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Transl Lung Cancer Res
2021 May 01;105:2118-2131. doi: 10.21037/tlcr-21-32.
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Earlier extracranial progression and shorter survival in ALK-rearranged lung cancer with positive liquid rebiopsies.
Christopoulos P
,
Dietz S
,
Angeles AK
,
Rheinheimer S
,
Kazdal D
,
Volckmar AL
,
Janke F
,
Endris V
,
Meister M
,
Kriegsmann M
,
Zemojtel T
,
Reck M
,
Stenzinger A
,
Thomas M
,
Sültmann H
.
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BACKGROUND: Liquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK+) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI). Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome.
METHODS: Clinical, molecular, and radiologic characteristics of consecutive TKI-treated ALK+ NSCLC patients were analyzed using prospectively collected plasma samples and the 17-gene targeted AVENIO kit, which covers oncogenic drivers and all TP53 exons.
RESULTS: In 56 patients, 139 instances of radiologic changes were analyzed, of which 133 corresponded to disease progression. Circulating tumor DNA (ctDNA) alterations were identified in most instances of extracranial progression (58/94 or 62%), especially if concomitant intracranial progression was also present (89%, P<0.001), but rarely in case of isolated central nervous system (CNS) progression (8/39 or 21%, P<0.001). ctDNA detectability correlated with presence of "short" echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants (mainly V3, E6:A20) and/or TP53 mutations (P<0.05), and presented therapeutic opportunities in <50% of cases. Patients with extracranial progression and positive liquid biopsies had shorter survival from the start of palliative treatment (mean 52 vs. 69 months, P=0.002), regardless of previous and subsequent therapy and initial ECOG performance status. Furthermore, for patients with extracranial progression, ctDNA detectability was associated with shorter next-line progression-free survival (PFS) (3 vs. 13 months, P=0.003) if they were switched to another systemic therapy (49/86 samples), and with shorter time-to-next-treatment (TNT) (3 vs. 8 months, P=0.004) if they were continued on the same treatment due to oligoprogression (37/86). In contrast, ctDNA detectability was not associated with the outcome of patients showing CNS-only progression. In 6/6 cases with suspicion of non-neoplastic radiologic lung changes (mainly infection or pneumonitis), ctDNA results remained negative.
CONCLUSIONS: Positive blood-based liquid rebiopsies in ALK+ NSCLC characterize biologically more aggressive disease and are common with extracranial, but rare with CNS-only progression or benign radiologic changes. These results reconcile the increased detection of ALK resistance mutations with other features of the high-risk EML4-ALK V3-associated phenotype. Conversely, most oligoprogressive patients with negative liquid biopsies have a more indolent course without need for early change of systemic treatment.
Figure 2. Liquid biopsy positivity according to the anatomical pattern of disease progression in ALK+ NSCLC. Liquid biopsies were positive in 8/39 (21%, 95% CI: 9–36%) instances of CNS-only progression, 33/67 (49%, 95% CI: 37–62%) instances of CNS (±extracranial) progression, 58/94 (62%, 95% CI: 51–72%) instances of extracranial (±CNS) progression, and 25/28 (89%, 95% CI: 72–98%) instances of concomitant extracranial and CNS progression.
Figure 3. Patient survival according to the results of liquid biopsies at disease progression. (A) The median overall survival (OS) from the time-point of liquid biopsy collection was 13 months (95% CI: 9.6–15.4 months) in case of positive vs. 28 months (95% CI: 25–29 months) in case of negative liquid biopsies (logrank P<0.001). (B) The median OS from start of palliative systemic treatment for stage IV disease was 45 months (95% CI: 39–52 months) in case of positive vs. 62 months (95% CI: 48–75 months) in case of negative liquid biopsies (logrank P=0.005). (C) The median OS from start of palliative systemic treatment with extracranial progression was 40 months (95% CI: 29–51 months; mean 52 months, 95% CI: 41–63 months) in case of positive vs. not-reached (mean 69 months, 95% CI: 56–83 months) in case of negative liquid biopsies (logrank P=0.002). (D) The median overall survival (OS) from start of palliative systemic treatment with intracranial only progression was 115 months (95% CI: not available) in case of positive vs. 62 months (95% CI: 46–77 months) in case of negative liquid biopsies (logrank P=0.19). (E) The median progression-free survival (PFS) for next-line treatment with immediate switched to another systemic treatment was 13 months (95% CI: 5–21 months) in case of negative vs. 3 months (95% CI: 2–4 months) in case of positive liquid biopsies (logrank P=0.003). (F) The median time-to-next-treatment (TNT) with continuation of the same systemic treatment beyond disease progression was 8 months (95% CI: 6–9 months) in case of negative vs. 3 months (95% CI: 2–5 months) in case of positive liquid biopsies (logrank P=0.004).
Figure 4. The phenotype of ALK+ NSCLC patients with positive liquid biopsies at disease progression. Baseline characteristics, clinical course, and outcome of ALK+ NSCLC patients with positive and negative liquid rebiopsies according to the findings of this study. Values on the time axis are based on the results shown in Table 1.
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