Table 1 Published prospective clinical trials of ICI therapy involving BM

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