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M. Cobo



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.06 - Oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P as first-line chemotherapy for non squamous (NS) metastatic or locally advanced non small cell lung cancer (M or LA NSCLC): Final results of a prospective randomised phase II trial (NAVoTrial 1) (ID 276)

      16:15 - 17:45  |  Author(s): M. Cobo

      • Abstract
      • Presentation
      • Slides

      Background
      NVBo and P are an established regimen in advanced NSCLC. The approval of Pem and P in NS NSCLC recognises histology as treatment driver even if the higher chemosensitivity of NS NSCLC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). NVBo + P also showed better survival in NS NSCLC than in Squamous NSCLC (Tan. Ann.Oncol. 2009). The current randomised (2:1) phase II trial assessed disease control (DCR) (SD + PR + CR) of NVBo/CDDP or PEM/CDDP in NS NSCLC.

      Methods
      Stage IIIB/IV untreated/relapsed NS NSCLC pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² + P 75 mg/m² D1 (Arm B). After 4 cycles of combination, non PD pts received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to Stage (IIIB - IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre.

      Results
      From 11/09 to 02/11, 153 patients were enrolled in 31 centers and randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period Grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively.

      Conclusion
      Both doublets reported good efficacy and acceptable tolerability. The maintenance allowed continuation of effective treatment with either oral vinorelbine or pemetrexed as single agent, with an acceptable safety with both agents. These results are sufficiently compelling to consider whether a phase III randomised non inferiority study with oral vinorelbine maintenance after induction vinorelbine/cddp could be as effective as pemetrexed maintenance. An oral maintenance may be a definite advantage over intravenous maintenance.

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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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      P2.11-022 - Phase IV, single-arm study of first-line gefitinib in Caucasian patients with epidermal growth factor receptor (EGFR) mutation-positive, advanced non-small-cell lung cancer (NSCLC): post-hoc exploratory analyses of EGFR mutations in plasma-derived cfDNA samples (ID 1868)

      09:30 - 16:30  |  Author(s): M. Cobo

      • Abstract

      Background
      Study NCT01203917 assessed the efficacy and safety/tolerability of the EGFRTKI gefitinib in Caucasians with EGFR mutation-positive NSCLC (previously reported). Here we report post-hoc EGFR mutation analyses of plasma-derived, circulating-free DNA (cfDNA), including efficacy (objective response rate [ORR] and progression-free survival [PFS]) by mutation subtype (Exon 19 deletions; L858R point mutations).

      Methods
      Patients: Caucasians; ≥18 yrs; PS 0-2; histologically confirmed Stage IIIA/B/IV EGFR mutation-positive NSCLC eligible for first-line treatment. Treatment: 250mg gefitinib once-daily until disease progression. Primary endpoint: ORR (investigator assessment); secondary endpoints: disease control rate, PFS, overall survival, and safety/tolerability (previously reported). Mandatory tumor and plasma samples were collected at baseline (all screened patients). Post-hoc exploratory analyses: correlation between clinical characteristics and baseline plasma cfDNA EGFR mutation status; concordance of plasma cfDNA mutation subtype determination (Exon 19 deletions; L858R) with tumor; gefitinib efficacy by plasma cfDNA mutation subtype (Exon 19 deletions; L858R).

      Results
      Of 1060 screened patients with NSCLC, 118 presented with activating, sensitizing EGFR mutations, 106 of whom were enrolled and treated with gefitinib (Full Analysis Set; 71% female; 97% adenocarcinoma; 64% never-smoker). Mutation rate for samples with known mutation status: 14% (118/859) in tumor, 10% (82/784) in plasma. Among 784 patients with baseline plasma samples of known mutation status, histology (adenocarcinoma vs non-adenocarcinoma; odds ratio [OR] 5.54; p=0.0012), smoking status (never- vs ever-smoker; OR 4.39; p<0.0001), and gender (female vs male; OR 2.68; p=0.0004) independently predicted plasma cfDNA mutation status. Concordance in 652 matched tumor and plasma- Exon 19 deletions: 96% (confidence interval [CI]: 95-98); L858R: 98% (CI: 96-99). Using tumor mutation status as reference, EGFR mutation test sensitivity in cfDNA (Exon 19 deletions) was 68% (CI: 56-78), specificity was 100% (CI: 99-100); positive predictive value: 100% (CI: 93-100); negative predictive value: 96% (CI: 94-98); results were similar for L858R, with numerically lower sensitivity (62%; CI 44-78%). ORR for patients with both EGFR mutation-positive tumor and plasma for Exon 19 deletions (n=45): 82% (CI: 69-91); L858R (n=20): 65% (CI: 41-85) (Table). Median PFS for patients with both EGFR mutation-positive tumor and plasma for Exon 19 deletions (25 events): 10.3 months (CI: 8.5-12.4); L858R (11 events): NC. Table

      ORR with gefitinib: baseline tumor vs plasma samples
      Tumor Plasma
      N Responders ORR, % 95% CI N Responders ORR, % 95% CI
      All mutations 106 74 70 61-78 65 50 77 65-86
      Exon 19 deletions 69 50 73 61-82 45 37 82 69-91
      L858R point mutations 33 21 64 47-78 20 13 65 41-85
      Median PFS with gefitinib for baseline tumor vs plasma samples
      Tumor (FAS, N=106) Plasma (N=65)
      Events, N PFS, months 95% CI Events, N PFS, months 95% CI
      All mutations 61 9.7 8.5-11.0 36 10.2 8.5-12.5
      Exon 19 deletions 41 9.6 8.0-11.0 25 10.3 8.5-12.4
      L858R point mutations 19 NC NC 11 NC NC
      NC, not calculated

      Conclusion
      EGFR mutation status assessment of common mutations from plasma-derived cfDNA can be considered when tumor tissue is unavailable. In this context, cfDNA might be used to guide treatment decisions with EGFRTKI therapy, as patients with mutation-positive cfDNA, regardless of mutation subtype, appear to have similar ORR to tumor mutation-positive patients.

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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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      P3.11-020 - Epidermal growth factor receptor (EGFR) mutation analyses in tumor and plasma samples from a Phase IV, single-arm study of first-line gefitinib in Caucasian patients with EGFR mutation-positive, advanced non-small-cell lung cancer (NSCLC) (ID 1807)

      09:30 - 16:30  |  Author(s): M. Cobo

      • Abstract

      Background
      Study NCT01203917 assessed the efficacy, and safety/tolerability of the EGFR tyrosine kinase inhibitor gefitinib in Caucasians with EGFR mutation-positive NSCLC, and compared mutation status in tumor-derived DNA and plasma-derived circulating-free DNA (cfDNA).

      Methods
      Patients: Caucasians; ≥18 yrs; PS 0-2; histologically confirmed Stage IIIA/B/IV EGFR mutation-positive NSCLC eligible for first-line treatment. Treatment: 250mg gefitinib once-daily until disease progression. Primary endpoint: objective response rate (ORR; investigator assessment). Secondary endpoints: disease control rate (DCR; complete/partial response or stable disease ≥6 wks), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objectives: comparison of EGFR mutation status in tumor versus mandatory, duplicate plasma samples (all screened patients) collected at baseline (plasma1 and 2) and one optional plasma at progression.

      Results
      Of 1060 screened patients with NSCLC, 118 presented with activating, sensitizing EGFR tumor mutations, 106 of whom were enrolled and treated with gefitinib (Full Analysis Set; 71% female; 97% adenocarcinoma; 64% never-smoker). ORR (70%), DCR (90.6%), median PFS (9.7m), and median OS (19.2m) indicated gefitinib efficacy, with rash (45%), and diarrhea (31%) the most common adverse events (AEs; any grade; serious AEs: 19%) (previously reported at EMCTO 2013). Mutation rate for samples with known mutation status: 14% (118/859) in tumor, 10% (82/784) in plasma1. In 201 screened patients, tumor mutation status could not be detected due to technical reasons; however, 12 had a mutation in plasma1. Mutation status concordance in 652 matched tumor and plasma1: 94% (CI: 92-96; mutation subtype/frequencies in Table). Using tumor mutation status as reference, EGFR mutation test sensitivity in cfDNA was 66% (CI: 56-75), specificity was 100% (CI: 99-100); positive predictive value: 99% (CI: 92-100); negative predictive value: 94% (CI: 92-96). Mutation status concordance in 224 duplicate plasma samples: 97% (CI: 94-99) (subtype/frequencies in Table). ORR (post-hoc) for patients with both EGFR mutation-positive tumor and plasma1 or 2 (n=66): 77% (CI: 66-86); ORR for patients with EGFR mutation-positive tumor and EGFR mutation-negative plasma1 or 2 (n=37): 60% (CI: 44-74). Of 12 patients with baseline and progression plasma samples, 4 differences were observed: no mutations were detected at progression in 3 patients in which exon 19 deletions were detected at baseline; one patient with an exon 19 deletion at baseline acquired an additional mutation, T790M (75% concordance; CI: 43-95). Table

      Baseline tumor EGFR mutation subtype results and corresponding plasma 1 results for 652 patients with matched tumor and plasma1 samples
      Plasma1,n TOTAL
      Positive: Exon 19 deletions Positive: L858R Positive: L858R & T790M Negative
      Tumor, n Positive: Exon 19 deletions 48 0 0 23 71
      Positive: L858R 0 21 0 12 33
      Positive: L858R & T790M 0 0 0 1 1
      Negative 0 1 0 546 547
      TOTAL 48 22 0 582 652
      Baseline plasma1 EGFR mutation subtype results and corresponding plasma2 results for 224 patients with duplicate plasma1 and 2 samples
      Plasma2, n TOTAL
      Positive: Exon 19 deletions Positive: L858R Negative
      Plasma1, n Positive: Exon 19 deletions 43 0 4 47
      Positive: L858R 0 20 1 21
      Negative 1 1 154 156
      TOTAL 44 21 159 224

      Conclusion
      First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. EGFR mutation status assessment from plasma-derived cfDNA can be considered when tumor tissue is unavailable.