ALK Treatment

What are the treatment options for advanced or metastatic lung cancer?

What are tyrosine kinase inhibitors (TKIs)?

TKIs are the key treatment for ALK+ lung cancer. They are oral tablets which work by blocking the signalling pathway that the mutated ALK-fusion proteins are using to tell the cancer cell to grow and replicate.

The journey from the discovery of ALK rearrangements in NSCLC (non-small cell lung cancer) in 2007 to the first approval of a TKI in 2013 in the UK is a remarkable success story in medicine.

Crizotinib, a first-in-class, first-generation inhibitor, was the first drug approved for treating ALK+ lung cancer. Over the following decade, advances in biochemistry have led to the development and approval of next-generation inhibitors with enhanced properties. These newer inhibitors offer improved central nervous system (CNS) penetration and increased efficacy against on-target resistant mutations.

These developments have had a significant, positive impact on the treatment landscape for ALK+ lung cancer.

How do TKIs work – and why do they stop working?

The TKIs manipulate the signalling pathways in cancer cells. These signalling pathways refer to a series of molecular interactions and biochemical signals that regulate key cellular processes like growth, division, survival, and apoptosis (programmed cell death).

These pathways normally help maintain cellular homeostasis, but in cancer, they often become dysregulated, leading to uncontrolled cell proliferation, resistance to cell death, and metastasis. The image below shows how the signalling pathways are used within the cancer cell.

How is a TKI selected?

The selection of a TKI is based on these factors:

Availability: which TKIs are available within the NHS (in the UK) for the patient's specific setting
Efficacy: how well the TKI is likely to work
Safety: different TKIs have different side effects. Patients may have other health conditions that can influence the choice of treatment.

The TKIs which are currently approved in the UK are crizotinib (first generation); ceritinib, alectinib and brigatinib (second generation), and lorlatinib (third generation). Lorlatinib is currently only approved for use in previously-treated ALK+ lung cancer in the UK. It is not yet approved as a first-line treatment, but may be in the near future.

A dark blue image with the word 'crizotinib' and a graphic illustrating two oral tablets

1st generation

In clinical trials, crizotinib was shown to be more effective than chemotherapy in treating ALK+ lung cancer (Solomon et al., 2014; Shaw et al., 2013). However, crizotinib has several limitations, including poor penetration into the CNS; a lack of specificity, and the development of on-target resistance mutations which prevent crizotinib from binding effectively to the ALK protein. Therefore, tumour progression typically occurs within one year of starting therapy.

2nd generation

Ceritinib, alectinib, and brigatinib were shown to be effective in ALK+ patients whose tumours had progressed on crizotinib (Yang et al., 2023). Both alectinib and brigatinib were also found to be more effective than crizotinib in the first-line setting (Camidge et al., 2018; Peters et al,. 2017). However, tumour progression typically happens after an average of 2-3 years, caused by both on-target mutations and off-target mutations.

A dark blue image with the word 'lorlatinib' and a graphic illustrating two oral tablets

3rd generation

Lorlatinib has shown to be effective in patients who had previously progressed on first and/or second-generation inhibitors (Solomon et al., 2018). When compared to crizotinib in the first-line setting, lorlatinib also showed an impressive improvement in progression-free survival and was shown to be effective in the brain (Solomon et al., 2018). Lorlatinib can work effectively against many on-target mutations; however, the tumour usually becomes resistant due to off-target mutations.

There are several things we don’t yet know. Currently, no trials compare second- and third-generation ALK inhibitors directly in a first-line setting. Therefore, we don’t have sufficient evidence to definitively say that any one TKI is superior to the others. There is also not enough evidence to support a specific sequencing strategy (the order in which the TKIs are used).

The flowchart below shows the order in which TKIs are currently given in the UK, according to guidance from NICE (the National Institute for Health and Care Excellence). Your oncology team will select a first-line treatment depending on your particular cancer and circumstances. If this treatment stops working, or needs to be stopped due to side effects, you will usually be given the second-line treatment as shown below.

(Flowchart last updated February 2025)

Download flowchart

Click here for the full NICE guidelines (see page 28)

You can find out more about the clinical trials that influenced the use of TKIs in the resources section.

Why do TKIs eventually stop working?

As the TKIs target a specific dysregulated pathway, over time, cancer cells develop resistance to the treatment by different mechanisms. These mechanisms are:

On-target mutations	Off-target mutations
These mutations change the structure of the ALK protein. This means the TKI can no longer bind to it effectively.	This is where the tumour cell uses alternative signalling pathways to bypass the TKI. This means the message telling the cell to grow and replicate can get through again.

The video below illustrates the way in which off-target mutations allow the cancer cells to use alternative signalling pathways to bypass the TKIs.

These are the steps that might be taken if your cancer progresses while on a TKI treatment (use the arrows to scroll through the four possible steps).

The sequencing of ALK TKIs depends on the generation of the inhibitor used as the initial treatment. If a patient starts on a first-generation ALK TKI, such as crizotinib, progression typically leads to the use of a second-generation inhibitor like alectinib, brigatinib, or ceritinib. In the event of further progression, a third-generation inhibitor like lorlatinib can be employed due to its efficacy against resistant mutations. If a patient begins treatment with a second-generation ALK TKI, subsequent progression might directly lead to lorlatinib. The choice of subsequent therapies is influenced by the specific resistance mechanisms that arise and the patient's overall clinical profile. Currently, there is insufficient evidence to support a specific sequencing strategy.

When a patient experiences disease progression, obtaining a new biopsy from a growing or new lesion is increasingly common. This biopsy helps rule out transformations to small cell or squamous cell carcinoma, which can significantly influence subsequent treatment decisions. Additionally, it may provide opportunities for the patient to participate in clinical trials. However, the decision to perform a new biopsy must be carefully weighed, considering both the risks and potential benefits for the patient.

If a tumour is growing in one/a few locations while the disease is otherwise under control (oligoprogressive disease), local treatment (mainly radiotherapy, although surgery can also be considered) combined with continuing the same TKI may be an option. The most common local treatments given are stereotactic ablative radiotherapy (SABR) for extracranial lesions and stereotactic radiosurgery (SRS) for brain metastases. These 'targeted radiotherapy' approaches deliver a high radiation dose to specific locations while sparing normal tissue. However, if the number or size of progressive lesions means that local treatments are not possible, a change in systemic treatment must be considered.

Once a patient progresses on a third-generation ALK inhibitor, chemotherapy becomes the standard of care. For most patients with ALK+ lung cancer, the preferred treatment is a combination of carboplatin and pemetrexed, administered intravenously every three weeks. If the tumour continues to progress on this regimen and the patient remains fit, the next line of treatment is docetaxel, with or without nintedanib (according to NICE guidelines, correct as of March 2025). This sequential approach aims to manage the disease effectively while considering the patient's overall health and ability to tolerate further treatment.

What are the treatment options for early stage lung cancer?

In early-stage ALK+ lung cancer, if the tumour can be resected (and surgery is suitable for the patient), surgery is usually carried out. This is sometimes accompanied by neoadjuvant or adjuvant chemotherapy.

However, in November 2024, NICE (the National Institute for Health and Care Excellence) approved the use of alectinib after surgery for early-stage ALK+ non-small cell lung cancer (in the UK).

This is because clinical trials showed that when patients were given alectinib after surgery, their cancer was less likely to return than if they were given chemotherapy after surgery (Wu et al., 2024).

Alectinib can be used as adjuvant treatment in adults with tumours staged as 1B to 3A, after the tumour has been completely resected. It can be offered for up to two years with the aim of delaying or preventing the cancer from coming back (NICE, 2024).

For tumours which cannot be removed by surgery, the standard treatment is chemoradiotherapy.

How are brain metastases managed?

Management of brain metastases

Treatment for brain metastases usually consists of two different approaches: systemic therapy (for example, TKI treatment), or local treatment (for example, surgery).

What surveillance should I have after my diagnosis?

There is no ‘one size fits all’ approach to how often and what type of regular tests are needed to monitor lung cancer after diagnosis.

Below is some general information about the surveillance that is often recommended, depending on the stage of the cancer.

Earlier stage lung cancer

Earlier stage lung cancer here refers to cancers which are staged between stage 1 and 3a, which tend to be treated with a curative intent.

While there is no standard follow-up pathway, patients are usually monitored for at least 5 years after the curative treatment (for example, after surgery), with a mix of CT scans and chest x-rays.

Check-ups will usually be between 3 and 6 months apart, and will often be more frequent in the first years after the treatment, then become less frequent over time if nothing concerning is found.

There is also no standard approach to including head scans as part of this monitoring. Some patients will be given occasional head scans if they are thought to be higher risk, for example those with stage 3 disease.

More advanced or metastatic cancer

This refers to a cancer which is at stages 3b – 4. These cancers tend to be treated with palliative intent. The majority of ALK+ lung cancer cases are diagnosed at stage 4.

Patients with later stage ALK+ lung cancer are likely to be treated with ALK inhibitors following diagnosis, for as long as the treatment is working and any side effects are manageable.

While there is no standard follow-up, patients will often have a monthly clinical review, which may become less frequent over time depending on the side effects experienced. Patients will also usually be given a regular CT scan (most commonly every 3 months), which will normally be used to check the chest, abdomen and pelvis.

Other areas may be included in the regular scan, depending on where the cancer is in the body, and patients are also likely to be given head scans.

What are the side effects of TKIs?

In this conversational video, lung cancer clinical nurse specialist Delyth McEntee speaks to Debra Montague, chair of ALK Positive UK, about how healthcare professionals can support patients with side effects from ALK treatment. The topics covered include:

Debra’s experience of side effects, including photosensitivity, gastrointestinal (GI) effects and cognitive effects
How nurses and patients can work together to alleviate side effects, including the use of supportive medications
The self-care measures patients can take and the benefits of joining a support group

Below are some of the side effects that can arise from the ALK targeted treatments currently funded by NICE in the UK. These TKIs are crizotinib, alectinib, ceritinib, brigatinib and lorlatinib.

Please note that each treatment also has cautions and contraindications associated with its use.

As well as side effects which may be experienced/noticed by patients, these medications can also cause changes to the levels of enzymes and other components found in the body, which can indicate an effect on areas such as the liver or pancreas. Regular monitoring, including blood tests, can highlight whether any medication changes or supportive measures are needed.

If patients experience side effects:

There are a number of ways we can support patients:

Recommending self-support measures: for example, if patients experience photosensitivity, it is important that they avoid prolonged sun exposure (during treatment and for at least seven days after discontinuation if treatment is stopped). They should also use broad-spectrum UVA/UVB sun screen and lip balm (SPF ≥50).
Offering supportive treatments: for example, creams can be prescribed to help with rashes, or medications to help with gastrointestinal symptoms such as diarrhoea.
Treatment breaks, dose reductions or changes in treatments: a short break in treatment may be recommended to allow toxicities to settle. The dose of a medication can also be reduced. If side effects become too severe, patients may need to stop taking that particular TKI and move to a different treatment.

Can my patients take part in clinical trials?

Clinical trials aim to help us reduce the incidence of cancer; diagnose cancer earlier; treat cancer more effectively (and with fewer or more manageable side effects), and learn how to effectively support people who have cancer, along with their family, friends and carers. Many clinical trials have informed the current treatment for ALK+ lung cancer that we use today.

Many patients have questions about clinical trials and exactly what they involve. The information in this section may help you in discussing the clinical trials process with your patients.

What happens in a clinical trial?

In this video, clinical research nurse team leader Sharon Woolley talks about the importance of clinical trials in cancer. The topics covered include:

The phases of clinical trials
The role of randomisation
The stages of clinical trials, including pre-screening, screening and monitoring during and after treatment
Finding out about clinical trials
Other ways to be involved in clinical research

Types of clinical trials

Clinical trials are designed in different ways, depending on what needs to be learned from them.

Type of trial	Treatment details
Randomised controlled trial	Equal groups of randomly selected people receive different treatments or no treatments
Open label not randomised trial	Both the patients and those running the trial know which treatment trial participants are going to receive before the trial starts
Blind trial	The participants don’t know which type of treatment they’re receiving
Double blind trial	Neither the participants, nor those running the trial, know which treatment participants are receiving
Placebo controlled trial	One group in the trial is receiving a treatment, while another group isn’t. The participants don’t know which group they are in

Phases of clinical trials

All new treatments have to go through several phases of clinical trials before they can be approved for use, to make sure they are safe for patients.

Phase 1 (early) trials measure areas such as side effects and dose - often for the first time - in small groups of people with cancer.

Phase 2 trials look at things like side effects, the effects of one treatment compared with another (or compared with no treatment) over several years in larger groups of people with cancer.

Phase 3 trials examine safety, the effectiveness of different doses and combinations, and patients’ quality of life on a much wider scale. These can involve thousands of people with cancer in several places, often internationally, and are usually randomised.

Phase 4 trials can sometimes be needed to monitor the effectiveness, safety and side effects in large and diverse populations.

References

Please be aware that the following links are current (as of December 2024), some may reside behind a paywall.

Camidge, D.R. et al. (2018) ‘Brigatinib versus Crizotinib in ALK -Positive Non–Small-Cell Lung Cancer’, New England Journal of Medicine, 379(21), pp. 2027–2039. Available at: https://doi.org/10.1056/NEJMoa1810171.

Gillespie, C.S. et al. (2023) ‘Genomic Alterations and the Incidence of Brain Metastases in Advanced and Metastatic NSCLC: A Systematic Review and Meta-Analysis’, Journal of Thoracic Oncology. Elsevier Inc., pp. 1703–1713. Available at: https://doi.org/10.1016/j.jtho.2023.06.017.

Hendriks, L.E. et al. (2023) ‘Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up’, Annals of Oncology, 34(4), pp. 339–357. Available at: https://doi.org/10.1016/j.annonc.2022.12.009.

NICE (2024), ‘Alectinib for adjuvant treatment of ALK-positive non-small-cell lung cancer’, Overview | Alectinib for adjuvant treatment of ALK-positive non-small-cell lung cancer | Guidance | NICE. Accessed 15 January 2025.

NHS Commissioning Board Clinical Commissioning Policy: Stereotactic Radiosurgery / Radiotherapy for Cerebral Metastases, 2013. D05-P-d-comm-policy-srs-cerebral-metastases.pdf. Accessed 27 November 2024.

Peters, S. et al. (2017) ‘Alectinib versus Crizotinib in Untreated ALK -Positive Non–Small-Cell Lung Cancer’, New England Journal of Medicine, 377(9), pp. 829–838. Available at: https://doi.org/10.1056/NEJMoa1704795.

Shaw, A.T. et al. (2013) ‘Crizotinib versus Chemotherapy in Advanced ALK -Positive Lung Cancer’, New England Journal of Medicine, 368(25), pp. 2385–2394. Available at: https://doi.org/10.1056/NEJMoa1214886.

Solomon, B.J. et al. (2014) ‘First-Line Crizotinib versus Chemotherapy in ALK -Positive Lung Cancer’, New England Journal of Medicine, 371(23), pp. 2167–2177. Available at: https://doi.org/10.1056/NEJMoa1408440.

Solomon, B.J. et al. (2018) ‘Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study’, The Lancet Oncology, 19(12), pp. 1654–1667. Available at: https://doi.org/10.1016/S1470-2045(18)30649-1.

Solomon, B.J. et al. (2024) ‘Lorlatinib Versus Crizotinib in Patients With Advanced ALK -Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study’, Journal of Clinical Oncology, 42(29), pp. 3400–3409. Available at: https://doi.org/10.1200/JCO.24.00581.

Wu, Y.-L. et al. (2024) ‘Alectinib in Resected ALK -Positive Non–Small-Cell Lung Cancer’, New England Journal of Medicine, 390(14), pp. 1265–1276. Available at: https://doi.org/10.1056/NEJMoa2310532.

Yang, J.C.-H. et al. (2023) ‘Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial’, Journal of Thoracic Oncology, 18(12), pp. 1743–1755. Available at: https://doi.org/10.1016/j.jtho.2023.08.010.

Electronic Medicines Compendium (eMC). Alecensa 150 mg Hard Capsules – Summary of Product Characteristics (SmPC) – (emc); Alunbrig 180 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc); Lorviqua 100 mg film coated tablets – Summary of Product Characteristics (SmPC) – (emc). Accessed 5 November 2024.

Treatment – 4 HCPs

Resources

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ALK Treatment

What are the treatment options for advanced or metastatic lung cancer?

What are tyrosine kinase inhibitors (TKIs)?