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D. Planchard



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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): D. Planchard

      • 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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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.05 - Epidemiology of PI3K pathway alterations in patients with metastatic non-small cell lung cancer (NSCLC): findings from the international BASALT-1 study (ID 1810)

      10:30 - 12:00  |  Author(s): D. Planchard

      • Abstract
      • Presentation
      • Slides

      Background
      Buparlisib (BKM120) is an oral PI3K inhibitor that inhibits all four isoforms of class I PI3K (α, β, γ, δ) and has demonstrated antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. NSCLC cell lines with PIK3CA mutations (muts) have demonstrated increased sensitivity to buparlisib in vitro. BASALT-1 – an ongoing, multicenter, open-label, two-stage Phase ll study (NCT01297491) – evaluates the safety and efficacy of single-agent buparlisib in patients (pts) with NSCLC and an activated PI3K pathway. Here we report data on the prevalence of PI3K pathway alterations in pts with squamous (sq) or non-squamous (non-sq) NSCLC prescreened for entry into BASALT-1.

      Methods
      Pts prescreened for BASALT-1 were ≥18 years of age with previously treated metastatic NSCLC of sq or non-sq histology. PI3K pathway activation (defined as PIK3CA mut and/or PTEN mut and/or PTEN negative [neg; <10% protein expression at 1+ by immunohistochemistry]) was measured in archival or newly acquired tumor tissue collected at prescreening. PIK3CA (exons 1, 5, 7, 9, and 20) and PTEN (exons 1–9) muts were detected primarily using Sanger sequencing in a centralized fashion. Local analysis was permitted at selected sites where a SnapShot approach was most commonly used.

      Results
      As of April 10, 2013, 1183 pts had submitted tumor samples to be assayed (1179 tumors had known histology). PI3K pathway activation was detected in 16.0% of sq and 11.3% of non-sq tumors. In sq tumors (N=612), loss of PTEN protein expression (8.2%) was the most common single alteration observed, followed by PIK3CA mut only (3.1%) and PTEN mut only (2.9%). In non-sq tumors (N=567), PTEN mut only was the most common alteration (4.9%), followed by PIK3CA mut only (2.6%) and PTEN neg only (2.1%). Frequencies of co-existing genetic alterations were: PTEN mut + PTEN neg only (1.0% sq vs 0.4% non-sq), PIK3CA mut + PTEN neg only (0.7% sq vs 0.4% non-sq), PIK3CA mut + PTEN mut only (0% sq vs 0.9% non-sq), and PIK3CA mut + PTEN mut + PTEN neg (0.2% sq vs 0% non-sq). No clear gender, age or ethnicity effects were observed (Table). Figure 1

      Conclusion
      The findings from our large dataset indicate that genetic alterations in the PI3K pathway occur in a clinically significant proportion of pts with sq and non-sq relapsed NSCLC. An accurate characterization of PI3K pathway alteration frequencies in NSCLC will help guide the design of future clinical trials of PI3K inhibitors.

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    O27 - Clinical Trials and Practice (ID 142)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Other Topics
    • Presentations: 1
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      O27.07 - Molecular multidisciplinary tumor board (MMTB) for lung cancer patients: 2-year experience report (ID 2865)

      16:15 - 17:45  |  Author(s): D. Planchard

      • Abstract
      • Presentation
      • Slides

      Background
      Molecular analysis (MoA) of non-small cell lung cancer has led to definition of many subgroups that require dedicated treatments, strategy and trials. We created a monthly MMTB dedicated to lung cancer patients (pts) with potential driving molecular abnormalitie(s). MMTB includes physicians from the lung tumor board and the phase I unit, pathologists and biologists. A medical report summarizes the findings and treatment recommendations. We report 2 years of activity of MMTB.

      Methods
      All consecutive files discussed in MMTB in Gustave Roussy were reviewed. Tumor and pts characteristics were collected as well as treatment. Pts outcome was calculated from the MMTB.

      Results
      245 pt files were discussed between February 2010 and March 2012. 53% were male, 27% never-smokers, 89% had PS 0 or 1, median age was 59. Clinical initial stage was III-IV in 17 pts (7%) and 78%/11%/11% were adenocarcinoma/squamous cell carcinomas/others NSCLC. Time from diagnosis to MMTB was 7 months (m) (1-222), 102 (42%) of pts received more than 1 line of treatment before MMTB. Biopsy for MoA mostly came from CT guided biopsies (61%), surgery (22%) or endoscopy (15%). Biopsy was repeated in 20% of pts to get enough material for MoA. The MoA results were ALK rearrangement in 10%, exon 18/19/21 EGFR mutation (mut) in 2/14/8%, KRAS mut in 30%, PI3KCA mut in 0.4%, BRAF mut in 3%, HER2 mut in 1%, FGFR1 amplification in 3%, other rare mutations in 14%. MMTB recommendations were: a clinical trial in 75 pts (31%), receive an EMA-approved drug in 49 pts (20%), an off-label commercial drug in 18 pts (7%), an expanded access program in 18 pts (7%), none in 85 pts (35%). Out of the 160 MMTB pts with treatment recommendations, 63 (42%) received the proposed targeted therapy and 16 (11%) might receive it at the time of disease progression. After MMTB, 84 pts (34%) received 1 line, 66 pts (27%) 2 lines or more, 56 pts (23%) no treatment (unknown in 39 pts). Median follow-up is 20.6 m. Progression-free (in 224 pts) and overall survivals (OS, in 221 pts) from MMTB are 3.5 and 13.4 m. In univariate analysis for OS, the pts who received the recommended treatment from the MMTB had a better prognosis (hazard ratio [HR]: 0.56, p=0.002), confirmed in multivariate analysis (HR=0.61 [95% confidence interval: 0.42-0.88], p=0.009) after taking into account histology, previous platinum-based treatment and the number of previous treatment lines.

      Conclusion
      MMTB leads to treatment recommendations in a majority of the pts, fosters inclusion in clinical trials or expanded access programs, and limits the use of off labelled drugs. Updated data 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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      P2.11-004 - A Phase Ib, open label, dose escalation study of the safety and pharmacology of PI3-Kinase (PI3K) Inhibitor GDC 0941 in combination with either Paclitaxel (Pac) and Carboplatin (Carbo) with or without Bevacizumab (Bev), or Pemetrexed (Pem), Cisplatin (Cis), and Bev in patients with advanced Non–Small Cell Lung Cancer (NSCLC). (ID 885)

      09:30 - 16:30  |  Author(s): D. Planchard

      • Abstract

      Background
      The PI3K pathway has been implicated as a mechanism for cell survival and resistance to chemotherapy. PI3K may be an important target in NSCLC based on genetic alterations such as PIK3CA amplification, PTEN loss and PI3K mutations. Preclinical NSCLC models show that concurrent dosing of GDC-0941 improved activity of taxanes, platinums, and anti-VEGF therapy. This Phase 1b study aims to establish the safety and tolerability of GDC-0941 in combination with four frontline standard of care regimens in patients with advanced NSCLC.

      Methods
      This study contains two Carbo/Pac containing arms: Arm A (GDC-0941 + Carbo + Pac), open to squamous (Sq) patients and Bev-ineligible non-squamous (NSq) patients; and Arm B (GDC-0941 + Carbo + Pac + Bev) for NSq patients. The study also aims to evaluate two Cis/Pem containing arms in NSq patients: Arm C (GDC-0941 + Cis + Pem + Bev); and Arm D (GDC-0941 + Cis + Pem). Study objectives are to evaluate safety and pharmacokinetics (PK), and to determine the maximum tolerated/administered dose (MTD or MAD) of GDC-0941 in combination with chemotherapy regimens in all arms. Patients received GDC-0941 with 4-6 cycles of chemotherapy every 3 weeks (Q3W): Pac (200 mg/m[2]), Carbo (AUC 6 mg/mL·min), Cis (75 mg/m2), Pem (500 mg/m2), and Bev(15 mg/kg) . In all arms, GDC was given PO qd on Days 1-14 of a 21-day cycle. GDC-0941 +/- Bev were given until progression or toxicity.

      Results
      As of 1 February 2013, Arms A, B and C have completed enrollment, with 18, 24 and 13 patients, respectively; no patients have been enrolled in Arm D to date. The most common Grade 3/4 treatment-related adverse events (TAEs) reported in ≥10% of patients were as follows: Arm A: neutropenia (50%), anemia (17%), febrile neutropenia (17%), leukopenia (11%) and thrombocytopenia (11%); Arm B: neutropenia (38%), lymphopenia (13%); Arm C: fatigue (31%), dehydration (15%) and hypertension (15%). The MTD/MAD in Arms A, B and C is 340 mg GDC-0941 in combination with either Carbo + Pac +/- Bev or with Cis + Pem + Bev, respectively. PK characteristics in all Arms were similar to historical profiles for the respective chemotherapy agents, as well as to the single-agent GDC-0941 profile. Confirmed partial responses (PRs) for patients with at least one post-baseline scan are as follows: 6 of 10 (60%) Sq patients; 11 of 28 (39%) NSq (Arms A and B) and 9 of 12 (75%) NSq patients (Arm C).

      Conclusion
      The combinations of GDC-0941 with either Pac + Carbo (+/- Bev), or Cis + Pem + Bev have been well tolerated at doses consistent with target PK exposures based on preclinical activity. Promising responses rates have been observed with all combinations evaluated. Evaluation of GDC-0941 + Cis + Pem is ongoing. A randomized Phase 2 study of GDC-0941 + Pac + Carbo (+/- Bev) in NSq and Sq patients is ongoing.