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T. Ciuleanu



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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)

      10:30 - 10:40  |  Author(s): T. Ciuleanu

      • Abstract
      • Presentation
      • Slides

      Background
      Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

      Methods
      We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

      Results
      Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

      Conclusion
      Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

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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): T. Ciuleanu

      • 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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    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 - 09:30  |  Author(s): T. Ciuleanu

      • 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 - 09:30  |  Author(s): T. Ciuleanu

      • 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.