What is ALK-Positive Cancer?

Genes carry the instructions that help our cells function normally. In ALK-positive lung cancer, part of the ALK gene breaks off and fuses with another gene. This “fusion” acts like a stuck accelerator pedal, driving cancer growth.

It’s important to remember:

• The change is acquired, not inherited. It develops in cells over time and is not something you were born with.
• Having ALK-positive lung cancer does not mean you did anything to cause it.
• Many people diagnosed with ALK-positive NSCLC have never smoked or have only a light smoking history.
• Because ALK-positive cancer is driven by a specific change, it can often be treated more precisely than lung cancers without a clear target.

ALK-positive cancers can occur in both children and adults, including:

• Certain non-small cell lung cancers (NSCLC)
• Some lymphomas
• Rare cancers

Anyone can develop ALK-positive lung cancer, but it is more commonly seen in:

• People who are never-smokers or light smokers.
• People diagnosed at a younger age than the typical lung cancer population (often under 60).

It is important that the ALK-positive biomarker is identified early, as there are specific treatment options for it.

Fortunately, there are advanced targeted therapies designed specifically to block the faulty ALK signal. These treatments are taken as pills and work by slowing or even stopping the growth of cancer cells driven by the ALK fusion—without affecting healthy cells as much as traditional treatments often do.

Thanks to these therapies:

• Many people with ALK-positive cancer are able to live active, full lives.
• Treatment can remain effective for years, including in the brain, for some patients.
• Side effects can often be managed with dose adjustments, supportive care, and specialist input.

In Canada, commonly prescribed treatments include alectinib and lorlatinib. Research is also progressing rapidly, with promising new options like neladalkib by Nuvalent.

Learn more about targeted therapies such as TKIs here.

Having ALK-positive cancer means that testing was done to confirm it. Here is an overview of that testing and when to re-test.

Why full molecular testing matters before starting treatment

Before you begin treatment, your medical team will run molecular testing on your tumour. This step is essential—it confirms the ALK fusion and may reveal other genetic changes (such as TP53) that can influence how well a treatment works and how the cancer might respond over time. Getting this complete picture upfront helps your team choose the most effective therapy from the start.

The most thorough approach is called next-generation sequencing (NGS), which examines many genes at once rather than testing for one change at a time.

How ALK is tested

There are two main ways to test for ALK:

1. Tissue biopsy – A small sample of tumour tissue is taken and examined in the lab. Pathologists use techniques such as immunohistochemistry and NGS to confirm the ALK fusion. Tissue biopsy remains the gold standard because it gives the most detailed view of the tumour, including its structure and cell type.
2. Liquid biopsy (blood test) – A simple blood draw that looks for tumour DNA circulating in the bloodstream (called ctDNA). It can detect ALK fusions and resistance mutations, often with results back days faster than tissue testing. It’s less invasive and can be especially helpful when a tissue biopsy is difficult to obtain or when starting treatment quickly is a priority. Note that this is not standard across Canada and is still being explored as a standard test.

These are the common types of biomarker testing:

• 🧬 NGS (Next-Generation Sequencing) → “broad scan”
• 🎯 IHC (Immunohistochemistry) → “protein detection”
• 🔍 FISH (Fluorescence In Situ Hybridization) → “gene mapping”

When re-testing is recommended

If your cancer begins to grow while you’re on a targeted therapy, your team may recommend re-testing to find out why. Understanding the specific resistance mechanism—any mutations or other changes that caused the treatment to stop working—helps guide what comes next.

How long can targeted therapy work?

One of the most encouraging things about ALK-positive cancer is that modern targeted therapies can keep the disease under control for years—including in the brain, which has historically been harder to treat. For example, five-year data from the CROWN trial showed that lorlatinib, when used as a first treatment, provided lasting benefit in slowing cancer progression and maintaining control of brain metastases, with no unexpected side effects emerging over time.

This durability is a significant reason why getting the right treatment from the start matters greatly.

Managing side effects

Like all medications, targeted therapies come with potential side effects—and each drug has its own profile. For instance, lorlatinib may affect cholesterol levels or cause changes in mood or thinking, while other ALK-targeted therapies may affect muscles or liver function.

The important thing to know is that side effects are usually manageable. Dose adjustments are common and often help restore comfort without losing the treatment’s effectiveness. Your medical team will monitor you closely and can make changes as needed—so it’s always worth speaking up about how you’re feeling.

What happens if treatment stops working?

Over time, cancer cells can develop new changes that allow them to grow despite therapy. This is called resistance, and it doesn’t mean you’ve run out of options—it means your team needs to understand what changed so they can plan the best next step.

There are two main types of resistance:

• On-target resistance: The ALK gene itself develops new mutations that prevent the current drug from blocking it effectively.
• Off-target resistance: The cancer finds an alternative way to grow that doesn’t rely on ALK, or in rare cases, the cancer’s cell type changes.

Once the type of resistance is identified (through re-testing, as described above), they can determine the best path forward. That might mean switching to a different targeted therapy, adding a focused local treatment such as radiation to a specific area that’s growing, or exploring a clinical trial with newer agents.

Research in this area is moving quickly, and new treatment options continue to emerge for people whose cancer has developed resistance.

Medical disclaimer

This information is educational and does not replace medical advice. Always speak with your oncology team about your specific situation.