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M. Reck



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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.02 - Randomized Phase-3 trial (INSPIRE) of Necitumumab plus Cisplatin-Pemetrexed versus Cisplatin-Pemetrexed Alone as First-Line Therapy in Stage IV Non-Squamous NSCLC (ID 2337)

      10:40 - 10:50  |  Author(s): M. Reck

      • Abstract
      • Presentation
      • Slides

      Background
      Necitumumab is a human IgG1 anti-EGFR1 monoclonal antibody that competes for the binding of natural ligands to this receptor and prevents receptor activation. EGFR1 is detectable in approximately 85% of advanced NSCLC tumors. This phase 3 study investigated necitumumab in combination with first-line chemotherapy in advanced non-squamous NSCLC.

      Methods
      Patients with histologically or cytologically proven stage IV non-squamous NSCLC were randomized 1:1 to either Arm A: cisplatin 75mg/m[2] i.v.-pemetrexed 500mg/m[2] i.v. (Cis + PEM) on Day 1+ necitumumab 800mg i.v. on Days 1 and 8 of a 21-day cycle or Arm B: Cis+PEM alone. Patients received these regimens for up to six cycles. For patients in Arm A with at least stable disease, necitumumab continued until PD or intolerable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and EGFR protein expression level by immunohistochemistry (H-score) utilizing archived tumor tissue based on a mandatory tissue collection. The planned sample size of this study was 947 patients (assuming a hazard ratio [HR] of 0.8 would allow 85% power at 2-sided alpha level of 0.05). After 633 patients, enrollment was stopped (after Feb 2011) following an Independent Data Monitoring Committee (IDMC) recommendation.

      Results
      Between Nov 2009 and Feb 2011 633 patients were randomized (315 Arm A; 318 Arm B). Baseline characteristics were balanced between the arms; 67.0% were male and 33.0% female; ECOG-PS 0/1 94.2 % and PS 2 5.7 %. No difference between treatment arms was observed for OS (median 11.3 vs 11.5 months; HR 1.01 95%-CI [0.84, 1.21]), PFS (median 5.6 vs 5.6 months, HR 0.96 95%-CI [0.80, 1.16]) and ORR (31.1 vs 32.1%; Odds ratio 0.96 95%-CI [0.68, 1.34]). The exploratory analysis in 490 patients assessable for H-score revealed no association between H-score and differences in efficacy between treatment arms (H-score < 200: mOS 8.97 vs 9.72 months, HR 1.07, mPFS 4.90 vs 4.76 months, HR 0.95, ORR 27.1 vs 26.0%; H-score ≥ 200: mOS 15.01 vs 13.34 months, HR 1.03, mPFS 5.59 vs 5.62 months, HR 0.94, ORR 39.6 vs 39.4%). Grade ≥ 3 treatment-emergent adverse events (AEs) occurring more frequently in Arm A included skin or subcutaneous disorders (14.1 vs 0.3%), thromboembolic events (9.5 vs 6.4%), hypomagnesaemia (7.6 vs 2.2%), asthenia (6.9 vs 1.9%), vomiting (6.6 vs 3.2%), dyspnea (5.3 vs 2.6%) and diarrhea (4.3 vs 2.2%). The frequency of study drug related deaths was 4.9% and 2.9% in Arms A and B, respectively.

      Conclusion
      In this study, the addition of necitumumab did not improve the efficacy outcome over cisplatin plus pemetrexed alone in advanced non-squamous-NSCLC. The EGFR H-score did not seem to predict the efficacy outcomes of necitumumab in combination with cisplatin plus pemetrexed. The addition of necitumumab resulted in a higher frequency of grade ≥ 3 AE (skin reaction, GI, asthenia and other) and an imbalance of grade ≥ 3 thromboembolic events. Further biomarker studies are ongoing.

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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)

      11:15 - 11:25  |  Author(s): M. Reck

      • 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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    O29 - Cancer Control & Epidemiology IV (ID 132)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O29.08 - DISCUSSANT (ID 3997)

      11:45 - 12:00  |  Author(s): M. Reck

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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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      P1.06-022 - Investigating the utility of plasma derived circulating free DNA for the detection of epidermal growth factor receptor (EGFR) mutations in European and Japanese patients with advanced non-small-cell lung cancer (NSCLC): ASSESS study design (ID 1801)

      09:30 - 09:30  |  Author(s): M. Reck

      • Abstract

      Background
      In patients with NSCLC, accurate and accessible EGFR mutation testing is important for guiding treatment decisions. Current procedures involve the testing of biopsy or cytology samples, which are not always available from all patients. However, plasma of patients with advanced NSCLC contains circulating-free tumor-derived DNA (cfDNA) that is suitable for mutational analysis. The large, multi-center, non-interventional, non-comparative ASSESS diagnostic study (NCT01785888) will evaluate the utility of plasma-based testing compared with tissue or cytology-based testing as a less invasive methodology by which to assess EGFR mutation status in patients with NSCLC.

      Methods
      A total of 1300 patients (age ≥18 years in Europe; ≥20 years in Japan) with newly diagnosed locally advanced/metastatic (Stage IIIA/B/IV) chemotherapy-naïve NSCLC who are not eligible for curative treatment, or patients with recurrent disease after surgical resection with/without adjuvant chemotherapy, will be screened for EGFR mutation status in tumor and plasma across Japan and 7 European countries over 18 months. To allow determination of sensitivity between tumor and plasma-based EGFR screening (95% confidence interval [CI] 40-60%, assuming 50% sensitivity), 100 patients each with mutation-positive NSCLC in Europe (EGFR mutation frequency: ~10%) and Japan (EGFR mutation frequency: ~30%) will be required; 1000 and 300 patients will therefore be enrolled from Europe and Japan, respectively. Provision of tumor (biopsy/cytology/other tumor cell sample) and plasma samples for EGFR mutation testing will be mandatory. Precise clinical phenotyping will be performed, and clinical information about first line (all patients) and second line (patients with mutation-positive NSCLC) therapy decisions will be recorded. EGFR testing will be performed according to local practices, with Exon 19 deletions and L858R point mutations assessed as a minimum. The primary objective is determination of concordance between EGFR mutation status obtained via tissue/cytology and plasma-based testing (concordance rate, sensitivity, specificity, positive and negative predictive values, and exact 2-sided 95% CIs). Secondary objectives: determination of EGFR mutation frequency (including mutation subtypes) in patients with adenocarcinoma/non-adenocarcinoma NSCLC; description of first-line (all patients) and second-line (all available patients) therapy following mutation testing; characterization of current EGFR testing practices; correlation between EGFR mutation status identified in tumor/plasma samples and demographic/disease status data. Pre-planned exploratory objective: investigation of exploratory biomarkers which may help to define molecular features of NSCLC (prevalence, co-occurrence, correlation with demographic data) using optional, additional tumor (biopsy/cytology/other) samples. The secondary analyses from the study will help define the current status of EGFR mutation testing procedures across Japan and Europe, and provide further information regarding mutation frequency across patient subgroups, and the relationship between EGFR mutation status and therapy decisions.

      Results
      Not applicable.

      Conclusion
      Not applicable.

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    P2.08 - Poster Session 2 - Radiotherapy (ID 198)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P2.08-019 - Palliative radiation during pemetrexed plus cisplatin first-line treatment or pemetrexed continuation maintenance treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): A report of patient safety in the PARAMOUNT trial (ID 2364)

      09:30 - 09:30  |  Author(s): M. Reck

      • Abstract

      Background
      Patient (pt) safety is of utmost concern to radiation oncologists. Pemetrexed (Pem) is an effective and well-tolerated treatment for advanced nonsquamous NSCLC. The safety of palliative radiation (XRT) during Pem treatment was studied in this subset of pts in the PARAMOUNT trial.

      Methods
      In PARAMOUNT, a randomized, double-blind study, 939 pts received 4 cycles of induction Pem (500 mg/m[2]) + cisplatin (Cis) (75 mg/m[2]) on day 1 every 21 days. Patients without progressive disease (PD) and with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1 (n=539) were then randomized (2:1) to maintenance Pem (500 mg/m[2], day 1) + best supportive care (BSC) (Arm A) or placebo + BSC (Arm B) until PD. Best supportive care (BSC) was defined as treatment without a specific antineoplastic regimen and included palliative XRT to extrathoracic structures. Safety was assessed via the incidence of adverse events (AEs) by maximum grade (Gr; CTCAE, v3).

      Results
      The 55 pts who received palliative XRT to extrathoracic structures during treatment had stage IV nonsquamous NSCLC. The majority of pts were male (58%), with an ECOG PS of 1 (75%). Patients’ median age was 61 yrs (range, 32-74) yrs, with 13% of pts ≥70 yrs. The most common location irradiated was bone (43/55 pts). Non-bone locations were: lymph node (3), mediastinum (2), chest (2), and adrenal gland, intraocular, lung, brain, and abdomen (1 each). Forty-five pts received XRT during Pem+Cis induction, 3 of whom also received XRT during maintenance. Seven pts (Arm A) and 6 pts (Arm B) received palliative XRT during maintenance. Total XRT doses ranged from 8-66 Gy. The time interval between day 1 of last chemotherapy cycle and the start of palliative XRT ranged from 0-28 days. Of 55 pts, 12 (22%) had ≥1 AE(s) during XRT considered possibly related to Pem and/or XRT (Table 1). All pts except 1 experienced the AE during induction. The most common AE was Gr 2 anemia. Three pts had Gr 3/4 anemia. Five pts had nonhematologic toxicities. One pt in Arm B, who received a total dose of 20 Gy in the hip during maintenance treatment, had pneumonitis. No AEs were reported for pts who received palliative XRT during Pem maintenance treatment.

      Table 1: AEs during palliative XRT or within 2 weeks after the end of the last fraction in both phases of the PARAMOUNT trial.
      Pts receiving palliative XRT (N=55)
      Patients with AEs during induction and/or maintenance (n=12, 22%)
      Toxicity Gr 1, n (%) Gr 2, n (%) Gr 3-4, n (%)
      Hematologic
      Hemoglobin 1 (1.8) 4 (7.3) 3 (5.5)
      Leukocytes 0 2 (3.6) 1 (1.8)
      Platelets 0 1 (1.8) 0
      Nonhematologic
      Rash/dermatitis 1 (1.8) 1 (1.8) 0
      Rash/desquamation 1 (1.8) 1 (1.8) 0
      Pneumonitis 0 0 1 (1.8)*
      *Pneumonitis was the only event reported for a pt during the maintenance phase. The pt was assigned to placebo.

      Conclusion
      Conclusions: In PARAMOUNT, palliative XRT is well tolerated and can be safely administered at low and high doses during Pem+Cis chemotherapy or Pem monotherapy to pts with advanced nonsquamous 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: 1
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      P3.06-053 - A diagnostic study to determine the prevalence of epidermal growth factor receptor (EGFR) mutations in Asian and Russian patients with non-small cell lung cancer (NSCLC) of adenocarcinoma and non-adenocarcinoma histology: IGNITE study design (ID 1610)

      09:30 - 09:30  |  Author(s): M. Reck

      • Abstract

      Background
      EGFR mutation status is widely accepted as an important biomarker in NSCLC. To assess the current status of EGFR mutation testing, including testing procedures, sample types, mutation prevalence across demographic/histological subgroups (adenocarcinoma and non-adenocarcinoma histologies), and impact of EGFR mutations on personalized therapy choice, a large, multinational, diagnostic, non-comparative, interventional study (NCT01788163; IGNITE) of EGFR mutation status in patients with locally advanced/metastatic NSCLC of adenocarcinoma and non-adenocarcinoma histology will be conducted across centers in the Asia Pacific region and Russia.

      Methods
      Approximately 3500 patients (age ≥18 years) with chemotherapy naïve, Stage IIIA/B/IV NSCLC (newly diagnosed or recurrent disease after surgical resection) that is not suitable for curative treatment will be recruited over ~18 months from Asia Pacific (including 25 centers in China) and Russia. To give similar precision for the estimation of EGFR mutation frequency in the key non-adenocarcinoma subgroup in Asia Pacific and Russia, 2500 patients from Asia Pacific (assumptions: 20% patients non-adenocarcinoma histology, with 10% EGFR mutation frequency [one-fifth of the 50% prevalence in adenocarcinoma]; precision ±3%) and 1000 patients from Russia (assumptions: 20% patients non-adenocarcinoma histology, with 4% EGFR mutation frequency [one-fifth of the 20% prevalence in adenocarcinoma]; precision ±4%) need to be screened. Provision of diagnostic tumor samples for testing will be mandatory for all patients; additionally, plasma samples, which contain circulating-free tumor derived DNA (cfDNA), will be collected for EGFR mutation testing of plasma from a subset of 2500 patients in Russia, China, Taiwan and Korea. EGFR testing will be performed according to local practices, with Exon 19 deletions and L858R point mutations assessed as a minimum. The first-line (all patients) and second-line (patients with mutation-positive NSCLC; estimated 50% will progress to second-line treatment by study cutoff) therapy choices will be recorded. The primary objective is to determine EGFR mutation (and subtype) frequency in patients with adenocarcinoma and non-adenocarcinoma NSCLC (overall and by country/region). Secondary objectives are: to describe first-line therapy following EGFR mutation testing and second-line therapy following discontinuation of first-line treatment in patients with EGFR mutation-positive NSCLC confirmed by tissue/cytology; to determine concordance between EGFR mutation status determined using tissue/cytology versus plasma; to summarize current EGFR testing practices (methods, sample types, mutation detection rate, turnaround time, and reasons for not performing testing); to determine correlations between EGFR mutation status (derived from tumor or plasma) and demographic data and disease status. The secondary analyses in this study will provide information on current testing and therapeutic practices in advanced NSCLC across the Asia Pacific region and Russia, as well as an assessment of the utility of cfDNA as a less invasive methodology for the assessment of EGFR mutation status in patients with NSCLC.

      Results
      Not applicable.

      Conclusion
      Not applicable.