“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.
Currently, Dr. Baik says 10 molecular subtypes can be treated with FDA-approved targeted therapies:
Molecular target: KRAS G12C
Targeted therapy: FDA-approved treatments include:
Molecular target: EGFR Mutation, Non-Exon 20 Insertion
Targeted therapy: Several FDA-approved first, second, and third generation tyrosine kinase inhibitors (TKIs) exist. Options for first-line treatments include:
Molecular target: EGFR Exon 20 Insertion
Targeted therapy: This subtype is not sensitive to the above TKIs. FDA-approved treatments include:
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.
Molecular target: HER2 Exon 20 Insertion
Targeted therapy: FDA-approved treatments include only:
Note: Some patients taking trastuzumab deruxtecan may develop pneumonitis. Early recognition and discontinuation of the drug is important.
Molecular target: MET Exon 14 Skipping Mutation
Targeted therapy: This mutation is common in older patients and those with sarcomatoid NSCLC. Two FDA-approved TKIs include:
Molecular target: RET Rearrangement
Targeted therapy: This oncogene occurs across different solid tumors and is more common in thyroid cancer. Two FDA-approved TKIs include:
Note: These drugs have similar mechanisms of action, so they are unlikely to work in sequence.
Molecular target: ALK Rearrangement
Targeted therapy: FDA-approved TKIs for first-line therapy include:
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.
Molecular target: ROS1 Rearrangement
Targeted therapy: Two FDA-approved first-line TKIs are:
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.
Molecular target: BRAF V600E Mutation
Targeted therapy: The sole FDA-approved regimen involves:
Molecular target: NTRK Rearrangement
DNA-based molecular testing has limited sensitivity for this oncogene, which RNA testing often detects. FDA-approved TKIs include:
Among the molecular targets, evidence varies for using targeted therapy as a first-line treatment, Dr. Baik says. For example:
Targeted therapy is approved as second-line treatment for EGFR exon 20, KRAS G12C, and HER2 exon 20.
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 agents (Immune checkpoint inhibitors, ICIS)
Chemoimmunotherapy regimens for non-squamous NSCLC
Chemoimmunotherapy regimens for squamous NSCLC
Compared to chemotherapy, immunotherapy and chemoimmunotherapy result in better response rates and overall survival:
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:
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.
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:
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
*Exceptions: TKIs are second-line treatment for EGFR exon20, HER2 exon20, and KRAS.
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 1.800.4UW.DOCS.
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