Table 2.
Overview of BM Screening, Follow-Up Methods, Eligibility Criteria, and Outcomes in Phase 3 Randomized Controlled ALK-TKI Trials
| Trial | Treatment | Enrollment period/protocol available | Prespecified BM-related outcome/stratification factor | BM-screening at baseline (image modality) | Follow-up BM-screening | BM inclusion criteria | % included BM/% of patients with BM with intracranial radiotherapy | Outcomes in patients with BM/BM-related outcomes |
|---|---|---|---|---|---|---|---|---|
| PROFILE-100732 2013 |
Second-line crizotinib vs chemotherapy |
2010–2012/Yes | No /Yes | All patients (CT or MRI) | Brain imaging every 6 weeks if BM at baseline | Asymptomatic (untreated) or treated and stable BM for 2 weeks | 35% (120/347)/NR | PFS HR: BM 0.67 (BM present) vs. 0.43 (BM absent) in favor of crizotinib |
| PROFILE-101433,43 2014 |
First-line crizotinib vs chemotherapy |
2011–2013/Yes | Yes/Yes | All patients (CT or MRI) | Brain imaging every 6 weeks if BM at baseline otherwise every 12 weeks | Only treated, stable BM without steroids for 2 weeks | 27% (92/343)/NRa | PFS HR: BM 0.57 (BM present) vs 0.46 (BM absent) in favor of crizotinib. IC-TTP (HR, 0.60; 95% CI 0.34–1.05) in favor of crizotinib. IC-DCR at 24 weeks: 56% in crizotinib vs 25% in chemotherapy group (P = .006). BM group: 38% IC-PD only in crizotinib group vs 23% in chemotherapy. No BM group: 19% IC-PD only in crizotinib compared to 6% in chemotherapy. |
| PROFILE-102934 2018 |
First-line crizotinib vs chemotherapy |
2012–2014/No | Yes/No | NR | Brain imaging every 6 weeks if BM at baseline | Only treated, stable BM | 26% (53/207)/NRa | PFS HR: BM 0.50 (BM present) vs 0.37 (BM absent), Median ICC-TTP HR 0.67 (95% CI 0.34–1.34) favoring crizotinib. 17% (14/83) of patients without baseline BM developed new BM in the crizotinib group compared to 7% (5/71) in the chemotherapy group. |
| ASCEND-435 2017 |
First-line ceritinib vs chemotherapy |
2013–2015/Yes | Yes/Yes | All patients (CT or MRI) | Brain imaging every 6 weeks if BM at baseline | Asymptomatic or treated and stable BM for 2 weeks, stable dose of corticosteroids allowed | 32% (121/376)/42% (40% ceritinib, 42% chemo) | Median PFS in months in the BM group 10.7 (ceritinib) vs 6.7 (chemotherapy). IC-ORR: ceritinib 46% (73% in patients with measurable BM). Ceritinib BM group 48% (15/31) IC-PD only, ceritinib no BM group: 30% IC-PD only |
| ASCEND-536 2017 |
Ceritinib vs chemotherapy after previous chemotherapy and crizotinib | 2013–2015/No | Yes/Yes | All patients (CT or MRI) | Brain imaging every 6 weeks if BM at baseline | Asymptomatic (untreated) or treated and stable BM without steroids | 58% (134/231)/56% (56% ceritinib, 57% chemo) | Median PFS in months in BM group 4.4 ceritinib and 1.5 chemotherapy. In the BM group 51% had IC-PD only (21/41). In the no BM group 15% had IC-PD only. IC-ORR in patients with measurable BM 35% |
| ALUR37 2018 |
Alectinib vs chemotherapy after chemotherapy and crizotinib | 2015–2017/No | Yes/Yes | All patients (CT or MRI) | All patients every 6 weeks | Symptomatic BM ineligible for radiotherapy allowed, treated and stable BM or asymptomatic (untreated) | 71% (76/107)/54% (53% alectinib, 54% chemo) | PFS BM group in months: 9.7 (alectinib) vs 1.4 (chemotherapy). IC-ORR: alectinib 36% (54.2% in patients with measurable BM). IC-DCR alectinib 80%. |
| ALEX38,44 2017 |
First-line alectinib vs crizotinib | 2014–2016/Yes | Yes/Yes | All patients (CT or MRI) | All patients every 8 weeks | Asymptomatic (untreated) BM or treated with radiotherapy and stable for 2 weeks | 40% (122/303)/38% (39% alectinib, 36% crizotinib) | IC-PFS, alectinib vs crizotinib, HR 0.40 (in BM group) and HR 0.51 (no BM group). Patients BM group: CNS progression without prior non-CNS PD alectinib 18.8% and crizotinib 56.9%. Patients no BM group: CNS progression without prior non-CNS PD alectinib 6.8% and crizotinib 37.6%. IC-ORR in patients without prior RT: alectinib 74% (78.6% in patients with measurable BM) vs 24.3% (40% in patients with measurable BM) in crizotinib. |
| J-ALEX39,45 2017 |
First-line alectinib vs crizotinib |
2013–2015/No | Yes/No | All patients (NR) | All patients every 8 weeks | Only asymptomatic BM, untreated or treated without steroids for 2 weeks and after finishing radiotherapy (2 weeks for SRT and 4 weeks for WBRT) | 21% (43/207)/46% (38% alectinib, 52% crizotinib) | BM group: Time to CNS progression HR 0.51 (95% CI 0.16–1.64) in favor of alectinib. No BM group: Time to CNS progression 0.19 (95% CI 0.07–0.53) in favor of alectinib. |
| ALESIA40 2019 |
First-line alectinib vs crizotinib |
2016–2017/No | Yes/Yes | All patients (MRI) | All patients every 8 weeks | Asymptomatic (untreated) or treated and stable for 2 weeks | 36% (67/187)/17% (18% alectinib, 22% crizotinib) | Time to CNS progression, alectinib vs crizotinib, csHR 0.14. IC-ORR: alectinib 73% (94% in patients with measurable BM) vs 22% (29% in patients with measurable BM) in crizotinib |
| ALTA-1L41 2018 |
First-line brigatinib vs crizotinib |
2016–2017/Yes | Yes/Yes | All patients (MRI) | All patients every 8 weeks | Treated or asymptomatic untreated and treated BM without increasing dose of steroids or need for anticonvulsants | 29% (81/275)/46% (45% brigatinib, 46% crizotinib) | IC-ORR: brigatinib 83% (78% in patients with measurable BM) vs 33% (29% in patients with measurable BM) in crizotinib. 12-month survival without icPD in BM group: brigatinib 67%, crizotinib 21% |
| CROWN42,46 2020 |
First-line lorlatinib vs crizotinib |
2017–2019/Yes | Yes/Yes | All patients (MRI) | All patients every 8 weeks | Asymptomatic treated (4 weeks before enrollment) or untreated BM, stable corticosteroid dose allowed | 26% (78/296)/23% (21% lorlatinib, 25% crizotinib) | IC-ORR: lorlatinib 60% (92% in patients with measurable BM) vs 11% (33% in patients with measurable BM) in crizotinib. Percentage of patients who were alive without CNS progression at 12 months was 96% with lorlatinib and 60% with crizotinib. Median time to IC- progression at 5 years for lorlatinib was NR (95% CI NR–NR) and 16.4 months (95% CI 12.7–21.9) with crizotinib; HR 0.06 (95% CI 0.03–0.12) |
aSince BM had to be locally treated before enrollment likely a very high percentage received previous cranial radiotherapy.
Abbreviations: BM, brain metastases; NR, not reported; CT, computed tomography; MRI, magnetic resonance imaging; TKIs, tyrosine kinase inhibitor; NA, Not applicable; PFS, progression-free survival; ORR, objective response rate; DoR, duration of response; DCR, disease control rate; CNS, central nervous system; IC, intracranial; PD, progressive disease; cs, cause specific; HR, Hazard ratio; CI, confidence interval; NR (in outcomes), not reached; RT, radiotherapy.