Updated guidelines for stage IV NSCLC

White ribbon as a symbol of lung cancer and stethoscope lying on the lung x-ray.

The American Society of Clinical Oncology (ASCO) has released updated versions of its living guidelines for the treatment of stage IV non-small cell lung cancer (NSCLC) both with and without driver alterations. These guidelines were published in the Journal of Clinical Oncology:

ASCO’s guidelines are based on an ongoing systematic review of randomized clinical trials, with the latest time frame spanning February to October 2023. The evidence-based recommendations have been updated to address first, second and subsequent treatment options.

NSCLC with driver alterations

The revised guidelines recommend conducting comprehensive genomic biomarker testing in patients who have stage IV NSCLC with driver alterations and using the results to guide treatment. First-line treatment could include a selection of targeted agents based on the mutation type. Patients who do not have targeted options or who have already received all targeted options can receive the standard treatments outlined in the guidelines for patients without driver alterations.

EGFR mutations:

Patients with exon 19 deletions, or exon 21 L858R substitutions who develop EGFR T790M resistance alterations after first- or second-generation EGFR tyrosine kinase inhibitors, can receive osimertinib as second-line or later treatment (a strong recommendation based on high-quality evidence).

For patients whose disease has progressed on osimertinib or other EGFR tyrosine kinase inhibitors but who have not developed resistance mutations, second-line or later treatment can consist of platinum-based chemotherapy following the guidelines for patients without driver alterations (a strong recommendation based on moderate-quality evidence).

Patients with exon 20 insertions who received prior platinum-based chemotherapy can receive amivantamab as second-line or later treatment (a strong recommendation based on low-quality evidence).

ALK rearrangements:

Patients with ALK rearrangements can receive alectinib, brigatinib or lorlatinib as first-line treatment (a strong recommendation based on high-quality evidence). If these options are not available, patients can receive ceritinib or crizotinib (a strong recommendation based on high-quality evidence).

For patients who previously received crizotinib, second-line or later treatment can consist of alectinib, brigatinib, ceritinib or lorlatinib (a strong recommendation based on moderate-quality evidence).

Patients who previously received alectinib, brigatinib or other ALK inhibitors can receive lorlatinib as second-line or later treatment (a strong recommendation based on low-quality evidence).

ROS1 rearrangements:

Patients with ROS1 rearrangements can receive crizotinib or entrectinib as first-line treatment (a strong recommendation based on moderate-quality evidence). If these options are unavailable, patients can receive ceritinib or lorlatinib (a weak recommendation based on low-quality evidence).

Patients who previously received crizotinib, entrectinib or ceritinib can receive lorlatinib as second-line or later treatment (a weak recommendation based on low-quality evidence).

These patients can also receive platinum-based chemotherapy in second-line or later treatment, following the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

BRAF mutations:

Patients with BRAFV600E mutations can receive dabrafenib plus trametinib or encorafenib plus binimetinib as first-line treatment (a strong recommendation based on low-quality evidence). If these options are unavailable, patients can receive standard first-line treatment following the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

Patients with BRAFV600E mutations who have not received BRAF-targeted therapy can receive dabrafenib plus trametinib or encorafenib plus binimetinib as second-line or later therapy (a strong recommendation based on low-quality evidence).

For patients with BRAFV600E mutations who previously received BRAF- or MEK-targeted therapy, second-line or later treatment can consist of the standard first-line therapy outlined in the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

Patients with BRAF alterations other than V600E can receive standard second-line treatment according to the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

MET exon 14 skipping mutations:

Patients with MET exon 14 skipping mutations can receive capmatinib or tepotinib as first-line treatment (a strong recommendation based on low-quality evidence). If these options are unavailable, patients can receive standard first-line treatment following the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

For patients who have not received MET-targeted therapy, second-line or later treatment can consist of capmatinib or tepotinib (a strong recommendation based on low-quality evidence).

For patients who previously received MET-targeted therapy, second-line or later treatment can consist of standard therapy outlined in the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

RET rearrangements:

Patients with RET rearrangements can receive selpercatinib (a strong recommendation based on high-quality evidence) or pralsetinib if selpercatinib is unavailable (a strong recommendation based on moderate-quality evidence) as first-line treatment. If these options are unavailable, patients can receive standard first-line treatment following the guidelines for patients without driver alterations (a weak recommendation based on low-quality evidence).

For patients who have not received a RET inhibitor, second-line or later treatment can consist of selpercatinib or pralsetinib (a strong recommendation based on moderate-quality evidence). If these options are unavailable, patients can receive treatment according to the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

NTRK rearrangements:

Patients with NTRK rearrangements can receive entrectinib or larotrectinib as first-line treatment (a strong recommendation based on low-quality evidence). If these options are unavailable, patients can receive standard first-line treatment following the guidelines for patients without driver alterations (a weak recommendation based on low-quality evidence).

For patients who have not received an NTRK inhibitor, second-line or later treatment can consist of entrectinib or larotrectinib (a strong recommendation based on low-quality evidence). If these options are unavailable, patients can receive standard platinum-based chemotherapy, as outlined in the guidelines for patients without driver alterations (a strong recommendation based on low-quality evidence).

HER2 mutations:

Patients with HER2 mutations can receive platinum-based chemotherapy as first-line treatment. These patients can also receive trastuzumab deruxtecan in second-line or later treatment (a strong recommendation based on low-quality evidence).

KRAS G12C mutations:

Patients with KRAS G12C mutations should receive standard first-line treatment with immune checkpoint inhibitor therapy and/or chemotherapy following the guidelines for patients without driver alterations.

These patients can also receive sotorasib in second-line or later treatment (a strong recommendation based on moderate-quality evidence) or adagrasib (a strong recommendation based on low-quality evidence). 

Patients with poor performance status can receive tyrosine kinase inhibitor therapy as first-line treatment based on drug access and toxicity profile (a weak recommendation based on low-quality evidence).

NSCLC without driver alterations

The revised guidelines recommend using PD-L1 expression and histology to guide treatment for patients who have stage IV NSCLC without driver alterations or targetable mutations. 

Non-squamous cell carcinoma:

Patients with a PD-L1 tumor proportion score (TPS) of at least 50% can receive single-agent pembrolizumab, cemiplimab or atezolizumab as first-line treatment (a strong recommendation based on high-quality evidence).

These patients can also receive any of the following combinations as first-line treatment (weak recommendations based on moderate-quality evidence):

  • Pembrolizumab plus carboplatin and pemetrexed
  • Cemiplimab plus carboplatin and pemetrexed
  • Atezolizumab plus carboplatin and nab-paclitaxel, with or without bevacizumab
  • Nivolumab plus ipilimumab, with or without two cycles of platinum-based chemotherapy
  • Durvalumab plus tremelimumab and platinum-based chemotherapy

Patients with a PD-L1 TPS of 1% to 49% can receive pembrolizumab plus carboplatin and pemetrexed or cemiplimab plus carboplatin and pemetrexed as first-line treatment (a strong recommendation based on moderate-quality evidence).

These patients can also receive any of the following combinations as first-line treatment (weak recommendations based on moderate-quality evidence):

  • Atezolizumab plus carboplatin and (nab)-paclitaxel, with or without bevacizumab
  • Nivolumab plus ipilimumab, with or without two cycles of platinum-based chemotherapy
  • Durvalumab plus tremelimumab and platinum-based chemotherapy
  • Anti-PD-1 monotherapy for patients who are ineligible for or decline treatment with doublet platinum chemotherapy, with or without anti-PD-(L)1 therapy

Patients with a PD-L1 TPS of less than 1% or an unknown PD-L1 status can receive any of the following combinations as first-line treatment (weak recommendations based on moderate-quality evidence):

  • Pembrolizumab plus carboplatin and pemetrexed
  • Cemiplimab plus carboplatin and pemetrexed
  • Atezolizumab plus carboplatin and (nab)-paclitaxel, with or without bevacizumab
  • Nivolumab plus ipilimumab, with or without two cycles of platinum-based chemotherapy
  • Durvalumab plus tremelimumab and platinum-based chemotherapy

Squamous cell carcinoma:

Patients with a PD-L1 TPS of at least 50% can receive single-agent pembrolizumab, cemiplimab or atezolizumab as first-line treatment (a strong recommendation based on high-quality evidence).

These patients can also receive any of the following combinations as first-line treatment (weak recommendations based on moderate-quality evidence):

  • Pembrolizumab plus carboplatin and (nab)-paclitaxel
  • Cemiplimab plus carboplatin and paclitaxel
  • Nivolumab plus ipilimumab, with or without two cycles of platinum-based chemotherapy
  • Durvalumab plus tremelimumab and platinum-based chemotherapy

Patients with a PD-L1 TPS of 1% to 49% can receive pembrolizumab plus carboplatin and (nab)-paclitaxel or cemiplimab plus carboplatin and paclitaxel as first-line treatment (a strong recommendation based on moderate-quality evidence).

These patients can also receive any of the following combinations as first-line treatment (weak recommendations based on moderate-quality evidence):

  • Nivolumab plus ipilimumab, with or without two cycles of platinum-based chemotherapy
  • Durvalumab plus tremelimumab and platinum-based chemotherapy
  • Anti-PD-1 monotherapy for patients who are ineligible for or decline treatment with doublet platinum chemotherapy, with or without anti-PD-(L)1 therapy

Patients with a PD-L1 TPS of less than 1% or an unknown PD-L1 status can receive any of the following combinations as first-line treatment (weak recommendations based on moderate-quality evidence):

  • Pembrolizumab plus carboplatin and (nab)-paclitaxel
  • Cemiplimab plus carboplatin and paclitaxel
  • Nivolumab plus ipilimumab, with or without two cycles of platinum-based chemotherapy
  • Durvalumab plus tremelimumab and platinum-based chemotherapy

Unspecified history:

Patients with advanced lung cancer should be referred for palliative care alongside first-line active cancer treatment (a strong recommendation based on high-quality evidence).

Patients who are ineligible for immune checkpoint inhibitor therapy can receive platinum doublet chemotherapy as first-line treatment (a strong recommendation based on high-quality evidence).

Patients with contraindications to platinum chemotherapy can receive nonplatinum first-line therapy (a weak recommendation based on moderate-quality evidence).

Use of bevacizumab:

Patients should not receive bevacizumab if they have squamous cell carcinoma, clinically significant hemoptysis, inadequate organ function, performance status greater than 1, clinically significant cardiovascular disease or medically uncontrolled hypertension (a strong recommendation based on high-quality evidence).

Giving maintenance bevacizumab with pemetrexed does not provide a survival advantage and confers increased toxicity when compared to maintenance pemetrexed or bevacizumab alone (a weak recommendation based on moderate-quality evidence).

Additional therapy:

Patients with good performance status who were previously treated with immune checkpoint inhibitors without chemotherapy can receive platinum doublet chemotherapy as second-line or later treatment (a strong recommendation based on low-quality evidence).

Patients with good performance status who were previously treated with platinum-based chemotherapy and immune checkpoint inhibitor therapy can receive:

  • Docetaxel, with or without ramucirumab as second-line or later treatment (a strong recommendation based on low-quality evidence)
  • Pemetrexed or gemcitabine as second-line or subsequent treatment (a weak recommendation based on low-quality evidence)
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