Tumor response
Nineteen studies [17, 21, 22, 25–28, 30–38, 40–42] reported the long-term (more than six weeks) performance of the combination treatment of atezolizumab and bevacizumab in advanced HCC. All 19 studies reported the long-term OR following atezolizumab plus bevacizumab therapy evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), and the pooled OR rate was 26% (95% CI, 23–29%, I2 = 55.99%, p = 0.00, Fig. 2A). Eighteen [17, 21, 22, 25–28, 30–33, 35–38, 40–42] of the 19 studies reported the long-term CR and PR evaluated with RECIST, and the pooled CR and PR rates were 2% (95% CI, 1–4%, I2 = 74.54%, p = 0.00, Fig. 3A) and 23% (95% CI, 21–25%, I2 = 22.65%, p = 0.19, Fig. 4A), respectively. In addition, eight [17, 22, 23, 28, 30, 37, 40, 41] of the 19 studies reported the long-term OR, CR, and PR evaluated with modified RECIST (mRECIST), and the pooled OR rate was 33% (95% CI, 26–40%, I2 = 71.31%, p = 0.00, Fig. 2B), while the pooled CR and PR rates were 4% (95% CI, 1–9%, I2 = 80.54%, p = 0.00, Fig. 3B) and 27% (95% CI, 22–32%, I2 = 59.42%, p = 0.02, Fig. 4B), respectively.
Four studies [24, 29, 30, 37] reported the short-term (six weeks) performance of atezolizumab combined with bevacizumab in advanced HCC. All four studies reported the short-term OR evaluated with RECIST, and the pooled OR rate was 13% (95% CI, 9–17%, I2 = 47.23%, p = 0.13, Fig. 2C). Three [24, 29, 30] of the four studies reported the short-term CR and PR evaluated with RECIST, and the pooled CR and PR rates were 0% (95% CI, 0–1%, I2 = 0.00%, p = 0.97, Fig. 3C) and 15% (95% CI, 7–23%, I2 = 64.79%, p = 0.06, Fig. 4C), respectively. Moreover, all four studies reported the short-term OR evaluated with mRECIST, and the pooled OR rate was 25% (95% CI, 20–30%, I2 = 37.64%, p = 0.19, Fig. 2D), while three [24, 29, 30] of the four studies reported the short-term CR and PR evaluated with mRECIST, and the pooled CR and PR rates were 3% (95% CI, 0–5%, I2 = 0.00%, p = 0.74, Fig. 3D) and 24% (95% CI, 18–30%, I2 = 32.04%, p = 0.23, Fig. 4D), respectively.
Four studies [22, 33, 37, 38] reported the performance of atezolizumab in combination with bevacizumab on the basis of the treatment lines. In the first-line treatment of the combination, the pooled OR rates were 29% (95% CI, 22–37%, I2 = 0.00%, p = 0.43, Supplemental Fig. 1A) and 35% (95% CI, 27–44%, I2 = 0.00%, p = 0.98, Supplemental Fig. 1B), the pooled CR rates were 0% (95% CI, 0–2%, I2 = 0.00%, p = 0.93, Supplemental Fig. 2A) and 2% (95% CI, 0–17%, I2 = 71.26%, p = 0.03, Supplemental Fig. 2B), and the pooled PR rates were 26% (95% CI, 20–32%, I2 = 22.23%, p = 0.28, Supplemental Fig. 3A) and 29% (95% CI, 19–40%, I2 = 0.00%, p = 0.56, Supplemental Fig. 3B) when evaluated with RECIST and mRECIST, respectively. In the second-line and above treatments, the pooled OR rates were 13% (95% CI, 8–19%, I2 = 0.00%, p = 0.42, Supplemental Fig. 1C) and 19% (95% CI, 9–28%, I2 = 55.38%, p = 0.08, Supplemental Fig. 1D), the pooled CR rates were 0% (95% CI, 0–4%, I2 = 0.00%, p = 0.44, Supplemental Fig. 2C) and 0% (95% CI, 0–4%, I2 = 0.00%, p = 0.51, Supplemental Fig. 2D), and the pooled PR rates were 16% (95% CI, 8–23%, I2 = 0.00%, p = 0.59, Supplemental Fig. 3C) and 17% (95% CI, 6–29%, I2 = 60.17%, p = 0.08, Supplemental Fig. 3D) when evaluated with RECIST and mRECIST, respectively.
The IMbrave150 trial's inclusion criteria were as follows: no prior systemic therapy for advanced HCC; a Child-Pugh score (CPS) of A; and the score of the Eastern Cooperative Oncology Group (ECOG) was 0 or 1 [15]. Six studies [17, 21, 25, 35, 37, 42] reported the OR of atezolizumab combined with bevacizumab treatment in the IMbrave-IN group who fulfilled the inclusion criteria, and the pooled OR rate evaluated with RECIST was 30% (95% CI, 28–33%, I2 = 5.13%, p = 0.38, Supplemental Fig. 4A). Two studies [21, 37] reported the OR in the IMbrave-OUT group who met at least one of the exclusion criteria of the IMbrave150 study (patients receiving the combination treatment of atezolizumab and bevacizumab as non-first-line therapy, a CPS of B, or ECOG ≥ 2) [21, 37], and the pooled OR rate assessed with RECIST was 13% (95% CI, 6–19%, I2 = 0.00%, Supplemental Fig. 4B). Seventeen studies [17, 21, 25–28, 30–37, 40–42] reported the OR of the standard-dose therapy (1200 mg of atezolizumab plus 15 mg/kg of bevacizumab) [15], and the pooled OR rate assessed with RECIST was 26% (95% CI, 23–29%, I2 = 59.03%, p = 0.00, Supplemental Fig. 4C). Two studies [22, 38] reported the OR of the low-dose therapy (1200 mg of atezolizumab plus 5–7.5 mg/kg of bevacizumab), and the pooled OR rate evaluated with RECIST was 22% (95% CI, 15–30%, I2 = 0.00%, Supplemental Fig. 4D).
Toxicity
Twelve studies [17, 22, 25, 26, 28, 31, 32, 35, 37, 38, 40, 42] reported the incidence of all-grade AEs, and the pooled incidence was 83% (95% CI, 77–89%, I2 = 94.17%, p = 0.00, Fig. 6A). The most common all-grade AEs included aspartate transaminase (AST) increase, alanine aminotransferase (ALT) elevation, proteinuria, hypertension, fatigue, thrombocytopenia, appetite loss, pyrexia, peripheral edema, pruritus, nausea, rash, and blood bilirubin increase (Table 3). Fourteen studies [17, 22–28, 31, 32, 35, 37, 40, 42] reported the incidence of grade ≥ 3 AEs, and the pooled incidence was 30% (95% CI, 23–37%, I2 = 91.10%, p = 0.00, Fig. 6B). The most common grade 3 and above AEs included AST increase, hypertension, proteinuria, ALT elevation, gastrointestinal hemorrhage, thrombocytopenia, blood bilirubin increase, pyrexia, fatigue, pulmonary embolism, pneumonia, and colitis (Table 3).
Table 3
Pooled results of common adverse events
Adverse Event | All Grade | | ≥ Grade 3 |
| ES, % (95% CI) | I2, % | | ES, % (95% CI) | I2, % |
AST increase | 31 (22–40) | 92.10 | | 5 (3–7) | 55.13 |
ALT elevation | 24 (16–32) | 89.08 | | 3 (2–4) | 0.00 |
Proteinuria | 24 (18–30) | 94.07 | | 4 (3–6) | 72.72 |
Hypertension | 24 (19–29) | 90.94 | | 5 (3–8) | 82.19 |
Fatigue | 23 (20–27) | 79.42 | | 1 (0–1) | 31.31 |
Thrombocytopenia | 20 (11–29) | 96.90 | | 2 (1–4) | 59.06 |
Appetite loss | 19 (16–23) | 76.14 | | 0 (0–1) | 35.49 |
Pyrexia | 17 (10–23) | 89.81 | | 1 (0–2) | 0.00 |
Peripheral edema | 17 (0–34) | 93.97 | | 0 (0–1) | 18.37 |
Pruritus | 13 (9–16) | 51.63 | | 0 (0–1) | 35.36 |
Nausea | 10 (6–14) | 75.86 | | 0 (0–1) | 0.00 |
Rash | 10 (9–12) | 35.05 | | 0 (0–1) | 0.00 |
Blood bilirubin increase | 10 (4–16) | 92.15 | | 2 (1–3) | 13.35 |
Colitis | 8 (5–10) | 84.15 | | 1 (0–1) | 40.44 |
Thyroid dysfunction | 5 (3–7) | 75.73 | | 0 (0–0) | 0.00 |
Gastrointestinal hemorrhage | 4 (2–5) | 73.19 | | 3 (1–5) | 64.59 |
Pulmonary embolism | 1 (0–2) | 0.00 | | 1 (0–2) | 0.00 |
Pneumonia | 1 (1–2) | 0.00 | | 1 (0–1) | 0.00 |
Hand-foot syndrome | 1 (1–2) | 45.23 | | 0 (0–0) | 0.00 |
ES, effect size; CI, confidence interval; AST, aspartate transaminase; ALT, alanine aminotransferase.