ALK Treatment
When you visit your oncologist it’s natural to have a lot of questions – and you have the right to ask as much or as little as you’d like. ALK Positive UK has put together a guide, ‘Good Practice from the Patients’ Perspective’, which includes a list of key questions you may wish to ask your oncologist, helping you to feel empowered and informed about your treatment.
All patients can ask for a second opinion regarding their diagnosis or treatment plan, either privately or within the NHS.
This is usually related to the treatment plans, rather than the diagnosis, and the second opinion will be from an oncologist.
Before asking for a second opinion, you should ask your oncologist or specialist nurse to go over anything you feel unsure about, like your treatment options. Your healthcare team will be happy to explain things, and sometimes there may be no need for a second opinion.
The NHS does not have to provide a second opinion, but you have the right to ask for one. Most doctors will be happy to refer you, and this will not have an impact on your patient-doctor relationship. You may ask for a second opinion in any NHS trust, regardless of where you live. Note that each trust and their clinicians have the right to accept or decline referrals for second opinions, often guided by the service capacity and volume of referrals.
The oncologist who will provide a second opinion will rely on a detailed referral letter and the copies of all relevant exams, such as biopsies, blood results or CT scans. Therefore, to proceed with a second opinion, a referral will be required, ideally from a medical professional currently involved with your care.
This referral is often from the current oncologist (at your request), but alternatively it may also be from your GP. A referral from the current oncologist is preferred, since the GP relies on the information passed on from the oncologist, and they may not have all your relevant test results. Some GPs may not feel they have enough information to request a second opinion on behalf of a patient. Sometimes the oncologist doing a second opinion may also need additional information, so it helps if they are directly in contact with your current oncology team.
Getting a second opinion will take time and it may involve travelling to a different hospital. That means it may delay your treatment which may affect your wellbeing. It is important to be open with your oncology team and discuss this.
A second opinion is not a transfer of care. After your second opinion, you may continue under your current oncologist or you may wish to ask for a transfer of care. A transfer of care needs to be formally accepted by the new oncologist and arranged between the current and the new medical teams to ensure there is no negative impact on your care.
Macmillan Cancer Support offers further advice on getting a second opinion: Getting a second opinion – Macmillan Cancer Support.
TKIs are the key treatment for ALK-positive lung cancer. TKIs work by blocking the signalling pathway activated by the mutated ALK-fusion proteins, which would otherwise 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 targeted therapy in 2016 in the UK is a remarkable success story in medicine. Since then, advancements in biochemistry have made TKIs even more effective.
The newer generation ALK inhibitors are:
These developments have significantly advanced the treatment landscape for ALK-positive lung cancer.
There are two reasons why TKIs fail:
| On-target mutations | Off-target mutations |
| Mutations can develop which change the structure of the ALK protein. This prevents the TKI from binding to it effectively. | This is where the tumour cell uses alternative signalling pathways to bypass the TKI. |
It can be useful to think of off-target mutations in terms of a subway system:
In ALK-positive lung cancer, the fused ALK-EML4 gene creates mutated ALK-fusion proteins. The ALK-fusion proteins trigger messages, telling the cell to grow and replicate.
Each message can be thought of as a passenger on a subway train. The message travels towards the cell’s nucleus via a signalling pathway in the cell – or a subway line. TKIs work by blocking this pathway, so the message – or the train – has to stop.
Eventually, though, the passenger realises that they can take another subway line to reach their same destination. In the same way, the tumour cell protein finds another signalling pathway that can be used to send the message.
Once the message reaches the nucleus – the structure in a centre of a cell which controls the cell’s behaviour – the cell is instructed to grow and multiply.
| 1st First generation: crizotinib |
2nd Second generation: ceritinib, alectinib, and brigatinib |
3rd Third generation: lorlatinib |
| Crizotinib showed a higher overall response rate and longer progression-free survival compared to chemotherapy, when used as both the first-line treatment and the second-line treatment. These results led to crizotinib’s approval by the FDA in the USA 2011, and in 2016 by NICE in the UK. Limitations of crizotinib First-generation ALK inhibitors have several disadvantages that make them less effective, including:
This means that tumour progression typically occurs within one year of starting therapy, with the brain being one of the most common sites of progression. |
Ceritinib, alectinib, and brigatinib were shown to be effective in ALK-positive patients whose tumours had progressed on crizotinib. Both alectinib and brigatinib were also compared with crizotinib in the first-line setting. They showed longer progression-free survival and better central nervous system outcomes. However, tumour progression typically happens after an average of two to three years, caused by both on-target mutations and off-target mutations. |
Lorlatinib is the only third-generation ALK inhibitor approved in the UK. It has shown to be effective in patients who had previously progressed on first- and/or second-generation inhibitors. Additionally, when compared to crizotinib in the first-line setting, lorlatinib showed an impressive improvement in progression-free survival and was shown to be effective in the brain. Lorlatinib is not yet approved in the first-line setting in the UK, but may be in the near future. Lorlatinib can work effectively against many on-target mutations; however, the tumour usually becomes resistant due to off-target mutations, in which the ‘grow and replicate’ message finds another signalling pathway to use. You can find out more about the clinical trials that influenced the use of TKIs in the resources section. |
Current approachThe standard approach for patients diagnosed with early-stage ALK-positive lung cancer is similar to that for non-small cell lung cancer patients without ALK. The approach aims to maximize the chances of a cure or long-term control. |
Future directionsRecently, results from a phase III clinical trial comparing alectinib to chemotherapy after surgery in early-stage non-small cell lung cancer (NSCLC) were published. The trial demonstrated that the percentage of patients alive without disease progression was significantly higher in those who received alectinib. Additionally, alectinib was associated with a significantly lower incidence of brain metastases. These promising results suggest that alectinib may become a viable option for adjuvant therapy in early-stage NSCLC in the near future. |
Treatment for brain metastases generally consists of two different approaches:
There is no universal agreement on the frequency and type of regular investigations needed to monitor a lung cancer after diagnosis.
Earlier stage lung cancer here refers to cancers which are staged between stage 1 and 3a according to the TNM (Tumour, Node, Metastasis) system.
See this guidance from Cancer Research for further information about the TNM stages: TNM staging for lung cancer | Cancer Research UK) or visit our ‘What are the different cancer stages?’ section.
These cancers have not yet become particularly big nor spread too far and therefore often tend to be treated with a ‘curative intent’ – that is, with treatments chosen to give the best chance of eliminating the cancer.
Whilst there is no accepted standard follow up pathway for these patients after the curative intent treatment (e.g., surgery), typically patients are followed up for at least 5 years after treatment and will have a mix of CT scans and chest X-rays during this surveillance period. The frequency for these reviews varies from 3 to 6-monthly and it is often more intense in the first years after the treatment, decreasing in frequency over time in the absence of any concerning findings. There is no consensus either on the use of regular head scans as part of the surveillance, with some considering occasional head scans for higher risk patients, such as those with stage 3 disease.
This refers to a cancer which is at stages 3b – 4, meaning that the cancer has spread significantly within the chest and/or beyond. (See this guidance from Cancer Research for further information about the TNM stages: TNM staging for lung cancer | Cancer Research UK or visit our ‘What are the different cancer stages?’ section.)
These cancers tend to be treated with ‘palliative intent’; that is, with the aim of controlling the cancer helping help people live longer and more comfortably – for example by using treatments which shrink tumours. The majority of ALK-positive lung cancer cases are diagnosed at stage 4.
Similarly to those with earlier stage lung cancer, there is no accepted standard follow-up. Patients with ALK+ve lung cancer at this stage will likely be on long-term treatment with ALK inhibitors following their diagnosis. These treatments are continued generally for as long as patients benefit from them and in the absence of severe toxicity. Patients often have a monthly clinical review, which over time may become less frequent in the absence of side effects. Additionally, a CT scan including all the relevant areas to monitor (usually, chest-abdomen-pelvis) is done on regular intervals, most commonly every 3 months. Other areas may be included in the regular scan (e.g., neck) depending on the locations of the cancer. Heads scans (preferably MRI) should be considered alongside the body CT scans and discussed with patients.
See the brain metastasis section for more details.
Clinical trials (often called clinical research) are extremely important in cancer care and treatment. Clinical trials aim to help us:
Many clinical trials have informed the current treatment for ALK-positive lung cancer that we use today.
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. |
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.
The phases of a trial are:
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 comparted 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.
