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R. Chiari
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ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J.W. Neal, Q. Zhou
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL16.01 - Tyrosine Kinase Inhibitors (TKIs) for the Treatment of Brain Metastases (BMs) from Advanced Lung Cancer : A Large Retrospective Cohort Study (ID 2824)
10:45 - 10:56 | Author(s): R. Chiari
- Abstract
- Presentation
Background:
BMs are found in up to 30% of patients (pts) with advanced non small cell lung cancer (NSCLC), and are associated with a poor prognosis despite radiotherapy treatment, with a median survival of 6 months (mo). Several data are suggesting the potential brain activity of tyrosin kinase inhibitors (TKIs) alone in NSCLC pts with activating mutations. We retrospectively identified EGFR mutated and ALK rearranged NSCLCs with BMs, to evaluate the efficacy of TKIs and their role in the upfront setting.
Methods:
Out of a cohort of 270 never smoker (NS) NSCLC patients (pts) treated at our Institution from 2/2006 to 2/2015, 89 (32.9%) NSCLCs BMs were identified, synchronous in 27 pts (30.3%). 38 pts (42.7%) harboured an EGFR mutation, 33 pts (37.1%) were ALK rearranged, 18 pts (20.2%) negative for both, were used as a control cohort. Among the EGFR mutated, an in-frame deletion in exon 19 (mostly E746-A750) was found in 26 (68.4%) patients, while a point mutation in exon 21 (L858R) was detected in 10 (26.4%), 1 (2.6%) exon 18 mutation and 1 (2.6%) exon 20 insertion were identified. The majority of EGFR and ALK positive (+) pts with BMs were female (53.9%), median age 52, adenocarcinoma histology, and a good performance status.
Results:
Out of the 71 NSCLCs with BMs EGFR/ALK+, 58 pts (81.7%) received at least one line of chemotherapy, while 13 pts (18.3%) were only treated with TKIs. Of the entire series, 40 pts (56.3%) were treated with standard radiotherapy (WBRT or radiosurgery) prior to TKIs treatment, while 31 (43.7%) received a TKI upfront, distributed as follows: 13 pts (37.9%) were treated with an EGFR inhibitor (gefitinib/erlotinib/afatinib), while 18 pts (62.1%) with an ALK TKI (crizotinib/ceritinib/alectinib). All the pts in the molecular negative cohort, received WBRT and, at least, one line of chemotherapy. Within the entire series, Overall Intracranial Response Rate (OIRR: complete response CR + partial response PR) was evaluated: EGFR+ 31 pts (81.5%), ALK+ 28 pts (84.8%), control cohort 6 pts (33.3%) (p,0.003). Median [95% CI] overall survival (OS) for EGFR mutans, ALK + and EGFR/ALK negative was: 52 months (mo) (32.6-74.4),74 mo (not reached), 25 mo (9.4-40.03) (p,0.003). In the subgroup who received a TKI upfront, all EGFR+ achieved a PR, while all ALK+ obtained an objective response: 4 (22.2%) a CR and 14 (77.8%) a PR. No significant difference in OS between EGFR/ALK+ BMs treated with a TKI upfront versus further line.
Conclusion:
This retrospective study confirms that TKIs are strongly active in patients with BMs from NSCLCs harbouring a sensitive mutation. Brain disease control was achieved in an impressive 81.5% of the EGFR+ pts and 84.8% of the ALK+ subset. Of particular note, is the highest response rate in the TKI upfront arm, with 22.2% attaining a complete remission. We conclude that the use of TKIs in first line setting for BMs treatment may be a reasonable option for asymptomatic subgroup of patients with a long survival expectation, for whom WBRT may be postponed at a later disease stage.
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ORAL 38 - Liquid Biopsies (ID 147)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M.S. Tsao, J. Wang
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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ORAL38.07 - Quantification of EGFR Mutations in Plasma of NSCLC Patients: An Early Predictor of Clinical Response to Tyrosine Kinase Inhibitors (ID 2242)
17:50 - 18:01 | Author(s): R. Chiari
- Abstract
- Presentation
Background:
As DNA analytical methods have become more sensitive, attempts to develop accurate clinical tests to assess tumor mutation status by means of patient plasma samples are now being pursued. The potential to accurately quantify EGFR mutations in plasma from non-small cell lung cancer (NSCLC) patients would enable more rapid and more frequent analyses to assess disease status; however, the utility of such analyses for clinical purposes has only recently started to be explored.
Methods:
Plasma samples were obtained from 69 NSCLC patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next generation sequencing (NGS). A semi-quantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by RECIST 1.1 criteria and expressed as percent tumor shrinkage.
Results:
The sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100%, and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (P<0.001). EGFR testing at baseline and serially at 4–60 days during TKI therapy revealed a progressive decrease in SQI , starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (P<0.0001); at 14 days it was more than 50% in 70% of patients (rapid responders) (Fig.1A-B). In 2 patients with slow response (Fig.1B), an early increase in the circulating levels of the T790M mutation was observed. These patients were defined as early resistant (Fig.1C). No early T790M mutations were seen in plasma samples of rapid responders, suggesting that slow responders are more prone to develop early resistance.
Conclusion:
Quantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI during therapy and clinical response with relevant implications for patient management. With the strong correlation between EGFR SQI in plasma and clinical outcome, this study opens the way to prospectively design clinical trials to confirm these data and evaluate the diagnostic value of this test. Figure 1
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