Table 1.
Summary of studies investigating targeted therapies for IMD secondary to breast cancer, NSCLC, and melanoma.
| Drug | Trial/Study | Study design | Total participants (n) | Study arms | Median OS (months) | Findings | |
|---|---|---|---|---|---|---|---|
| Breast cancer | Trastuzumab | Slamon et al. (100) | RCT | 469 | Standard chemotherapy ± trastuzumab in all breast cancer patients | 25.1 vs. 20.3 (p=0.046) | Relative risk reduction of death at 30-month follow-up: 20% |
| Park et al. (101) | Retrospective cohort study | 251 | Palliative chemotherapy ± trastuzumab in all breast cancer patients | 31.7 vs. 16.7 (p=0.001) | Incidence of BrM: 37.8 vs. 25% (p=0.028) TTD from BrM: 14.9 vs. 4.0 months (p=0.0005) |
||
| Park et al. (102) | Retrospective cohort study | 78 | Trastuzumab after BrM diagnosis vs. trastuzumab before BrM diagnosis only vs. no trastuzumab | 13.6 vs. 5.5 vs. 4.0 (p<0.001) | Median TTP of BrM: 7.8 vs. 3.9 vs. 2.9 months (p=0.006) HR for death in patients with BrM: 0.5 (p=0.017) |
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| Okita et al. (103) | Retrospective cohort study | 62 | Trastuzumab vs. no trastuzumab | 38.4 vs 8.4 (p=0.0005) | Median second brain metastatic-free survival time: 7.0 vs. 5.6 months (p=0.057) | ||
| Dawood et al. (104) | Retrospective cohort study | 598 | Trastuzumab vs. no trastuzumab vs. HER2-negative | 11.6 vs. 6.1 vs. 6.3 (p<0.0001) | – | ||
| Lapatinib | Lin et al. (105) | Single-arm clinical trial | 39 | Lapatinib | – | CNS ORR: 2.6% | |
| Lin et al. (106) | Single-arm clinical trial | 242 | Lapatinib, lapatinib and capecitabine (n = 50) | – | CNS ORR: 6% (lapatinib alone), 20% (with capecitabine) ≥20% BrM volume reduction: 21% (lapatinib alone), 40% (with capecitabine) |
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| Metro et al. (107) | Retrospective cohort study | 30 | Lapatinib and capecitabine | 27.9 vs. 16.7 (p=0.01) | CNS ORR: 31.8% Disease stabilization: 27.3% |
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| Bachelot et al. (108) | Single-arm clinical trial | 45 | Lapatinib and capecitabine | 17.0 | Median TTP: 5.5 months CNS ORR: 65.9% Disease stabilization: 36% |
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| Neratinib | Freedman et al. (109) | Single-arm clinical trial | 49 | Neratinib and capecitabine in lapatinib-naïve and lapatinib-treated patients | 13.3 and 15.1 | CNS ORR: 49% and 33% Median PFS: 5.5 and 3.1 months |
|
| Hurvitz et al. (110) | RCT | 101 | Neratinib and capecitabine vs. lapatinib and capecitabine | 13.9 vs. 12.4 (p=0.635) | Median PFS: 5.6 vs. 4.3 months (p=0.074) | ||
| Tucatinib | Lin et al. (111) | RCT | 291 | Trastuzumab and capecitabine with or without tucatinib | 18.1 vs. 12.0 (p=0.005) | Median PFS: 9.9 vs. 4.2 months, HR 0.32, P<0.0001 iORR: 47.3% vs. 20%, p=0.03 |
|
| Trastuzumab emtansine (T-DM1) | Bartsch et al. (112) | Retrospective cohort study | 10 | T-DM1 | – | iORR: 30% | |
| Jacot et al. (113) | Single-arm clinical trial | 2002 | T-DM1 | – | – | ||
| Krop et al. (114) | RCT | 991 | T-DM1 vs. capecitabine and laptinib | 26.8 vs. 12.9 (HR 0.38, p=0.008) |
Median PFS: 5.9 vs. 5.7 months (HR 1.00, p=1.0) | ||
| Montemurro et al. (115) | Single-arm clinical trial | 2002 | T-DM1 | 18.9 | Median PFS: 5.5 months ORR: 21.4% |
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| Trastuzumab deruxtecan (T-DXd) | Barsch et al. (116) | Single-arm clinical trial | 10 | T-DXd | – | CNS ORR: 83.3% | |
| Jerusalem et al. (117) | Single-arm clinical trial | 24 | T-DXd | – | Median PFS: 18.1 months ORR: 58.3% CNS ORR: 50% |
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| Abemaciclib | Tolaney et al. (118) | Non-randomized clinical trial | 104 | Abemaciclib ± hormone therapy | 12.5 | CNS ORR: 5.2% | |
| Abemaciclib and trastuzumab | 10.1 | CNS ORR: 0% Median intracranial PFS: 2.7 months |
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| Palbociclib | Brastianos et al. (119) | Single-arm clinical trial | 15 | Palbociclib | 6.4 | Intracranial disease benefit rate: 53.3% | |
| Iniparib | Anders et al. (120) | Single-arm clinical trial | 37 | Iniparib and irinotecan | 7.83 | CNS ORR: 12% | |
| Talazoparib | Litton et al. (121) | RCT | 431 | Talazoparib vs. chemotherapy | – (HR 0.671, 95% CI 0.366-1.229) |
– | |
| NSCLC | Crizotinib | Solomon et al. (122) | RCT | 343 | Crizotinib vs. pemetrexed + platinum-based chemotherapy | – | Median PFS: 9.0 vs. 4.0 months, HR 0.40, P<0.001 iORR: 77% vs. 28%, p<0.001 |
| Ceritinib | Crinò et al. (123) | Single-arm clinical trial | 140 | Ceritinib | – | Median PFS: 5.4 months Intracranial ORR: 33% |
|
| Alectinib | Gadgeel et al. (124) | Single-arm clinical trial | 47 | Alectinib | – | iORR: 52% | |
| Peters et al. (125) | RCT | 303 | Alectinib vs. crizotinib | – | PFS rate: 12% vs. 45%, HR 0.51, p<0.001 | ||
| Brigatinib | Camidge et al. (126) | RCT | 275 | Brigatinib vs. crizotinib | – | 12-month PFS rate: 67% vs. 21%, HR 0.27 Intracranial median TTP: HR 0.30 iORR: 78% vs. 29%, OR 10.42 |
|
| Lorlatinib | Shaw et al. (127) | RCT | 296 | Lorlatinib vs. crizotinib | – | 12-month PFS rate: 96% vs. 60%, HR 0.07 iORR: 82% vs. 23%, OR 16.83 |
|
| Shaw et al. (128) | Single-arm clinical trial | 364 | Lorlatinib | – | CNS ORR (TKI-naive): 64% CNS ORR (previous crizotinib): 50% |
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| Ensartinib | Horn et al. (129) | RCT | 290 | Ensartinib vs. crizotinib | – | Median PFS (baseline BrM): 11.8 vs. 7.5 months (HR 0.55, p=0.05) Median PFS (no baseline BrM): NR vs. 16.6 months (HR 0.46, p=0.003) |
|
| Lazertinib | Ahn et al. (130) | Single-arm clinical trial | 127 | Lazertinib | – | CNS ORR: 44% | |
| Cho et al. (131) | Single-arm clinical trial | 78 | Lazertinib | – | CNS ORR: 85.7% | ||
| Furmonertinib | Shi et al. (132) | Single-arm clinical trial | 130 | Furmonertinib | – | Median PFS: 9.9 months CNS ORR: 58.8% |
|
| Shi et al. (133) | Single-arm clinical trial | 220 | Furmonertinib | – | CNS ORR (measurable BrM): 66% CNS ORR (measurable/non-measurable BrM): 34% Median PFS (measurable/non-measurable BrM): 11.6 months |
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| Amivantamab | Park et al. (134) | Single-arm clinical trial | 81 | Amivantamab | – | ORR: 39% | |
| Gefitinib | Ceresoli et al. (135) | Single-arm clinical trial | 41 | Gefitinib | – | Median PFS: 3.0 months iORR: 10% DCR: 27% |
|
| Hotta et al. (136) | Retrospective cohort study | 57 | Gefitinib | – | iORR: 42.9% | ||
| Lee et al. (137) | Single-arm clinical trial | 37 | Gefitinib | – | iORR: 70% | ||
| Chiu et al. (138) | Single-arm clinical trial | 76 | Gefitinib | – | iORR: 33.3% DCR: 63.2% |
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| Kim et al. (139) | Double-arm clinical trial | 23 | Gefitinib or erlotinib | 18.8 | Median PFS: 7.1 months iORR: 73.9% Overall ORR: 69.6% Overall DCR: 82.6% |
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| Park et al. (140) | Double-arm clinical trial | 28 | Gefitinib or erlotinib | 15.9 | Median PFS: 6.6 months Overall ORR: 83% Overall DCR: 93% |
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| Osimertinib | Mok et al. (141) | RCT | 419 | Osimertinib vs. pemetrexed with platinum-based chemotherapy | – | Median PFS: 8.5 vs. 4.2 months, HR 0.32 | |
| Soria et al. (142) | RCT | 456 | Osimertinib vs. erlotinib or gefitinib | – | Median PFS: 15.2 vs. 9.6 months, HR 0.47, p<0.001 | ||
| Sotorasib | Skoulidis et al. (143) | Single-arm clinical trial | 126 | Sotorasib in all KRASG12C-positive patients | 12.5 | Median PFS: 6.8 months Overall ORR: 37.1% |
|
| Selpercatinib | Drilon et al. (144) | Single-arm clinical trial | 105 | Selpercatinib | – | CNS ORR: 91% | |
| Pralsetinib | Gainor et al. (145) | Single-arm clinical trial | 233 | Pralsetinib | – | CNS ORR: 56% | |
| Repotrectinib | Drilon et al. (146) | Single-arm clinical trial | – | Repotrectinib | – | – | |
| Tepotinib | Paik et al. | Single-arm clinical trial | 152 | Tepotinib | – | Median PFS: 10.0 months ORR: 55% |
|
| Capmatinib | Wolf et al. | Single-arm clinical trial | 364 | Capmatinib | – | CNS ORR: 53.8% | |
| Laprotrectinib | Hong et al. | Single-arm clinical trial | 159 | Laprotrectinib | – | CNS ORR: 66.7% | |
| Entrectinib | John et al. | Single-arm clinical trial | 16 | Entrectinib | – | CNS ORR (measurable BrM): 62.5% CNS ORR (measurable/non-measurable BrM): 50% |
|
| Melanoma | Dabrafenib | Long et al. (147) | Single-arm clinical trial | 172 | Dabrafenib in BRAFV600E-positive melanoma patients with treatment-naïve IMD or progressive IMD | 7.64 and 7.25 | Median PFS: 3.72 and 3.83 months iORR: 39.2% and 30.8% |
| Davies et al. (148) | Single-arm clinical trial | 125 | Dabrafenib and trametinib in BRAFV600E-positive melanoma patients with treatment-naïve IMD or progressive IMD | 10.8 and 24.3 | Median PFS: 5.6 and 7.2 months iORR: 58% and 56% |
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| Vemurafenib | McArthur et al. (149) | Single-arm clinical trial | 146 | Vemurafenib in BRAFV600-positive melanoma patients with treatment-naïve IMD or progressive IMD | 8.9 and 9.6 | Median PFS: 3.7 and 4.0 months iORR: 18% and 18% |
Median overall survival marked with a dash if the data was 1) not reported or 2) reported for the entire population, including patients without IMD.
BrM, brain metastases; CI, confidence interval; CNS, central nervous system; DCR, disease control rate; HER2, human epidermal growth factor 2; HR, hazard ratio; IMD, intracranial metastatic disease; iORR, intracranial ORR; NR, not reached; NSCLC, non-small cell lung cancer; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RCT, randomized control trial; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; TKI, tyrosine kinase inhibitor; TTD, time to death; TTP, time to progression.