ALK-positive NSCLC: Current landscape

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Published: 29 Apr 2019
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Dr Antonio Passaro and Prof Rafal Dziadziuszko

Dr Antonio Passaro chairs a discussion with Prof Rafal Dziadziuszko on the current landscape and latest developments in ALK-positive non-small-cell lung cancer (NSCLC).

In this video, Prof Dziadziuszko outlines the current guidelines for patients with ALK-positive NSCLC; in which first-line treatments should involve the use of ALK inhibitors - as these have demonstrated improved progression-free survival (PFS) and quality of life compared to using traditional chemotherapy.

He also describes the historic use of fluorescent in-situ hybridisation (FISH) to identify ALK-positive translocations; however, due to its inefficiency, immunohistochemistry and next-generation sequencing are now the preferred methods of diagnosis.

For the first-line setting, Prof Dziadziuszko emphasises the importance of considering the toxicity and efficacy profiles of each inhibitor (both within the brain and in systemic regions) for the treatment of ALK-positive NSCLC.

He also anticipates that the next generation ALK inhibitors (such as alectinib, brigatinib, lorlatinib and ensartinib) will improve patient outcomes.

For the second-line setting, the use of stereotactic radiation combined with the continued use of the original ALK inhibitor used in the first-line setting should be considered for these patients. However, there have been encouraging data that support the use of third-generation ALK inhibitors (e.g. brigatinib or lorlatinib) for patients who fail the standard-of-care drug, crizotinib.

Prof Dziadziuszko describes the success of alectinib by improving PFS; as well as decreasing CNS progression during the phase III ALEX trial.

Prof Dziadziuszko concludes the discussion by highlighting the importance of evaluating CNS progression and toxicity when using ALK inhibitors -stating that the toxicity profile of alectinib is favourable.

New developments and guidelines about ALK-positive NSCLC
ALK-positive NSCLC treatment options in the first-line setting
ALK-positive NSCLC treatment options in the second-line setting
Highlights from the ALEX clinical trial study


This programme has been supported by Roche.

Dr Antonio Passaro – European Institute of Oncology, Milan, Italy
Professor Rafal Dziadziuszko – Medical University of Gdańsk, Gdańsk, Poland

AP: Welcome to ecancer interactive discussion. Today we are in Geneva in the European Lung Cancer Congress about ALK lung cancer and we’ll discuss with you the new evidence and the developments in ALK positive non-small cell lung cancer. I’m Antonio Passaro, I’m a thoracic oncologist in the European Institute of Oncology in Milan.

RD: I’m Rafal Dziadziuszko, I’m a clinical oncologist from the Medical University of Gdańsk in Poland.

AP: Professor Dziadziuszko, what do you think about the new developments and guidelines about ALK positive non-small cell lung cancer?

RD: It’s now ten years since we know that ALK positive non-small cell lung cancer is a different disease entity within the non-small cell lung cancer category that needs to be treated in a very specific way, different than we treat other patients. Over the last ten years we were able to diagnose these patients who harbour ALK translocations in their tumours in a much better way. Now, it’s evident that these patients with advanced ALK positive non-small cell lung cancer should be treated with ALK inhibitors in the first line treatment. Numerous trials have demonstrated that ALK inhibitors are superior in terms of progression free survival, response rate and other indices as quality of life over chemotherapy. Now, according to international guidelines, including ESMO guidelines, we have a number of ALK inhibitor options in the first line treatment, including crizotinib, alectinib, ceritinib and also, according to other guidelines, other ALK inhibitors. In the guidelines it is emphasised that the best possible option for patients is a drug that penetrates well to the brain and demonstrates efficiency, with alectinib being the preferred option. That is based on the data on progression free survival which is the longest for alectinib versus the other agents but also superior central nervous system activity. It should be noted that ALK positive patients have a prevalence of brain dissemination that goes up to 40% at presentation. That probably has to do with the biology of ALK positive disease simply because the ALK gene and protein is involved in the development of CNS early in embryonal life; it is probably because of that that patients with ALK translocated non-small cell lung cancer have this specific feature of CNS penetration.

AP: Do speak about the detection rate also. We saw that in the first randomised clinical trial about crizotinib the ALK translocation was evaluated only by FISH. The next clinical trial we saw that the immunohistochemistry was the new method for evaluating the ALK translocation. What do you think about for the future detection of ALK?

RD: I think that there is sufficient data to say that based on validated immunohistochemistry patients who are ALK positive can be treated with ALK inhibitor in the first line setting. That has been established based on several trials, including the ALEX study with alectinib, however, historically we have first screened for the presence of ALK translocations with FISH testing. FISH is genomic testing, it is quite costly and also inefficient in terms of labour and infrastructure because it requires a FISH microscope in the pathology department. So we moved away from FISH diagnostics to immunohistochemistry and now we are also moving to next generation sequencing platforms. So I would say with well-developed immunohistochemistry profiles we can identify those patients fast and quite reliably. I would add to that that I personally like to have genomic confirmation of ALK positivity in many of my patients unless I need to rush to the treatment, which is also happening on numerous occasions. In our centre probably we will more and more focus on quick turnaround next generation sequencing because it covers not only ALK translocations but also other gene drivers that are so important in advanced lung adenocarcinoma patients.
So it’s ongoing waters, it’s an ongoing river that we are just going into. I think in five to ten years from now most of the patients will be diagnosed by NGS with respect to other molecular drivers beyond ALK that are important to take into consideration when determining the best possible treatment for our patients.

AP: And swimming in this river of progress, how do you consider the first line setting for ALK positive non-small cell lung cancer based from the results of all randomised clinical trials published to date?

RD: I think we should generally realise that outcomes of patients with ALK positive disease change tremendously over historical values. First of all, ten years ago we didn’t know that it existed but probably the median survival of these patients was 10-15 months. Right now I have a number of patients with advanced non-small cell lung cancer, ALK positive, who survive over five years after their diagnosis and most of them have brain metastases. The patient that I have been treating in the original crizotinib trial is already nine years treated on an outpatient basis and she’s doing really great. So the chance of patients surviving several years after diagnosis is very different than it was several years ago. That’s why it’s so important to have the drug which has the best possible toxicity profile but also the best possible efficacy within the brain but also systemically.  Definitely the next generation of ALK inhibitors, including first of all alectinib but also brigatinib and ceritinib and lorlatinib, drugs that are currently in development, will change the outcomes of our patients for even better outcomes.

AP: And using the best option in first line setting, what do you think for the second line setting always for ALK positive non-small cell lung cancer?

RD: Well, it depends very much on how these patients progress. You have situations in which patients progress in one spot of the disease, one site, and then you can consider local treatment options, especially if this is a vulnerable area such as the brain. So stereotactic radiotherapy and continuation of original ALK inhibitor may be considered in this specific subset of patients. Then you also have data of the efficacy of next generation, third generation, ALK inhibitors such as brigatinib or lorlatinib in patients who fail crizotinib or alectinib. These data show response rates, depending on particular situations, in the range of 50%, so very encouraging. There are also some data on ceritinib post-progression on crizotinib, for example, which are also quite favourable. So we have quite a number of options. These options probably will depend on the mechanism of resistance to previous ALK inhibitors. We, as of today, do not routinely test for the mechanism of resistance but we are shifting towards this direction and that’s the case also in my home institution in Gdańsk where we try to biopsy the patients and establish whether the mechanism of progression is ALK related or ALK unrelated. In the latter case chemotherapy probably is the best possible option. Then if it’s ALK related then we try to look for the specific mutation that is present. For example, a mutation in the kinase domain in the position of 1202 will simply point towards lorlatinib as the best possible option and data on lorlatinib supports this observation.
On top of that, research now indicates that you can also try to establish the mechanism of progression from the circulating tumour DNA. So the area of research that is transforming current practice will probably be towards guiding informed decisions on the mechanism of progression but, as of today, for those patients for whom we cannot obtain the biopsy third generation ALK inhibitors are recommended, if available on the clinical study, or standard of care chemotherapy.

AP: One of the outcomes of the ALEX trial, in the phase III trial comparing alectinib and crizotinib for the first line treatment. What do you think about in particular from the great results that changed our clinical practice?

RD: I did enjoy participating in the study because the study was designed to answer several questions, to establish progression free survival and also overall survival data for alectinib versus standard of care crizotinib in ALK positive first line treatment but also evaluate in detail the data for central nervous system incidence of brain metastasis and progression under each of the treatments. The trial demonstrated that progression free survival on alectinib exceeds 30 months as compared to 11 months for crizotinib which is a really great result. But, most importantly, progression in the CNS is as high as 40% with brain MRIs to evaluate patients on crizotinib versus something around 10% for alectinib which is demonstrating the CNS activity of alectinib. That trial really opened the discussion whether alectinib should be used up front and the CNS data really supports that quite extensively because there’s nothing worse than having your patients progress in the brain, as you know from the clinical perspective.
We also learned quite a lot of other important data that are already out in the publication; the recent publication in The Journal of Thoracic Oncology gives the detailed information about the variant of the translocation and the efficacy of alectinib versus crizotinib according to the variant of translocation. So basically three different variants, variant one, two and three, are most prevalent to describe the translocation and in all three variants we have seen better activity of alectinib versus crizotinib. So probably the type of variant will not matter on what drug should be selected to treat our patients but we also could understand the outcomes of patients according to molecular variants of ALK translocations a bit better than in the previous studies. Such a biological correlation with clinical outcomes are now vital to understand profoundly what are the outcomes of our patients.

AP: Yes, the ALEX trial is like the golden trial of the precision medicine era because it’s a trial that evaluated a drug that’s very active, less toxic and with a methodological view of the biology of the disease. What do you think about the activity and the penetration of the alectinib in the brain mets compared to the other drugs that we have in clinical practice or evaluating in clinical trials?

RD: If you look at the data, and if I can summarise that with some simplification, crizotinib, a drug which I like very much and which was the first in class ALK inhibitor, produces 11 months progression free survival and has CNS penetration below 1% of systemic penetration. For ceritinib we don’t know the exact CNS penetration but probably it is around 15% based on animal data and progression free survival in the first line treatment is around 17 months. With alectinib and CNS penetration around 70-80% of plasma concentrations we come to progression free survival of around 30 months. So clearly the CNS penetration, which is a key for targeted therapies and we know it also from other fields such as the EGFR field and osimertinib, the CNS penetration plays a vital role on how these patients progress and how the local concentrations may matter in terms of progression in our patients.
The other important point is toxicity. In the ALEX trial we have enjoyed a very good toxicity profile of alectinib – grade 3 toxicity in the single digit number. Crizotinib is also very well tolerated, it was slightly higher toxicity, specifically liver toxicity, nausea, vomiting and ocular toxicity. On the other hand, some other ALK inhibitors such as ceritinib have more profound toxicity effects such as elevated enzymes that are more frequently seen than for alectinib, for example. So the toxicity of alectinib is clearly quite favourable, especially in the situation of long exposure to the drug, as observed in the ALEX study. We will see how the new generation drugs will play a role here; I am talking about brigatinib or lorlatinib. The data on these two drugs are now accumulating in existing clinical studies. Brigatinib is available to our American colleagues, as you know; the drug is also very active in the central nervous system with a relatively good toxicity profile except, perhaps, some pneumonitis that we rarely observed with the other drugs. But it’s also a drug that is on the horizon to complement the armamentarium of drugs that we have today. Lorlatinib has a very good potency against resistance mechanisms to all the other ALK inhibitors so I have no hesitation to believe that this drug has a great future to benefit our patients further.

AP: Of course these results confirm the high activity of all the class of agent, the ALK inhibitors, in this particular cohort of patients. This achieved a median survival of more than 30 months. We thank you for listening from ecancer.