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J. Soria
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-016 - Next-Generation Sequencing Shows Mechanisms of Intrinsic Resistance in ALK-Positive NSCLC Patients Treated with Crizotinib (ID 9514)
09:30 - 16:00 | Author(s): J. Soria
- Abstract
Background:
Crizotinib (XALKORI®) is a small molecule ALK, ROS1, and c-MET tyrosine kinase inhibitor approved for the treatment of patients with ALK-positive or ROS1-positive metastatic NSCLC. PROFILE 1005 was a single arm phase 2 study of the safety and efficacy of crizotinib in previously treated patients with advanced NSCLC that is ALK-positive as determined by the investigational use only FISH test or on a case-by-case basis using a local FISH, IHC or RT-PCR laboratory developed test. In this study 54.1% of patients exhibited a confirmed complete or partial response to crizotinib (responders) by investigator assessment, while 9.9% had a best overall tumor response of progressive disease (progressors). The objective of this analysis was to investigate mechanisms of intrinsic resistance to crizotinib by comparing progressors with responders through a targeted cancer gene panel of next-generation sequencing (NGS).
Method:
Archival tumor tissue used to screen patients for enrollment was analyzed using the FoundationOne NGS panel (Cambridge, MA). Results of the analyses from tumor tissue positive by ALK FISH were compared for a subgroup of progressors (N=22) with a randomly selected subgroup of responders (N=25).
Result:
There was a higher proportion of patients who were ALK-negative by NGS in progressors (8 of 22; 36%) as compared to responders (3 of 25; 12%) (p=0.083), including 5 patients with oncogenic driver mutations in KRAS (G12S, Q61H, amp), EGFR (L858R) and BRAF (G469A). Among responders, 4 patients (16%) had non-EML4 ALK fusions (KIDINS220, EDC4, DTWD2, AFF2) while no such case was detected in progressors. TP53 mutations were detected in 10 progressors (45%) and 5 responders (20%) (p=0.115). Excluding NGS-negative patients, TP53 mutations were detected in 7 of 14 progressors (50%) and 3 of 22 responders (13%) (p=0.026).
Conclusion:
In the small percentage of patients with ALK-positive NSCLC with a best response of progression upon treatment with crizotinib, a higher proportion are ALK-negative by NGS, representing either a technical false-positive or an accurate FISH result reflecting a non-activating gene rearrangement that is not detected by NGS. TP53 mutations were observed at a higher frequency in progressors than in responders in patients with ALK-positive NSCLC by both FISH and NGS. Both technical and biologic factors thus may contribute to apparent intrinsic resistance in patients with ALK-positive NSCLC treated with crizotinib.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-005 - Impact of Baseline Leptomeningeal and Brain Metastases on Immunotherapy Outcomes in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 7958)
09:30 - 16:00 | Author(s): J. Soria
- Abstract
Background:
Central nervous system (CNS) involvement is frequent in NSCLC patients and associated with poor prognosis. However, its impact on immune checkpoints inhibitors’ (ICI) outcomes remains unknown.
Method:
We retrospectively collected the clinical and imaging data of a cohort of 271 patients treated with ICI in our institute from Nov. 2012 to April 2017. We analyzed overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR), and CNS outcomes using brain CT scan and/or MRI. Both body and CNS outcomes were assessed prospectively by investigators.
Result:
With a median follow up of 17 months (95% IC 15-21), 259 patients were evaluated, 48 (19%) had CNS involvement before immunotherapy; 225 were (87%) smokers, 78% had PS ≤1, with median age of 63.1; 166 (64%) had adenocarcinoma; 67 (26%) were KRASmut, 14 (5%) EGFRmut and 3 (1%) ALK positive. PDL1 was ≥1% by immunohistochemistry in 68 (28%), negative in 28 (11%) and unknown in 163 patients. Median number of prior lines was 1 (0-11). The global ORR was 20%. The median OS was 8 months (95% IC 6-11). No difference was observed in OS between CNS+ vs. CNS- population (p= 0.09). The global ORR was 18% vs. 20%, in CNS+ and CNS- patients, respectively (p=1). To date, CNS–relative data are available for 36 patients: n= 32 brain metastasis, n=7 meningeal carcinomatosis, including 4 cytological positivity, n=2 leptomeningeal and n=1 medullar metastasis. Thirty-one patients (86%) had brain target lesions and 15 were evaluable for CNS outcome (CNS progressive disease (PD) before starting ICI and/or no brain radiation therapy (RT) in the previous 6 months. Median interval between consecutive CNS assessments was 2 months. Twenty-two had CNS PD before immunotherapy: 41% (9/22) received radiation therapy (RT) the month before immunotherapy (4 whole brain RT, 5 stereotactic). No differences were observed according to prior RT, with a median OS of 10 months (95%IC 2-NR) vs. 8 months. (95%IC 5-NR) for prior vs. no prior RT (p=0.79). The median OS for the 7 patients with meningeal carcinomatosis was 2 months (0 to 20). The CNS ORR was 27% (4/15, 3 partial, 1 complete response) and CNS DCR was 60% (9/15). One CNS pseudo progression (7%) and one dissociated brain response (7%) were observed.
Conclusion:
CNS involvement did not seem to be associated with a negative impact on immunotherapy outcomes in advanced NSCLC patients. Final analysis of the entire cohort will be presented.
