TABLE I.
Efficacy of second and next/third-generation ALK inhibitors after progression on crizotinib
| Variable | Reference (study name) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| Shaw et al., 201722 (ASCEND-5) | Novello et al., 201823 (ALUR) | Ahn et al., 201724 (ALTA) | Shaw et al., 201825 (B7461001) | ||||||
| Investigational agent | Ceritinib (second generation) | Alectinib (second generation) | Brigatinib (next/third-generation) | Lorlatinib (next/third-generation) | |||||
|
| |||||||||
| Study type | Phase III | Phase III | Randomized phase II | Phase II (cohorts 2–5)a | |||||
|
| |||||||||
| Review type | IRC | Investigator | Investigator | IRC | |||||
|
| |||||||||
| Line of treatment | Third (88%) Fourth (12%) |
Third | ≥Second | ≥Second | |||||
|
| |||||||||
| Prior therapies | ≥1 Lines of CTx and crizotinib | Platinum CTx and crizotinib | Crizotinib-refractory with (74%) or without (26%) prior CTx | Crizotinib ±CTx | Non-crizotinib TKI±CTx | 2–3 prior TKIs±CTx | |||
|
| |||||||||
| Dosage | Ceritinib 750 mg daily | Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 every 3 weeks | Alectinib 600 mg twice daily | Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 every 3 weeks | Brigatinib 180 mg dailyb (Brig-90/180) | Brigatinib 90 mg daily (Brig-90) | Lorlatinib 100 mg daily | ||
|
| |||||||||
| Patients (n) | 115 | 116 | 72 | 35 | 110 | 112 | 59 | 27 | 111 |
|
| |||||||||
| Median follow-up (months) | 16.6 | 16.4 | Not reportedc | 18.6 | 16.8 | Not reported | |||
|
| |||||||||
| Intention-to-treat ORR (%) | 39.1 | 6.9 | 37.5 | 2.9 | 55 | 46 | 69 | 33 | 39 |
| 95% Confidence interval | 30.2 to 48.7 | 3.0 to 13.1 | 26 to 50 | 0 to 15 | 44 to 66d | 35 to 57d | 56 to 81 | 16 to 54 | 30 to 49 |
|
| |||||||||
| Median PFS (months) | 5.4 | 1.6 | 9.6 | 1.4 | 15.6 | 9.2 | Not yet reached | 5.5 | 6.9 |
| Hazard ratio | 0.49 | 0.15 | 0.64e | ||||||
| 95% Confidence interval | 0.36 to 0.67 | 0.08 to 0.29 | 0.45 to 0.91 | Not reported | |||||
| p Value | <0.0001 | <0.001 | Not reported | ||||||
|
| |||||||||
| Median OS (months) | 18.1f,g | 20.1f,g | 12.6f | Not yet reachedf | 27.6 | Not yet reached | Not reported | ||
| Hazard ratio | 1.0 | 0.89 | 0.67 | Not reported | |||||
| 95% Confidence interval | 0.67 to 1.49 | 0.35 to 2.24 | 0.42 to 1.06 | ||||||
| p Value | 0.50 | Not reported | Not reported | Not reported | |||||
Treatment cohorts included cohorts 2 and 3A [prior crizotinib only or prior crizotinib plus 1–2 lines of prior CTx (n = 59)]; cohort 3B [prior non-crizotinib ALK TKI with or without CTx (n = 27)]; and cohorts 4 and 5 [2–3 prior ALK TKIs with or without CTx (n = 111)].
After a 7-day lead-in with brigatinib 90 mg daily.
Median safety follow-up was 6.5 months for the alectinib arm and 5.8 months for the CTx arm.
97.5% Confidence interval for the primary endpoint.
At a median follow-up of 8.0 months, median PFS was 12.9 months for Brig-90/180 and 9.2 months for Brig-90 (hazard ratio: 0.55; 95% confidence interval: 0.35 to 0.86)26.
OS data were immature at the time of analysis.
Investigator-assessed.
IRC = independent review committee; CTx = chemotherapy; TKI = tyrosine kinase inhibitor; PFS = progression-free survival; OS = overall survival; ORR = overall response rate.