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S. Ignatius Ou
MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
MA07.01 - Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC (ID 5354)
11:00 - 12:30 | Author(s): S. Ignatius Ou
Based on two single-arm, multicentre, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]), the FDA approved the ALK inhibitor alectinib for use in ALK+ NSCLC patients after prior crizotinib. Alectinib was well tolerated in both phase II studies and showed efficacy against both systemic and central nervous system (CNS) disease, the latter being a common progression site in ALK+ NSCLC. This analysis uses pooled data from the latest cut-offs (22 Jan 2016 for NP28761; 1 Feb 2016 for NP28673) to examine the long-term CNS efficacy of alectinib.
Both studies enrolled crizotinib-refractory patients ≥18 years with ECOG PS 0–2 and locally advanced or metastatic ALK+ NSCLC (confirmed by FDA-approved test). CNS metastases were permitted if asymptomatic. Patients received 600mg oral alectinib BID. The primary endpoint in both studies was objective response rate (ORR) by independent review committee; secondary CNS endpoints included CNS ORR, CNS duration of response (DoR), and CNS disease control rate (DCR). CNS response and progression were determined by RECIST v1.1. All patients had baseline imaging to assess CNS metastases, with further imaging every 6 or 8 weeks for NP28761 and NP28673, respectively.
The overall pooled analysis population comprised 225 patients (n=87 from NP28761; n=138 from NP28673); median follow-up for this updated analysis was 18.8 (0.6–29.7) months (>6 months additional follow-up). At baseline, 50 patients had measurable and 86 had non-measurable CNS disease; together, these groups comprised 136 patients, 60% of the overall pooled population. Seventy percent of patients had prior CNS radiotherapy; 58% of these completed radiotherapy >6 months before study entry. Updated CNS data are shown in the Table and are consistent with systemic results.
Measurable CNS disease at baseline (n=50) Measurable and non-measurable CNS disease at baseline (n=136) CNS ORR, n (%) [95% CI] 32 (64.0) [49.2–77.1] 60* (44.1) [35.6–52.9] Complete response (CR), n (%) 11 (22.0) 39* (28.7) CNS DCR, n (%) [95% CI] 45 (90.0) [78.2–96.7] 117 (86.0) [79.1–91.4] Median CNS DoR, months [95% CI] Patients with event, n (%) 11.1 [7.6–NE] 18 (56.3) 13.8 [11.0–21.5] 32 (53.3) * N.B. Non-measurable disease response can only be classified as CR, non-CR/non-progressive disease (PD) or PD
This updated pooled analysis with mature data confirms that alectinib can provide long-term control of CNS metastases in ALK+ NSCLC, with a high CR rate.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
P1.02-061 - Kinase Fusions in Non-Small Cell Lung Carcinoma Identified by Hybrid Capture Based ctDNA Assay (ID 7014)
14:30 - 15:45 | Author(s): S. Ignatius Ou
For the detection of genomic driver alterations in NSCLC, comprehensive genomic profiling(CGP) or focused molecular testing of biopsied tissue is a well-accepted approach for matching targeted therapies in first line treatment. For NSCLC patients where invasive biopsy represents a serious risk, assessment of circulating tumor DNA(ctDNA) is an emerging alternative.
In patients with clinically advanced NSCLC, two 10 mL aliquots of peripheral, whole blood were collected and plasma was isolated. ctDNA was extracted to create adapted sequencing libraries prior to hybrid capture and sample-multiplexed sequencing on an Illumina HSQ2500 to >5000x unique coverage. Results were analyzed with a proprietary pipeline to call substitutions, indels, rearrangements and copy number amplifications.
In 288 NSCLC patients evaluated, 20 (6.9%) harbored kinase fusions. 17/20 (85%) were adenocarcinomas, all stage IV. Median patient age was 61 years (range 41-81), and 59% were female. 13 (4.5%) cases harbored ALK fusions with partners as follows: nine EML4 (one each of novel partners PPFIBP1 and CACNB4), and two with unidentified partners. All but one case had breakpoints in ALK intron 19, the remaining harboring a novel intron 17 breakpoint. Three cases (1%) harbored KIF5B-RET (canonical breakpoint intron 12), three (1%) had CD74-ROS1 (breakpoints: ROS1 intron 33(2) and intron 32(1)), and one had FGFR3-TACC3. ALK, RET, and ROS1 fusions were observed by tissue testing of NSCLC in the FoundationCore database with similar frequencies. Five patients had a biopsy with insufficient tissue for CGP; three had both sufficient tissue and ctDNA available. The remainder had no tissue available. For one patient, EML4-ALK fusion was detected in both ctDNA and tissue, collected six days apart. For another, CGP identified EGFR L858R + EGFR L709K and the patient had a durable response to afatinib/cetuximab. After progression, ctDNA assay identified FGFR-TACC3 as well as EGFR L858R. For a pre-menopausal, therapy naïve never smoker, female of east Asian heritage, both assays detected a CD74-ROS1 fusion, whereas ROS1 rearrangement was not identified by the prior use of another commercially available ctDNA test. The patient had a major radiographic response by the second cycle of crizotinib treatment.
Hybrid capture based ctDNA assay can identify kinase fusions in NSCLC when CGP of biopsied tissue cannot be performed and can direct rational use of first line TKIs. This series identified a novel mechanism of acquired resistance to EGFR inhibitors, novel fusion partners and intronic breakpoints for ALK, and a case of false negative testing by another ctDNA assay.