Skip to main content
. 2021 Oct 21;13(21):5277. doi: 10.3390/cancers13215277

Table 3.

Key messages from pharmacovigilance studies regarding ir thyroid disorders.

Ref. Type of Study/Methods Key Messages
[5] Review and critical appraisal of 30 pharmacovigilance studies addressing irAEs as of 25 February 2020 using both a disproportionality and
descriptive approach.
The aim of the
review was to provide a global perspective for the management of irAEs in clinical practice.
  • ⮚

    Endocrinopathies rank first among other irAEs, with thyroid disorders being the most common endocrine irAE.

  • ⮚
    Relative frequencies:
    • Endocrinopathies: 8.6%
    • All thyroid disorders: 3.8%
    • Hypothyroidism: 1.8%
    • Hyperthyroidism: 1.5%
  • ⮚

    The lower than expected reporting registered for hypothyroidism (compared to RCTs) may be ascribed to report of multiple irAEs in the same patient.

  • ⮚

    Median time of onset of thyroid disorders related to anti-PD-1/PD-L1 mAbs: 92 days.

  • ⮚

    Thyroid disorders were preferentially recorded with anti-PD-1/PD-L1 mAbs.
[7] Disproportionality analysis of signals of irAEs.
Data source: the FAERS database from the respective FDA approval dates for each specific druga through 2017 Q2.
Evaluation of signals of disproportionality reporting using the pharmacovigilance index reporting odds ratio (ROR) with 95% CI.
  • ⮚
    Thyroid disorders:
    • NIVO: N = 289; ROR, 18.36 (95% CI, 16.25–20.73)
    • PEMBRO: N = 52; ROR, 10.11 (95% CI, 7.66–13.34)
    • IPI: N = 166; ROR, 7.76 (95% CI, 6.64–9.06)
    • IPI + NIVO: N = 50; ROR, 26.89 (95% CI, 20.143–5.91)
  • ⮚

    Higher association of thyroid disorders with NIVO or PEMBRO compared to IPI monotherapy.

  • ⮚

    Association of combination of IPI plus NIVO with higher risk of thyroid dysfunction than either agent alone.

  • ⮚

    Signal strength:

Hypothyroidism:

  • NIVO: N = 160; ROR, 41.85 (95% CI, 35.38–49.51)

  • PEMBRO: N = 27; ROR, 20.34 (95% CI, 13.86–29.87)

  • IPI: N = 56; ROR, 8.16 (95% CI, 6.26–10.64)

  • IPI plus NIVO: N = 20; ROR, 40.34 (95% CI, 25.77–63.16)

Hyperthyroidism:

  • NIVO: N = 50; ROR, 16.83 (95% CI, 12.64–22.42)

  • PEMBRO: N = 7; ROR, 7.36 (95% CI, 3.49–15.50)

  • IPI: N = 29; ROR, 8.74 (95% CI, 6.05–12.62)

  • IPI plus NIVO: N = 19 cases, ROR, 54.61 (95% CI, 34.45–86.59)

Thyroiditis:

  • NIVO: N = 16; ROR, 30.22 (95% CI, 18.03–50.6)

  • PEMBRO: N = 3; ROR, 17.39 (95% CI, 5.54–54.53)

  • IPI: N = 14; ROR, 25.42 (95% CI, 14.87–43.44)

  • IPI plus NIVO: N = 10; ROR, 159.50 (95% CI 83.76–303.75)

TSH decreased:

  • NIVO: N = 14; ROR:, 29.89 (95% CI, 17.21–51.90)

  • PEMBRO: N = 4; ROR, 26.47 (95% CI, 9.79–71.57)

  • IPI: N = 26; ROR, 39.18 (95% CI, 26.31–58.33)

  • IPI plus NIVO: N = 2

TSH increased

  • NIVO: N = 36; ROR, 29.06 (95% CI, 20.60–41.01).

  • PEMBRO: N = 3; ROR, 7.28 (95% CI, 2.3–22.69).

  • IPI: N = 16; ROR, 10.30 (95% CI, 6.28–16.90).

  • IPI plus NIVO: N = 6; ROR, 38.81 (95% CI, 17.27–87.25).
[46] Retrospective disproportionality analysis of FAERS database from 2014 Q1 through 2019 Q1.
Disproportionality was calculated by the informataion component (IC) or ROR with full database as comparator, and only ROR when comparing different drug strategies.
A signal was considered significant if lower limit of the 95% confidence interval (ROR025) > 1, with at least 3 cases.
Threshold for statistical signal detection IC025 > 0 (IC025: lower end of a 95% confidence interval for the IC).
  • ⮚

    Hypothyroidism (N = 885, 14.14%) ranks 1st and hyperthyroidism (N = 472, 7.54%) ranks 4th among endocrine irAEs.

  • ⮚

    Stronger association of hypothyroidism and hyperthyroidism with anti-PD-1 mAbs and combination of NIVO plus IPI regimen.

  • ⮚

    Most endocrine irAEs were related to anti-PD-1 mAbs (N = 3398, 54.28%), corresponding to IC025, 2.20 and ROR025, 4.82.

  • ⮚

    Anti-CTLA-4 mAbs were responsible for a small proportion (N = 708, 11.31%) but stronger signal values (IC025, 2.84, ROR025, 7.68).

  • ⮚

    IPI showed the strongest signal of IPi-associated endocrine irAEs (IC025 = 2.84, ROR025, 7.69).

  • ⮚

    Higher association of hypothyroidism/hyperthyroidism with NIVO or PEMBRO compared to IPI monotherapy.

  • ⮚

    Significant lower reporting frequencies of hypothyroidism (ROR, 0.68; 95%CI, 0.59–0.78) and hyperthyroidism (ROR,  0.77; 95%CI, 0.63–0.93) for males compared to females.

  • ⮚

    Hypothyroidism showed higher reporting frequency than hyperthyroidism (885 vs. 472).
[47] Observational, retrospective, and disproportionality analysis based on the VigiBase database, reporting suspected ir thyroid disorders from 1 January 2011 to 6 March 2019.
  • ⮚

    Most reports are related to lung cancer and melanoma.

  • ⮚

    Male predominance of ir thyroid disorders.

  • ⮚
    Over-report for the full database of:
    • hypothyroidism (1125 reports for ICPi vs. 12495 for all drugs; IC, 4.28 (95% CI, 4.18–4.35)
    • hyperthyroidism (926 reports vs. 7538 reports; IC, 4.66 (95% CI, 4.55–4.74)
    • thyroiditis: 294 reports vs. 1237 reports; IC, 5.40 (95% CI, 5.21–5.54)
    • thyrotoxic crisis: 11 reports vs. 288 reports; IC, 3.55 (95% CI, 2.61–4.20)
  • ⮚
    Over-report for patients treated with ICPi combination vs. ICI monotherapy for:
    • hypothyroidism: ROR, 1.3 (95% CI, 1.1–1.7)
    • hyperthyroidism: ROR, 1.9 (95% CI, 1.5–2.4)
    • thyroiditis: ROR, 3.3 (95% CI, 2.3–4.8)
    • thyrotoxic crisis: ROR, 11.5 (95% CI, 2.4–53.8)
  • ⮚

    All 11 thyrotoxic crisis cases occurred in malignant melanoma patients, of which seven were related to ICPi combination.

  • ⮚
    Anti-PD monotherapy vs. anti-CTLA-4 monotherapy showed over-report of:
    • hypothyroidism: ROR, 2.4 (95% CI, 1.8–3.1)
    • hyperthyroidism: ROR, 3.6 (95% CI, 2.5–5.3)
    • thyroiditis: ROR, 1.9 (95% CI, 1.1–3.2)
  • ⮚

    NIVO was associated with most cases of: hypothyroidism (578 cases, 51.38%), hyperthyroidism (447 cases, 48.27%) thyroiditis (128 cases, 43.54%)

  • ⮚
    Time to onset of hypothyroidism significantly earlier with ICPi combination:
    • anti-PD: 92 days (IQR: 53–146)
    • anti-CTLA-4: 63 days (IQR: 42–70)
    • ICPi combination: 46 days (IQR: 23–87)
  • ⮚

    Media duration of thyrotoxicosis: 35.5 days (IQR: 9–62.55).

  • ⮚

    Recovery or remission after standard treatment in most cases.

  • ⮚

    10 cases (0.68%) resulted in major or fatal consequences, including 6 cases of hypothyroidism, 2 cases of thyrotoxic crisis, 1 case of hyperthyroidism and 1 case of thyroiditis.

  • ⮚

    Recovery in 59.81% of hypothyroidism, 78.35% of hyperthyroidism, and 75.16% of thyroiditis patients (comparison between hypothyroidism and hyperthyroidism, p < 0.0001; comparison between hypothyroidism and thyroiditis, p = 0.002).

  • ⮚

    Most reports came from patients with lung cancer and melanoma.

  • ⮚

    Male predominance of ir thyroid disorders.

a: Data on nivolumab (22 December 2014), pembrolizumab (4 September 2014), ipilimumab (25 March 2011), and nivolumab plus ipilimumab (25 March 2011) were analyzed from their respective FDA approval dates for each specific drug through 2017 Q2. Statistically greater RORs (i.e., ROR > 2, which means that the odds for this adverse event when using this drug is at least twice as much as for all the other drugs) are highlighted in bold. Abbreviations: anti-CTL-A4, anti-cytotoxic T-lymphocyte antigen 4; anti-PD-1, anti-programmed cell death 1; anti-PD-L1, anti-programmed cell death ligand 1; CI, confidence interval; FAERS, FDA Adverse Event Reporting System; IC, information component; ICPi, immune checkpoint inhibitors; IQR, interquartile range; IPI, ipilimumab; irAE (s), immune-related adverse event(s); mAbs, monoclonal antibodies; N, number of patients; NIVO, nivolumab; PEMBRO, pembrolizumab; Q, quarter; Ref, reference; RCTs, randomized controlled trials; ROR, reporting odds ratios.