Last updated March 14, 2022

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations

Recommendations


EGFR First-line 

1.1 For patients with a sensitizing (L858R/exon 19 deletion, with or without a concomitant T790M mutation) EGFR mutation with stage IV NSCLC and a performance status of 0–2 who have not had previous systemic therapy, clinicians should offer osimertinib monotherapy. (H)
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1.2 For patients with a sensitizing (L858R/exon 19 deletion) EGFR mutation with stage IV NSCLC and a performance status of 0–2, previously untreated with systemic therapy and for whom osimertinib is not available, clinicians may use combination gefitinib with doublet chemotherapy (platinum/pemetrexed with maintenance pemetrexed) . (H)
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1.3 For patients with a sensitizing (L858R/exon 19 deletion) EGFR mutation with stage IV NSCLC and a performance status of 0–2, previously untreated with systemic therapy and for whom osimertinib is not available, clinicians may use dacomitinib monotherapy. (H)
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1.4 For patients with a sensitizing (L858R/exon 19 deletion) EGFR mutation with stage IV NSCLC and a performance status of 0–2, who have not had previous systemic therapy, and do not have access to osimertinib, clinicians may use monotherapy with afatinib or erlotinib/bevacizumab or erlotinib/ramucirumab. (H)
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1.5 For patients with a sensitizing (L858R/exon 19 deletion) EGFR mutation with stage IV NSCLC and a performance status of 0–2, who have not had previous systemic therapy, and do not have access to other regimens, clinicians may use monotherapy with gefitinib, erlotinib, or icotinib. (H)
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1.6 For patients with a sensitizing (L858R/exon 19 deletion) EGFR mutation with stage IV NSCLC and a performance status of 3, who have not had previous systemic therapy, monotherapy with an EGFR tyrosine kinase inhibitor may be given, with the choice dependent on access and toxicity profile of each agent. (L)
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1.7 For patients with an activating EGFR mutation other than exon 20 insertion mutations, T790M, L858R or exon 19 deletion, (e.g., G719X, L861Q, S768I), and a performance status of 0–2, who have not had previous systemic therapy, 
  • clinicians may offer afatinib monotherapy 

(IC, , L, M)
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  • or osimertinib 
(IC, , L, W)
618
  • or standard treatment based on the ASCO/OH non-driver mutation guideline.
(IC, , L, M)
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1.8 For patients with any activating EGFR mutation, regardless of PD-L1 expression levels (including exon 20 insertion mutations), single agent immunotherapy should not be used as first-line therapy. (L)
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1.9 For patients with an exon 20 insertion mutation causing resistance to first- and second-generation EGFR tyrosine kinase inhibitors, clinicians may offer platinum doublet chemotherapy with or without bevacizumab or standard treatment outlined in the ASCO/OH non-driver mutation guideline may be offered. (L)
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EGFR Second-line 

2.1 For patients with a sensitizing (L858R/exon 19 deletion) EGFR mutation with stage IV NSCLC and a performance status of 0–2, who have had previous EGFR-targeted therapy (who did not receive osimertinib) and subsequently have an EGFR T790M resistance mutation at the time of progressive disease, clinicians should offer osimertinib. (H)
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2.2 For patients with any EGFR mutation whose disease has progressed on EGFR tyrosine kinase inhibitors with no T790M mutation OR whose disease has progressed on osimertinib, clinicians may treat based on ASCO/OH non-driver mutation guideline. (L)
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ALK First-line 

3.1 For patients with an ALK rearrangement, a performance status of 0–2, and previously untreated NSCLC, clinicians should offer alectinib or brigatinib. (H)
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  • If alectinib and brigatinib are not available, clinicians should offer ceritinib or crizotinib.
(EB, B, H, S)
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ALK Second-line 

4.1 For patients with an ALK rearrangement, a performance status of 0–2, and have previously received alectinib or brigatinib, clinicians may offer lorlatinib. (L)
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4.2 For patients with an ALK rearrangement, a performance status of 0–2, and have previously received crizotinib in the first-line setting, clinicians should offer alectinib, brigatinib, or ceritinib in the second-line setting. (H)
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4.3 For patients with an ALK rearrangement, a performance status of 0–2, and have received prior crizotinib in the first-line setting and either alectinib, brigatinib, or ceritinib in the second-line setting, clinicians may offer lorlatin (L)
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  • or clinicians may offer standard therapy based on the ASCO/OH non-driver mutation guideline in the third-line setting.

(IC, , L, W)
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ROS1 First-line 

5.1 For patients with ROS1 rearrangement, a performance status of 0–2, previously untreated NSCLC, clinicians may offer crizotinib or entrectinib. (L)
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5.2 For patients with ROS1 rearrangement, a performance status of 0–2, previously untreated NSCLC, clinicians may offer standard therapy based on the ASCO/OH non-driver mutation guideline. (L)
618
5.3 For patients with ROS1 rearrangement, a performance status of 0–2, previously untreated NSCLC, clinicians may offer ceritinib or lorlatinib. (L)
618


ROS1 Second-line 

6.1 For patients with ROS1 rearrangement, a performance status of 0–2, previously treated with ROS1-targeted therapy, clinicians should offer standard therapy based on the ASCO/OH non-driver mutation guideline. (L)
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6.2 For patients with ROS1 rearrangement, a performance status of 0–2, previously treated with non-targeted therapy first-line, clinicians may offer crizotinib or entrectinib or ceritinib. (L)
618


BRAF First-line 

7.1 For patients with a BRAF V600E mutation, clinicians may offer dabrafenib/trametinib as first-line. (L)
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7.2 For patients with a BRAF V600E mutation, clinicians may offer standard first-line therapy based on the ASCO/OH non-driver mutation guideline. (L)
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BRAF Second-line

8.1 For patients with a BRAF V600E mutation who have had previous BRAF/MEK (dabrafenib/trametinib) targeted therapy, clinicians should offer standard first-line therapy based on the ASCO/OH non-driver mutation guideline. (L)
618
8.2 For patients with a BRAF V600E mutation, if BRAF-targeted therapy was not given in the first-line setting, 
  • clinicians may offer dabrafenib/ trametinib 

(IC, , L, M)
618
  • or dabrafenib alone 

(IC, , L, W)
618
  • or vemurafenib.

(IC, B, L, W)
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8.3 For patients with a BRAF V600E mutation who have had previous chemotherapy, immunotherapy, and/or BRAF-targeted therapy in the first- or subsequent-line setting, clinicians should offer standard treatment based on the ASCO/OH non-driver mutation guideline. (L)
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8.4 For patients with BRAF mutations other than BRAF V600E mutations, clinicians should offer standard therapy based on the ASCO/OH non-driver mutation guideline. (L)
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MET First-line 

9.1 For patients with a MET exon 14 skipping mutation, a performance status of 0–2, previously untreated NSCLC, clinicians may offer MET-targeted therapy with capmatinib or tepotinib. (L)
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9.2 For patients with a MET exon 14 skipping mutation, a performance status of 0–2, previously untreated NSCLC, clinicians may offer standard first-line therapy based on the ASCO/OH non-driver mutations guideline. (L)
618


MET Second-line 

10.1 Patients with MET abnormalities other than exon 14 skipping mutations, a performance status of 0–2, or those previously treated with MET-targeted therapy, clinicians should offer standard therapy based on the ASCO/OH non-driver mutations guideline. (L)
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10.2 For patients with a MET exon 14 skipping mutation, a performance status of 0–2, who have previously received or been ineligible for first-line chemotherapy with or without immunotherapy, clinicians may offer MET-targeted therapy with capmatinib or tepotinib. (L)
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RET Rearrangement First-line 

11.1 For patients with a RET rearrangement, a performance status of 0–2, previously untreated NSCLC, clinicians may offer selpercatinib. (L)
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11.2 For patients with a RET rearrangement, a performance status of 0–2, previously untreated NSCLC, clinicians may offer standard therapy based on the ASCO/OH non-driver mutation guideline. (L)
618
11.3 For patients with a RET rearrangement, a performance status of 0–2, previously untreated NSCLC, clinicians may offer pralsetinib.*  (L)

* provisionally included pending confirmatory data 

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RET Rearrangement Second-line 

12.1 For patients with RET rearrangement who have had previous RET-targeted therapy, clinicians may offer treatment based on the ASCO/ OH non-driver mutation. (L)
618
12.2 For patients with RET rearrangement, if RET-targeted therapy was not given in the first-line setting, clinicians may offer selpercatinib. (L)
618
12.3 For patients with RET rearrangement, if RET-targeted therapy was not given in the first-line setting, clinicians may offer pralsetinib.*  (L)

* provisionally included pending confirmatory data 

618


NTRK First-line 

13.1 For patients with an NTRK fusion, a performance status of 0–2, previously untreated NSCLC, clinicians may offer entrectinib or larotrectinib. (L)
618
13.2 For patients with an NTRK fusion, a performance status of 0–2, previously untreated NSCLC, clinicians may offer standard therapy based on the ASCO/OH non-driver mutation guideline. (L)
618


NTRK Second-line 

14.1 For patients with an NTRK fusion, if NTRK-targeted therapy was not given in the first-line setting, clinicians may offer standard therapy based on the ASCO/OH non-driver mutation guideline. (L)
618
14.2 For patients with an NTRK fusion previously treated NSCLC who have not received an NTRK inhibitor, clinicians may offer entrectinib or larotrectinib. (L)
618

Recommendation Grading

Overview

Title

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations

Authoring Organizations

Publication Month/Year

March 20, 2021

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Female, Male, Adult

Health Care Settings

Ambulatory, Home health, Hospital, Outpatient

Intended Users

Social worker, physician, nurse practitioner, nurse

Scope

Management, Treatment

Diseases/Conditions (MeSH)

D002289 - Carcinoma, Non-Small-Cell Lung

Keywords

non-small cell lung cancer, Targeted Therapy, Clinical guidelines, ROS-1 fusions, BRAF V600e mutations, RETfusions, MET exon 14 skipping mutations, NTRK fusions

Supplemental Methodology Resources

Data Supplement, Evidence Tables