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Mihaela Aldea



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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP07.11 - Circulating Tumor DNA (ctDNA) Clearance as a Biomarker in Patients With Locally Advanced NSCLC Following Chemoradiation (ID 1432)

      00:00 - 00:00  |  Author(s): Mihaela Aldea

      • Abstract
      • Presentation
      • Slides

      Introduction

      Circulating tumor DNA (ctDNA) testing has the potential to identify patients at high risk for recurrence following completion of concurrent chemoradiation (CRT) for locally advanced non-small cell lung cancer (LANSCLC). The objective of this analysis is to examine the feasibility of ctDNA testing on a commercially available focused gene panel to predict outcomes in patients with LANSCLC.

      Methods

      A total of 43 patients were prospectively enrolled between 09/2017 and 10/2019. Plasma for ctDNA testing was collected at the time of CRT initiation (D1), CRT completion (V1), quarterly follow up appointments for 12 months (FU1, 2, 3 and 4 respectively) after CRT completion, and at the time of relapse (R). ctDNA analysis was performed using InVisionFirst®-Lung, to detect the presence of SNVs, indels and CNAs in 37 cancer-related genes. ctDNA clearance was defined as the absence of D1 variants at V1. Patients without detectable D1 variants or in whom V1 samples were not collected were excluded from this analysis.

      Results

      Nineteen of 43 patients (44%) had detectable variants at D1. In this cohort of 19 patients, the median age at diagnosis was 65 years (range 43 - 82), with the majority of patients being smokers (16/19, 84%). The stage distribution was as follows: IIA (5%), IIIA (37%), IIIB (52%) and IIIC (5%). Nine patients (47%) had squamous cell carcinoma, 7 (37%) had adenocarcinoma, and 3 (16%) had poorly differentiated or NSCLC NOS. A median of 2 mutations per sample (range 1 - 5) were detected with a median of mean allelic frequency (AF) of 0.53 (range 0.05 - 16.28) at D1. Mutations in TP53 were the most commonly detected (17/19, 89%) at D1, followed by mutations in PIK3CA (5/19, 26%), CDKN2A (4/19, 21%), and EGFR (3/19, 16%). Two patients died from non-cancer related causes before FU1 and were excluded from further analysis (1 cleared ctDNA, another did not). All (3/3) patients who did not clear ctDNA had tumor relapse with a median time to relapse of 74 days (30-238), while 50% (7/14) of those who cleared ctDNA have not relapsed after a median follow-up of 469 days (range 130-710). Median time to relapse in patients who cleared ctDNA was 217 days (range 53-587 days).

      Conclusion

      Our results demonstrate that it is feasible to employ ctDNA testing to identify LANSCLC patients who are at high risk for disease recurrence following CRT. This finding requires validation in future studies.

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    P34 - Pathology - Liquid Biopsy (ID 104)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P34.06 - The Clinical Utility of Liquid Biopsy by Digital Droplet PCR in Patients with Advanced NSCLC (ID 3190)

      00:00 - 00:00  |  Author(s): Mihaela Aldea

      • Abstract
      • Slides

      Introduction

      EGFR mutations occur in 15% of Caucasian and up to 50% of Asian patients with advanced NSCLC. Tissue genomic profiling is the gold standard but the liquid biopsy is a good surrogate of the tissue for molecular diagnosis. The digital droplet PCR (ddPCR) is a rapid and low-cost liquid biopsy technique for genomic analyses. We aimed to evaluate the clinical utility of the ddPCR for genomic profiling of advanced NSCLC with EGFR mutations.

      Methods

      The ddPCR technique was prospectively applied in a cohort of advanced EGFR mutant (EGFRmut) NSCLC patients either at baseline or at the time of at failure to tyrosine kinase inhibitor (TKI). Ten ml of blood sample were collected and centrally analyzed. Blood samples were centrally analyzed by ddPCR. Clinical and molecular data were also recorded. We assessed the liquid biopsy sensitivity at baseline for activating EGFR mutations (EGFRmut) and at progression for activating and T790M resistance EGFR mutations.

      Results

      A total of 70 samples (15 collected at baseline and 55 at disease progression) were collected in 41 patients included (27 (66%) with EGFR exon 19 [Del19], 14 (34%) with EGFR exon 21 mutations [L858R], median age of 62 years, 27 (66%) were females, 27 (66%) never-smokers and 37 (90%) had adenocarcinoma). At the moment of sample collection, patients had a median number of 3 metastatic sites [range: 1-6].

      At baseline, ddPCR detected 87% of cases (13/15) with an EGFRmut; 90% (9/10) and 80% (4/5) for Del19 and L858R, respectively. The 2 negative cases had single sites of progression in bone and pleura, respectively.

      At disease progression, EGFRmut by ddPCR was detected in 55% (30/55); 58% (22/38) for Del19, and 47% (8/17) for L858R. Of note, brain was the most common site of progression (42%). Among the cases with activating EGFRmut detected in blood at progression after first and second generation TKI, the EGFR T790M mutation was found in 35% (6/17) samples. The median number of metastatic sites was 4 [2-4] in T790M-positive vs. 2 [1-5] in T790M-negative.

      In patients with isolated central nervous system progression (iCNS), EGFRmut was detected in 33% (5/15), and 2 cases had EGFR T790M. In patients with isolated thoracic progression, 60% (9/15) had positive EGFRmut, among who one case had the EGFR T790M mutation.

      Conclusion

      Liquid biopsy by digital PCR is a high sensitive tool for EGFR detection at diagnosis. At progression, liquid biopsy positivity for activating and resistance mutations was more likely observed in case of systemic progression and a high tumor burden. ddPCR could be used to provide a rapid molecular result to guide treatment selection in NSCLC.

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    P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P84.01 - The ARIA Study: Activity of Next-Generation ALK TKIs Based on ALK Resistance Mutations Detected by Liquid Biopsy in ALK Positive NSCLC Patients. (ID 3092)

      00:00 - 00:00  |  Author(s): Mihaela Aldea

      • Abstract
      • Slides

      Introduction

      Detection of resistance mechanisms to tyrosine kinase inhibitors (TKI), in particular ALK mutations (ALKm), could help to select the subsequent treatment in ALK-positive NSCLC patients. Liquid biopsy can identify these ALKm from ctDNA in up to 29% of patients after 2nd-generation TKI-failure. We assessed the activity of next-gen TKIs based on the presence of ctDNA ALKm.

      Methods

      Patients with ALK-positive advanced NSCLC pretreated with 1st and/or 2nd-generation ALK-TKI were selected in 9 European centers. Liquid biopsy was collected immediately before starting brigatinib or lorlatinib. ALKm were defined by commercial or homemade next-generation sequencing run on ctDNA and covering ALK exon 22/23/25. We correlated the activity of brigatinib or lorlatinib based on three ctDNA molecular groups: presence ALKm (if one: single; if ≥2: complex); other mutations and no detectable mutations. We assessed progression-free survival (PFS), objective response rate (ORR), intracranial ORR according to the clinical routine of each center and overall survival (OS).

      Results

      62 patients were identified, 58 evaluable at cutoff data (Jul-20): 16 before brigatinib and 42 before lorlatinib. Median age was 53 [27-80], 64% were female, 67% nonsmoker; 97% with adenocarcinoma; 7% and 10% with isolated thoracic and brain disease, respectively. The median (m) number of TKIs was 3 [2-7]; 90% received 2nd-generation TKIs. The mFU since liquid biopsy was 24.8 months. ALKm were detected in 28% (3 brigatinib; 13 lorlatinib), 9 single and 7 complex; others were detected in 17% (n=10) and none in 55% (n=32). The most common mutation was G1202R (7 before lorlatinib), followed by G1269A and F1174L in 3 cases each, all pretreated with 2nd-generation TKIs. The TKI outcomes according to the ctDNA molecular groups is summarized in table 1. In the ALKm group, lorlatinib showed an ORR of 46% and 56% of intracranial ORR with mPFS of 6.5 months (7=single/6=complex) while no responses were observed in the 3 cases treated with brigatinib, with mPFS of 3.5 months (2=single/1=complex).Those 7 cases harboring the G1202Rmut (4=complex) had an ORR of only 14% but an intracranial ORR of 50%; mPFS was 3.6 mo. No differences were observed among ctDNA molecular groups.

      Overall

      ALK mutations

      Others

      None

      BRIGATINIB

      N=16

      n= 3

      n=3

      n= 10

      PFS, median (95% CI)

      5.6 months

      (4.27-16.79)

      3.5 months

      (2.63-NR)

      6.2 months

      (4.27-NR)

      8.1 months

      (4.40-NR)

      12 months-PFS rate

      27.3 %

      (11.9-62.6)

      33.3%

      (6.7-100)

      0%

      40%

      (18.7-85.5)

      ORR

      27%

      (4/15)

      0%

      (0/3)

      67%

      (2/3)

      22%

      (2/9)

      ORR CNS

      50%

      (6/12)

      0%

      (0/2)

      100%

      (2/2)

      50%
      (4/8)

      OS*, median (95% CI)

      62.6 months

      (31.7-not reached)

      38.4 months

      (31.7-NR)

      62.6 months

      (21 .4-NR)

      NR

      (24.5-NR)

      LORLATINIB

      N= 42

      n= 13

      n= 7

      n= 22

      PFS, median (95% CI)

      7.6 months

      (5.26- 11.14)

      6.5 months

      (3.61-NR)

      7.6 months

      (5.22-NR)

      7.3 months

      (4.63-NR)

      12 months-PFS rate

      29.5%

      (17.7-49.1)

      30%

      (12.0-74.7)

      28.6%

      (8.9-92.2)

      30%

      (14.6-61.6)

      ORR

      38%

      (16/58)

      46%

      (6/13)

      71%

      (5/7)

      23%

      (5/22)

      ORR CNS

      62%

      (18/29)

      56%

      (5/9)

      60%

      (3/5)

      67%

      (10/15)

      OS*, median (95% CI)

      55.5 months

      (45.0-NR)

      62.6 months

      (54.8-NR)

      45.0 months

      (24.5-NR)

      NR

      (41.9-NR)

      PFS: progression-free survival; ORR: objective response rate; CNS: central nervous system; OS: overall survival; *since systemic therapy start

      Conclusion

      In our study, lorlatinib showed activity in heavily-pretreated patients with ALK-positive NSCLC, regardless the ctDNA molecular groups. Poor outcomes were observed for brigatinib in 3 heavily-pretreated patients with ctDNA ALKm. The recent use of 2nd-gen TKI upfront calls for similar studies to confirm if ctDNA may be a biomarker for guiding the sequential therapy.

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