Expert recommendations for treating metastatic non-small cell lung cancer

“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:

Molecular target: KRAS G12C

Prevalence: 10-13%

Targeted therapy: FDA-approved treatments include:

• Sotorasib (approved as second-line therapy, typically after chemoimmunotherapy)
• Adagrasib (recently FDA approved as second-line therapy)

Molecular target: EGFR Mutation, Non-Exon 20 Insertion

Prevalence: 10-15%

Targeted therapy: 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

Molecular target: EGFR Exon 20 Insertion

Prevalence: 2-3%

Targeted therapy: 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. 

Molecular target: HER2 Exon 20 Insertion

Prevalence: 1-2%

Targeted therapy: 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. 

Molecular target: MET Exon 14 Skipping Mutation

Prevalence: 3-4%

Targeted therapy: 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). 

Molecular target: RET Rearrangement

Prevalence: 1-2%

Targeted therapy: 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.

Molecular target: ALK Rearrangement

Prevalence: 3-5%

Targeted therapy: 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.

Molecular target: ROS1 Rearrangement

Prevalence: 1-2%

Targeted therapy: 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. 

Molecular target: BRAF V600E Mutation

Prevalence: 1-2%

Targeted therapy: The sole FDA-approved regimen involves:

• Dabrafenib with trametinib 

Molecular target: NTRK Rearrangement

Prevalence: <1%

Targeted therapy: 

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)

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 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

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:

Treatment strategy if identified molecular target*          

1. TKI
2. Platinum chemotherapy (+/- ICI)
3. Taxane or ICI (if no previous ICI)
4. Possible TKI retrial

Treatment strategy if no molecular target

PD-L1 ³50% + SMOKING HISTORY                            

1. ICI monotherapy
2. Platinum doublet chemotherapy
3. Taxane chemotherapy

PD-L1 <50% + SMOKING HISTORY

1. Chemoimmunotherapy or Ipi/nivo
2. Platinum doublet or Taxane chemotherapy

NO SMOKING HISTORY, HIGH DISEASE BURDEN

1. Chemoimmunotherapy
2. Taxane chemotherapy

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

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 1.800.4UW.DOCS. 

For Patient Referrals, Contact:

Phone: 206.606.1024

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