8 ms·

Tyrosine kinase, when mutated, causes uncontrolled cell growth. TKIs: Crizotinib (1st gen), alectinib. >> Lorlatinib is a third-generation, highly potent, mac

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://www.nature.com/articles/s44276-024-00055-9 https://en.wikipedia.org/wiki/Lorlatinib https://en.wikipedia.org/wiki/Lorlatinib https://en.wikipedia.org/wiki/Tyrosine_kinase https://en.wikipedia.org/wiki/Tyrosine_kinase

JumpCrisscross 2y ago
> advantage of Lorlatinib is high penetration of the blood-brain barrier Why is this essential to fighting lung cancer?
- ma2t 2y ago
  Brain is among the top sites where NSCLC tumors tend to metastasize https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251107 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251107
  - JumpCrisscross 2y ago
    Wow. Thanks. How do the cancer cells cross the blood-brain barrier?
    - newzisforsukas 2y ago
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633769/#:~:text=The%20Tumor%20Cell%20of%20Origin%20for%20Brain%20Metastases%20and%20Its%20Road%20to%20the%20Brain https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633769/#:~:tex...
- at_a_remove 2y ago
  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.
  - LeroyRaz 2y ago
    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.
  - adamredwoods 2y ago
    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'm currently reading this book to help me understand (latest edition): https://www.google.com/books/edition/Molecular_Biology_of_Cancer/n8owEAAAQBAJ https://www.google.com/books/edition/Molecular_Biology_of_Ca...
- therealcamino 2y ago
  From the article: > 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.”
- ulfw 2y ago
  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

JumpCrisscross 2y ago

> advantage of Lorlatinib is high penetration of the blood-brain barrier Why is this essential to fighting lung cancer?

ma2t 2y ago
Brain is among the top sites where NSCLC tumors tend to metastasize https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251107 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251107
- JumpCrisscross 2y ago
  Wow. Thanks. How do the cancer cells cross the blood-brain barrier?
  - newzisforsukas 2y ago
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633769/#:~:text=The%20Tumor%20Cell%20of%20Origin%20for%20Brain%20Metastases%20and%20Its%20Road%20to%20the%20Brain https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633769/#:~:tex...
at_a_remove 2y ago
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.
- LeroyRaz 2y ago
  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.
- adamredwoods 2y ago
  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'm currently reading this book to help me understand (latest edition): https://www.google.com/books/edition/Molecular_Biology_of_Cancer/n8owEAAAQBAJ https://www.google.com/books/edition/Molecular_Biology_of_Ca...
therealcamino 2y ago
From the article: > 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.”
ulfw 2y ago
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