Author of

• 11745

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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
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11767

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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. Milenkova
    • 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.

• 12648

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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
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12668

    +

    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. Milenkova
    • 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.