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H.J.M. Groen



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-054 - Targeting MCL1 amplification in NSCLC through anthracycline-mediated transcriptional suppression (ID 3213)

      09:30 - 09:30  |  Author(s): H.J.M. Groen

      • Abstract

      Background
      Targeting oncogene dependency for effective therapy has been one of the most successful strategies for managing metastatic non-small cell lung cancer (NSCLC). Although validating therapeutically tractable oncogenic driver mutations are a major focus, non-driver mutations may also confer dependencies that may also be exploitable. The prosurvival BCL2 protein, MCL1 prevents mitochondrial apoptosis by blocking interaction of proapoptotic BH3 only proteins with their multidomain proapototic counterparts, BAX and BAK. MCL1 is often mutated in cancers, and ranks as one of the most frequently amplified loci at 1q21.2. MCL1 amplified tumours exhibit addiction to this oncogene. Anthracyclines have been shown to transcriptionally suppress MCL1. Phase IIA studies in NSCLC have shown that epirubicin has useful single agent activity in unselected patients, with a significantly greater response rate than that achieved with standard chemotherapy. We therefore set out to evaluate MCL1 addiction in NSCLC, its correlation with anthracyline induced apoptosis and the prevalence of 1q21.2amplification to support a planned 1q21.2 stratified phase II trial in NSCLC, (EORTC-1303-LCG).

      Methods
      RNAi targeting MCL1was conducted in NCI-H460, NCI-H1299, NCI-H28 and NCI-H23 cell lines. Doxorubicin activity was measured by viability assay and apoptosis was assessed by western blot. gDNA from cell lines was obtained by Phenol-Chloroform extraction. The QIAamp DNA FFPE Tissue Kit was used to extract gDNA from FFPE tissues. MCL1 amplification was quantified by real-time PCR with a set of two primers and one probe (minor groove-binding (MGB) hydrolysis probe assay) for the gene of interest MCL1 and the two reference genes CCT3 and H6PD. Tonsil samples were used as a control diploid population.

      Results
      MCL1 silencing efficiently induced apoptosis in a subset of NSCLC cells, however we identified two cell lines that were resistant to MCL1 knockdown (NCI-H1299 and NCI-H28). Doxorubicin efficiently induced apoptosis in MCL1 addicted cells but exhibited significantly less activity in cells that were not addicted. We developed a genomic DNA based quantitative real time PCR assay to evaluate copy number variation (CNV) at the 1q21.2 locus. A clear correlation r[2] >0.91 was observed for 1q21.2 CNV compared with reference Conan Copy Number Analysis Tool (Cancer genome project, Sanger). Increased 1q21.2 copy number was consistently associated with MCL1addiction; however addiction also occurred in cells lacking 1q21.2 CNV, suggesting that MCL1 amplification represents a subset of MCL1 dependence. The concentration of doxorubicin was titrated against MCL1 protein downregulation into therapeutically sub-micromolar concentration range and we observed that MCL1 downregulation occurred coincidently with cleavage of poly-ADP ribose polymerase. We then screened DNA isolated from 19 adenocarcinomas, and identified 1q21.2 CNVs in 36.8%, with high level amplification (CNV >5) in 1q21.2 in 10.5%.

      Conclusion
      Targeting MCL1 addiction in 1q21.2 amplified NSCLC induces apoptosis and this dependence can be exploited by anthracyclines at therapeutically relevant concentrations. Given its significant prevalence in NSCLC, our data suggests that 1q21.2 amplification could be a novel non-driver mutation predictive for anthracycline response.

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    P2.04 - Poster Session 2 - Tumor Immunology (ID 154)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.04-001 - Myeloid derived suppressor cells (MDSC) are increased in patients with advanced non-squamous lung cancer (aNSQ) compared to healthy controls and early stage non-squamous lung cancer (eNSQ) and are related to the WHO performance status. Subanalysis of the NVALT12 study (ID 1802)

      09:30 - 10:30  |  Author(s): H.J.M. Groen

      • Abstract

      Background
      Background: recent evidence shows a role for immunotherapy via checkpoint antibodies in a subgroup of patients with non-small cell lung cancer (NSCLC). We have recently published the complex interplay between tumors and the immune system[1]. The modulating effect of the tumor on the immune system, mainly immunosuppressive, is challenging. MDSC are described to play a major role in this tumor associated immune suppression by inhibiting cytotoxic Tcell function. The aim of the present study is to relate the number of MDSC to two well-known prognostic factors in NSCLC: stage of the disease and WHO performance status.

      Methods
      Methods: MDSC were determined in peripheral blood mononucleair cell fractions of 195 treatment-naive NSCLC patients (185 stage IV (aNSQ), 10 stage I-III(eNSQ), and 20 healthy controls (HC)). WHO performance status was determined by experienced investigators prior to the start of treatment. In this abstract the relation between clinical data and polynucleair MDSC are presented. Flowcytometric analysis was performed within 5 hours after the blood was drawn. MDSC were characterized as CD16low,CD11b+,CD14-,HLA-DR-,CD15+, and CD33+.

      Results
      Results: A large variation in the number of MDSC was observed in patients with NSCLC, also in the same stage of the disease and WHO performance status. In a subgroup of patients with eNSQ high MDSC levels were found, but also in patients with aNSQ low levels of MDSC were found. For the group as a whole, however, an increased number of MDSC was found in patients with aNSQ compared to HC and eNSQ (p<.001, in both comparisons). Comparison of the limited number of patients with of eNSQ and HC no statistical difference was found but there is a tendency for an increase in the number of MDSC per stage of NSCLC. The number of MDSC increased with worse WHO performance status ( p=0.05 between 0 and 2). Whether the number of MDSC has prognostic or predictive value to response to chemotherapy in all patients is subject of current research. Follow up data in all patients with response to chemotherapy, progression free survival and overall survival are at present collected.

      Conclusion
      Conclusion: Peripheral blood MDSC levels are increased in patients with aNSQ compared to eNSQ and HC. MDSC are increased in patients with worse WHO performance status. The number of MDSC shows large variation between patients with similar stage of the disease, showing the complex interplay between tumor and immune system. 1 Aerts JG, Hegmans JP, Cancer Research 2013

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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 - 09:30  |  Author(s): H.J.M. Groen

      • 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.

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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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      P3.11-037 - A phase II study of sorafenib and metformin in patients with stage IV non-small cell lung cancer (NSCLC) with a KRAS mutation (ID 2701)

      09:30 - 09:30  |  Author(s): H.J.M. Groen

      • Abstract

      Background
      Previously we reported a phase II study of sorafenib, a multi tyrosine kinase inhibitor, in advanced NSCLC patients with a KRAS mutation [1]. While sorafenib was found active in this group of patients, progression free survival (PFS) and overall survival (OS) were disappointing. Concurrent inhibition of multiple pathways may improve treatment outcome. Metformin is a save and well known antidiabetic drug. It has been described that metformin has inhibitory effects against mTOR, downstream of PI3K. An in vitro study of our group has shown synergistic effects of sorafenib and metformin which provided the rationale for this study [2]. In a post hoc analysis of the previous study, metformin users appeared to be among the longest survivors.

      Methods
      Patients with advanced NSCLC with a KRAS mutation, pretreated with platinum containing chemotherapy were included. Other inclusion criteria were: ECOG performance score (PS) 0-1, adequate organ reserve, creatinine clearance >60 ml/min and provided written informed consent according to local IRB regulations. A tumor biopsy was mandatory to confirm the presence of a KRAS mutation, prior to start of treatment. Treatment consisted of sorafenib 400 mg BID and metformin 1000 mg BID until disease progression or unacceptable toxicity. Dose reductions and discontinuations were specified per protocol in the face of CTC toxicities grade 3 and 4. Primary endpoint: disease control rate (DCR) at 6 weeks according to RECIST version 1.1. Secondary endpoints: duration of response, progression free survival (PFS), overall survival and treatment related toxicities. A 2-stage design was implemented (Simon's optimal design; p0=50%, p1=70%, alpha=0.05, beta=0.20) for a total of 45 evaluable patients.

      Results
      Fifty-five patients were included between 1[st] of July 2012 and 1[st] of June 2013. Median age was 60 (range 34-77) years, 28 female (51 %), ECOG PS 0/1/2 16/32/1, all patients had stage IV disease. Of 47 patients disease evaluation after 6 weeks was available (Fig. 1). Two patients had a partial response, 23 stable disease and 22 patients had progressive disease. DCR was 53%. Results of secondary endpoints will be available at time of the conference.

      Conclusion
      This preliminary analysis suggests that the addition of metformin did not improve DCR, compared to previous reported results of sorafenib monotherapy in pretreated stage IV NSCLC patients with a KRAS mutation. [1] Dingemans AM et al. Clin Cancer Res. 2013 Feb 1;19(3):743-51 [2] Groenendijk FH et al. EJC. 2012 Nov; 48 (suppl. 6): p 48 Figure 1

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    P3.13 - Poster Session 3 - SCLC (ID 202)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.13-006 - Docetaxel-Carboplatin (DC) as Second Line Treatment in Patients With Small Cell Lung Cancer (SCLC): A phase II study. (ID 1877)

      09:30 - 09:30  |  Author(s): H.J.M. Groen

      • Abstract

      Background
      Patients with relapsing SCLC have a poor prognosis and options for treatment are limited. Paclitaxel in combination with platinum has demonstrated activity in first and second-line treatment. We conducted a phase II study to investigate the anti-tumor activity and safety profile of Docetaxel/Carboplatin (DC) in patients with refractory or relapsing SCLC.

      Methods
      SCLC patients who were refractory to or relapsed after first-line treatment and who did not receive platinum based chemotherapy within the 3 months before inclusion, were treated with Docetaxel (75 mg/m[2], day 1 iv) followed by Carboplatin (area under the curve 6, day 1 iv.) once every 3 weeks for 4-6 cycles. Primary endpoint was response rate (RR) and secondary endpoints were time to progression (TTP), overall survival (OS) and safety profile. Tumor response was measured according to RECIST version 1.1. Toxicity was evaluated according to Common Toxicity Criteria of the National Cancer Institute.

      Results
      50 patients (29 male and 21 female) were included with a median (range) age of 67 years (46-82). The majority of patients had an Eastern Cooperative Oncology Group performance status of 1; median time off first-line treatment was 12 weeks. Average number of treatment cycles was 4 (range 1-6). Evaluable for response and toxicity were 45 and 48 patients, respectively. A complete response was achieved in 1 patient, a partial response in 24 patients, stable disease in 16 patients, and progressive disease in 4 patients (RR 73.5%; 95% confidence interval, 59 to 88). Median time to progression was 133 days (range 89-177). Median overall survival was 198 days (range 77-322). One-year survival rate was 34%. Hematologic toxicity grade 3 and 4 was leukopenia 19% and 8%, thrombocytopenia 10% and 2%, and anemia 4% and 0%, respectively, in a total of 186 cycles. Nonhematologic toxicity was diarrhea grade 3-4 (15%), stomatitis grade 3 (4%) and hyponatriemia grade 3 and 4 in one patient each. Seven patients were hospitalized due to neutropenic fever; no toxic deaths occurred.

      Conclusion
      Second-line DC in refractory or relapsing SCLC patients yielded a high RR and toxicity was relatively mild in these poor-prognosis patients. NCT00686985

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    PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL03.01 - Lung cancer probability in subjects with CT-detected pulmonary nodules (ID 1578)

      08:15 - 08:27  |  Author(s): H.J.M. Groen

      • Abstract
      • Slides

      Background
      The main challenge in computed tomography (CT) screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Thresholds for nodule size and growth rate, which determine which nodules require additional diagnostic procedures, should be based on the lung cancer probability of the individual.

      Methods
      Diameter, volume and volume-doubling time (VDT) of 9,681 non-calcified nodules detected by CT screening in 7,155 subjects were used to quantify lung cancer probability. Complete coverage on all lung cancer diagnoses was obtained by linkages with the national cancer registry. The nodule management algorithm recommended by the ACCP was evaluated and an improved algorithm, based on lung cancer probability, was proposed.

      Results
      Lung cancer probability was low in subjects with a nodule volume <100mm³ (≤0.7%) or maximum transverse diameter <5mm (≤0.6%) Moreover, probability in these subjects was not significantly different from that in subjects without nodules (0.4%). Lung cancer probability was 0.9-5.8% for nodules with a volume 100-300mm³ or a diameter 5-10mm; the VDT further stratified the probability: 0.0-0.9% for VDTs>600days, 4.0% for VDTs 400-600days and 6.7-25.0% for VDTs<400days. Lung cancer probability was high for participants with nodule volumes ≥300mm³ (8.9-26.1%) or diameters ≥10mm (11.1-26.2%), even with long VDTs. Finally, raising the thresholds for nodule size recommended by the ACCP for an indeterminate result from 4mm to 5mm and for a positive result from 8mm to 10mm, would yield fewer follow-up CT examinations (from 29.8% to 22.2%) and fewer additional diagnostic procedures (from 8.9% to 5.3%) while maintaining the sensitivity at 94.2%.

      Conclusion
      Small nodules (volume <100mm³ or diameter <5mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for subjects with large nodules (volume ≥300mm³ or diameter ≥10mm) and only for subjects with nodules of intermediate size is VDT assessment advocated.

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