[HN Gopher] Trial results for new lung cancer drug are 'off the ...
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Trial results for new lung cancer drug are 'off the charts'
Author : charlieirish
Score : 113 points
Date : 2024-05-31 16:21 UTC (6 hours ago)
(HTM) web link (www.theguardian.com)
(TXT) w3m dump (www.theguardian.com)
| noncoml wrote:
| Lung cancer is not the death penalty that it use to be if you are
| "lucky" to have one of the mutations that this, and other similar
| drugs, target.
| admissionsguy wrote:
| According to a (very) quick google search:
|
| - the drug is for "ALK positive Non-small cell lung cancer
| (NSCLC)"
|
| - NSCLC is 85% of all lung cancers, of which 3% to 5% are ALK+.
|
| so it would appear to apply to at most 4% of all lung cancers.
| Are the numbers correct? Even so, huge deal for tens of
| thousands of people each year.
| odyssey7 wrote:
| "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.
| admissionsguy wrote:
| > 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.
| jghn wrote:
| 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.
| odyssey7 wrote:
| Thanks, this is just the sort of information I was hoping
| for.
| noncoml wrote:
| There are similar drugs(eg osimertinib) for EGFR+ cancers,
| which are estimated to be 10-33% of NSCLC.
| hooverd wrote:
| 4% here, 4% there. Maybe you don't have a generalized
| treatment, but treatments for different subtypes add up.
| maherbeg wrote:
| True, but each advance adds up. Just look at a history of
| curing hodgkin's lymphoma which omits a lot of detail still h
| ttps://www.hematology.org/about/history/50-years/milestones..
| .
| hnpolicestate wrote:
| Still no progress with small cell lung cancer?
|
| It killed my 43 year old aunt in less than two months back in
| 2002. Smoker though.
| dannykwells wrote:
| Durva is starting to show some benefit here.
|
| https://www.cancernetwork.com/view/durvalumab-significantly-...
| adamredwoods wrote:
| My condolences, SCLC is rough. Sadly, it is different than
| large-cell, and the mutations are different.
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038650/
| zzzeek wrote:
| Why do all the new cancer drugs coming out end in the letter "B"?
| abracadaniel wrote:
| I think the *mab ones are monoclonal antibodies, and the *nib
| ones are inhibitors. I don't think it's a hard rule though.
| andyjohnson0 wrote:
| 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.
|
| [1] https://en.wikipedia.org/wiki/Drug_nomenclature
| adamredwoods wrote:
| 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.
|
| https://www.nature.com/articles/s44276-024-00055-9
|
| https://en.wikipedia.org/wiki/Lorlatinib
|
| https://en.wikipedia.org/wiki/Tyrosine_kinase
| JumpCrisscross wrote:
| > _advantage of Lorlatinib is high penetration of the blood-
| brain barrier_
|
| Why is this essential to fighting lung cancer?
| dannykwells wrote:
| Note that this drug is not new - it is fully approved for ALK+
| NSCLC and has been since 2015.
|
| 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
| westcort wrote:
| 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].
|
| [0] https://www.nejm.org/doi/full/10.1056/NEJMoa2027187
|
| [1] https://ascopubs.org/doi/10.1200/JCO.24.00581
|
| [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597761/
| benmarten wrote:
| RCT? Doesn't look like it...
| ilya_m wrote:
| It is:
|
| > 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).
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