Table 1.
Efficacy of Targeted Therapies in Non-small Cell Lung Cancer (NSCLC) with Central Nervous System (CNS) Metastases.
| Trial | Phase | Systemic Therapy | Setting/CNS Inclusion Criteria | Sample Size (with CNS Disease) | Key Results (CNS Outcomes) | Publication Year | Reference |
|---|---|---|---|---|---|---|---|
| EGFR Typical Mutations (Exon 19 Deletions and Exon 21 L858R Mutations) | |||||||
| AURA 3 | III | Osimertinib (Osi) vs. Platinum-based chemotherapy (chemo) | T790M+ NSCLC patients with asymptomatic, stable BM following POD with prior EGFR-TKI | Measurable BM: Osi (n = 30) vs. Chemo (n = 26) All BM: Osi (n = 75) vs. Chemo (n = 41) |
All BM: CNS ORR, Osi (40%) vs. chemo (17%), OR 3.24 (p = 0.014) CNS median DOR: Osi (8.9 mo) vs. Chemo (5.7 mo) Median iPFS: Osi (11.7 mo) vs. Chemo (5.6 mo) Median PFS: Osi (8.5 mo) vs. Chemo (4.2 mo); HR 0.32; 95% CI: 0.21–0.49) |
2018 | [25] |
| FLAURA | III | Osimertinib (Osi) vs. SOC EGFR-TKI | Treatment-naïve EGFR-mutated NSCLC Patients with asymptomatic or stable BM Symptomatic pts must have stable neurologic status ≥ 2 weeks following definitive local therapy |
Measurable BM: Osi (n = 22), SOC EGFR-TKI (n = 19) All BM: Osi (n = 61) vs. SOC EGFR-TKI (n = 67) |
All BM CNS ORR: Osi (66%) vs. SOC EGFR-TKI (43%) CNS Median DOR: Osi (15.2 mo) vs. SOC EGR-TKI (18.7 mo) Median iPFS: Osi (NR) vs. SOC EGFR-TKI (13.9 mo) PFS at 18 months: 58% (95% CI: 40–72) in osimertinib group OS (BM subgroup): HR 0.83 (0.53–1.30) |
2018 | [26] |
| EGFR Exon 20 Insertion | |||||||
| NCT02716116 | I, II | Mobocertinib | Previously treated Patients with active and symptomatic BM included |
N = 12 | CNS ORR: N/A Overall CNS ORR: 25%, among the patients with BM |
2021 | [25] |
| Combined EGFR and VEGF Inhibition | |||||||
| NEJ026 | III | Erlotnib vs. Erlotinib/bevacizumab | EGFR-positive advanced NSCLC Patients with BM requiring anti-edema drugs excluded |
All BM: Erlotnib (n = 36) vs. Erlotinib/bevacizumab (n = 36) |
OS (BM subgroup): HR 0.839 (0.432–1.629) | 2021 | [27] |
| ALK Rearrangement | |||||||
| NCT02075840 | II | Alectinib | Disease progression on crizotinib Patients with stable, treated brain and/or leptomeningeal metastases or asymptomatic untreated brain and/or leptomeningeal metastases were allowed |
All BM (n = 84) | CNS ORR 57% (95% CI, 39% to 74%) CNS disease control rate 83% (95% CI, 74% to 91%), CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months) CNS CR in 43% of patients with baseline CNS metastases |
2016 | [28] |
| ALEX | III | Alectinib vs. Crizotinib | Treatment of naïve patients with asymptomatic BM (treatment with local therapy allowed) | All BM: Alectinib (n = 64) vs. Crizotinib (n = 58) Measurable BM: Alectinib (n = 21) vs. Crizotinib (n = 22) |
All BM: CNS ORR, Alectinib (36%) vs. Crizotinib (28.6%) with prior radiation; Alectinib (74.4%) vs. Crizotinib (24.3%) without prior radiation CNS Median DOR: Alectinib (NR) vs. Crizotinib (17.3 mo) |
2018 | [29] |
| J-ALEX | III | Alectinib vs. Crizotinib | Treatment naïve, or failed one line of chemotherapy regimen Asymptomatic BM (treated or untreated allowed) |
Alectinib (n = 14) vs. Crizotinib (n = 29) | Time to CNS progression (alectinib superior): HR = 0.51, p = 0.2502 with baseline BM vs. HR = 0.19, p = 0.0004 without baseline BM 1-year CNS Cumulative Incidence Rate: Alectinib (5.9%) vs. Crizotinib (16.8%) |
2018 | [30] |
| ALTA | II | Brigatinib (Arm A—90 mg QD, Arm B—180 mg QD) | Disease progression on crizotinib | All BM: 154 | CNS ORR 42% in arm A and 67% in arm B | 2018 | [31] |
| ALTA-1L | III | Brigatinib vs. Crizotinib | Treatment-naïve Patients with asymptomatic or stable BM not requiring steroids or anticonvulsive therapy 7 days prior to randomization |
All BM: Brigatinib (n = 47) vs. Crizotinib (n = 49) Measurable BM: Brigatinib (n = 18) vs. Crizotinib (n = 23) |
Measurable BM: CNS ORR, Brigatinib (78%) vs. Crizotinib (26%), OR 11.67 (p = 0.0014) Median iPFS: Brigatinib (24 mo) vs. Crizotinib (5.6 mo) in patients with baseline BM; 32.3 mo (Brigatinib) vs. Crizotinib (NR) in patients without baseline BM |
2020 | [31,32] |
| ASCEND-4 | III | Ceritinib vs. Platinum-based chemotherapy | Treatment-naïve Patients with asymptomatic brain metastases (prior treatment allowed) |
All B: Ceritinib (n = 59) vs. Chemotherapy (n = 80) | CNS ORR ceritinib (72.7%) vs. chemotherapy (27.3%) Median CNS DOR ceritinib (16.6 mo-NR) vs. chemotherapy (NE) |
2017 | [33] |
| ASCEND-5 | III | Ceritinib vs. Single-agent chemotherapy | Progression following crizotinib and platinum-based doublet chemotherapy Patients with brain metastases |
All BM: Ceritinib (n = 47) vs. chemotherapy (n = 48) | CNS ORR ceritinib (35%) vs. chemotherapy (5%) DOR ceritinib 6.9 mo (95% CI 2·7–8·3 vs. chemotherapy (not evaluable) |
2017 | [34] |
| NCT01970865 | II | Lorlatinib | Treatment-naïve (cohort 1), progression on crizotinib (cohort 2), progression on crizotinib and chemotherapy (cohort 3), progression on non-crizotinib ALK inhibitor +/- chemotherapy, progression on 2 or 3 non-crizotinib ALK inhibitors +/- chemotherapy (cohort 4) Patients with asymptomatic BM (prior treatment allowed) |
All BM: 141 Measurable BM: cohort 1 (n = 3), cohort 2 (n = 23), cohort 3 (n = 9), cohort 4 (n = 49) |
CNS ORR cohort 1 (66.7%), cohort 2 (87%), cohort 3 (55.6%), cohort 4 (53.1%) Median DOR (months), cohort 1 [NR (NR–NR)], cohort 2 [NR (8·4–NR)], cohort 3 [NR (4·1–NR)], |
2018, 2021 | [35,36] |
| CROWN | III | Lorlatinib vs. Crizotinib | Treatment-naïve Patients with asymptomatic BM (prior treatment allowed) |
All BM: Lorlatinib (n = 38) vs. Crizotinib (n = 40) Measurable BM: Lorlatinib (n = 17) vs. Crizotinib (n = 13) |
All BM: CNS ORR, Lorlatinib (66%) vs. Crizotinib (20%); OR 8.41 (95% CI: 2.59–27.23) Measurable BM: CNS ORR, Lorlatinib (82%) vs. Crizotinib (23%); OR 16.83 (95% CI: 1.95–163.23) 12-month iPFS: Lorlatinib (95%) vs. Crizotinib (60%); HR 0.07 (95% CI: 0.03–0.17) |
2020 | [37] |
| ROS1 Rearrangement | |||||||
| ALKA-372-001 STARTRK-1 STARTRK-2 |
I or II | Entrectinib | Treatment- naïve and previously treated Patients with asymptomatic or stable BM with pretreatment |
All BM (n = 46) Measurable BM (n = 24) |
All BM: CNS ORR, 52.2%; Median DOR: 12.9 mo; iPFS: 8.3 mo Measurable BM: CNS ORR, 79.2%; Median DOR: 12.9 mo; iPFS: 12 mo |
2021 | [38] |
| NCT01970865 | II | Lorlatinib | Treatment- naïve and previously treated Patients with asymptomatic BM (prior treatment allowed) |
Treatment-naïve (n = 11) Previously treated (n = 24) |
Treatment-naïve: CNS ORR, 64%; Median DOR: NR (95% CI: 5.7 to NR) Previously treated: CNS ORR, 50%; Median DOR: NR (95% CI: 11.0 to NR) |
2019 | [39] |
| TRIDENT-1 | II | Repotretinib | Treatment- naïve and previously treated Patients with asymptomatic BM (prior treatment allowed) and/or asymptomatic leptomeningeal disease included |
Treatment- naïve (n = 3) Previously treated (n = 4) |
Treatment- naïve: CNS ORR, 100% (3/3) Previously treated: CNS ORR, 50% (2/4) |
2019 | [40] |
| KRAS G12C | |||||||
| CodeBreak 100 | II | Sotorasib | Previously treated Patients with active BMs were excluded |
N = 26 | No CNS results reported | 2021 | [41] |
| KRYSTAL-1 | I | Adagrasib | Previously treated Patients with active and/or stable previously treated BMs included |
N = 42 | CNS ORR 33% | 2022 | [42] |
| BRAF V600E Mutation | |||||||
| NCT01336634 | II | Dabrafenib and trametinib | Treatment -naïve and previously treated patients Patients with asymptomatic BM (if untreated, BM must be <1 cm, and if treated, must be stable for at least 3 weeks prior to enrollment) |
All BM: (n = 3); Treatment naïve (n = 2) vs. Previously treated (n = 1) | Treatment- naïve group: (n = 2), best response of non-CR or non-PD reported Previously treated: (n = 1), N/A |
2016, 2017 | [43,44] |
| NTRK1/2/3 Gene Fusion | |||||||
| ALKA-372-001 STARTRK-1 STARTRK-2 |
I or II | Entrectinib | TRK inhibitor-naïve patients Patients with asymptomatic BMs (prior treatment allowed) |
All BM: (n = 16) Measurable BM: (n = 8) |
All BM: CNS ORR, 50%; Median iPFS: 8.9 mo Measurable BM: CNS ORR, 62.5%; Median iPFS 10.1 mo |
2020 | [45] |
| NCT02576431, NCT02637687 | I or II | Larotrectinib | Non-primary CNS malignancy with BM or primary CNS malignancy Patients with asymptomatic BM |
All BM: (n = 5) BM in lung cancer: (n = 3) |
All BM: CNS ORR, 60% | 2019 | [46] |
| MET Exon 14 Skipping | |||||||
| GEOMETRY | II | Capmatinib | Treatment-naïve and previously treated patients Patients with non-enlarging BM (steroids therapy allowed, but no dose escalation in 2 weeks before enrollment) |
All BM: (n = 13) | CNS ORR: 54% | 2020 | [47] |
| VISION | II | Tepotinib | Treatment-naïve and previously treated patients Patients with asymptomatic BM |
All BM: (n = 15) Measurable BM: (n = 7) |
CNS ORR: 71% (5/7) CNS DOR: 87% (13/15) |
2022 | [48] |
| RET Rearrangement | |||||||
| ARROW | I or II | Pralsetinib | Treatment-naïve and previously treated patients Patients with stable, non-enlarging BM and absence of neurologic symptoms |
Measurable BM (n = 9) | CNS ORR: 56%, all complete responders | 2021 | [49] |
| LIBRETTO-001 | I or II | Selpercatinib | Treatment-naïve and previously treated patients Patients with stable neurologic diseases at baseline (steroids allowed, 14 days before enrollment; no neurosurgery or radiation for 28 days; SRS allowed, 14 days before enrollment) |
Measurable BM (n = 22) | Overall CNS ORR 81.8%; Prior RT (85.7%) vs. RT-naïve (75%) CNS Median DOR: 9.4 mo |
2021 | [50] |
| ERBB2 (HER2) Mutation Positive | |||||||
| DESTINY-Lung01 | II | Trastuzumab Deruxtecan | Patients with asymptomatic brain metastases Progression following standard of care |
BM (n = 33) | PFS was 7.1 mo (95% CI, 5.5 to 9.8) and OS 13.8 mo (95% CI, 9.8 to 20.9) No CNS-specific outcomes |
2022 | [51] |
Abbreviations: non-small cell lung cancer (NSCLC); progression of disease (POD); tyrosine kinase inhibitor (TKI); brain metastases (BM); central nervous system (CNS); objective response rate (ORR); odds ratio (OR); duration of response (DOR); intracranial progression-free survival (iPFS); progression-free survival (PFS); hazard ratio (HR); confidence interval (CI); standard of care (SOC); overall survival (OS); complete response (CR); not reached (NR); radiotherapy (RT).