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P.A. Jänne



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.01 - Clinical benefit of continuing crizotinib beyond initial disease progression in patients with advanced <em>ALK</em>-positive non-small-cell lung cancer (ID 2843)

      16:15 - 17:45  |  Author(s): P.A. Jänne

      • Abstract
      • Presentation
      • Slides

      Background
      Crizotinib is approved multinationally to treat advanced ALK-positive non-small-cell lung cancer (NSCLC). Most patients with crizotinib-treated ALK-positive NSCLC ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition beyond PD is clinically beneficial and the clinicopathologic characteristics associated with patients who experience clinical benefit.

      Methods
      Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials (the molecularly enriched expansion cohort of the phase I trial PROFILE 1001 and the phase II trial PROFILE 1005) who developed RECIST-defined PD were allowed to continue crizotinib if, in the investigator's opinion, they were deriving ongoing clinical benefit. In the present retrospective analyses, continuation of crizotinib beyond PD (CBPD) was defined as >3 weeks of crizotinib treatment after PD documentation. Baseline and post-progression characteristics, sites of PD, progression-free survival (PFS), and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed.

      Results
      Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A higher proportion of patients who continued CBPD responded to initial crizotinib treatment (74% vs. 55%), had an ECOG performance status of 0/1 at PD (96% vs. 82%), and had brain (56% vs. 28%) and/or bone (20% vs. 9%) as sites of PD compared with patients who did not continue CBPD. CBPD patients also had numerically longer median PFS from initial crizotinib treatment (7.3 months vs. 5.7 months) and significantly longer OS from the time of PD (median 16.4 months vs. 3.9 months; HR, 0.27; 95% CI: 0.17−0.42; P<0.0001; Figure 1). Multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS post-PD after adjusting for relevant factors. Figure 1. OS of patients who continued CBPD versus those who did not, from the time of PD. Shaded areas are 95% Hall-Wellner confidence bands. Figure 1

      Conclusion
      Continuing ALK inhibition after PD may provide survival benefit to a majority of patients with advanced ALK-positive NSCLC. Prolonged PFS on initial crizotinib, good performance status at PD, and progression in brain and/or bone are characteristics that were commonly found in patients who benefited from continued ALK inhibition.

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.06 - A prospective internet-based study of patients with lung cancer harboring baseline EGFR T790M to identify germline carriers and characterize familial risk (ID 1667)

      16:15 - 17:45  |  Author(s): P.A. Jänne

      • Abstract
      • Presentation
      • Slides

      Background
      The EGFR T790M mutation, commonly seen with acquired resistance to EGFR kinase inhibitors, has also been described rarely as a germline mutation in association with familial lung cancer. In a prior study (Oxnard et al, JTO, 2012), the presence of EGFR T790M at diagnosis was associated with a 50% chance of carrying an underlying germline T790M mutation. This suggests that by studying patients whose cancer was shown to carry T790M at diagnosis, it is possible to efficiently screen for a germline allele that otherwise is rare among patients with non-small cell lung cancer. We therefore initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize phenotype and cancer risk.

      Methods
      Subjects are eligible if they (1) have a cancer harboring EGFR T790M (excluding acquired T790M), (2) are a relative of a known germline carrier, or (3) are already known to carry a germline EGFR mutation on prior testing. Subjects may present at a participating cancer center or may enroll remotely using a study website (www.dana-farber.org/T790Mstudy/). Eligible subjects receive genetic counseling in person or over the phone, and then submit a saliva and/or blood specimen for central testing in a CLIA lab. Results are disclosed to the subject if they wish but do not enter the medical record. Those subjects carrying germline EGFR mutations are given the option of inviting relatives to participate. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule prevalence and characteristics. Available tumor specimens are collected for central pathology review and advanced genomic analysis.

      Results
      The trial was registered to clinicaltrials.gov (NCT01754025) and began accrual in December 2012. To date, 7 subjects have been enrolled and 5 are actively being screened, including 4 kindreds. More than half of the subjects have participated remotely via the study website. Of 4 probands with lung cancer and germline T790M, 3 have a family history of lung cancer, 2 of whom have children with CT scans showing multiple sub-centimeter ground-glass nodules. The fourth proband has no family history of lung cancer, suggesting variable penetrance or a de novo germline event. All cancers in germline T790M carriers have also harbored secondary EGFR kinase domain mutations.

      Conclusion
      Using a novel trial design, including remote accrual, genetic counseling by phone, and germline testing by mail, we have begun collecting a sizeable cohort of families affected by germline EGFR mutations. By leveraging referrals from commercial laboratories and contributing academic centers, we aim to study 100 patients over a three year period in order to better understand the natural history and risk associated with this unique familial cancer syndrome. Supported by grants from the Conquer Cancer Foundation of ASCO, the Bonnie J. Addario Lung Cancer Foundation, and the National Cancer Institute.

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.12 - Impact of <em>KRAS</em> codon sub-types in a Phase II second-line trial in <em>KRAS</em>-mutant advanced non-small cell lung cancer (NSCLC) of selumetinib plus docetaxel versus docetaxel alone (ID 3331)

      16:15 - 17:45  |  Author(s): P.A. Jänne

      • Abstract
      • Presentation
      • Slides

      Background
      Phase II data from patients with KRAS mutation-positive NSCLC, selumetinib (AZD6244, ARRY-142886) plus docetaxel showed promising efficacy versus placebo plus docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47). Median OS was 9.4 months (95% CI 6.8–13.6) in the selumetinib group and 5.2 months (95% CI 3.8–non-calculable) in the placebo group (HR for death 0∙80, 80% CI 0.56–1.14; one-sided p=0.21). Median PFS was 5.3 months (95% CI 4.6–6.4) and 2.1 months (95% CI 1.4–3.7), respectively (HR for progression 0∙58, 80% CI 0.42–0.79; one-sided p=0.014). 37% of patients in the selumetinib group and 0% in the placebo group had an objective response (two-sided p<0.0001). The KRAS mutation codon subtype might impact on prognosis and/or response to therapy. The BATTLE trial suggested that G12V or C KRAS mutations confer relatively poorer outcome within the KRAS mutant NSCLC sub-type (Ihle et al. J Natl Cancer Inst 2012;104:228–39). In cell lines carrying these codons, Akt phosphorylation but not ERK phosphorylation was low compared with other codons, suggesting these codons might confer greater dependence upon MEK/ERK signaling. We sought to understand if any codons or combinations of codons selected for striking treatment effects either between or within treatment groups in the Phase II study.

      Methods
      Post-hoc analysis explored the hypotheses that patients whose tumours carried G12C or G12V KRAS mutations would have a worse prognosis and that these patients would have a better outcome with the addition of selumetinib. Clinical benefit was measured by PFS, OS and ORR.

      Results
      G12V or G12C mutations were present in 57% of patients and whilst not reaching statistical significance, trends for PFS, OS and ORR support the hypothesis (see table, PFS). Patients with G12V mutations responded better to selumetinib plus docetaxel than other patients as measured by change in tumour size at week 6 (G12V=-62%, G12C=-8%, G12D=+3%, reduction across all codons=-18%; two sided p=0.007). It is therefore possible that trends supporting the primary hypothesis were driven by effects in the small number of G12V codons (n=9). Table. Summary of analysis of progression-free survival (PFS): MITT by mutation subgroup

      Subgroup Selumetinib + docetaxel, n (number of PFS events) Docetaxel, n (number of PFS events) Selumetinib + docetaxel vs docetaxel, PFS HR (80% CI)
      G12C or G12V 24 (18) 23 (21) 0.48 (0.31–0.74)
      Other 19 (17) 17 (15) 0.72 (0.44–1.16)
      Overall 43 (35) 40 (36) 0.58 (0.42–0.79)

      Conclusion
      Any impacts of codon sub-type on the treatment effect in this trial were not sufficiently significant to be detected in this small Phase II trial of 87 patients, but the trends observed in this retrospective subgroup analysis warrant monitoring of the impact of specific codons or groups of codons in future clinical trials.

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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.12 - AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC (ID 2289)

      10:30 - 12:00  |  Author(s): P.A. Jänne

      • Abstract
      • Presentation
      • Slides

      Background
      The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced EGFR mutant NSCLC but many patients ultimately develop disease progression due to acquired resistance. The EGFR T790M mutation is the most common mechanism of acquired drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for NSCLC patients with EGFR T790M.

      Methods
      AZD9291 is an oral, irreversible, third generation inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M). The mechanistic and functional activity of AZD9291 was characterised in vitro across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Efficacy of AZD9291 was further evaluated across a number of different EGFR-mutant xenograft and transgenic models in vivo. One open label, dose escalation phase I study of AZD9291 (NCT01802632) is ongoing to determine the safety and tolerability [primary measure], pharmacokinetics and preliminary efficacy profiles of AZD9291, in patients with advanced NSCLC who have progressed following EGFR TKI. Sequential cohorts of 3-6 patients with advanced NSCLC who have had at least one prior regimen containing an EGFR TKI agent (with confirmed EGFRm+ status or Jackman criteria), were treated with AZD9291 once daily. Other key inclusion criteria were PS 0-1, measurable disease, and no prior history of ILD. RECIST assessments were scheduled 6 weekly. Dose escalation can occur after ≥ 3 patients complete both single dose and the first 21-day cycle of AZD9291 multiple dosing with no DLT.

      Results
      AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (PC9; 14nM) and EGFRm+/T790M (H1975; 13nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (LoVo; 400nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 treatment caused profound growth regression across multiple EGFRm+ (PC9; 250% growth inhibition) and EGFRm+/T790M (H1975; 132% growth inhibition) tumour models in vivo, at doses as low as 5mg/kg after 14 days. Tumour growth inhibition was associated with profound inhibition of EGFR activity and key downstream signaling pathways. Chronic long-term treatment of in vivo PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response. In the phase I study, clinical activity with RECIST responses have already been observed at the starting dose level of 20mg once daily, with good tolerability, no reported events of EGFR wild-type rash, and only grade 1 diarrhoea (based on preliminary data, unvalidated and subject to change).

      Conclusion
      Preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M) whilst sparing wild-type EGFR and, early clinical data have been promising. Taken together, these data support the further clinical investigation of AZD9291 in advanced EGFR mutant NSCLC.

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    MS27 - Mechanisms of Acquired Resistance to Targeted Therapy (ID 44)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Medical Oncology
    • Presentations: 1
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      MS27.3 - Clinical Definition of TKI Resistance and How to Overcome It (ID 591)

      10:30 - 12:00  |  Author(s): P.A. Jänne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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)

      10:30 - 12:00  |  Author(s): P.A. Jänne

      • 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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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P3.06-003 - Correlative Analysis of Circulating Biomarkers from a Phase 1b/2 trial of Cabozantinib (C) with or without Erlotinib (E) in Patients (Pts) with Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (ID 266)

      09:30 - 16:30  |  Author(s): P.A. Jänne

      • Abstract

      Background
      Cabozantinib (C) is a potent ATP-competitive inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2) along with KIT, RET, AXL, TIE2, and FLT3. Hepatocyte growth factor (HGF), the ligand of MET, and VEGF act synergistically to promote angiogenesis. There are currently no widely accepted prognostic or predictive biomarkers for anti-angiogenic agents.

      Methods
      This is a retrospective correlative biomarker study from the phase 1b/2 trial of C+/-E in stage IIIB-IV NSCLC. All pts had to fail prior therapy with E. Both drugs are oral and dosed daily. C dosing is in the free-base equivalent weight. In phase I, there was a 2 week lead in with E and the cohorts included: 1A (60 mg C+150 mg E), 2A (60 mg C+100 mg E), 3A (100 mg C+100 mg E), 4A (100 mg C+50 mg E), and 2B (40 mg C+150 mg E). In phase II, both drugs started simultaneously: Arm A (100 mg C) and Arm B (100 mg C+50 mg E). Pts were included in the study if a pre-E+C and post-C > day 29 plasma sample was available. The Milliplex 13-plex and Luminex 51-plex assays were used. For this preliminary analysis, select markers previously implicated in angiogenesis (bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12, IL-17, PDGF-BB, ICAM-1, VCAM-1) and those of interest (ligands of KIT and MET- SCF and HGF, respectively) were analyzed. Log transformed mean fluorescence intensity (MFI) values and Wilcoxon Rank paired sum tests were used to detect changes from day 1-29. A change from baseline was noted to be significant if at least 15% (median) with α<0.05 (2-sided) and a trend if 10-15% (median) with α<0.08 (2-sided).

      Results
      73 pts included: 52 phase I and 21 phase II; median age 60 years; 23M/50F; 56.2% nonsmoker; 91.8% adenocarcinomas. The pts with samples from both time points were divided into two groups due to limited sample size and included: Group R (complete/partial response and stable disease> 6 months; n=22) and Group NR (stable disease< 6 months and progressive disease; n=51). The only marker that changed in a single direction in all subjects within a group was sVEGFR2 in group R. Overall, significant decreases were noted in sVEGFR1-3, IL-6, PDGF-BB, and trended in IL12p70 and IL-17. By subgroups: Group R had significant decreases in bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12(p40+p70), IL-17, PDGF-BB, SCF, and trended in HGF (median 10.1% ↓, p=0.0275); and Group NR had significant decreases in sVEGFR2-3, IL-6, PDGF-BB, and trended in sVEGFR-1, IL-6, and IL-17.

      Conclusion
      Both groups R+NR had a decrease in sVEGFR-2, suggesting that this is a marker of treatment with C rather than a marker of response. However, overall group R had larger dynamic decreases of immune markers than group NR. HGF, which is targeted downstream by C and plays a role in angiogenesis and E resistance, had a trend to decrease in group R but not group NR. This study is retrospective with a small sample size, imbalanced numbers per response subgroup, and is exploratory in nature.

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      P3.06-054 - Development of a clinical-grade quantitative assay for non-invasive measurement of tumor genotype in cell-free plasma DNA (cfDNA) using next-generation quantitative genotyping (ID 741)

      09:30 - 16:30  |  Author(s): P.A. Jänne

      • Abstract

      Background
      Non-invasive genotyping of cfDNA has been shown to be feasible using highly sensitive assays. However, for detection of uncommon genomic events, specificity must approach 100% or false positive results impair clinical utility. Digital droplet PCR (ddPCR) is a quantitative genotyping technology that emulsifies input DNA into ~20,000 droplets which are PCR amplified, fluorescently labeled, and read as mutant or wildtype in a droplet flow cytometer. Using this quantitative technology, we aimed to develop a clinical-grade assay for non-invasive plasma genotyping and serial disease monitoring.

      Methods
      Patients with advanced NSCLC known to harbor EGFR or KRAS mutations were studied in an IRB-approved fashion. Plasma was collected in 10cc EDTA-tubes. Extracted DNA was quantified with a PCR for LINE1 and genotyped using ddPCR. Specificity of EGFR genotyping was determined using patients with KRAS-mutant lung cancer as gold standard negative cases. Serial assessment was piloted on EGFR-mutant cases receiving first-line erlotinib.

      Results
      To minimize risk of false positive results, we identified the “normal range” for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancers as 0-1 and 0-8 copies/mL of plasma, respectively. Using this threshold for positive, ddPCR for EGFR sensitizing mutations had 67% sensitivity and 100% positive predictive value (Figure 1). Sensitivity was 100% with LINE-1 levels between 60-60000 pg/mcL but was poor with higher or lower cfDNA concentrations. Serial assessment on erlotinib (Figure 2) demonstrated pretreatment detection of EGFR mutations with ddPCR, complete plasma response on erlotinib, and subsequent reemergence of plasma EGFR up to 16 weeks prior to objective progression. Figure 1 Figure 2

      Conclusion
      Plasma genotyping of cfDNA using ddPCR has 100% specificity when using a rigorously defined threshold for a positive result. Sensitivity is highest in specimens with optimal cfDNA concentration. Clinical development is underway to use this non-invasive assay to guide genotype-directed 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: 2
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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 - 16:30  |  Author(s): P.A. Jänne

      • 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.

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      P3.11-029 - The SELECT-1 study design: selumetinib in combination with docetaxel for second-line treatment of <em>KRAS</em> mutation-positive locally advanced or metastatic non-small cell lung cancer (ID 2231)

      09:30 - 16:30  |  Author(s): P.A. Jänne

      • Abstract

      Background
      KRAS mutations are the most common mutation type in patients with non-small cell lung cancer (NSCLC) with adenocarcinoma histology (Califano et al. Drugs 2012;72[Suppl 1:]28–36). The presence of the KRAS mutation has been associated with a poor prognosis (Mascaux et al. Br J Cancer 2005;92:131–139) and a therapy targeting Ras has yet to be proven in clinical trials. Selumetinib (AZD6244, ARRY-142886) is an orally available, potent and selective, non-ATP-competitive MEK1/2 inhibitor. MEK1/2 are proteins downstream of Ras in the Ras/Raf/MEK/ERK pathway. It is anticipated that inhibition of MEK activity should inhibit transduction of the mitogenic and survival signals via this pathway, resulting in an inhibition of tumour proliferation, differentiation and survival. A randomised Phase II study evaluating docetaxel plus selumetinib or placebo in pretreated patients with KRAS mutation-positive advanced NSCLC has previously demonstrated a significant improvement in terms of response rate, progression-free survival (PFS) and patient-reported outcomes (PROs) in favour of the combination arm (Jänne et al. Lancet Oncol 2013;14:38–47).

      Methods
      The SELECT-1 study is a randomised, double-blind, placebo-controlled Phase III study that will assess the efficacy and safety of selumetinib in combination with docetaxel in patients receiving second-line treatment for KRAS mutation-positive locally advanced or metastatic NSCLC (Stage IIIB–IV). Eligible patients will have centrally confirmed KRAS mutation-positive locally advanced or metastatic NSCLC, be suitable for second-line treatment and have had no prior treatment with docetaxel or a MEK inhibitor. Patients must have measurable disease, histologically or cytologically confirmed locally advanced or metastatic NSCLC and a WHO performance status (PS) of 0–1. Patients will be randomised in a ratio of 1:1 to receive selumetinib (75 mg, orally twice daily [BID]) or matching placebo BID in combination with docetaxel (intravenously 75 mg/m[2], on Day 1 of every 21-day cycle) until objective disease progression, intolerable toxicity or occurrence of another discontinuation criterion. Approximately 4000 patients will need to be screened from 220 centres globally to identify 634 KRAS mutation-positive patients for the study. Patients will be stratified at randomisation based on their WHO PS (1/0) and tumour histology (squamous/non-squamous). Following randomisation, patients will attend for visits on Day 8, 15, 22, 43 and every 3 weeks thereafter for as long as they are receiving study treatment. Tumour evaluation according to Response Evaluation Criteria in Solid Tumors version 1.1 guidelines will be performed at screening, Week 6, Week 12 and every 6 weeks thereafter, relative to the date of randomisation. The primary study endpoint is PFS; secondary endpoints include overall survival and objective response rate. Efficacy data will be analysed on an intent-to-treat basis using randomised treatment. Blood samples will be taken to assess the pharmacokinetics of selumetinib. The study will also evaluate PROs and safety for the selumetinib/docetaxel combination compared with placebo/docetaxel. In addition, outcome based on KRAS mutation type will be assessed.

      Results
      Not applicable.

      Conclusion
      This Phase III study will confirm the efficacy of selumetinib in combination with docetaxel in patients with NSCLCs that harbour mutations of KRAS and who are eligible for second-line treatment.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-004 - A practice-based analysis to gauge the feasibility of genotype-directed induction therapy for stage III non-small cell lung cancer (NSCLC) (ID 1343)

      09:30 - 16:30  |  Author(s): P.A. Jänne

      • Abstract

      Background
      Genotype-directed therapies are transforming the care of patients with advanced NSCLC, but these have not yet been incorporated into curative therapy for early stage disease. Because trials are in development which will study genotype-directed induction therapy for stage III NSCLC, we retrospectively examined practice patterns to identify strategies for maximizing the feasibility of this approach.

      Methods
      Patients with stage IIIA NSCLC who were treated at our institution with upfront concurrent chemoradiotherapy between 1/2004 and 5/2012 were identified from an institutional database. Management prior to start of definitive therapy was reviewed. For this analysis, biopsies were considered adequate for genotyping while cytology specimens were considered inadequate. To gauge the feasibility of genotyping, we compared the intervals between biopsy and treatment and between first oncologist appointment and treatment with a range of hypothetical turnaround times for genotyping (i.e. time between when test is ordered and when results are available).

      Results
      150 patients were identified in an initial query. 57 were excluded from the analysis: 46 due to treatment at an outside hospital, 5 due to upfront surgery, and 6 due to sequential chemotherapy and radiation. 89 patients were included in the study population with the following characteristics: median age at diagnosis 61 (range 33-86), 45% adenocarcinoma, 25% squamous, 2% neuroendocrine, and 28% NSCLC NOS. Clinical stage: 17% T1N2M0, 42% T2N2M0, 3% T3N1M0, 24% T3N2M0, 9% T4N0M0, 6% T4N1M0. Staging evaluation: 86% underwent bronchoscopy, 86% underwent mediastinoscopy; 100% underwent PET-CT, 100% underwent brain imaging. Best biopsy for genotyping: 51% surgical biopsy, 20% endobronchial biopsy, 7% CT-guided core biopsy, 22% cytology. The median time between best biopsy and treatment initiation was 34 days (IQR: 23-45). The median time between first oncologist appointment and treatment initiation was 18.5 days (IQR: 14-25). Simulating reflex genotyping versus oncologist-ordered genotyping for a range of hypothetical turnaround times (Figure), reflex genotyping may increase the number of patients genotyped in time for start of therapy when turnaround time exceeds 8 days. Figure 1

      Conclusion
      In this practice-based analysis of patients with stage IIIA NSCLC receiving definitive chemoradiotherapy, 78% of patients had a biopsy expected to be adequate for genotyping. To maximize the feasibility of genotype-directed induction therapy for NSCLC, reflex genotyping of staging biopsies may be needed, particularly when genotyping turnaround time exceeds 8 days.