Not mentioned in the article is the fact that lorlatinib, original studied in the phase 3 CROWN trial, was used in frontline management of advanced ALK-mutated non-small cell lung cancer (NSCLC) [0]. Five-year data indicate a significant progression-free survival benefit, with 60% of patients free of progression. Even after 60.2 months of follow-up, the median progression-free survival has not yet been reached [1]. It is the durability of progression-free survival that are most impressive and surprising here. That said, only 4% to 8% of patients with NSCLC will have ALK mutations/rearrangements, so while amazing, this finding is not applicable to all patients [2].
I believe the median progression-free survival is the length of time where 50% of people are still free from progression. The numbers you mentioned would mean that we don't know how long that is for this treatment but it's definitely longer than 5 years. That sounds pretty good depending on the type of cancer and stage when treatment started.
> it is fully approved for ALK+ NSCLC and has been since 2015.
Not exactly. FDA granted it an orphan drug designation in 2014, and then full approval for second- or third-line therapies in 2018 (on the basis of a Phase I/II study). The Phase III study (NCT03052608) is the gift that keeps on giving - it ran 2017-2020, and the progression-free survival in the lorlatinib arm is 60% vs 8% for the control.
“Lorlatinib and crizotinib are both ALK tyrosine kinase inhibitors (TKIs). ALK TKIs are targeted treatments that bind to the ALK protein found in ALK-positive non-small cell lung cancer and stop the growth of tumour cells.”
Great, so this is a targeted approach that works 60% of the time (in the case of Lorlatinib) in one highly specific area of the highly diverse space of possible cancers, many of which have never been observed before and for which you could never enroll enough patients to have a robust clinical trial.
How can this approach be generalized and scaled, meaning that for a given patient with a given cancer, you can run an algorithm and synthesize molecules that will work?
In CS the paradigm involves knowing how to solve an unseen problem instance, not just remembering solutions to specific, well-studied problem instances.
> meaning that for a given patient with a given cancer, you can run an algorithm and synthesise molecules that will work?
The paradigm is called rational drug design (+ personalised medicine) and its scope is quite limited at the current level of technology. To achieve what you describe, we need to solve all of the following:
- a way to recognise the molecular mechanism of a particular cancer and identify potential drug targets
- a way to characterise the targets - in the previous step you identified a protein, now you need to know its shape (X-ray crystallography (potentially years), AlphaFold). We need to know how the target should be modified to disrupt the disease.
- a way to design a molecule that binds the target specifically and in the desired way
- a way to synthesise the molecule quickly & efficiently
- a way to predict the molecule's interactions at all stages of metabolism, taking into account the patient's individual phenotype (different people have significant variations in drug-digesting enzymes)
Significant (decades at the current rate) progress in all of these areas is needed before this sort personalised medicine has a chance of becoming feasible.
Also the question of how to handle clinical trials when the treatment is by design n=1. This world is getting less murky but as far as I know isn't yet 100% straightforward.
My dad has survived ~10 years now with ALK lung cancer due to this family of drugs. It was surprise stage 4, with no warning. Had a 6 month prognosis, but instead he's still with us and doing really well.
Tyrosine kinase, when mutated, causes uncontrolled cell growth.
TKIs: Crizotinib (1st gen), alectinib.
>> Lorlatinib is a third-generation, highly potent, macrocyclic ALK/ROS1 TKI that competitively binds to the adenosine triphosphate‐binding pocket, blocking ALK‐dependent oncogenic signaling. The advantage of Lorlatinib is high penetration of the blood-brain barrier by decreasing p‐glycoprotein‐1‐mediated efflux. Besides, it has broad‐spectrum activity against most known resistance mutations that develop during treatment with first and second‐generation ALK TKIs, including ALK G1202R mutation. The introduction of Lorlatinib to salvage these patients has shown the potential to add life. This has been shown in a global phase II study and other real-world studies, however, data is scant from LMIC. The most common toxicities were peripheral edema (9–48%), hyperlipidemia (47–94%), weight gain (3–25%), peripheral neuropathy (30%), fatigue (15–30%) and cognitive effect (6–18%) in earlier studies. The treatment discontinuation rate varied from 3–14% due to toxicity.
> In about 25% of [study patients] their lung cancer had already spread to the brain when the study began.
and
> “Lorlatinib is the only ALK TKI that has reported five-year progression-free survival, and even after this time, the majority of patients continue to have their disease controlled, including control of disease in the brain.”
I sometimes think our chosen vocabulary for cancer is a bit self-defeating. I am sure oncologists have a more nuanced view than mine, but there's three big components which stick out to me. First, where did the cancer start (organ is good, tissue specific is even better)? Second, what mutations were involved? Third, where has it gone from there? All three give a more complete picture than just the point of origin.
You mean terms like carcinoma, adenocarcinoma, and squamous cell carcinoma? You're correct oncologists do talk in fairly advanced terms as you've described.
We laypeople use general terms where it starts: breast cancer, lung cancer, skin cancer. Metastatic when it invades other places, and we give it grades. Stage II, stage III, stage IV (and sometimes finer grades). General terms help us define what to focus on. This probably fits with your third point. For specific destinations, different cancers like to metastasize to specific places, but not always. We don't know why, it is still being investigated, but there are patterns.
Your second point is more advanced. Cancer cells have specific characteristics, in general we call them expressions or mutations, usually identified through biopsy and/or liquid biopsies. PD-L1, HER2, ALK+, PTEN, BRCA, BRAF, KRAS, PI3K, etc. We learn new ones all the time and sadly cancer will mutate and turn on/off characteristics. Cells are adaptable and duplicate with these adaptations.
I think point of origin makes a huge amount of sense. All the actual cells of the cancer will be of the origin type! E.g., even if it is in the brain it is still a clump of lung tissue cells.
Lung cancer rarely kills you on it's own. It's the plethora of metastases it forms that does. My poor mom was ultimately taken by brain metastases of NSCLC
Its a side-effect of the naming convention for generic drug naming [1]. Small molecule inhibitors end with “ib”. Monoclonal antibodies end with “mab”. Etc.
Or just not paid for at all, as is common in EU countries (cancer survivability is much worse in the EU and if it weren’t for American obesity would push EU lifespans below the US)
Zooming out - if the US were like France, these drugs would not be developed in the first place. France is lucky that there are other countries willing to shoulder R&D costs for them.
> Or just not paid for at all, as is common in EU countries (cancer survivability is much worse in the EU and if it weren’t for American obesity would push EU lifespans below the US)
Not really. If they’re expensive, in France the health system might decide to not pay for it. Or pay for it in very restricted cases.
You wouldn’t know about it though, your doctors would just tell you that they are out of therapeutic options and to gather with your loved ones, unaware of the fact that your cancer is actually treatable.
Source: Am French, happened to a very good friend of mine 5years ago. They ended up surviving after a gofundme paid for a US treatment, administered in a private hospital in Barcelona. They made it and are doing well now, thanks to the “evil US private capitalist health system”
It’s such a tough thing. To me my life is worth infinite money and every possible dollar I can get ahold of. If that applied to everyone then we go literally bankrupt and spend every available dollar of GDP very quickly.
> In the phase 3 trial, 296 patients with advanced forms of non-small cell lung cancer were randomly assigned to receive either lorlatinib (149 patients) or crizotinib (147 patients, of whom 142 ultimately received treatment).
It's not clear why these data are just coming out now or what is different from the original trials run in this setting.
https://en.wikipedia.org/wiki/Lorlatinib