Table 1:
Systematic review of the studies evaluating the correlation between the development of immune-related thyroid dysfunction and clinical outcomes secondary to immune checkpoint inhibitors
| Number | Reference | Study type | Primary tumor site | Treatment | N= | ITB | irAE of interest | Outcomes (thyroid irAE vs. no thyroid irAE) | Summary | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| OS | PFS | Positive/Negative study | |||||||||
| 1 | Freeman-Keller et al (2016)54 | Retrospective | Melanoma | Anti-PD-1 ± peptide vaccination (nivolumab + peptide vaccine or nivolumab alone) | 148 | Yes | General, thyroid | NS | Not reported | Negative | Non-significant OS for endocrinopathies, including thyroid irAE |
|
| |||||||||||
| 2 | Kim et al (2017)18 | Retrospective | NSCLC | Anti-PD-1 (nivolumab or pembrolizumab) | 58 | No | Thyroid | 118 vs. 71 days, (p=0.025) Adjusted HR 0.11, (p=0.041) |
118 vs. 61 days, (p=0.014) Adjusted HR 0.38, (p=0.018) |
Positive | thyroid irAE was an independent predictive factor for favorable outcome |
|
| |||||||||||
| 3 | Fujisawa et al (2017)63 | Retrospective | Melanoma | CTLA-4 post PD-1 (ipilimumab post nivolumab) | 60 | Yes | General, endocrine | Adjusted RR 0.22, (p=0.015) | Not reported | Positive | Endocrine irAEs were significant factors associated with survival |
|
| |||||||||||
| 4 | Osorio et al (2017)20 | Prospective | NSCLC | Anti-PD-1 (pembrolizumab) | 51 | No | Thyroid | 40 vs 14 months, HR 0.29, (p=0.029) | NS | Positive | OS was significantly longer in patients who developed thyroid irAE |
|
| |||||||||||
| 5 | Grangeon et al (2018)21 | Retrospective | NSCLC | Anti-PD-1 or anti-PD-L1 (not specified) | 270 | No | General, thyroid | NR vs 18.2 months, HR 0.46, (p=0.01) | 8.05 vs. 2.59 months, HR 0.56, (p=0.005) | Positive | thyroid irAE was correlated with better clinical outcomes |
|
| |||||||||||
| 6 | Haratani et al (2018)22 | Retrospective | NSCLC | Anti-PD-1 (nivolumab) | 134 | Yes | General, endocrine | NS | Adjusted HR 0.237, (p=0.02) | Positive | Endocrine irAEs were correlated with better PFS, but not OS |
|
| |||||||||||
| 7 | Owen et al (2018)23 | Retrospective | NSCLC | Anti-PD-1 or anti-PD-L1 (nivolumab, pembrolizumab, atezolizumab) | 91 | Yes | General, thyroid | NR vs. 6.5 months, (0.018) 3-month landmark NR vs. 16.2 months, (p=0.0296) |
Not reported | Positive | thyroid irAE was correlated with longer OS |
|
| |||||||||||
| 8 | Ricciuti et al (2018)24 | Retrospective | NSCLC | Anti-PD-1 (nivolumab) | 195 | No | General, endocrine | Adjusted HR 0.45, (p=0.001) | Adjusted HR 0.59, (p=0.011) | Negative | Endocrine irAEs were correlated with better clinical outcomes |
|
| |||||||||||
| 9 | Ahn et al (2019)51 | Retrospective | NSCLC | Anti-PD-1 (nivolumab or pembrolizumab) | 155 | Yes | General, endocrine | NR vs. 12.58 months, (p=0.037) Adjusted HR NS |
NS | Negative | Endocrine irAEs were not identified as significant positive predictive factors of better clinical outcomes |
|
| |||||||||||
| 10 | Campredon et al (2019)52 | Retrospective | NSCLC | Anti-PD-1 (nivolumab) | 105 | Yes | Thyroid | NS | NS | Positive | A non-statistically significant tendency toward improvement of the overall survival was observed in the thyroid irAE group |
|
| |||||||||||
| 11 | Cortellini et al (2019)25 | Retrospective | NSCLC | Anti-PD-1 (nivolumab or pembrolizumab) | 559 | Yes | General, endocrine | Adjusted HR 0.55, (p=0.0044) | Adjusted HR 0.63, (p=0.0084) | Positive | Endocrine irAEs correlated with improved ORR and PFS and improved OS |
|
| |||||||||||
| 12 | Funazo et al (2019)26 | Retrospective | NSCLC | Anti-PD-1 (nivolumab) | 111 | No | Thyroid | Low fT4: NR vs. 556 days HR 0.139, (p=0.020) |
Low fT4: NR vs. 67 days HR 0.297, (p=0.010) |
Positive | In the patients with advanced NSCLC, low fT4 after nivolumab treatment was associated with significantly longer PFS and OS |
|
| |||||||||||
| 13 | Koyama et al (2019)27 | Retrospective | NSCLC | Anti-PD1 (nivolumab or pembrolizumab) | 132 | No | Thyroid | NR vs. 14.1 months, (p=0.011) | 9.8 vs. 1.8 months, (p=0.012) | Negative | thyroid irAE was correlated with better OS and PFS in NSCLC patients |
|
| |||||||||||
| 14 | Ksienski et al (2019)53 | Retrospective | NSCLC | Anti-PD-1 (nivolumab or pembrolizumab) | 254 | Yes | General, thyroid | NS | Not reported | Positive | thyroid irAE was not correlated with OS after nivolumab or pembrolizumab treatment |
|
| |||||||||||
| 15 | Lei et al (2019)28 | Retrospective | Melanoma, RCC, NSCLC | Anti-PD-1 (nivolumab or pembrolizumab) | 103 | No | Thyroid | NR vs. 12.9 months, HR 0.40, (p=0.014) | 10.1 vs. 3.7 months HR 0.45, (p=0.002) | Positive | thyroid irAE was correlated with better clinical outcomes OS, PFS and ORR |
|
| |||||||||||
| 16 | Maeda et al (2019)29 | Retrospective | Melanoma | Anti-PD-1 (nivolumab) | 73 | Yes | General, endocrine | 20-week landmark (p=0.27) | 20-week landmark (p=0.07) | Positive | Endocrine irAEs were correlated with better clinical outcomes |
|
| |||||||||||
| 17 | Peiro et al (2019)30 | Prospective | Majority NSCLC, melanoma, lymphoma | Anti-PD-1 (nivolumab) | 73 | No | Thyroid | NSCLC & TD: HR, 0.4, (p=0.035) | Not reported | Positive | In patients with NSCLC, nivolumab-induced thyroid dysfunction appears to be correlated with better OS |
|
| |||||||||||
| 18 | Sakakida et al (2019)31 | Retrospective | Majority NSCLC, melanoma, lymphoma, RCC, head and neck, gastric, urothelial | Anti-PD-1 (nivolumab or pembrolizumab) | 174 | Yes | Thyroid | 156 vs. 59 weeks, HR 0.34, (p=0.01) Adjusted HR 0.42, (p=0.04) |
66 vs 27 weeks, HR 0.50, (p=0.02) Adjusted HR NS |
Positive | thyroid irAE was an independent prognostic factor for longer OS |
|
| |||||||||||
| 19 | Verzoni et al (2019)32 | Prospective | RCC | Anti-PD-1 (nivolumab) | 398 | Yes | General, endocrine | 1-year OS 92.3% (p = 0.001) | Not reported | Negative | Endocrine irAEs were correlated with improved OS |
|
| |||||||||||
| 20 | Yamauchi et al (2019)5 | Retrospective | Lung, melanoma, others | Anti-PD-1 (nivolumab) | 200 | Yes | Thyroid | 16.1 vs. 13.6 months, HR 0.61, (p = 0.022) Lung & TD: NR vs.14.2 months, HR 0.51 CI 0.27-0.92, (p=0.025) Melanoma & TD: NS |
4.9 vs. 2.9 months, HR 0.66 (p = 0.023) Lung &TD: 5.8 vs.2.3 months, HR 0.55 CI 0.33-0.88, (p=0.012) Melanoma & TD: 3.3 vs 4.1 months, HR 0.94 CI 0.41-2.00, (p=0.885) |
Positive | thyroid irAE related to good prognosis in lung cancer but might be inconclusive in melanoma |
|
| |||||||||||
| 21 | Al Mushref et al (2020)56 | Retrospective | Melanoma | Anti-PD-1 or CTLA-4 (ipilimumab, pembrolizumab or nivolumab) | 186 | No | Thyroid | NS | Not reported | Positive | Thyroid irAEs did not appear to be associated with change in survival |
|
| |||||||||||
| 22 | Basak et al (2020)33 | Prospective | Melanoma, NSCLC, RCC | Anti-PD-1 (nivolumab or pembrolizumab) | 168 | Yes | Thyroid | 1-year OS rates 94 vs. 59%, HR 0.18, (p=0.020) | 1-year PFS rates 64 vs. 34%, HR 0.39, (p=0.050) | Positive | thyroid irAE is associated with improved OS and PFS |
|
| |||||||||||
| 23 | Cortellini et al (2020)64 | Retrospective | NSCLC w PD-L1 expression >50% | Anti-PD-1 (pembrolizumab) | 1010 | Yes | General, thyroid | Adjusted HR 0.30, (p<0.0001) | Adjusted HR 0.40, (p<0.0001) | Positive | Endocrine irAEs were significantly related to improved OS, PFS and ORR |
|
| |||||||||||
| 24 | Economopoulou et al (2020)35 | Retrospective | Head and neck | Anti-PD-1 (nivolumab) | 89 | No | General, endocrine | (p=0.014) | Not reported | Positive | The development of endocrine irAEs is a predictor of improved survival in patients with advanced HNSCC treated with nivolumab. |
|
| |||||||||||
| 25 | Eggermont et al (2020)36 | RCT (secondary analysis) | Melanoma | Anti-PD-1 (Pembrolizumab) | 1011 | Yes | General, endocrine | Not reported | HR 0.34, (p=0.03) | Positive | Occurrence of endocrine irAEs were associated with a longer PFS in the pembrolizumab arm |
|
| |||||||||||
| 26 | Espana et al (2020)37 | Retrospective | NSCLC, melanoma, urothelial | Anti-PD-1 +/− anti-CTLA-4 or anti-CTLA-4 (pembrolizumab, nivolumab, atezolizumab, ipilimumab or combination therapy) | 188 | No | Endocrine | NR vs. 31.4 months (p=0.001) Adjusted HR 0.42, (p=0.008) |
56.7 vs. 27.7 months, (p=0.008) | Positive | Endocrine irAEs were significantly associated with improved OS and PFS |
|
| |||||||||||
| 27 | Lima-Ferreira et al (2020)38 | Retrospective | Melanoma, NSCLC, lymphoma, urothelial and head and neck | Anti-PD-1 or anti-CTLA-4 (pembrolizumab, nivolumab or ipilimumab) | 161 | No | Thyroid | 3.26 vs. 1.76 years, (p=0.030) | Not reported | Positive | Primary and central thyroid dysfunction can be a predictive clinical biomarker of a better response to ICI across several neoplasms |
|
| |||||||||||
| 28 | Kelly et al (2020)39 | Prospective | Majority NSCLC | Anti-PD-L1 (avelumab) | 1783 | Yes | General, thyroid | HR 0.53, CI 0.39-0.71 | Not reported | Positive | thyroid irAE was significantly associated with improved OS |
|
| |||||||||||
| 29 | Kijima et al (2020)40 | Retrospective | Urothelial | Anti-PD-1 (pembrolizumab) | 97 | No | General, endocrine | (p=0.04) | Not reported | Positive | Endocrine irAEs were associated with increased ORR and longer OS |
|
| |||||||||||
| 30 | Kotwal et al (2020)41 | Retrospective | Lung (85%), Uroepithelial, Merkel cell, prostate, penis | Anti-PD-L1 (atezolizumab or avelumab) | 91 | No | Thyroid | NR vs 9.8 months, (p=0.027) Adjusted HR 0.49, CI 0.25-0.99, (p=0.034) |
Not reported | Negative | thyroid irAE appears to be associated with improved OS |
|
| |||||||||||
| 31 | Maillet et al (2020)42 | Retrospective | Melanoma, NSCLC, RCC, urothelial | Anti-PD-L1 or anti-CTLA-4 (not specified) | 410 | Yes | General, thyroid | HR 0.53, CI 0.3-0.94 | HR 0.5, CI 0.3-0.84 | Negative | thyroid irAE is correlated with better OS and PFS |
|
| |||||||||||
| 32 | Matsuo et al (2020)55 | Retrospective | Head and neck squamous cell | Anti-PD-1 (nivolumab) | 108 | No | General, endocrine | Not reported | NS | Positive | No correlation between endocrine irAEs and clinical outcomes |
|
| |||||||||||
| 33 | Shankar et al (2020)6 | Retrospective | NSCLC | Anti-PD-1, anti-PD-L1 (not specified) | 623 | No | General, thyroid | NS | NS | Positive | No correlation between thyroid irAE and clinical outcomes observed |
|
| |||||||||||
| 34 | Al Ashi et al (2021)50 | Retrospective | NSCLC, melanoma, RCC, bladder | Anti-PD-1 anti-PD-L1 or anti-CTLA-4 (nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab or ipilimumab) | 551 | No | Endocrine | Adjusted HR 0.56, CI 0.42-0.76, p<0.001 | Not reported | Negative | The development of endocrine irAEs was associated with a longer OS |
|
| |||||||||||
| 35 | Bai et al (2021)43 | Retrospective | Lung, melanoma, esophageal, urothelial, gastric | Anti-PD-1, anti-PD-L1 or combination therapy (not specified) | 103 | No | General, endocrine | Not reported | 13.3 vs. 4.13 months (p=0.01) | Positive | Endocrine irAEs were associated with better PFS |
|
| |||||||||||
| 36 | D’Aiello et al (2021)57 | Retrospective | NSCLC, SCLC | Anti-PD-1 or anti-PD-L1 (pembrolizumab, nivolumab, durvalumab or atezolizumab) | 205 | Yes | Thyroid | Not reported | NS | Negative | There were no observed differences in PFS between those that developed thyroid irAE and those that did not |
|
| |||||||||||
| 37 | Frelau et al (2021)44 | Retrospective | Melanoma | Anti-PD-1 +/− CTLA-4 or CTLA-4 (pembrolizumab or nivolumab or combination therapy) | 110 | No | General, thyroid | 43.9 vs. 9.8 months, (p=0.0021) Adjusted HR 0.4, 95% CI 0.21-0.76, (p=0.005) |
18.1 vs. 3.9 months, (p=0.0085) NS |
Negative | thyroid irAE appeared to be associated with better OS |
|
| |||||||||||
| 38 | Holstead et al (2021)62 | Retrospective | Melanoma | Anti-PD-1 (nivolumab or pembrolizumab) | 87 | Yes | General, thyroid | NS | Not reported | Positive | There appeared to be a trend towards better OS in individuals with endocrine irAEs |
|
| |||||||||||
| 39 | Lui et al (2021)61 | Retrospective | HCC, lung, breast, melanoma, RCC, CC pancreas, colorectal, gastric, NET | Anti-PD-1/anti-CTLA-4 combination therapy (nivolumab/pembrolizumab and ipilimumab) | 103 | Yes | Endocrine | 17.9 vs.5.7 months (p<0.001) Adjusted HR 0.34, 95% CI 0.17-0.71, (p=0.004) 3-month landmark: HR 0.42, CI 0.13-1.36, (p=0.135) |
Not reported | Negative | thyroid irAE may have prognostic significance in individuals with advanced cancer and combination therapy |
|
| |||||||||||
| 40 | Luongo et al (2021)45 | Retrospective | NSCLC, melanoma, RCC | Anti-PD-1 (nivolumab or pembrolizumab) | 96 | No | Thyroid | HR 0.41, CI 0.2-0.87, p=0.0197 | NS | Positive | thyroid irAE was associated with an improved 2-year OS when compared to euthyroid patients |
|
| |||||||||||
| 41 | Morimoto et al (2021)60 | Retrospective | NSCLC | Anti-PD-1 or anti-PD-L1 combined with chemotherapy | 70 | No | General, thyroid | NS | HR 0.46, CI 0.17-1.29, (p=0.14) | Negative | Endocrine irAEs were associated with a trend towards improved PFS |
|
| |||||||||||
| 42 | Muir et al (2021)46 | Retrospective | Melanoma | Anti-PD-1 +/− CTLA-4 or CTLA-4 (ipilimumab, pembrolizumab or nivolumab or combination therapy) | 1246 | No | Thyroid | Adjusted HR 0.57, 95% CI 0.39-0.84, (p=0.005) | Adjusted HR 0.68, 95% CI 0.49-0.94, (p=0.02) | Negative | Overt thyrotoxicosis appeared to be associated with better OS and PFS. No association was observed for hypothyroidism |
|
| |||||||||||
| 43 | Paderi et al (2021)59 | Retrospective | RCC | Anti-PD-1 +/− CTLA-4 (nivolumab or combination therapy) | 43 | Yes | General, thyroid | Not reported | Adjusted HR 0.34 CI 0.13-0.87, (p=0.025) 16-week landmark (p=0.160) |
Positive | At the 16-week landmark analysis, thyroid irAE showed a trend towards improved PFS |
|
| |||||||||||
| 44 | Rubino et al (2021)58 | Retrospective | NSCLC, melanoma | Anti-PD-1 (pembrolizumab or nivolumab) | 251 | No | General, endocrine | NS | NS | Positive | Endocrine irAEs were not associated with OS or PFS |
|
| |||||||||||
| 45 | Street et al (2021)47 | Retrospective | Melanoma, breast, gastrointestinal, genitourinary, head and neck, hematologic, neurologic, thoracic | Anti-PD-1, anti-PD-L1 or CTLA-4 or combination therapy (not specified) | 6596 | Yes | Thyroid | Adjusted HR 0.8, CI 0.71-0.89), (p=<0.001) | Not reported | Positive | Thyroid irAE was associated with improved OS even after accounting for immortal time biases |
|
| |||||||||||
| 46 | Thuillier et al (2021)48 | Retrospective | NSCLC | Anti-PD-1 (nivolumab) | 194 | No | Thyroid | 29.8 vs. 8.1 months, (p<0.001) Adjusted HR 0.32, (p<0.001) |
8.7 vs. 1.7 months, (p<0.001) Adjusted HR = 0.36 (p<0.001) |
Positive | thyroid irAE appeared to be correlated with better OS, PFS and ORR |
|
| |||||||||||
| 47 | Zhou et al (2021)49 | Retrospective | NSCLC | Anti-PD-1 (pembrolizumab or nivolumab) | 191 | No | General, thyroid | 16.8 vs. 11.1 months, (p< 0.001) | 10.4 vs. 5.5 months, (p<0.001) | Positive | thyroid irAE appeared to be correlated with better OS and PFS |
Cholangiocarcinoma (CC), complete response (CR), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), hazards ratio (HR), head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), immune checkpoint inhibitor (ICI), immune-related adverse event (irAE), immune-related thyroid dysfunction (thyroid irAE), number (N), non-small cell lung cancer (NSCLC), not reached (NR), not significant (NS), overall survival (OS), programmed cell death receptor 1 (PD-1), programmed cell death ligand (PD-L1), progression-free survival (PFS), renal cell carcinoma (RCC), small cell lung cancer (SCLC), 95% confidence interval (CI), thyroid dysfunction (TD)