Table 1.
Landmark Clinical Trials of EGFR TKIs as First-Line Therapy for Advanced NSCLC.
| Drug(s) | Trial (NCT #) |
Phase | Population Characteristics |
Treatment Regimen /Cohorts |
Outcomes | Side Effects | Rate of Discontinuation from Toxicity |
FDA Approval Date |
|---|---|---|---|---|---|---|---|---|
| Erlotinib | EURTAC (NCT00446225) |
III | N = 173 Stages IIIB/IV Adenocarcinoma only -Race: White (99%) -EGFR Mutations: ex19del and L858R -Asymptomatic brain metastases were allowed |
Cohort A: Erlotinib 150 mg daily Cohort B: Platinum-based chemotherapy |
ORR: 63.6% (A) vs. 17.8% (B) mPFS: 9.7 months (A) vs. 5.2 months (B) p < 0.0001 mOS: 19.3 months (A) vs. 19.5 months (B) p = 0.87 |
Overall grade ≥3 AE: 45% (A) vs. 67% (B) | 13% (A) vs. 23% (B) | 14 May 2013 |
| Gefitinib | IPASS (NCT00322452) |
III | N = 1217 Stage IIIB/IV Adenocarcinoma only -Race: Asian (98%) -EGFR Mutations: ex19del, L858R, T790M, other -Excluded patients with untreated brain metastases |
Cohort A: Gefitinib 250 mg daily Cohort B: Platinum-based chemotherapy |
ORR: 84.8% (A) vs. 43.2% (B) mPFS: not reported; HR, 0.48 (95% CI, 0.34 to 0.67) for those with EGFR mutation mOS: 18.8 months (A) vs. 17.4 months (B) p = 0.109 |
Overall grade ≥3 AE: not reported * | 6.9% (A) vs. 13.6% (B) | 13 July 2015 |
| NEJ-002 (N/A–Japan) |
III | N = 230 Stage IIIB/IV NSCLC -Race: Asian/Japanese (100%) -EGFR Mutations: ex19del, L858R, and other (6.1%) -Asymptomatic brain metastases were allowed |
Cohort A: Gefitinib 250 mg daily Cohort B: Platinum-based chemotherapy |
ORR: 73.7% (A) vs. 30.7% (B) mPFS: 10.8 months (A) vs. 5.4 months (B) p < 0.001 mOS: 27.7 months (A) vs. 26.6 months (B) p = 0.483 |
Overall grade ≥3 AE: 41.2% (A) vs. 71.7% (B) | Not reported | ||
| WJTOG3405 (N/A–Japan) |
III | N = 118 Stage IIIB/IV NSCLC -Race: Asian/Japanese (100%) -EGFR Mutations: ex19del and L858R -Asymptomatic brain metastases were allowed |
Cohort A: Gefitinib 250 mg daily Cohort B: Platinum-based chemotherapy |
ORR: 62.1% (A) vs. 32.2% (B) mPFS: 9.2 months (A) vs. 6.3 months (B) p < 0.0001 mOS: 34.9 months (A) vs. 37.3 months (B) p = 0.2070 |
Overall grade ≥3 AE: not reported * | Not Reported | ||
| IFUM (NCT01203917) |
IV | N = 106 Stage IIIA/B/IV NSCLC -Race: White (100%) -EGFR Mutations: ex19del, L858R. T790M, S768I -Inclusion of brain metastatic disease not mentioned |
Single-Arm: Gefitinib 250 mg daily |
ORR: 69.8% mPFS: 9.7 months mOS: 19.2 months |
Overall grade ≥3 AE: 15% | 7.5% | ||
| Afatinib | LUX-Lung 3 (NCT00949650) |
III | N = 345 Stage IIIB/IV Adenocarcinoma only -Race: White (26.5%), Asian (71.7%), Other (1.7%) -EGFR Mutations: ex19del, L858R, Other (10.3%) -Asymptomatic stable brain metastases were allowed |
Cohort A: Afatinib 40 mg daily Cohort B: Platinum-based chemotherapy |
ORR: 56% (A) vs. 23% (B) mPFS: 11.1 months (A) vs. 6.9 months (B) p = 0.0004 mOS: 28.2 months (A) vs. 28.2 months (B) p = 0.39 mOS ex19del: 33.3 months (A) vs. 21.1 months (B) p = 0.0015 mOS L858R: 27.6 months (A) vs. 40.3 months (B) p = 0.29 |
Overall grade ≥3 AE: 49% (A) vs. 48% (B) | 8% (A) vs. 12% (B) | Approval for EGFR exon 19 deletions or exon 21 (L858R): 23 July 2013 Expansion of indication to all non-resistant EGFR mutations: 12 January 2018 |
| LUX-Lung 6 (NCT01121393) |
III | N = 364 Stage IIIB/IV Adenocarcinoma only -Race: Asian 100% -EGFR Mutations: ex19del, L858R, other (11%) -Asymptomatic, stable brain metastases were allowed |
Cohort A: Afatinib 40 mg daily Cohort B: Platinum-based chemotherapy |
ORR: 66.9% (A) vs. 23% (B) mPFS: 13.7 months (A) vs. 5.6 months (B) p < 0.0001 mOS: 23.1 months (A) vs. 23.5 months (B) p = 0.61 mOS ex19del: 31.4 months (A) vs. 18.4 months (B) p = 0.023 mOS L858R: 19.6 months (A) vs. 24.3 months (B) p = 0.34 |
Overall grade ≥3 AE: 36% (A) vs. 60.2% (B) | 5.9% (A) vs. 39.8% (B) | ||
| LUX-Lung 7 | IIb | N = 319 Stage IIIB/IV Adenocarcinoma only -Race: Asian (59%), White (30%), Black (1%), not available (11%) -EGFR Mutations: ex19del and L858R -Active brain metastases (symptomatic or requiring treatment) excluded |
Cohort A: Afatinib 40 mg daily with escalation to 50 mg daily if well tolerated after 4 weeks Cohort B: Gefitinib 250 mg daily |
ORR: 70% (A) vs. 56% (B) mPFS: 11.0 months (A) vs. 10.9 months (B), HR 0.73 p < 0.017 mOS: 27.9 months (A) vs. 24.9 months (B) p = 0.258 |
Overall grade ≥3 AE: 57% (A) vs. 52% (B) | 6% (A) vs. 6% (B) | ||
| Dacomitinib | ARCHER 1050 (NCT01774721) |
III | N = 452 Stage IIIB/IV NSCLC -Race: Asian (75%), Black (<1%), White (25%) -EGFR Mutations: ex19del, L858R -Brain or leptomeningeal metastases excluded |
Cohort A: Dacomitinib 45 mg daily Cohort B: Gefitinib 250 mg daily |
ORR: 75% (A) vs. 72% (B) mPFS: 14.7 months (A) vs. 9.2 months (B) p < 0.0001 mOS: 34.1 months (A) vs. 26.8 months (B) p = 0.438 |
Overall grade ≥3 AE: 63% (A) vs. 41% (B) | 10% (A) vs. 7% (B) | 27 September 2018 |
| Osimertinib | FLAURA (NCT02296125) |
III | N = 556 Stage IIIB/IV NSCLC -Race: Asian (62%), White (36%), Other (1%) -EGFR Mutations: ex19del, L858R -Asymptomatic, stable brain metastases were allowed |
Cohort A: Osimertinib 80 mg daily Cohort B: Gefitinib 250 mg daily or Erlotinib 150 mg daily |
ORR: 80% (A) vs. 76% (B) mPFS: 18.9 months (A) vs. 10.2 months (B) p < 0.001 mOS: 38.6 months (A) vs. 31.8 months (B) p = 0.046 |
Overall grade ≥3 AE: 42% (A) vs. 47% (B) | 15% (A) vs. 18% (B) | 18 April 2018 |
| Erlotinib + ramucirumab | RELAY (NCT02411448) |
III | N = 449 Stage IV NSCLC -Race: Asian (77%), White (22.3%), Other (1%) -EGFR Mutations: ex19del, L858R -Brain or leptomeningeal metastases excluded |
Cohort A: Erlotinib 150 mg daily + ramucirumab 10 mg/kg once every 2 weeks Cohort B: Erlotinib 150 mg daily + placebo once every 2 weeks |
ORR: 76% (A) vs. 75% (B) mPFS: 19.4 months (A) vs. 12.4 month p ≤ 0.0001 mOS: Not available |
Overall grade ≥3 AE: 72% (A) vs. 54% (B) | 13% (A) vs. 11% (B) | 29 May 2020 |
* Only individual grade ≥3 AEs are reported; Abbreviations: AEs, adverse events; FDA, Food and Drug Administration; mPFS, median progression-free survival; mOS, median overall survival; ORR, overall response rate; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.