Table 1.
Published prospective clinical trials of ICI therapy involving BM
| App | Drug | Team (Ref.) | NCT No. | Phase | Time | Scale* | Add | Tumor Type | Cohorts/Arms (patients) | IR† /ICB‡ (95% CI) | imPFS, months (95% CI) | mOS, months (95% CI) | LOS rates (95% CI) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Single | Pembrolizumab | Goldberg et al. [138] | 02085070 | II | 2008.07–2011.04 | 36 | USA | Mm NSCLC |
A: melanoma (13); B: NSCLC (13) |
A: 22%† (7–48); B: 33%† (14–59) |
– |
A: 7.7 (3.5-NR); B: NR |
– |
| Pembrolizumab | Kluger et al. [139] | 02085070 | II | 2014.03–2015.06 | 23 | USA | Mm | – | 26%† (10–48) | 2 (2-NR) | 17 (10-NR) | 48% (31–73) at 2Y | |
| Pembrolizumab | Goldberg et al. [140] | 02085070 | II | 2014.03–2017.01 | 42 | USA | NSCLC |
A: PD-L1 expression ≥ 1% (37); B: PD-L1 expression < 1% (5) |
A: 29.7%† (15.9–47.0); B: 0 |
A: 2.3 (1.9-NR) | A: 9.9 (7.5–29.8) |
A: 40% (30–64) at 1Y; 34% (21–54) at 2Y |
|
| Atezolizumab | Gadgeel et al. [142] | 02008227 | III | 2014.03–2018.01 | 850 | Global | NSCLC |
Aα: atezolizumab (no BM history, 364); Aβ: atezolizumab (BM history, 61); Bα: Docetaxel (no BM history, 343); Bβ: Docetaxel (BM history, 62) |
– |
Aα: NR; Aβ: NR; Bα: NR; Bβ: 9.5 (5.8–20.1) |
Aα: 13.2 (11.1–15.5); Aβ: 16.0 (10.6–20.1); Bα: 9.3 (8.6–11.1); Bβ: 11.9 (7.0–14.1) |
Aα: 31.6% (26.7–36.5) at 2Y; Aβ: 26.6% (15.1–38.1); Bα: 21.4% (16.9–25.9); Bβ: 19.3% (8.2–30.4) |
|
| Ipilimumab | Margolin et al. [141] | 00623766 | II | 2014.03–2018.05 | 72 | USA | Mm |
A: asymptoms & no steroid (51); B: symptoms & steroid (21) |
A: 18%‡ (8–31); B: 5%‡ (0.1–24) |
A: 1.5 (1.2–2.5); B: 1.2 (1.2–1.3) |
A: 7.0 (4.1–10.8); B: 3.7 (1.6–7.3) |
A: 55% (41–68) at 0.5Y, 31% (18–44) at 1Y, 26% (14–39) at 2Y; B: 38% (17–59) at 0.5Y, 19% (2–36) at 1Y, 10% (0–22) at 2Y | |
| Pembrolizumab | Naidoo et al. [122] | 03091478 | II | 2016.02–2018.09 | 13 | USA | LM | – | 38%†(13.9–68.4) | 2.9 (1.3-NR) | 4.9 (3.7-NR) | 3/13 at cutoff | |
| Nivolumab | Flippotet al. [149] | 03013335 | II | 2017.02–2019.12 | 73 | FRA | RCC |
A: BM untreated (39); B: BM pretreated (34) |
A: 11.8%† (3.3–27.5); B: \ |
A: 2.7 (2.3–4.6); B: 4.8 (3.0–8.0) |
/ |
A: 69.2% (52.2–81.2) at 0.5Y, 66.7% (49.6–79.1) at 1Y; B: 70.6% (52.2–83.0) at 0.5Y, 58.8% (40.6–73.2) at 1Y |
|
| Dual | Nivolumab Ipilimumab | Long et al. [143] | 02374242 | II | 2013.01–2018.09 | 79 | AUS | Mm |
A: nivolumab + ipilimumab (asymptomatic untreated, 36); B: mono-Nivolumab (asymptomatic untreated, 27); C: mono-Nivolumab (poor prognostic, 16) |
A: 46%†(29–63); B: 20%† (7–41); C: 6%† (0–30) |
A: NR (2.9–NR); B: 2.5 (1.7–2.8); C: 2.3 (1.4–4.3) |
A: NR (8.5–NR); B: 18.5 (6.9–NR); C: 5.1 (1.8–NR) |
A: 78% (65–94) at 0.5Y; B: 68% (52–89); C: 44% (25–76) |
| Nivolumab Ipilimumab | Tawbi et al. [144] | 02320058 | II | 2014.11–2017.08 | 94 | USA | Mm | / | 57%‡ (47–68) | NR | NR |
92.3% (84.5–96.3) at 0.5Y; 82.8% (73.1–89.3) at 0.75Y; 81.5% (71.5–88.2) at 1Y |
|
| Nivolumab Ipilimumab | Tawbi et al. [145] | 02320058 | II | 2015.02–2017.11 | 119 | USA | Mm |
A: asymptoms (101); B: symptoms and/or steroid (18) |
A: 58.4%‡ (48.2–68.1); B: 22.2%‡ (6.4–47.6) |
A: NR (6.5-NR); B: 1.2 (0.7–1.3) |
A: NR; B: 8.7(8.8-NR) |
A: 82.4% (73.2–88.7) at 1Y, 75.2% (64.9–82.8) at 1.5Y; B: 65.8% (39.1–83.0) at 0.5Y |
|
| Nivolumab Ipilimumab | Tawbi et al. [146] | 02320058 | II | 2015.02–2018.05 | 119 | USA | Mm |
A: asymptoms (101); B: symptoms and/or steroid (18) |
A: 57.4%‡ (47.2–67.2); B: 16.7%‡ (3.6–41.4) |
A: 39.3 (7.5–45.8); B: 1.2 (0.7–NR) |
A: NR; B: 8.7 (8.9-NR) |
A: 71.9% (61.8–79.8) at 3Y; B: 36.6% (14.0–59.8) at 3Y |
|
| Nivolumab Ipilimumab | Giacomo et al. [147] | 02460068 | III | 2015.02–2020.12 | 80 | ITA | Mm |
A: mono-fotemustine (27); B: ipilimumab + fotemustine (26); C: ipilimumab + nivolumab (27) |
A: 0; B: 19.2%†(4.1–34.4); C: 44.4%† (25.7–63.2) |
A: 3.0 (2.3–3.6); B: 3.3 (1.2–5.4); C: 8.7 (0.0–19.9) |
A: 8.5 (4.8–12.2); B: 8.2 (2.2–14.3); C: 29.2 (0–65.1) |
A: 34.8% (15.4–54.2) at 1Y, 21.7% (4.9–38.5) at 2Y, 16.3% (0.6–32.0) at 3Y, 10.9% (0–24.4) at 4Y; B: 38.5% (19.9–57.1) at 1Y, 19.2% (4.1–34.3) at 2Y, 15.4% (1.5–29.3) at 3Y, 10.3% (0–22.6) at 4Y; C: 66.7% (48.9–84.5) at 1Y, 51.9% (33.1–70.7) at 2Y, 47.9% (28.9–66.9) at 3Y, 41.0% (20.6–61.4) at 4Y |
|
| Nivolumab Ipilimumab | Emamekhoo et al. [150] | 02982954 | IIIb/IV | 2017.01–2021.10 | 28 | USA | RCC | – | 32%†(14.9–53.5) | 9.0 (2.9–12.0) | NR (14.1-NE) |
85.6% (66.0–94.3) at 1Y; 67.0% (46.1–81.3) at 1.5Y; 63.2% (42.4–78.3) at 2Y |
|
| Nivolumab Ipilimumab | Reck et al. [151] | 02477826 | III | 2015.08–2022.02 | 1739 | Global | NSCLC |
Aα: dual ICI (with baseline BM, 68); Aβ: ChT (with baseline BM, 66); Bα: dual ICI (without baseline BM, 515); Bβ: ChT (without baseline BM, 517) |
– |
Aα: 8.6 (5.7–19.5); Aβ: 8.7 (6.6–11.5) [5-years rates:Aα–16%Aβ–6%] |
Aα: 17.4(9.2–29.4); Aβ: 13.7(10.5–16.2); Bα: 17.2(15.3–20.0); Bβ: 13.9(11.8–15.3) |
Aα: 20% (12–31) at 5Y; Aβ: 6% (2–14); Bα: 23% (19–26); Bβ: 13% (10–16) |
|
| co-TT | Tremelimumab -/ + Trastuzumab | Page et al. [116] | 02563925 | NA | 2010.06–2014.07 | 26 | USA | BC |
A: HER2- (20); B: HER2 + (6) |
A: 15%†; B: 33%† |
A: 3.0[range:1.1–6.2]; B: 3.1[range:1.3–8.7] |
A: 4.9[range: 1.1–22.8 +]; B: 8.0[range: 1.3–15.1] |
– |
| co-RT | Ipilimumab | Williams et al. [152] | 01703507 | I | 2012.10–2014.08 | 16 | USA | Mm |
A: WBRT (5); B: SRS (11) |
– |
A: 2.5; B: 2.1 |
A: 8; B: NR |
– |
| co-ChT | Pembrolizumab + Platinum-based ChT | Powell et al. [134] |
02039674 02578680 02775435 |
II/III | Cutoff dates: 2017/2018 | 1298 | Global | NSCLC |
Aα: ICI + ChT(with BM, 105); Aβ: ChT (with BM, 66); Bα: ICI + ChT (without BM, 643); Bβ: ChT (without BM, 484) |
– | – |
Aα: 18.8 (13.8–25.9); Aβ: 7.6 (5.4–10.9); Bα: 22.5 (19.8–25.2); Bβ: 13.5 (11.3–15.8) |
Aα: 62.9% at 1Y; Aβ: 34.9%; Bα: 70.2%; Bβ: 53.6 |
| Ipilimumab + Fotemustine | Giacomo et al. [148] | 01654692 | II | 2015.09–2021.07 | 86 | ITA | Mm |
α: the whole (86); β: baseline BM (20) |
– |
α: 8.3 (4.7–11.8); β: 3.0 (2.9–3.1) |
α: 12.9 (7.1–18.7); β: 12.7 (2.7–22.7) |
α: 33.4% at 2Y, 28.5% at 3Y; β: 38.9% at 2Y, 27.8% at 3Y |
co-TT, combined with targeted therapy; co-RT, combined with radiotherapy; co-ChT, combined with chemotherapy; CI, confidence interval; imPFS, intracranial median progression-free survival; mOS, median overall survival; OS, overall survival; LOS, Long-term overall survival; Y, year. AEs, adverse events; NR, not reached; NA, not applicable; NE, not estimated; Mm, melanoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; BC, breast cancer; BM, brain metastases; LM, leptomeningeal metastases
*Patients enrolled into cohorts and finally analyzed
†IR, intracranial responses (complete response + partial response)
‡ICB, intracranial clinical benefit [complete response + partial response + stable disease ≥ 12 weeks (just NCT00623766) /6 months]