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. 2021 Oct 21;13(21):5277. doi: 10.3390/cancers13215277

Table 1.

Frequency of ir thyroid disorders according to the recent meta-analyses.

Ref.
Enrolled Studies/
Type of Studies
Ca Type (N * = Number of Studies; N ** = Number of Patients)		 ICPi Hypothyroidism Hyperthyroidism
[26]
35 trials addressing irAEs in advanced melanoma, involving 6331 patients. Systematic Review and Meta-analysis
Advanced Melanoma
(N * = 35, N ** = 6331)

  • IPI (N * = 21, N ** = 2726)

  • NIVO (N * = 7, N ** = 1017)

  • PEMBRO (N * = 5, N ** = 1632)

  • IPI: 2.84 (1.46–4.57)

  • NIVO: 7.02 (4.37–10.19)

  • PEMBRO: 8.34 (7.01–9.77)

  • PEMBRO + IPI: 16.34 (11.32–23.01)

  • NIVO + IPI: 16.39 (13.50–19.490

  • IPI then NIVO: 11.22 (0.03–33.98)

  • NIVO then IPI: 2.06 (13.85 –33.260

  • IPI: 0.90 (0.14–2.16)

  • NIVO: 3.01 (1.96–4.24)

  • PEMBRO: 3.34 (1.60–5.61)

  • PEMBRO + IPI: 11.11 (7.05–17.07)

  • NIVO + IPI: 10.16 (95.94–15.28)

  • IPI then NIVO: 0.00 (0.00–10.43)

  • NIVO then IPI: NR
[27]
9 RCTs addressing irAEs in advanced melanoma, involving 5051 patients.
Systematic review and network meta-analysis
Advanced melanoma
(N * = 9, N ** = 5051)

  • IPI

  • PEMBRO

  • NIVO

  • IPI 3 mg/kg every 3 weeks was the treatment regimen with the lowest probability to cause hypothyroidism (median rank, 2; 95% CrI, 1–5) a.

  • NIVO 3 mg/kg every 2 weeks was the treatment regimen with the lowest risk of severe hypothyroidism (median rank, 3; 95% CrI, 1–7) a.

 NS
[28]
13 studies addressing anti-PD-1/anti-PD-L1 toxicity, involving 6676 patients.
Systematic Review and meta-analysis

  • Metastatic non-small cell lung cancer (N * = 7)

  • Melanoma (N * = 3)

  • Renal Cell Carcinoma (N * = 1)

  • Bladder cell carcinoma (N * = 1)

  • Head and Neck squamous cell carcinoma (N * = 1)

  • NIVO (N * = 6, N ** = 1534)

  • PEMBRO (N * = 5, N ** = 1518 +/−)

  • ATE (N * = 2, N ** = 751)

  • Among patients exposed to anti-PD-1 drugs: 214/3803 developed hypothyroidism (5.6%).

  • In the control group: 24/3353 developed hypothyroidism (0.7%)

  • ⮚
    ATE:
    • All grades: 1.1 (0.5–2.1)
    • Serious: 0.1 (0.0–0.7)
  • ⮚
    NIVO:
    • All grades: 5.9 (4.7–7.2)
    • Serious: 0.2 (0.0–0.6)
  • ⮚
    PEMBRO:
    • All grades: 7.6 (6.4–9.1)
    • Severe: 0.1 (0.0–0.5)
  • ⮚
    TOTAL:
    • All grades: 5.6 (4.9–6.4)
    • Serious: 0.2 (0.1 to 0.3)
  • ⮚

    In the meta-analysis, patients treated with anti-PD-1 drugs were at a higher risk for any grade hypothyroidism (OR, 6.92, 3.25–14.75, p < 0.001) compared to controls who received standard treatment (chemotherapy, targeted drugs, or both).

 NS
[29]
11 studies addressing anti-CTLA-4 toxicity, involving 7088 patients.
Systematic Review and meta-analysis

  • Melanoma (N * = 4, N ** = 2862)

  • Metastatic non-small cell lung cancer (N * = 2, N ** = 1216)

  • Small cell lung cancer (N * = 2, N ** = 1126)

  • Metastatic castration-resistant prostate cancer(N * = 2, N ** = 799)

  • Mesothelioma (N * = 1, N ** = 569)

  • IPI (N * = 9, N ** = 3280)

  • TREME (N * = 2, N ** = 705)

 IPI:

  • All grades: 2.5 (2.0–3.1)

  • Serious: 0.3 (0.2–0.6)

  • TREME:

  • All grades: 2.7 (1.6–4.2)

  • Serious: 0.6 (0.2–1.4)

Total:

  • All grades: 2.5 (2.0–3.0)

  • Serious: 0.4 (0.2–0.6)

  • ⮚

    Higher risk of hypothyroidism (OR, 7.86; 95% CI, 4.10–15.04) in the intervention arms (IPI or TREME) compared to the control group (placebo, chemotherapy, radiation therapy, or vaccine).

  • ⮚

    Same trends for severe irAEs

 IPI:

  • All grades: 0.3 (0.1–0.5)

  • Serious:0.3 (0.1–0.5)

TREME:

  • All grades: 0.0 (0.0–0.5)

  • Serious:0.0 (0.0–0.5)

Total:

  • All (CTCAE) grades: 0.2 (0.1–0.4)

  • Serious: 0.2 (0.1–0.4)

  • ⮚

    No higher risk of hyperthyroidism (OR 3.78, 95% CI 0.94–15.17) in the intervention arms (IPI or TREME) compared to the control group (placebo, chemotherapy, radiation therapy, or vaccine).

  • ⮚

    Same trends for severe AEs.

[30]
101 studies addressing endocrine irAEs, involving
19,922 patients.
Systematic Review and meta-analysis

  • Melanoma (N * = 69/152)

  • Non-small cell lung carcinoma (N * = 31/152)

  • Renal cell carcinoma (N * = 11/152)

  • IPI (N ** = 4430)

  • TREME (N ** = 1171)

  • NIVO (N ** = 3317)

  • PEMBRO (N ** = 4485)

  • ATE (N ** = 998)

  • AVE (N ** = 316)

  • DUVRA (N ** = 191)

  • IPI: 3.8 (2.6–5.5)

  • ATE: 6.0 (4.2–8.4)

  • DUVRA: 4.7 (2.5–8.8)

  • NIVO: 8.0 (6.4–9.8)

  • PEMBRO: 8.5 (7.5–9.7)

  • AVE: 5.5 (3,5–8.7)

  • DURVA + TREME: 10.2 (5.6–17.9)

  • IPI + PEMBRO: 15.1 (10.6–21.8)

  • IPI + NIVO: 16.4 (11.7–22.5)

  • IPI: 1.4 (0.8–2.4)

  • NIVO: 2.8 (2.1–3.8)

  • PEMBRO: 3.7 (2.8–4.7)

  • AVE: 2.3 (0.6–8.6)

  • IPI + NIVO: 9.4 (7.1–12.3)

  • IPI + PEMBRO: 10.4 (6.6–16.1)
[31]
38 RCT addressing irAEs in advanced solid tumors, involving 7551 patients.
Systematic Review and meta-analysis

  • Melanoma (N * = 25, N ** = 3346)

  • Non-small cell lung cancer (N * = 10, N ** = 1906)

  • Renal cell carcinoma (N * = 6, N ** = 664)

  • NIVO (N ** = 2494)

  • PEMBRO (N ** = 2459)

  • IPI (N ** = 1013)

  • ATE (N ** = 4953)

 Overall incidence: 6.6 (5.5–7.8) Predicted incidence:

  • IPI: 3.8 (1.9–7.8)

  • Combination: 13.2 (6.9–23.8).

 Overall incidence: 2.9 (2.4–3.7)
Predicted incidence:

  • anti-PD-L1: 0.6 (0.2–1.8)

  • Combination: 8.0 (4.1‒15.3)
[32]
11 RCTs addressing irAEs of ICPi combination, involving 5307 patients.
Meta-analysis

  • Advanced/Metastatic melanoma (N * = 6, N ** = 2194)

  • Non-small cell lung cancer (N * = 1)

  • Small-cell lung cancer (N * = 1)

  • Recurrent glioblastoma (N * = 1, N ** = 40)

  • Advanced renal-cell carcinoma (N * = 1, N ** = 1096)

  • Recurrent metastatic sarcoma (N * = 1, N ** = 85)

  • NIVO (N * = 11, N ** = 3467)

  • IPI (N * = 11, N ** = 2976)

 Combination: RR for all-grade hypothyroidism: 1.71 (95% CI, 1.38–2.13; p < 0.00001) Combination: RR for all-grade hyperthyroidism: 2.84 (95% CI, 1.71–4.72, p < 0.0001
[33]
21 trials addressing irAEs, involving 11,454 patients.
Meta-analysis

  • Non-small cell lung cancer (N * = 8)

  • Melanoma (N * = 6)

  • Small cell lung cancer (N ** = 2)

  • Prostate cancer (N ** = 2)

  • Renal cell carcinoma (N * = 1)

  • Bladder cancer (N * = 1)

  • Squamous cell cancer of the head and neck (N * = 1)

  • IPI (N ** = 272)

  • NIVO (N ** = 1534)

  • PEMBRO (N ** = 1522)

  • ATE (N ** = 751)

 All ICPi:

  • All grades: 5.1 (3.8–6.8)

  • High grade: 0.3 (0.2–0.5)

Pooled RR for all grade:
6.81 (4.20–11) p < 0.001
Pooled RR for high grade: 1.15 (0.44–3.05)

  • anti-PD1/anti-PD-L1: RR: 8.05 (4.26–15.2)

  • anti-CTLA-4: RR: 2.02 (0.39–10.5)

 NS
[34]
10 clinical trials addressing irAEs, involving 5, 291 patients.
Meta-analysis

  • Malignant melanoma (N ** = 3868)

  • Castrate-resistant prostate cancer (N ** = 789)

  • Non-small cell lung cancer (N ** = 463)

  • IPI (N * = 5)

  • NIVO (N * = 3)

  • TREME (N * = 1)

  • PEMBRO (N * = 1)

 1.6–8.9
RR for all grades: 8.26 (95% CI: 4.67–14.62 p < 0.00001) 		0.4–3.5
RR for all grades: 5.48 (95% CI: 1.33–22.53; p = 0.02)
[35]
10 studies addressing irAEs, including 8 RCTs involving 2716 patients.
Meta-analysis

  • Lung cancer (N * = 2)

  • Melanoma (N * = 3)

  • Metastatic sarcoma (N * = 1)

  • Urothelial carcinoma (N * = 1)

  • Recurrent glioblastoma (N * = 1)

  • NIVO (N ** = 2359)

  • IPI (N ** = 1758)
  • ⮚

    Hypothyroidism any-grade ranks second among irAEs related to ICPi combinations.

  • ⮚

    Incidence of any-grade hypothyroidism in the ICPi combination vs. ICPi monotherapy group:

13.8 (194/1401 cases) vs. 7.2 (95/1315 cases).
  • ⮚

    Hyperthyroidism any-grade ranks fifth among irAEs related to ICPi combinations.

  • ⮚

    Incidence of any-grade hyperthyroidism in the ICPi combination vs. ICPi monotherapy group:

Values are percentages of incidence (95% confidence intervals) unless cited otherwise. All relative risks (RR) refer to comparison of ICPi arms to non-ICPi arms. N * = number of studies; N ** = number of patients. a: Ranking of the possibility of being the ICPi regimen with the lowest risk to cause ir thyroid disorders was based on an estimation of the median (95% CI) of the posterior distribution for the rank of each studied ICPi regimen. This analysis indicated IPI 3 mg/kg every 3 weeks as the treatment regiment associated with the lowest risk for any hypothyroidism (median rank, 2; 95% CI, 1–5) compared to: chemotherapy, ipilimumab 10 mg/kg every 3 weeks, pembrolizumab 10 mg/kg, every 2 weeks, nivolumab 1 mg/kg every 3 weeks and ipilimumab 3 mg/kg every 3 weeks, nivolumab 3 mg/kg every 2 weeks, pembrolizumab 10 mg/kg every 3 weeks, and pembrolizumab 2 mg/kg every 3 weeks. Abbreviations:.anti-CTLA-4, antibodies against cytotoxic T-lymphocyte antigen 4, anti-PD-1, antibodies against programmed cell death protein-1; anti-PD-L1, antibodies against PD-1 ligand molecule; ATE, atezolizumab; AVE, avelumab; Ca, cancer type; CI, confidence interval; CrI, credible interval; DUVRA, durvalumab; ICPi, immune checkpoint inhibitors; IPI, ipilimumab; N, number; NIVO, nivolumab; NS, not studied; OR, odds ratio; PEMBRO, pembrolizumab; RCT, randomized controlled trials; Ref, reference; RR, relative risk; TREME, tremelimumab; vs., versus.