What are the targeted therapies for patients with specific cancer mutations?

Targetable Cancer Mutations and Their Treatments

Non-Small Cell Lung Cancer (NSCLC)

EGFR Mutations

For patients with EGFR-mutated metastatic NSCLC, osimertinib is the preferred first-line treatment due to superior CNS penetration and efficacy, particularly in patients with brain metastases. 1

• Exon 19 deletions and L858R (exon 21) mutations: Erlotinib 150 mg daily demonstrates median PFS of 10.4 months versus 5.2 months with chemotherapy (HR 0.34, p<0.001) 2
• First-generation TKIs (erlotinib, gefitinib) and second-generation TKIs (afatinib) are established options with response rates of 65% in treatment-naïve patients 2
• Third-generation TKI osimertinib achieves CNS response rates >60% and is specifically recommended for patients with brain metastases 1
• T790M resistance mutation: Develops in 50-60% of patients progressing on first/second-generation EGFR TKIs; osimertinib demonstrates median PFS of 9.6 months in this setting 3
• Exon 20 insertion mutations: Generally resistant to standard EGFR TKIs (exception: rare FQEA insertion) 3

ALK Rearrangements

Alectinib or lorlatinib should be used as first-line therapy for ALK-positive NSCLC, with lorlatinib preferred for patients with brain metastases due to superior intracranial control. 3, 1

• First-line options: Alectinib, brigatinib, ceritinib, or lorlatinib (all Level I-A evidence) 3
• Crizotinib: Response rates >60% but inferior CNS penetration; now considered second-line after newer-generation ALK inhibitors 1
• At crizotinib resistance: Alectinib (ESMO-MCBS score: 4), brigatinib, or ceritinib are recommended 3
• After second-generation ALK TKI failure: Lorlatinib is the preferred option 3
• Brain metastases: Alectinib delays intracranial progression (Level I evidence); lorlatinib prolongs intracranial control and improves PFS (Level II evidence) 1

ROS1 Rearrangements

Crizotinib or entrectinib should be used first-line for ROS1-rearranged NSCLC, with entrectinib preferred in patients with brain metastases. 3

• Crizotinib: 56% response rate in ROS1-translocated NSCLC; approximately 70% response rate including complete responses 3, 1
• Entrectinib: Preferred over crizotinib for brain metastases due to superior CNS penetration (Level III-A, ESMO-MCBS score: 3) 3
• Repotrectinib: Available as first-line option in some regions (FDA approved, not EMA approved) 3
• Prevalence: 1-2% of NSCLC patients; more common in younger women with adenocarcinoma who are never smokers 1

KRAS G12C Mutations

Sotorasib or adagrasib should be used as subsequent therapy after progression on first-line immunotherapy-based treatment for KRAS G12C-mutated NSCLC. 4

• First-line approach: PD-L1-guided immunotherapy-based regimens are preferred; targeted therapies are NOT recommended first-line 4
• Sotorasib: Median OS 12.5 months, objective response rate 37.1% in previously treated patients (ESMO-MCBS score: 3) 3, 4
• Adagrasib: Median OS 12.6 months, objective response rate 42.9% (FDA approved, not EMA approved) 3, 4
• Important caveat: Do NOT switch between sotorasib and adagrasib at progression due to similar mechanism of action 4
• Prevalence: Approximately 25% of adenocarcinomas in North American populations; associated with cigarette smoking 4

BRAF V600E Mutations

Dabrafenib plus trametinib combination is recommended for BRAF V600E-mutated NSCLC. 3

• Response rate: 60% in 20 patients with BRAF V600E-mutated NSCLC 3
• Evidence level: Level III-A, ESMO-MCBS score: 2 3
• After progression: Platinum-based chemotherapy with or without immunotherapy (depending on smoking history) 3

MET Alterations

Capmatinib or tepotinib should be used for MET exon 14 skipping mutations in first or second line. 3

• MET exon 14 skipping: Capmatinib or tepotinib recommended first-line (Level III-A, ESMO-MCBS score: 3; FDA approved, not EMA approved) or second-line 3
• If no MET TKI available: Platinum-doublet chemotherapy with or without immunotherapy first-line 3

HER2 Mutations

Trastuzumab deruxtecan is recommended for HER2 exon 20 mutations following prior first-line therapy. 3

• Trastuzumab deruxtecan: Recommended post-first-line therapy (Level III-B; FDA approved, not EMA approved) 3
• Earlier evidence: Trastuzumab and dacomitinib showed signs of activity in HER2-mutated NSCLC 3

NTRK Gene Fusions

Larotrectinib or entrectinib should be used for NTRK gene fusion-positive NSCLC when no satisfactory treatment options exist. 3

• Evidence level: Level III-A, ESMO-MCBS score: 3 3
• Indication: Patients with no satisfactory alternative treatment options 3

EGFR Exon 20 Insertions

Amivantamab is the preferred treatment for EGFR exon 20 insertion-mutated NSCLC after prior therapy. 3

• Amivantamab: Level III-B, ESMO-MCBS score: 3 3
• Mobocertinib: Alternative option (Level III-C, ESMO-MCBS score: 2; FDA approved, not EMA approved) 3
• Note: These mutations are resistant to standard EGFR TKIs 3

RET Rearrangements

RET inhibitors (vandetanib or specific RET-targeted agents) may be considered based on limited clinical data. 3

• Evidence: RET inhibitors are effective growth inhibitors but clinical experience limited to isolated cases 3
• Recommendation strength: Level C, Evidence level V 3

Colorectal Cancer (CRC)

BRAF V600E Mutations

For BRAF V600E-mutated metastatic colorectal cancer, there is insufficient evidence to support triplet chemotherapy over doublet regimens in first-line treatment. 3

• First-line options: FOLFOX, FOLFIRI, or capecitabine plus oxaliplatin with bevacizumab 3
• FOLFOXIRI plus bevacizumab: Showed median OS of 19.0 months versus 10.7 months with FOLFIRI plus bevacizumab in TRIBE study (HR 0.54), but not confirmed in TRIBE-2 trial 3
• Anti-VEGF therapy: Patients with BRAF-mutated tumors benefit from bevacizumab similarly to BRAF wild-type tumors 3
• BRAF inhibitor monotherapy: Only 5% response rate; not recommended as single agent 3
• Vemurafenib plus cetuximab: Modest activity with 3.7% response rate, median PFS 3.7 months 3
• EGFR antibodies: Limited benefit; not recommended in BRAF-mutated CRC based on retrospective analyses 3

Multiple Myeloma

t(11;14) Translocation

Venetoclax in combination with dexamethasone should be used for patients with t(11;14) translocation who are refractory to available therapies. 3

• Response rate: Over 2/3 of patients previously refractory to available therapies 3
• Mechanism: Targets BCL-2 overexpression associated with this translocation 3

NRAS, KRAS, and BRAF Mutations

Molecularly targeted drugs corresponding to specific mutations (NRAS, KRAS, BRAF) can be evaluated in relapsed disease through umbrella trials. 3

• Approach: High-throughput drug screening and repurposing of existing drugs should be investigated 3
• Important consideration: Sub-clonal nature of many mutations requires careful selection criteria and response assessment 3

Critical Management Principles

Oligometastatic Progression on TKI

Continue TKI therapy and add local treatment (surgery or radiotherapy) for oligometastatic progression during targeted therapy. 3

• Evidence: Results in minimal toxicity and months to years of disease control 3
• Recommendation strength: Level C, Evidence level V 3
• Pre-treatment requirement: Full evaluation of disease extent including CNS imaging 3

Re-biopsy Considerations

Re-biopsy at progression is not mandatory but should be discussed with patients who may benefit from genotyping/phenotyping. 3

• Potential benefits: Detection of transformation to SCLC (~5% of EGFR TKI-resistant tumors), identification of T790M mutation, clinical trial eligibility 3, 1
• Recommendation strength: Level C, Evidence level III 3

Important Caveats

• Avoid PD-1/PD-L1 monotherapy in EGFR-positive NSCLC: Shows inferior efficacy with response rate of 3.6% versus 23% in patients without these alterations 1
• EGFR TKI + immunotherapy combination: Increased risk of adverse events, particularly pneumonitis 1
• Mutation exclusivity: KRAS mutations generally do not overlap with EGFR mutations, ALK rearrangements, or ROS1 rearrangements 1
• Testing requirement: Molecular testing for actionable mutations is essential before initiating any targeted therapy 3, 1