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C. Schumann



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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)

      10:30 - 12:00  |  Author(s): C. Schumann

      • 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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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-009 - An open label, multicenter, prospective non-interventional (NIS) post-authorization study to monitor the routine clinical practice of Bevacizumab in addition to platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC) in Germany (ID 1015)

      09:30 - 16:30  |  Author(s): C. Schumann

      • Abstract

      Background
      The objective of NIS AVAILABLE was the evaluation of safety and efficacy of Bevacizumab plus platinum-based chemotherapy for the first-line treatment of metastatic or locally advanced histologically confirmed NSCLC in routine practice to complement the data that emanates from pre-authorization randomized controlled trials. The trial also collected data on Bevacizumab dosage, combination partner, duration of treatment and causes for modifications or termination.

      Methods
      The NIS AVAILABLE was conducted in Germany from October 2007 until June 2013. Patients were recruited in 200 centers, which included office based and outpatient clinics specialized in oncology and pneumology to be widely representative of the NSCLC population. The study aimed to enroll 900 patients receiving chemotherapy and Bevacizumab according to physician’s decision and label instructions. For each patient baseline characteristics, treatment regime and results on efficacy and safety were documented. Progression-free survival (PFS) was estimated with the Kaplan-Meier-method.

      Results
      Preliminary results of the first interim analysis including 745 patients are presented with focus on baseline characteristics, treatment regimens, dosages and PFS under the perspective of histology and age (≥65/<65 years). The population consisted of 61.3% males, the median age was 62 years (range 29-84), 40.7% of the participants were >65 years of age. At diagnosis 88.6% presented with adenocarcinoma and 82.1% with stage IV disease. 62.0% of the patients had not received any previous treatment (radiation, surgery or chemotherapy) for lung cancer. Bevacizumab was most frequently administered in addition to platinum-based chemotherapy and a third-generation cytotoxic agent. A selection of the most frequently used combination therapies (>6%) and respective PFS values are shown (Table).

      Chemotherapy combinations Patients receiving the combination (%)* Median PFS in months (95% CI)
      Bevacizumab Carboplatin Gemcitabine 9.0 5.9 (4.7-9.8)
      Paclitaxel 35.3 6.7 (5.8-7.4)
      Pemetrexed 10.7 6.5 (4.2-8.5)
      Cisplatin Gemcitabine 12.1 6.0 (4.6-9.9)
      Pemetrexed 9.2 6.8 (3.5-8.4)
      Vinorelbin 6.8 5.9 (4.2-9.1)
      * multiple answers were allowed

      Conclusion
      In the interim analysis of the NIS AVAILABLE Bevacizumab was more frequently combined with carboplatin (64%) than cisplatin (32%) backbone chemotherapy highlighting carboplatin/paclitaxel plus Bevacizumab as the most prominent regime (35.3%). Overall Bevacizumab demonstrated a promising efficacy with a median PFS of 6.7 months in routine practice confirming findings from randomized controlled phase III trials such as E4599 or AVAiL. Although the study was not designed to compare PFS, the results indicate that there might be a difference across regimens.

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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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      P3.12-023 - International Tailored Chemotherapy Adjuvant Trial: ITACA Trial (ID 1452)

      09:30 - 16:30  |  Author(s): C. Schumann

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing-1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected Stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36).

      Methods
      For all the registered patients (pts) the expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein expression. It is assumed that the 5-year survival rate in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of pts is 700. The final statistical analysis will compare all pts in the control arms versus all those treated in the tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, pts in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis.

      Results
      Not applicable

      Conclusion
      Currently, 558 pts have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 19 patients/month). This is one of the pharmacogenomic-driven trial in the adjuvant setting in the European scenario.