Expert Recommendations for Treating Metastatic Non-Small Cell Lung Cancer

Clinical management of metastatic non-small cell lung cancer (NSCLC) relies on targeted therapy, immunotherapy, chemoimmunotherapy, and/or chemotherapy. Selecting the most effective treatment regimen is complex — and the choices are evolving rapidly. 

Fred Hutchinson Cancer Center medical oncologist Christina Baik, MD, MPH, recently shared the latest research on metastatic NSCLC and her treatment approach at the 13th Annual Comprehensive Hematology and Oncology Review Course. Fred Hutch was created by the merger of the Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center. 
 

Chemotherapy Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It may be given alone or with other treatments. Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy may be given by mouth, injection, infusion or on the skin, depending on the type and stage of the cancer being treated. It may be given alone or with other treatments, such as surgery, radiation therapy or biologic therapy. Immunotherapy A type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. A therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some immunotherapies only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG) and some monoclonal antibodies. Medical oncologist A physician who has special training in diagnosing and treating cancer in adults using chemotherapy, hormonal therapy, biological therapy and targeted therapy. A physician who has special training in diagnosing and treating cancer in adults using chemotherapy, hormonal therapy, biological therapy and targeted therapy. A medical oncologist is often the main health care provider for someone who has cancer. A medical oncologist also gives supportive care and may coordinate treatment given by other specialists. Metastatic A metastatic cancer is a cancer that has spread to other areas of the body by way of the lymph system or bloodstream. Targeted therapy A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. Some targeted therapies block the action of certain enzymes, proteins or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells, or they deliver toxic substances directly to cancer cells and kill them. Targeted therapy may have fewer side effects than other types of cancer treatment. Most targeted therapies are either small molecule drugs or monoclonal antibodies.
Dr. Christina Baik stands for a portrait in a lab setting.

“When selecting a first-line therapy for patients with metastatic NSCLC, we need three key pieces of information,” says Dr. Baik. “This information includes molecular testing, PD-L1 immunohistochemistry, and clinical characteristics.”

If molecular testing identifies an actionable genetic alteration, doctors usually use targeted therapy as first line treatment, though there are several exceptions. In the absence of a target, selection of therapy depends largely on PD-L1 expression and smoking history. 

Targeted Therapy Options for NSCLC Oncogenic Subtypes

Currently, Dr. Baik says 10 molecular subtypes can be treated with FDA-approved targeted therapies:
 

Metastatic A metastatic cancer is a cancer that has spread to other areas of the body by way of the lymph system or bloodstream. Targeted therapy A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. Some targeted therapies block the action of certain enzymes, proteins or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells, or they deliver toxic substances directly to cancer cells and kill them. Targeted therapy may have fewer side effects than other types of cancer treatment. Most targeted therapies are either small molecule drugs or monoclonal antibodies. Targeted therapy A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. Some targeted therapies block the action of certain enzymes, proteins or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells, or they deliver toxic substances directly to cancer cells and kill them. Targeted therapy may have fewer side effects than other types of cancer treatment. Most targeted therapies are either small molecule drugs or monoclonal antibodies. Molecular testing A method to check for certain genes, proteins or other molecules to help diagnose cancer, plan treatment, find out how well treatment is working or predict whether cancer will come back or spread.

A laboratory method that uses a sample of tissue, blood, or other body fluid to check for certain genes, proteins or other molecules that may be a sign of a disease or condition, such as cancer. Molecular testing can also be used to check for certain changes in a gene or chromosome that may increase a person’s risk of developing cancer or other diseases. Molecular testing may be done with other procedures, such as biopsies, to help diagnose some types of cancer. It may also be used to help plan treatment, find out how well treatment is working, make a prognosis or predict whether cancer will come back or spread to other parts of the body. Also called biomarker testing and molecular profiling.

MOLECULAR TARGET

PREVALENCE 

TARGETED THERAPY

KRAS G12C 10-13% FDA-approved treatments include:
  • Sotorasib (approved as second-line therapy, typically after chemoimmunotherapy)
  • Adagrasib (recently FDA approved as second-line therapy)
EGFR Mutation, Non-Exon 20 Insertion 10-15%

Several FDA-approved first, second, and third generation tyrosine kinase inhibitors (TKIs) exist. Options for first-line treatments include:

  • Osimertinib (preferred in U.S.)
  • Erlotinib +/- ramucirumab (if no brain metastases), afatinib, dacomitinib, gefitinib 

Note: When not using osimertinib, be sure to test for T790M at progression.  About half of patients will be positive and will benefit from osimertinib. 

EGFR Exon 20 Insertion 2-3%

This subtype is not sensitive to the above TKIs. FDA-approved treatments include:

  • Amivantamab (infusion drug)
  • Mobocertinib (oral drug; diarrhea is a near universal side effect, which may require dose reduction)

Note: Amivantamab and mobocertinib are second-line therapy, usually after chemotherapy. The two agents have different mechanisms of action, so sequencing may be an option. 

HER2 Exon 20 Insertion 1-2%

FDA-approved treatments include only:

  • Trastuzumab deruxtecan (approved as second-line therapy, typically after chemotherapy or chemoimmunotherapy)

Note: Some patients taking trastuzumab deruxtecan may develop pneumonitis. Early recognition and discontinuation of the drug is important. 

MET Exon 14 Skipping Mutation 3-4%

This mutation is common in older patients and those with sarcomatoid NSCLC. Two FDA-approved TKIs include:

  • Capmatinib 
  • Tepotinib

Notes:

  • Peripheral edema is the most common side effect with both drugs.
  • Both drugs have CNS efficacy.
  • The mechanism of action is similar for both drugs, so using them in sequence is unlikely to be effective (though clear data is lacking). 
RET Rearrangement 1-2%

This oncogene occurs across different solid tumors and is more common in thyroid cancer. Two FDA-approved TKIs include:

  • Selpercatinib 
  • Pralsetinib 

Note: These drugs have similar mechanisms of action, so they are unlikely to work in sequence.

ALK Rearrangement 3-5%

FDA-approved TKIs for first-line therapy include:

  • First generation: Crizotinib
  • Second generation: Alectinib, ceritinib, brigatinib
  • Third generation: Lorlatinib

Note: Alectinib is most commonly used, but brigatinib and lorlatinib are tolerable and have long progression-free survival. Use of these drugs in sequence can be effective.

ROS1 Rearrangement 1-2%

Two FDA-approved first-line TKIs are:

  • Crizotinib (unknown CNS efficacy)
  • Entrectinib (CNS efficacy; is not active in crizotinib-pretreated patients, so should not be used in sequence)

Note: Lorlatinib is a ROS1 inhibitor, though it does not have FDA approval as a first-line therapy. Lorlatinib is recommended for off-label use after crizotinib, per NCCN guidelines. 

BRAF V600E Mutation 1-2% The sole FDA-approved regimen involves:
  • Dabrafenib with trametinib 
NTRK Rearrangement <1% DNA-based molecular testing has limited sensitivity for this oncogene, which RNA testing often detects. FDA-approved TKIs include:
  • Entrectinib
  • Larotrectinib (demonstrates numerically higher response rate and longer progression-free survival than entrectinib)

 

Chemotherapy Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It may be given alone or with other treatments. Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy may be given by mouth, injection, infusion or on the skin, depending on the type and stage of the cancer being treated. It may be given alone or with other treatments, such as surgery, radiation therapy or biologic therapy. Mutation Any change in the DNA sequence of a cell. Mutations may be caused by mistakes during cell division, or they may be caused by exposure to DNA-damaging agents in the environment. Any change in the DNA sequence of a cell. Mutations may be caused by mistakes during cell division, or they may be caused by exposure to DNA-damaging agents in the environment. Mutations can be harmful, beneficial or have no effect. If they occur in cells that make eggs or sperm, they can be inherited; mutations that occur in other types of cells are not inherited. Certain mutations may lead to cancer or other diseases. A mutation is sometimes called a variant. Progression In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body. Side effects A problem that occurs when treatment affects healthy tissues or organs. Some side effects of cancer treatment are nausea, vomiting, fatigue, pain, decreased blood cell counts, hair loss and mouth sores. Molecular testing A method to check for certain genes, proteins or other molecules to help diagnose cancer, plan treatment, find out how well treatment is working or predict whether cancer will come back or spread.

A laboratory method that uses a sample of tissue, blood, or other body fluid to check for certain genes, proteins or other molecules that may be a sign of a disease or condition, such as cancer. Molecular testing can also be used to check for certain changes in a gene or chromosome that may increase a person’s risk of developing cancer or other diseases. Molecular testing may be done with other procedures, such as biopsies, to help diagnose some types of cancer. It may also be used to help plan treatment, find out how well treatment is working, make a prognosis or predict whether cancer will come back or spread to other parts of the body. Also called biomarker testing and molecular profiling.

Among the molecular targets, evidence varies for using targeted therapy as a first-line treatment, Dr. Baik says. For example:

  • Strong evidence for EGFR and ALK
  • Compelling evidence from single arm studies for ROS1, RET, NTRK, and BRAF, though randomized data is lacking
  • Limited evidence for MET exon 14, but targeted therapy considered reasonable

Targeted therapy is approved as second-line treatment for EGFR exon 20, KRAS G12C, and HER2 exon 20. 

Immunotherapy and Chemoimmunotherapy for Metastatic NSCLC

For patients without a specific oncogene, immunotherapy or chemoimmunotherapy are generally the first-line treatments. In this case, FDA-approved immunotherapy agents and chemoimmunotherapy regimens include:

Immunotherapy A type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. A therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some immunotherapies only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG) and some monoclonal antibodies. Targeted therapy A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. Some targeted therapies block the action of certain enzymes, proteins or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells, or they deliver toxic substances directly to cancer cells and kill them. Targeted therapy may have fewer side effects than other types of cancer treatment. Most targeted therapies are either small molecule drugs or monoclonal antibodies.
IMMUNOTHERAPY AGENTS (IMMUNE CHECKPOINT INHIBITORS, ICIS)
  • Pembrolizumab 
  • Atezolizumab 
  • Cemiplimab 
  • Ipilimumbab/nivolumab (ipi/nivo)

CHEMOIMMUNOTHERAPY REGIMENS FOR NON-SQUAMOUS NSCLC

  • Carboplatin, pemetrexed, pembrolizumab
  • Carboplatin, paclitaxel, bevacizumab, atezolizumab
  • Carboplatin, nab-paclitaxel, atezolizumab
  • Ipi/nivo, platinum doublet
  • Cemiplimab, platinum doublet
  • Tremelimumab, durvalumab, platinum doublet
CHEMOIMMUNOTHERAPY REGIMENS FOR SQUAMOUS NSCLC
  • Carboplatin, taxane,  pembrolizumab
  • Ipi/nivo, platinum doublet
  • Cemiplimab, platinum doublet
  • Tremelimumab, durvalumab, platinum doublet
Immunotherapy A type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. A therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some immunotherapies only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG) and some monoclonal antibodies.

Compared to chemotherapy, immunotherapy and chemoimmunotherapy result in better response rates and overall survival:

  • Pembrolizumab, atezolizumab and cemiplimab outperform chemotherapy for patients with high PD-L1 expression. 
  • Ipi/nivo is better than chemotherapy in both PD-L1 positive and negative cancers, though FDA approval is limited to PD-L1 positive NSCLC.
  • All chemoimmunotherapy regimens result in better outcomes than chemotherapy, regardless of PD-L1 expression.

An important question remains: When do you choose chemoimmunotherapy over immunotherapy? “In my personal practice, it depends on whether PD-L1 expression is high (50%) or low (<50%) and other patient-specific factors,” says Dr. Baik. She recommends:

  • High PD-L1 tumors (50%): Pembrolizumab, cemiplimab, or atezolizumab monotherapy, though no head-to-head data exists comparing these agents directly to chemoimmunotherapy 
  • High PD-L1 tumors in patients who never smoked or have symptomatic disease: Chemoimmunotherapy
  • Low PD-L1 tumors (1 to 49%): Chemoimmunotherapy, since pembrolizumab alone does not appear significantly better than chemotherapy alone
  • Low or intermediate PD-L1 tumors in patients who want to avoid chemotherapy: Ipilimumab/nivolumab

Dr. Baik advises caution when using targeted therapy agents too soon after immunotherapy. For example, studies have shown an increased risk of immune-related toxicities if doctors give EGFR and ALK TKIs within three to six months of ICIs. Recent data shows sotorasib given within three months of ICI therapy increases the risk of hepatitis. “We don’t have data on other oncogenic alterations, but I think it’s best to avoid TKIs with ICIs as general practice,” she says.

Summary of Treatment Recommendations

Overall, Dr. Baik’s general treatment approach for metastatic NSCLC draws upon the latest research and her extensive experience. Her recommendations weigh targeted therapy against immunotherapy and chemoimmunotherapy to provide optimal patient outcomes. 

“The only time we would use chemotherapy alone for metastatic NSCLC was if the patient had active autoimmune disease,” says Dr. Baik. Otherwise, she recommends the following sequencing:

Chemotherapy Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It may be given alone or with other treatments. Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy may be given by mouth, injection, infusion or on the skin, depending on the type and stage of the cancer being treated. It may be given alone or with other treatments, such as surgery, radiation therapy or biologic therapy. Immunotherapy A type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. A therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some immunotherapies only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG) and some monoclonal antibodies. Metastatic A metastatic cancer is a cancer that has spread to other areas of the body by way of the lymph system or bloodstream. Targeted therapy A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. A type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells while causing less harm to normal cells. Some targeted therapies block the action of certain enzymes, proteins or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells, or they deliver toxic substances directly to cancer cells and kill them. Targeted therapy may have fewer side effects than other types of cancer treatment. Most targeted therapies are either small molecule drugs or monoclonal antibodies.
TREATMENT STRATEGY IF IDENTIFIED MOLECULAR TARGET* TREATMENT STRATEGY IF NO MOLECULAR TARGET
PD-L1 ³50% + SMOKING HISTORY PD-L1 <50% + SMOKING HISTORY NO SMOKING HISTORY, HIGH DISEASE BURDEN
  1. TKI
  2. Platinum chemotherapy (+/- ICI)
  3. Taxane or ICI (if no previous ICI)
  4. Possible TKI retrial
  1. ICI monotherapy
  2. Platinum doublet chemotherapy
  3. Taxane chemotherapy
  1. Chemoimmunotherapy or Ipi/nivo
  2. Platinum doublet or Taxane chemotherapy
  1. Chemoimmunotherapy
  2. Taxane chemotherapy

*Exceptions: TKIs are second-line treatment for EGFR exon20, HER2 exon20, and KRAS.

Chemotherapy Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It may be given alone or with other treatments. Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy may be given by mouth, injection, infusion or on the skin, depending on the type and stage of the cancer being treated. It may be given alone or with other treatments, such as surgery, radiation therapy or biologic therapy.

Metastatic NSCLC Care at Fred Hutch

Fred Hutch offers leading-edge care for patients with metastatic NSCLC. As a national leader in cancer care, patients receive individualized treatment plans and have access to expanded treatment options through clinical trials. Our specialists coordinate with community physicians to treat patients in their own community when possible. 

To consult with a Fred Hutch physician, contact 800.4UW.DOCS

Metastatic A metastatic cancer is a cancer that has spread to other areas of the body by way of the lymph system or bloodstream.

For patient referrals, contact:

fax (206) 606-1025