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Lung Cancer and LM

Lung cancer is a type of cancer that begins in the tissues of the lungs. There are two main types of lung cancer, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

Non-Small Cell Lung Cancer

Nearly 9 out of 10 cases of lung cancer are NSCLC. The main subtypes of NSCLC are:

  • Adenocarcinoma
    • The most common type of lung cancer
    • Starts in the cells that line the surface of the lung and make mucus
    • Most commonly occurs in people who currently or used to smoke
    • Most common type of lung cancer in women and younger people who have never smoked.
  • Squamous Cell Carcinoma
    • Starts in the flat cells that line the inside of the airways
    • Typically occurs in the central part of the lungs near a main airway.
    • Linked to a history of smoking
  • Large Cell Carcinoma
    • Rarest of the lung cancers
    • Tend to grow quickly and are usually detected after they have spread to other parts of the body.

 

Small Cell Lung Cancer

About 1 in 10 cases of lung cancer are SCLCs. This is a very aggressive form of lung cancer that grows quickly and easily spreads to other parts of the body. There is also a high chance of this cancer returning, called recurrence.

Gulzina Griffin, diagnosed with stage 4 EGFR 19del lung cancer in 2018 and leptomeningeal spread in November 2024
Common Mutations in Lung Cancer

Cancer is caused by mutations in our DNA that allow cells to grow uncontrollably – and eventually invade surrounding tissue. Mutations in lung cancer (mostly found in NSCLC and not SCLC) include:

  • ALK (anaplastic lymphoma kinase)
  • BRAF and BRAF V600E
  • EGFR (epidermal growth factor receptor)
  • HER2 (Human epidermal growth factor receptor 2)
  • KRAS
  • MET and METex14 (Mesenchymal–epithelial transition)
  • NTRK
  • NRG1
  • PD-L1 and P1
  • RET
  • ROS1
  • STK11
  • TP53 (tumor protein p53)
  • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)

 

A person with lung cancer may have none of these mutations, and the mutations vary by what type of lung cancer it is.

Metastatic lung cancer, also known as advanced lung cancer, is when lung cancer spreads to other areas of the body, such as the liver, bones, brain, adrenal glands and lymph nodes. Brain metastases are very common in people with lung cancer, although it varies by the type of lung cancer and the mutations.

  • As many as 50% of people with lung cancer develop brain metastases as the cancer progresses.

Leptomeningeal metastases (also known as LM, leptomeningeal disease, LMD, or leptomeningeal cancer) differs slightly from brain metastases, as it means that the cancer is growing on the lining of the brain and spinal cord, called the leptomeninges. Most commonly, this occurs along with brain metastases.

 

As many as 10% to 13% of people with NCSLC and 11% of SCLC will develop LM.

  • In patients with EGFR mutations, 9% or more of people will develop LMD.
  • In patients with ALK mutation, up to 10% of people will develop LMD.

*For up-to-date guidelines for lung cancer treatment, visit the NCCN patient guidelines

Surgery:

  • Surgery is usually a treatment option for lung cancer in people who are healthy enough for surgery and when the tumor has been found early.
  • Surgery cannot be performed to remove the entire leptomeninges, and it is usually reserved for patients with symptomatic brain metastases in the parenchyma of the brain.
  • The role of surgery in leptomeningeal metastases is usually for placement of one the two devices:
    • A reservoir, commonly called an “Ommaya,” is placed under the scalp to ease the collection of cerebrospinal fluid (CSF) and administration of medications into the cerebrospinal fluid (CSF)
    • A ventriculoperitoneal shunt or VPS is inserted in your head to reduce pressure inside the brain by draining extra CSF into the abdomen

 

Chemotherapy: Chemotherapy may be used as the main form of treatment for lung cancer, or it may be used in combination with other treatments. Chemotherapy may be given before surgery to shrink the tumor or after surgery to kill any remaining cancer cells. It may be given along with radiation therapy or immunotherapy, depending on the type of lung cancer and how advanced it is.

  • Chemotherapy drugs used for NSCLC and SCLC include, but aren’t limited to:
    • Cisplatin
    • Carboplatin
    • Paclitaxel (Taxol)
    • Docetaxel (Taxotere)
    • Gemcitabine (Gemzar)
    • Vinorelbine (Navelbine)
  • Chemo specific to patients with NSCLC include:
    • Albumin-bound paclitaxel (nab-paclitaxel, Abraxane)
    • Pemetrexed (Alimta)
    • Etoposide (VP-16)
  • Chemo specific to patients with SCLC include:
    • Cisplatin and etoposide
    • Carboplatin and etoposide
    • Topotecan (Hycamtin)
    • Lurbinectedin (Zepzelca)
    • Irinotecan (Camptosar)
    • Temozolomide (Temodar)

Many systemic chemotherapies have limited activity in the leptomeningeal space, though they can be used creatively alone or in combination with other therapies.

Immunotherapy: Treatment for lung cancer can involve immunotherapy, mainly immune checkpoint inhibitors (ICIs).

How immunotherapy works:

The immune system is made up of organs and cells that help protect your body from viruses, bacteria and abnormal cells in your body, such as cancer cells.

While the immune system detects and attacks infections and abnormal cells, it also is designed to protect normal cells and tissues in the body. Immune checkpoints, which are proteins found on white blood cells called T cells, prevent an immune response from being so strong that it destroys your healthy cells. But sometimes, because of these checkpoints, the immune system ends up protecting cancer cells and allowing them to avoid being destroyed by your immune system. Cancer can find a way to avoid immune destruction.

Immunotherapy is medicine that increases the ability of a person’s own immune system to detect and destroy cancer cells.

Certain types of immunotherapies, called immune checkpoint inhibitors (ICIs), work by removing or blocking checkpoints in the immune system, allowing T cells to recognize and attack cancer cells. However, by blocking these checkpoints and allowing the T cells to become too powerful, the immune checkpoint inhibitor treatments can sometimes lead to side effects.

The immune system is complex, so unfortunately, while some patients benefit from immunotherapies, these treatments do not work for everyone and cancer can continue to grow or recur.

Immune checkpoints targeted in lung cancer include PD-1, PD-L1 and CTLA-4. Treatments that inhibit these immune checkpoints include:

  • PD-1 inhibitors: nivolumab (Opdivo), pembrolizumab (Keytruda), and cemiplimab (Libtayo)
  • PD-L1 inhibitors: atezolizumab (Tecentriq) and durvalumab (Imfinzi)
  • CTLA-4 inhibitor: ipilimumab (Yervoy) and tremelimumab (Imjudo)

Another targeted immunotherapy used for SCLC is tarlatamab (Imdelltra), a bispecific T-cell engager (BiTE).


Targeted therapy:

Targeted therapies are used most often for advanced stage lung cancers. They can be given either on their own or along with chemotherapy. They target mutations (changes) in certain genes. Many of these drugs have demonstrated activity in the central nervous system and may be used alone, or in combination with other treatments for leptomeningeal metastases. Targeted therapies for NSCLC include, but are not limited to:

  • ALK inhibitors:
    • Alectinib (Alecensa)
    • Brigatinib (Alunbrig)
    • Ceritinib (Zykadia)
    • Lorlatinib (Lorbrena)
  • BRAF inhibitors: BRAF inhibitors, such as vemurafenib (Zelboraf) or dabrafenib, are usually given with a MEK inhibitor:
    • Dabrafenib (Tafinlar) + trametinib (Mekinist)
    • Encorafenib (Braftovi) + binimetinib (Mektovi)
  • EGFR inhibitors:
    • Afatinib (Gilotrif)
    • Dacomitinib (Vizimpro)
    • Erlotinib (Tarceva)
    • Gefitinib (Iressa)
    • Lazertinib (Lazcluze)
    • Osimertinib (Tagrisso)
    • Sunvozertinib (Zegfrovy)
  • HER-2 inhibitors:
    • Ado-trastuzumab emtansine (Kadcyla)
    • Fam-trastuzumab deruxtecan (Enhertu)
    • Zenocutuzumab (Bizengri)
    • Zongertinib (Hernexeos)
  • KRAS inhibitors:
    • Adagrasib (Krazati)
    • Sotorasib (Lumakras)
  • MET inhibitors:
    • Capmatinib (Tabrecta)
    • Tepotinib (Tepmetko)
  • NTRK inhibitors:
    • Larotrectinib (Vitrakyi)
    • Entrectinib (Rozlytrek)
  • RET inhibitors:
    • Selpercatinib (Retevmo)
    • Pralsetinib (Gavreto)
  • ROS1 inhibitors:
    • Entrectinib (Rozlytrek)
    • Crizotinib (Xalkori),
    • taletrectinib (Ibtrozi)
  • Tyrosine kinase inhibitors:
    • Cabozantinib (Cometriq, Cabometyx)
    • Crizotinib (Xalkori)
    • Repotrectinib (Augtyro)

For metastatic lung cancer and leptomeningeal spread, some patients may benefit from receiving treatment intrathecally (directly into the spinal fluid) and depending on what is used, along with intravenous (into the bloodstream) treatment. Intrathecal treatment can be given through a lumbar puncture or an Ommaya port.

Intrathecal (IT) therapy for lung cancer and LM includes the use of pemetrexed, methotrexate, cytarabine, thiotepa, Herceptin and immunotherapy.

These treatments are usually given at a center that takes care of many patients with LM and has experience caring for patients who develop potential side effects.

Radiation Therapy:

  • Radiation therapy might be used before surgery to shrink your tumor or after surgery to kill off any remaining lung cancer cells. Sometimes it’s used as the main form of treatment if you’re not healthy enough for surgery or if the cancer has already spread to other parts of your body. It can also be used to improve your quality of life by treating certain symptoms of lung cancer like pain, bleeding or airway blockages.
  • For people with SCLC, radiation to the brain might be done to prevent brain metastases, though recommendations and guidelines have been shifting away from this approach in recent years.

For leptomeningeal cancer, radiation therapy to the whole brain and spine (called craniospinal irradiation or CSI) can be considered but should be approached with care. Side effects of CSI can limit the use of chemotherapy or other therapy and comes with risks of cognitive and functional impairment over time. Recent data suggest that proton radiation therapy may reduce the risk of systemic side effects (although it does not reduce the risk of nervous system side effects).

For more detailed information about lung cancer, please visit:

ALK Positive

American Lung Association  

GO2 for Lung Cancer

The International Association for the Study of Lung Cancer

LiveLung

Lung Cancer Foundation of America

Lung Cancer Research Foundation

Lungevity