Liquid Pulse: Reading ALK Fusions in Plasma — What the Assay Can and Can't Tell You

The clinical question

When a patient is diagnosed with non-small-cell lung cancer (NSCLC), one of the first molecular questions is whether the tumor harbors an ALK rearrangement — a gene fusion that keeps the ALK tyrosine kinase constitutively switched on. The stakes are practical: an ALK fusion gates eligibility for a whole class of therapies, the ALK tyrosine kinase inhibitors (TKIs), and there's now an adjuvant indication for early-stage ALK-positive disease as well [1]. So the biomarker isn't a nice-to-have; it's a fork in the road for treatment planning.

The trouble is that tissue isn't always available. Some patients present with lesions that are hard to biopsy safely, some biopsies yield too little tumor for reliable molecular work, and some patients are simply too unwell to send back for another core. That's the gap a plasma-based assay is meant to fill. The clinical question a liquid biopsy informs here is narrow and specific: Is there detectable ALK fusion signal in this patient's circulating tumor DNA, and can that finding stand in for — or complement — a tissue result to open the door to an ALK TKI? [1]

It's worth being clear up front about the direction of confidence. A positive plasma result is highly informative. A negative plasma result is not the same as a negative patient — it may simply mean the tumor isn't shedding enough DNA into the bloodstream to be caught.

What's measured, and how

The analyte is cell-free circulating tumor DNA (ctDNA) — fragments of tumor-derived DNA that spill into plasma as tumor cells turn over. In an ALK-rearrangement workflow, the assay is looking for the fusion breakpoint or fusion transcript that signals the rearrangement is present.

The FDA-approved anchor in this space is FoundationOne Liquid CDx, a plasma next-generation sequencing (NGS) companion diagnostic that includes ALK rearrangement detection among its approved biomarker calls [2]. As of 2024, Foundation Medicine also offers a FoundationOne RNA add-on for combined DNA-plus-RNA fusion detection. That combination matters mechanistically: fusion genes can involve large or variable intronic breakpoints that are hard to capture from DNA alone, so adding an RNA-based readout can raise sensitivity for fusion-positive calls that a DNA-only approach might miss [2].

The sensitivity caveat is the heart of the matter. Plasma assays are constrained by how much tumor DNA is actually circulating. A patient with low-volume, non-shedding, or intrathoracic-only disease may have vanishingly little ctDNA, which pushes the true fusion below the assay's limit of detection. This is why the specimen framework for ALK testing treats FFPE tissue and ctDNA as complementary paths rather than interchangeable ones, and why a screening-then-confirmation logic — a sensitive screen followed by molecular confirmation — remains the backbone of ALK workup [1].

The evidence

The case for plasma ALK detection has moved from scattered single-institution reports toward pooled quantification. A 2025 systematic review and meta-analysis of 14 studies examined the diagnostic accuracy of ctDNA for detecting ALK rearrangement in lung cancer, and its pooled sensitivity and specificity estimates support ctDNA as a reasonable non-invasive complement — or alternative — to tissue-based FISH and IHC in patients for whom biopsy isn't feasible [3]. The evidence suggests that when plasma is positive, it's trustworthy; the more instructive question, as always with fusion detection in blood, is how many true positives slip through when tumor shedding is low. A meta-analysis is the right tool to average across that heterogeneity, though readers should remember it inherits the design differences of its 14 component studies.

On the regulatory side, the picture is more settled. FoundationOne Liquid CDx holds FDA-approved companion-diagnostic status encompassing ALK fusion detection from plasma, which means its use to identify candidates for the relevant therapy class rests on formal companion-diagnostic validation rather than laboratory-developed-test discretion alone [2]. That's an important distinction for clinicians weighing how much regulatory weight sits behind a given result.

Access has been catching up to the science. A major US payer, Blue Cross Blue Shield of Michigan, issued a medical policy effective September 2024 that codifies coverage criteria for ctDNA liquid biopsy in NSCLC management and recognizes ALK rearrangement as a covered biomarker indication when tissue is insufficient [4]. Payer alignment of this kind doesn't change the biology, but it changes whether the plasma path is realistically available at the point of care — and it explicitly frames ctDNA testing as appropriate in the tissue-insufficient scenario, which is exactly where the clinical question bites hardest.

Where it stands

For frontline detection of ALK rearrangement, plasma NGS is on firm footing: there's an FDA-approved companion diagnostic, meta-analytic evidence supporting diagnostic accuracy, and formal payer coverage in the tissue-insufficient setting [2][3][4]. The reasonable reading of the current landscape is that a plasma-positive ALK result can open access to the ALK TKI class, and that ctDNA is a legitimate first move when tissue can't be obtained — with the standing caveat that a negative plasma result shouldn't close the door on tissue confirmation.

Where things remain genuinely investigational is the broader ambition of using ctDNA dynamically — for minimal (or molecular) residual disease monitoring and MRD-guided treatment decisions. The idea of tracking ALK-fusion ctDNA over time to catch relapse early, or to modulate therapy based on clearance, is biologically attractive and connects naturally to the adjuvant ALK-positive indication [1]. But the developments confirmed here speak to detection accuracy and companion-diagnostic use, not to validated MRD-guided decision-making. That distinction is worth holding firmly: using a plasma assay to find an ALK fusion at diagnosis is supported; using serial plasma to drive escalation or de-escalation of therapy is not yet established practice and should be regarded as investigational.

None of this substitutes for a treating clinician's judgment, and nothing here is treatment advice for an individual. What plasma ALK testing offers is a well-validated way to answer one specific, high-stakes question — fusion present or absent — when the tissue path is blocked, and to do so with enough regulatory and evidentiary backing that a positive result carries real clinical weight.

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References

1. Lung targeted therapy references and FDA alectinib adjuvant ALK NSCLC labeling (companion-diagnostic and adjuvant indication basis). 2025. [lung_targeted_2025; fda_alectinib_adjuvant_alk_nsclc]

2. Foundation Medicine. FoundationOne Liquid CDx — Test Overview and FoundationOne RNA Add-On. Foundation Medicine (foundationmedicine.com/test/foundationone-liquid-cdx), 2024. [FM-LiquidCDx-2024]

3. Unspecified (multi-author systematic review team). Diagnostic accuracy of circulating tumor DNA for detection of ALK rearrangement in lung cancer: A systematic review and meta-analysis of 14 studies. PMC / PubMed Central (NCBI), 2025. PMC12377591.

4. Blue Cross Blue Shield of Michigan / BCN. Medical Policy: Circulating Tumor DNA for Management of Non-Small-Cell Lung Cancer (Liquid Biopsy). BCBSM Medical Policy Document 2132866, 2024. [BCBSM-ctDNA-NSCLC-2024]