neutropenic events associated with SEL-DOC 75/75 (Kim et al. Mol Cancer Ther 2011;10[Suppl 1:B225). We evaluated whether pp-GCSF could influence the incidence of hospitalisation or infection during treatment with SEL-DOC 75/75 using bias-reduced logistic regression modelling and medical review of data from NCT00890825.

      Methods
      Neutrophil counts and events of hospitalisation or infection from the safety analysis set of study NCT00890825 were used for modelling. This included 86 patients with KRAS mutation-positive advanced NSCLC randomised to receive second-line treatment with SEL-DOC 75/75 or placebo bid plus docetaxel. The relationship between maximum reduction in absolute neutrophil count (mr-ANC) and infection or hospitalisation events was explored using bias-reduced logistic regression (Firth. Biometrika 1993;80:27–38; Kosmidis. brglm, v0.5-6: www.ucl.ac.uk/~ucakiko/software.html). Starting models included terms for treatment group, mr-ANC, interaction between treatment group and mr-ANC, and baseline ANC. The final fitted models were used to predict the proportion of patients with events across the range of mr-ANC. Reported reasons for hospitalisation, dose modification and treatment discontinuation were medically reviewed in the context of expected pp-GCSF effect.

      Results
      The fitted logistic regression model showed some evidence of a relationship between hospitalisation events and mr-ANC for both treatment groups. A zero mr-ANC (assumed effect of pp-GCSF) predicted hospitalisation in 30% of patients (80% prediction interval 18–44%) in the SEL-DOC 75/75 group and 10% (5–18%) in the placebo plus docetaxel group. The observed incidence of hospitalisations in study NCT00890825 was 48% (80% confidence interval [CI] 37–58%) and 19% (11–29%) of patients, respectively. There was limited evidence of a relationship between events of infection and mr-ANC, suggesting other factors (eg immunosuppression and altered integrity of gastrointestinal wall) may influence the incidence of infection reported with this combination. Medical review indicated that use of pp-GCSF could reduce hospitalisation incidence during SEL-DOC 75/75 from observed 48% to a point estimate of 34% (80% CI 25–45%), and dose modification due to febrile neutropenia or infection from 23% to 5% (80% CI 1–12%). Permanent discontinuation of SEL-DOC 75/75 for reasons other than disease progression did not appear to be affected by pp-GCSF use.

      Conclusion
      Prevention of ANC reduction is predicted to lower the incidence of hospitalisation events in patients receiving treatment with selumetinib plus docetaxel for NSCLC. These findings support pp-GCSF use to reduce the incidence of hospitalisations previously reported with the SEL-DOC 75/75 regimen.