If you had to have stage IV lung cancer, is ALK-positive the best type to have? | Dr Dilanka De Silva

A diagnosis of stage IV lung cancer is devastating.

But not all lung cancers behave in the same way—and today, the molecular result can be almost as important as the stage.

I recently met a 49-year-old woman from the Philippines who had never smoked. She had developed left-sided abdominal pain, and her general practitioner arranged imaging because a kidney stone was suspected.

The scan did identify a kidney stone.

However, it also showed something completely unexpected: a lung nodule.

Further investigation subsequently confirmed stage IV lung cancer, with disease involving both lungs.
She had gone for a scan because of abdominal pain and emerged with a completely unexpected cancer diagnosis.

Understandably, she was devastated.

However, I explained that we still did not have one of the most important pieces of information.

We knew where the cancer had spread, but we did not yet know what was driving it.

Comprehensive molecular sequencing subsequently identified an ALK fusion, confirming ALK positive lung cancer.

I told her:

“Nobody wants to have lung cancer. But once lung cancer has been diagnosed, finding an ALK fusion is one of the more favourable molecular results we can receive.”

This did not make the diagnosis disappear.

Stage IV lung cancer remains a serious illness and is usually not considered curable.

But it completely changed our expectations of what treatment might achieve.

Who is this article for?

This article may be helpful if:

• you have been diagnosed with ALK positive lung cancer;
• you are waiting for molecular testing after a diagnosis of advanced lung cancer;
• you have never smoked or smoked very little and have developed lung cancer;
• your oncologist has discussed lorlatinib, alectinib or brigatinib;
• you have brain metastases from ALK positive lung cancer; or
• you are wondering why molecular testing can change treatment so dramatically.

The question patients often ask

“If I have lung cancer, what is the best type to have?”

It is an uncomfortable question, but an entirely reasonable one.

If we are talking about advanced non-small cell lung cancer and are forced to compare molecular subtypes, ALK positive lung cancer is one of the most treatable forms we currently have.

I would avoid calling it definitively “the best,” because every patient and every cancer behaves differently.

But modern ALK-targeted treatments can produce deep responses, control cancer for years in some patients and provide particularly strong protection against progression within the brain.

In the landmark CROWN trial, approximately 60 in every 100 patients receiving first-line lorlatinib were still alive without their cancer progressing at five years.

The median progression-free survival had still not been reached.

In patient language, this means that even after five years, more than half of the patients treated with lorlatinib had still not reached the point at which their cancer had progressed.

That is an extraordinary result in stage IV lung cancer.

From chemotherapy to a small tablet

When I was training in oncology, EGFR-targeted therapy was one of the developments that completely changed how we thought about lung cancer.

Previously, patients with advanced lung cancer were generally treated with broad chemotherapy.

Chemotherapy attacks rapidly dividing cells, including cancer cells, but it can also affect normal tissues.

The discovery of EGFR mutations showed us something different.

In selected patients, we could identify the molecular signal driving the cancer and block it with a tablet designed specifically for that target.

It was one of the developments that helped establish precision medicine in lung cancer.

Soon afterwards, researchers identified another molecular driver: the ALK fusion.

This was not simply another mutation.

It revealed a distinct biological form of lung cancer—seen particularly in younger patients, people who have never smoked or smoked very little, and often people whose diagnosis comes as a complete shock.

EGFR mutation and ALK fusion: what is the difference?

A common EGFR alteration, such as L858R, involves a change in a single part of the EGFR protein.

An ALK fusion is created differently.

A section of the ALK gene becomes joined to another gene, most commonly EML4.

This rearrangement creates an abnormal fusion protein that continually sends signals telling the cancer cell to grow and survive.

It is tempting to say that ALK is a better treatment target because a fusion is a “bigger” genetic change than a single mutation.

That is not really how the biology works.

The physical size of the genetic alteration is not what determines whether treatment will work.

The more important idea is that some cancers become heavily dependent on one abnormal growth signal. In oncology, we call this oncogene addiction.

ALK positive lung cancer can become heavily dependent on the abnormal ALK signal.

If we block that signal effectively, the cancer can sometimes shrink dramatically.

EGFR-positive and HER2-mutant lung cancers can also be strongly driven by their molecular alteration and can respond very well to targeted treatment.

But differences in tumour biology, coexisting mutations, resistance pathways, drug design and brain penetration mean that the duration of control is not identical across every molecular subtype.

A better analogy than “a bigger target”

Imagine that a cancer cell is a building.

In some cancers, many different columns support the building. Removing one column may weaken it, but the structure remains standing.

An ALK-positive cancer may rely much more heavily on one abnormal central column.

ALK-targeted therapy is designed to strike that support.

The success of modern ALK treatment comes from a combination of three things:

1. the cancer’s strong dependence on ALK signalling;
2. our detailed understanding of how ALK changes when resistance develops; and
3. the deliberate engineering of newer drugs to overcome resistance and reach the brain.

How treatment for ALK positive lung cancer has evolved

The first important ALK inhibitor was crizotinib.

It produced responses that were remarkable at the time and established ALK as a genuine treatment target.

However, crizotinib had limitations.

Cancer could develop resistance, and the drug did not control disease in the brain as effectively as we wanted.

Scientists then developed more potent second-generation ALK inhibitors, including:

• alectinib
• brigatinib

These medicines improved cancer control throughout the body and were substantially more active in the brain.

Lorlatinib is a third-generation ALK inhibitor.

Lorlatinib was deliberately designed as a compact molecule that could bind strongly to ALK, overcome several resistance mutations and cross the blood-brain barrier—the protective barrier that makes it difficult for some medicines to enter the brain.

This is a remarkable example of medicinal chemistry directly influencing what happens to patients.

Lorlatinib did not appear by chance.

Researchers studied how earlier drugs interacted with ALK, identified structural changes that caused resistance and then deliberately designed a molecule capable of overcoming many of those problems.

What did the CROWN trial show?

The phase III CROWN trial compared first-line lorlatinib with crizotinib in 296 patients with advanced ALK-positive non-small cell lung cancer.

After approximately five years of follow-up:

• about 60 in every 100 patients treated with lorlatinib were alive without progression;
• compared with about 8 in every 100 receiving crizotinib;
• the relative risk of progression or death was reduced by approximately 81% with lorlatinib; and
• the median progression-free survival with lorlatinib had still not been reached.

These numbers need to be interpreted carefully.

They do not mean that 60% of patients were cured.

They mean that at the five-year time point, approximately 60% had not yet experienced disease progression or death.

For metastatic lung cancer, that degree of long-term disease control is remarkable.

Why the brain matters so much

The brain can behave like a sanctuary site in lung cancer.

Some treatments may control cancer elsewhere in the body but do not reach adequate concentrations inside the brain because of the blood-brain barrier.

Cancer cells can therefore survive or progress in the brain even while disease elsewhere remains controlled.

Lorlatinib was specifically designed to penetrate the brain.

In the five-year CROWN analysis, progression in the brain was much less common with lorlatinib than with crizotinib.

Among patients who had no brain metastases when lorlatinib was started, approximately 96 in every 100 remained free of new brain metastases at five years.

Only 4 of 114 patients developed new intracranial lesions during the reported follow-up.

For patients who already had brain metastases, lorlatinib also showed strong and often durable activity in the brain.

This ability to control existing brain metastases—and reduce the chance of new ones developing—is one of the major reasons modern ALK treatment has changed expectations so much.

Why does resistance still develop?

Targeted therapy places evolutionary pressure on a cancer.

Some cancer cells may acquire a new alteration within ALK itself.

This is called on-target resistance because the cancer changes the very target the drug is attacking.

Other cancers activate an alternative growth pathway.

Sometimes the cancer finds another growth pathway and works around the blocked ALK signal. This is called bypass resistance.

With earlier ALK inhibitors, the cancer could sometimes develop new ALK mutations that reduced how well the treatment worked.

Lorlatinib was specifically engineered to suppress many of them.

In the CROWN analysis, no new ALK resistance mutations were detected in the available blood samples that were analysed for circulating tumour DNA—small fragments of cancer DNA found in the bloodstream—at the end of lorlatinib treatment.

That finding should be interpreted cautiously because samples were available only from a subset of patients.

It does not mean resistance has been eliminated.

Rather, it suggests that modern drug design has made it more difficult for the cancer to escape through some of the usual ALK resistance pathways, while alternative bypass mechanisms can still emerge.

What about ROS1, EGFR and HER2?

ALK is not the only important molecular target in lung cancer.

ROS1

ROS1-positive lung cancer is also commonly driven by a gene fusion.

ALK and ROS1 share some structural similarities, and some medicines can inhibit both proteins.

However, they are not the same disease, and the evidence, approved treatments and treatment sequencing differ.

EGFR

EGFR-positive lung cancer remains one of the great successes of precision oncology.

Modern EGFR inhibitors such as osimertinib can produce prolonged disease control and have meaningful activity in the brain.

However, EGFR-positive cancers can develop several different resistance mechanisms, and their long-term outcomes should not simply be assumed to be identical to those seen in the CROWN ALK population.

HER2

HER2-mutant lung cancer is also becoming increasingly treatable.

Antibody-drug conjugates such as trastuzumab deruxtecan can produce meaningful responses, but the treatment is intravenous, the evidence comes from different clinical settings and toxicities such as interstitial lung disease require careful monitoring.

The point is not that ALK therapy works better because an ALK fusion is somehow a “larger” target.

ALK-positive lung cancer represents a particularly successful combination of:

strong tumour dependence + rational drug design + resistance-directed development + excellent brain penetration.

Does everyone with ALK positive lung cancer receive lorlatinib first?

Not necessarily.

Lorlatinib, alectinib and brigatinib are all highly active first-line treatment options for advanced ALK-positive NSCLC.

The choice depends on factors such as:

• whether brain metastases are present;
• other medical conditions;
• potential side effects;
• previous treatment;
• treatment availability;
• patient preference; and
• the treating oncologist’s assessment.

Lorlatinib has a distinctive side-effect profile.

Potential adverse effects include:

• increased cholesterol and triglycerides;
• fluid retention;
• weight gain;
• peripheral neuropathy, such as numbness or tingling in the hands or feet; and
• cognitive, mood or speech changes.

These effects require active monitoring.

Dose reduction can sometimes be appropriate, and available CROWN analyses suggest that early dose reduction did not appear to compromise progression-free survival, although this was not a randomised comparison specifically designed to answer that question.

Why comprehensive molecular sequencing matters

My patient’s CT scan could tell us that she had stage IV lung cancer.

It could not tell us how that cancer should be treated.

That required adequate tumour tissue and comprehensive molecular testing.

In advanced non-squamous non-small cell lung cancer, testing should appropriately assess clinically relevant alterations such as:

• ALK;
• EGFR;
• ROS1;
• BRAF;
• KRAS;
• MET;
• RET;
• NTRK;
• HER2/ERBB2; and
• other actionable genomic changes.

The method of testing matters as well.

Some gene fusions can be missed if the assay is not designed to detect them reliably.

Depending on the situation, RNA-based sequencing, comprehensive tissue testing or complementary blood-based testing may provide additional information.

If a patient is clinically stable, obtaining adequate molecular information before committing to systemic treatment can be extremely important.

If the patient is unwell and urgent treatment is required, decisions may need to be made more quickly.

A stage IV diagnosis tells us how far the cancer has travelled.

Molecular sequencing tells us what may stop it.

What would I usually consider?

When reviewing someone with newly diagnosed advanced non-squamous lung cancer, I would want to know:

• Was comprehensive molecular sequencing performed?
• Was the molecular test designed to detect gene fusions reliably?
• Was there enough tumour tissue?
• Could RNA-based testing help detect a gene fusion that another test may have missed?
• Would a liquid biopsy provide complementary information?
• Are there brain metastases?
• Which ALK inhibitor is most appropriate for this patient?
• What toxicities matter most in their individual circumstances?
• Are there access or clinical-trial considerations?
• Would a specialist molecular review or second opinion change the treatment plan?

The purpose is not simply to order the largest possible genomic panel.

It is to make sure we have identified the biology that actually matters.

The message I gave my patient

I could not tell this 49-year-old woman that her diagnosis was insignificant.

It was not.

I could not promise that treatment would cure her.

But I could tell her something honest and genuinely hopeful:

“The scan has found stage IV lung cancer. But the sequencing has found one of the most treatable forms of it. We now have tablets specifically designed for the biology driving your cancer, including medicines that can control disease in the brain. This is not the same treatment landscape that stage IV lung cancer had a decade ago.”

That is the power of precision oncology.

The most important question is no longer simply:

“Do I have lung cancer?”

It is:

“What is driving my lung cancer, and have we tested comprehensively enough to find it?”

For someone with ALK-positive lung cancer, the answer can completely change the treatment conversation.

Key takeaways

• ALK positive lung cancer is one of the most treatable molecular subtypes of advanced non-small cell lung cancer.
• In CROWN, about 60 in every 100 patients receiving first-line lorlatinib remained progression-free at five years.
• Modern ALK inhibitors provide particularly strong control within the brain.
• Lorlatinib, alectinib and brigatinib are all important first-line options; the best choice depends on the individual patient.
• Comprehensive molecular testing is particularly important because finding an ALK fusion can completely change the treatment strategy.

Key evidence

1. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200/JCO.24.00581
2. Puri S, Ismaila N, Azar IH, et al. Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO Living Guideline, version 2026.3.2. J Clin Oncol. Published online June 29, 2026. doi:10.1200/JCO-26-01479
3. Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014;57(11):4720-4744. doi:10.1021/jm500261q
4. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
5. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol. 2023;41(31):4852-4863. doi:10.1200/JCO.23.01361

Frequently asked questions (FAQs)

1. Is ALK-positive stage IV lung cancer curable?

Usually not with current systemic treatments. Treatment is generally aimed at long-term disease control rather than cure.

However, some patients can remain well with controlled cancer for many years, and outcomes are now substantially better than historical expectations for stage IV lung cancer.

2. Does every patient with ALK positive lung cancer receive lorlatinib first?

No.

Lorlatinib, alectinib and brigatinib are all highly active options. The choice depends on factors such as brain involvement, other health conditions, side effects, access and patient preference.

3. Can someone who has never smoked develop lung cancer?

Yes.

Lung cancer can occur in people who have never smoked. Molecular drivers such as ALK, EGFR and ROS1 are particularly important to look for in this group.

4. Does 60% progression-free at five years mean 60% are cured?

No.

It means that about 60 in every 100 patients treated with lorlatinib had not experienced disease progression or death by the five-year time point.

5. What side effects can lorlatinib cause?

Potential side effects include raised cholesterol and triglycerides, swelling, weight gain, peripheral neuropathy such as numbness or tingling in the hands or feet, and cognitive, mood or speech changes.

These effects should be monitored and can sometimes be managed with supportive treatment or dose adjustment.

6. Should I seek a second opinion?

A second opinion may be helpful if:

1. • molecular testing was incomplete;
   • only a limited mutation panel was performed;
   • an ALK fusion was detected but treatment has not yet started;
   • the cancer has progressed on an ALK inhibitor;
   • brain metastases are present; or
   • there is uncertainty about treatment sequencing or clinical trials.

Patients seeking a specialist review should ideally provide their pathology report, molecular sequencing results, imaging reports and treatment history. Where available, original pathology material and imaging files can also be useful.

About Dr Dilanka De Silva

Dr Dilanka De Silva is a Melbourne-based Medical Oncologist and Cancer Genetics Physician with experience in precision oncology, molecularly targeted treatment and complex cancer second opinions.

He completed fellowship training at Memorial Sloan Kettering Cancer Center in New York.

He reviews Australian and international patients, including patients from Malaysia, the Philippines and elsewhere in the Asia-Pacific region.

Dr Dilanka De Silva
MBBS, MRCP(UK), MRCP(UK SCE Oncology), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Memorial Sloan Kettering Cancer Center Fellow (New York, USA)