Table 3.
Clinical trials of next-generation TKIs in advanced NSCLC
| Targets and trial code | Trial Phase | Lines of treatment | EGFR mutations | Trial design | Outcomes | References |
|---|---|---|---|---|---|---|
| Second-generation irreversible TKIs | ||||||
| Afatinib (BIBW2992) | ||||||
| EGFR/HER2 | ||||||
| LUX-Lung 1 | IIb/III | Third/fourth | Unselected | Afatinib versus placebo in Asian patients | Improved PFS (3.3 versus 1.1 months) and ORR (7% versus 0.5%), no benefit in term of OS | 187 |
| LUX-Lung 2 | II | First/second | Positive | Afatinib after chemotherapy | ORR, 61% | 190 |
| LUX-Lung 3 | III | First | Positive | Afatinib versus pemetrexed + cisplatin | Improved PFS (11.1 versus 6.9 months) | 188 |
| LUX-Lung 4 | II | Second | Positive in 72.6% of patients | Afatinib after TKIs | ORR, 8.2%; median PFS: 4.4 months; median OS, 19 months | 186 |
| LUX-Lung 5 | III | Second | Unselected | Afatinib + chemotherapy versus chemotherapy after afatinib | Ongoing | |
| LUX-Lung 6 | III | First | Positive | Afatinib versus gemcitabine + cisplatin in Asian patients | Improved PFS (11.0 versus 5.6 months) | 189 |
| Dacomitinib (PF00299804) | ||||||
| EGFR/HER2/HER4 | ||||||
| NCT00769067 | II | Second/third | Unselected | Dacomitinib versus erlotinib after chemotherapy | Improved median PFS (2.86 versus 1.91 months) and median OS (9.53 versus 7.44 months) | 191 |
| NCT00548093 | II | Second/third | Positive | Dacomitinib | ORR, 8%; median PFS, 18 weeks | 196 |
| Neratinib (HKI-272) | ||||||
| EGFR, HER2 | ||||||
| Canertinib (CI-1033) | ||||||
| EGFR/HER2/HER4 | ||||||
| NCT00266877 | II | Second | Positive | Neratinib after TKIs | ORR, 3% (all in patients with G719X mutation) | 193 |
| NCT00050830 | II | Second | Unselected | CI-1033 after chemotherapy | 1-year survival rate, 26%–29%; ORR, 2%–4% | 197 |
| N/A | I/II | First | Unselected | CI-1033 + paclitaxel + carboplatin | ORR, 26%; median PFS, 5.1 months; median OS, 12.4 months | 198 |
| Third-generation irreversible TKIs | ||||||
| CO-1686/ | ||||||
| EGFR (T790M mutation) | ||||||
| NCT01526928 | I/II | Second | Positive | CO-1686 after TKIs | Ongoing | |
| AZD9291/ | ||||||
| EGFR (T790M mutation) | ||||||
| NCT01802632 | I/II | Second | Positive | AZD9291 after TKIs | Ongoing | |
| NCT02094261 | II | Second | Positive | AZD9291 in patients with T790M mutation after TKIs | Ongoing | |
| WZ4002/ | ||||||
| EGFR (T790M mutation) | Preclinical | |||||
Abbreviations: TKI, tyrosine kinase inhibitor; NSCLC, nonsmall cell lung cancer; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; PFS, progression free survival; ORR, overall response rate; OS, overall survival; HER4, human epidermal growth factor receptor 4.