What are the indications, efficacy, and uses of targeted therapy in cancer treatment, including pretreatment evaluation, adjuvant and metastatic settings?

Targeted Therapy in Cancer Treatment: Indications, Efficacy, and Applications

Overview of Targeted Therapy

Targeted cancer therapies should be prioritized for patients with identified genetic mutations, regardless of PD-L1 expression levels, due to higher response rates and better tolerability compared to conventional treatments. 1 These therapies are designed to interfere with specific molecular targets involved in tumor growth and progression rather than affecting all rapidly dividing cells as with traditional chemotherapy.

Targeted therapies include several major classes:

• Monoclonal antibodies (e.g., trastuzumab, cetuximab)
• Small molecule inhibitors (e.g., osimertinib, sotorasib)
• Antibody-drug conjugates (e.g., sacituzumab govitecan)
• Immunotherapies (e.g., pembrolizumab, atezolizumab)

Pretreatment Evaluation

Molecular Testing Requirements

All patients with advanced cancer who may be candidates for targeted therapy should undergo comprehensive molecular testing before initiating treatment 1. This testing should include:

• Tumor-specific genetic mutations (e.g., EGFR, ALK, ROS1, BRAF, KRAS G12C, MET, NTRK, HER2)
• Hormone receptor status (for breast cancer)
• PD-L1 expression (for immunotherapy consideration)
• Microsatellite instability/mismatch repair status
• Germline mutations (e.g., BRCA1/2) when applicable

Economic Considerations

Economic evaluation of targeted cancer interventions is essential due to their high costs. The targeting strategy significantly impacts cost-effectiveness, and analyses should consider both the accuracy of targeting tests and alternative targeting methods 2. Decision analysis can simulate factors like patient adherence that influence outcomes in routine practice settings.

Targeted Therapy in Specific Cancers

Non-Small Cell Lung Cancer (NSCLC)

Molecular testing should guide first-line treatment selection:

• EGFR mutations: Osimertinib for common mutations; amivantamab-vmjw plus chemotherapy for exon 20 insertions 1
• ROS1 rearrangements: Entrectinib, crizotinib, or repotrectinib (prioritize entrectinib or repotrectinib for brain metastases) 1
• KRAS G12C mutations: Immunotherapy ± chemotherapy first-line; adagrasib or sotorasib for second-line or later 1

Colorectal Cancer (CRC)

For metastatic CRC, molecular testing guides therapy:

• RAS wild-type: Anti-EGFR therapy (cetuximab or panitumumab) for left-sided tumors 2
• BRAF V600E mutations: Encorafenib plus cetuximab for previously treated disease 2
• HER2 amplification: Consider trastuzumab combinations or trastuzumab deruxtecan 2
• MSI-H/dMMR: Immune checkpoint inhibitors (PD-1 inhibitors) 2

For potentially resectable metastatic CRC, combination regimens with targeted therapy should be selected based on molecular profile 2:

• RAS wild-type: Consider FOLFOX/FOLFIRI + cetuximab/panitumumab
• RAS mutant: Consider FOLFOX/FOLFIRI + bevacizumab

Breast Cancer

Treatment depends on molecular subtype:

1. HER2-negative, HR-positive metastatic breast cancer:

   • After endocrine therapy failure: Consider single-agent chemotherapy or endocrine therapy with targeted agents 2
   • For germline BRCA1/2 mutations: PARP inhibitors (olaparib or talazoparib) may be offered rather than chemotherapy 2

2. Triple-negative breast cancer (TNBC):

   • PD-L1-positive: Immune checkpoint inhibitor (atezolizumab plus nab-paclitaxel or pembrolizumab plus chemotherapy) as first-line therapy 2
   • PD-L1-negative: Single-agent chemotherapy preferred over combination therapy unless disease is highly symptomatic 2
   • After ≥2 prior therapies: Sacituzumab govitecan 2
   • With germline BRCA1/2 mutations: PARP inhibitors rather than chemotherapy 2

3. Male breast cancer:

   • Targeted therapy guided by HR, HER2, PD-L1, PIK3CA, and germline BRCA mutation status using the same indications as for women 2

Efficacy and Outcomes

Targeted therapies have dramatically transformed treatment outcomes in certain settings:

• EGFR-mutated NSCLC: Osimertinib shows superior efficacy with longer median progression-free survival (18.9 vs. 10.2 months) and median overall survival (38.6 vs. 31.8 months) compared to first-generation EGFR TKIs 1

• BRAF V600E-mutant mCRC: Encorafenib plus cetuximab is recommended after disease progression on at least one previous line of therapy 2

• Triple-negative breast cancer: Sacituzumab govitecan shows high efficacy after at least two prior therapies 2

• BRCA-mutated breast cancer: PARP inhibitors demonstrate high response rates in patients with DNA repair defects 2

Sequencing and Combination Strategies

Sequencing Considerations

• For patients with targetable mutations, targeted therapy should be prioritized over immunotherapy regardless of PD-L1 expression 1
• If urgent treatment is needed before molecular testing results are available, consider using only platinum-based chemotherapy without immunotherapy 1

Combination Approaches

• Colorectal cancer: FOLFOXIRI ± bevacizumab can be cautiously used for highly selected potentially resectable patients 2
• Triple-negative breast cancer: Combination of immune checkpoint inhibitors with chemotherapy for PD-L1-positive disease 2

Monitoring and Management of Progression

• Response evaluation should be performed after 2 cycles of treatment and then every 2-4 cycles 1
• Upon disease progression, re-biopsy or liquid biopsy should be performed to determine resistance mechanisms 1
• For oligoprogression, consider local treatment (surgery, SBRT) with continuation of targeted therapy 1

Toxicity Management

Common Adverse Events

• Concurrent or rapid switching from immunotherapy to targeted therapy (particularly osimertinib) should be avoided due to increased toxicity risk 1
• EGFR TKIs can cause rash, diarrhea, and pneumonitis
• Immune checkpoint inhibitors can cause immune-related adverse events including thyroid dysfunction, colitis, and pneumonitis
• PARP inhibitors commonly cause hematologic toxicities

Special Populations

• Targeted therapies (e.g., EGFR TKIs) are recommended even for patients with poor performance status who have actionable mutations 1
• For elderly patients with actionable mutations, targeted therapies are preferred over chemotherapy 1

Future Directions

The field of targeted therapy continues to evolve rapidly:

• Tumor-agnostic drugs targeting specific mutations regardless of cancer type
• Novel combination strategies to overcome resistance mechanisms
• Improved methods for identifying predictive biomarkers
• Development of new targeted agents for currently undruggable targets

Conclusion

Targeted therapy has revolutionized cancer treatment by providing more effective and less toxic options for patients with specific molecular alterations. Comprehensive molecular testing is essential before initiating treatment to identify actionable targets. While targeted therapies have improved outcomes in many cancer types, challenges remain, including development of resistance, toxicity management, and high costs. Ongoing research continues to expand the arsenal of targeted therapies and improve patient selection strategies.