What are the outcomes of Epidermal Growth Factor Receptor (EGFR) inhibitor chemotherapy on non-small cell lung cancer?

From the Guidelines

EGFR-targeted therapies, not EGFR chemotherapy, are effective for treating EGFR-mutated non-small cell lung cancer (NSCLC). These targeted medications include first-generation drugs like erlotinib (Tarceva) and gefitinib (Iressa), second-generation drugs like afatinib (Gilotrif) and dacomitinib (Vizimpro), and third-generation drugs like osimertinib (Tagrisso) 1. Osimertinib is now preferred as first-line treatment at 80mg daily due to superior progression-free survival (18.9 months vs 10.2 months) and better brain penetration compared to earlier generations. These medications work by blocking the EGFR signaling pathway that drives cancer growth in tumors with specific mutations (most commonly exon 19 deletions or L858R point mutations) 1.

Key Points

• Common side effects include skin rash, diarrhea, and fatigue 1.
• Resistance typically develops after 9-13 months with first/second-generation drugs and after about 19 months with osimertinib 1.
• Regular monitoring with CT scans every 2-3 months and molecular testing upon progression are essential to detect resistance mechanisms and guide subsequent treatment options 1.
• The American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) recommend EGFR mutation analysis to determine whether an EGFR-TKI or chemotherapy is the appropriate first-line treatment for advanced NSCLC 1.

Treatment Recommendations

• Osimertinib is recommended as first-line treatment for patients with EGFR-mutated NSCLC due to its superior progression-free survival and better brain penetration compared to earlier generations 1.
• Erlotinib, gefitinib, and afatinib are also recommended as first-line systemic therapy in patients with sensitizing EGFR mutations 1.
• Patients with T790M-positive tumors may benefit from osimertinib as second-line or subsequent therapy 1.

From the FDA Drug Label

The efficacy and safety of gefitinib tablets for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or L858R substitution mutations was demonstrated in a multicenter, single-arm, open-label clinical study (Study 1) A total of 106 treatment-naive patients with metastatic EGFR mutation positive NSCLC received gefitinib tablets at a dose of 250 mg once daily until disease progression or intolerable toxicity. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1. 1 as evaluated by both a Blinded Independent Central Review (BICR) and investigators. Efficacy results from Study 1 are summarized below. Table 3 – Efficacy Results in Study 1 Efficacy Parameter BICR1 Assessment (n=106)2 Investigator Assessment (n=106) Objective Response Rate3 (95% CI) 50%(41,59) 70%(61,78) Complete Response Rate 0.9% 1.9% Partial Response Rate 49% 68% Median Duration of Response (months) (95% CI) 6.0(5.6,11.1) 8.3(7.6,11. 3)

The outcomes of Egfr chemotherapy on lung cancer are:

• Objective Response Rate: 50% (41,59) as evaluated by BICR and 70% (61,78) as evaluated by investigators 2
• Complete Response Rate: 0.9% as evaluated by BICR and 1.9% as evaluated by investigators
• Partial Response Rate: 49% as evaluated by BICR and 68% as evaluated by investigators
• Median Duration of Response: 6.0 months (5.6,11.1) as evaluated by BICR and 8.3 months (7.6,11.3) as evaluated by investigators Key points:
• The response rates were similar in patients whose tumors had EGFR exon 19 deletions and exon 21 L858R substitution mutations.
• Two partial responses were observed in both patients whose tumors had G719X substitution mutation with duration of response of at least 2.8 months and 5.6 months, respectively.
• One of two patients whose tumors had L861Q substitution mutation also achieved a partial response with duration of response of at least 2.8 months.

From the Research

Outcomes of EGFR Chemotherapy on Lung Cancer

• The clinical outcomes of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib in patients with non-small cell lung cancer (NSCLC) have been evaluated in several studies 3, 4, 5, 6.
• A study found that the median overall survival (OS) was 37.0 months, and progression-free survival (PFS) and OS did not differ among the three EGFR TKIs 3.
• Another study found that a combined approach of chemotherapy with EGFR TKIs significantly improved overall survival (OS) compared with EGFR TKI alone (HR = 0.47,95% CI = 0.31-0.72) 4.
• The study also found that the concomitant use of chemotherapy with TKIs significantly improved the progression-free survival (PFS) when compared to the use of TKIs alone (HR = 0.68,95% CI = 0.49-0.95) 4.
• A meta-analysis found that osimertinib, erlotinib, and gefitinib are safe and effective first-line treatment options for patients with EGFR-mutated advanced NSCLC, with osimertinib improving the objective response rate (ORR) by 72% (95% CI: 65%, 78%) compared with erlotinib and gefitinib 6.
• A network meta-analysis found that chemotherapy-based combination regimens, such as "Chemo_anti-PD-1/PD-L1_anti-VEGF" and "Chemo_Ami", are recommended as preferred treatment options for patients who experienced disease progression on EGFR-TKIs, due to their superior efficacy 7.

Factors Affecting Outcomes

• Factors such as gefitinib, EGFR TKI treatment duration, male sex, initial liver metastasis, and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation 3.
• The type of EGFR-TKI received, the mutation pattern, and the co-occurring partner mutant genes may also affect treatment responses and survival outcomes 5.
• The use of antiangiogenic agents may create a therapeutic window for immunotherapy in advanced NSCLC after progression on prior EGFR-TKI treatment 7.

Treatment Options

• EGFR TKIs such as gefitinib, erlotinib, and afatinib are approved for first-line treatment of advanced NSCLC with an activating EGFR mutation 3.
• Chemotherapy-based combination regimens, such as "Chemo_anti-PD-1/PD-L1_anti-VEGF" and "Chemo_Ami", may be effective treatment options for patients who experienced disease progression on EGFR-TKIs 7.
• Osimertinib, erlotinib, and gefitinib are safe and effective first-line treatment options for patients with EGFR-mutated advanced NSCLC 6.