Endocrine toxicities of immune checkpoint inhibitors

In the paper

“Several studies have suggested that thyroid dysfunction is associated with improved overall survival from a cancer standpoint, although the mechanism for this type of association is not well understood.39,40”

What the sources say

• ?Could not verify

  The Methods section includes autoimmune thyroid conditions among eligible diagnoses, but does not assess thyroid dysfunction as a predictor of survival. The Results report treatment response and find no association between autoimmune-disease flares and response; neither that section nor the Discussion addresses improved overall survival associated with thyroid dysfunction or its mechanism (page numbers unavailable). Searches for thyroid dysfunction, thyroiditis, survival, and the proposed association found no supporting passage. (LLM, conf=0.76)

  cites [39] Leonardi, G. C. et al. Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J. Clin. Oncol. 36, 1905–1912 (2018). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results > Safety section reports hypothyroidism in four patients, and Results > Efficacy reports overall survival for the cohort, but neither links thyroid dysfunction to improved survival. A search for thyroid dysfunction, hypothyroidism, survival, and a proposed mechanism found no passage addressing the claimed association; page numbers were not available in our copy. (LLM, conf=0.78)

  cites [40] Kanz, B. A. et al. Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction. J. Immunother. Cancer 4, 60 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Patients with pre-existing autoimmune disease may have somewhat higher risk of irAEs, although these usually relate to increased risks of low-grade flares of their pre-existing disease rather than de novo events.30–32”

What the sources say

• ?Could not verify

  The Results (Baseline patient characteristics; page unavailable) note that two of 60 patients had a personal history of autoimmune disease, but do not compare their irAE risk with that of other patients. The Introduction and Results passages do not say whether irAEs in patients with pre-existing autoimmune disease were usually low-grade flares rather than de novo events. Searches for pre-existing disease, flares, severity, and de novo events found no passage addressing that distinction. (LLM, conf=0.75)

  cites [30] Braaten, T. J. et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann. Rheum. Dis. 79, 332–338 (2020). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Introduction describes immune-related toxicities after ipilimumab, and the Results section on acute and chronic immune-related toxicities reports events in long-term survivors (page numbers unavailable). Neither addresses whether patients with pre-existing autoimmune disease have a higher risk of irAEs or whether their events are usually low-grade flares rather than new events. Searches for pre-existing autoimmune disease and flares found no passage establishing that comparison. (LLM, conf=0.73)

  cites [31] Johnson, D. B. et al. Survivorship in immune therapy: assessing chronic immune toxicities, health outcomes, and functional status among long-term ipilimumab survivors at a single referral center. Cancer Immunol. Res. 3, 464–469 (2015). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results section on acute immune-related toxicities reports their frequency and severity, but does not compare patients with and without pre-existing autoimmune disease. Searches for pre-existing autoimmune disease, flares, and de novo events found no passage addressing the claimed difference in risk or type of event. Page numbers were not available in our copy. (LLM, conf=0.72)

  cites [32] Patrinely, J. R. Jr. et al. Survivorship in immune therapy: assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand. Eur. J. Cancer 135, 211–220 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Hypothyroidism comprises the overwhelming majority of cases, and is preceded by a destructive thyroiditis in 30-40% of anti-PD-1/PD-L1 induced cases, and up to two-thirds of combination-induced cases.”

In the paper

“One meta-analysis reported that ~68% of patients with thyroiditis progressed to hypothyroidism, with a median of 6 weeks from thyroiditis diagnosis to hypothyroid diagnosis47”

What the sources say

• Not checked yetcites [47] Winther, K. H. et al. Disease-specific as well as generic quality of life is widely impacted in autoimmune hypothyroidism and improves during the first six months of levothyroxine therapy. PLoS ONE 11, e0156925 (2016). source

In the paper

“endocrine events typically do not require the first two pillars of management (drug discontinuation or high-dose steroids) since the long-term hormone insufficiency usually occurs regardless of treatment.”

In the paper

“Toxicities from ICI are autoimmune in nature and may affect any organ system in an unpredictable fashion, commonly including endocrine manifestations involving the thyroid, pituitary, adrenal, and pancreas.”

In the paper

“Thyroid events occur in approximately 10% of patients treated with anti-PD-1/PD-L1 monotherapy, and up to 15-20% of those treated with combination PD-1/CTLA-4 blockade (as opposed to only 5% of those treated with ipilimumab monotherapy).9,38”

What the sources say

• Not checked yetcites [9] Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018). source
• Not checked yetcites [38] Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016). source

In the paper

“Most other systems are affected by transient inflammation that resolves with steroid therapy and restoration of normal organ function (although up to half of rheumatologic events and rarely other toxicities also become chronic in nature).25,26”

What the sources say

• Not checked yetcites [25] Iwama, S. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6, 230ra45 (2014). This paper reports a preclinical model of hypophysitis with translational correlates. source
• Not checked yetcites [26] US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf (2017).

In the paper

“The median time to onset of thyroid dysfunction, most of which is hypothyroidism, is 6 weeks after ICI initiation47, although this may occur essentially any time on therapy.”

What the sources say

• Not checked yetcites [47] Winther, K. H. et al. Disease-specific as well as generic quality of life is widely impacted in autoimmune hypothyroidism and improves during the first six months of levothyroxine therapy. PLoS ONE 11, e0156925 (2016). source

In the paper

“ICI-related thyrotoxicosis is characterized by an elevated FT4 or total T3 and a low or suppressed TSH.”

In the paper

“These are distinct events from those caused by traditional cytotoxic chemotherapy or even newer molecular targeted therapies, which rarely cause endocrine dysfunction.”

In the paper

“ICI-related hypothyroidism, which is related to thyroiditis, may present with fatigue, depressed mood, mild weight gain, constipation, and altered cognition when severe, though many patients are completely or relatively asymptomatic.”

In the paper

“supportive management (in the form of hormone replacement) is the foundation of treatment and is particularly critical to achieving optimal patient outcomes. Lifelong hormone supplementation of the deficient gland is generally required.”

In the paper

“While ICI-induced endocrinopathies are rarely fatal, these conditions can have dramatic effects on patients’ quality of life, and initiation of hormone therapy often markedly improves their sense of well-being.”

In the paper

“Symptoms typically present within 6 months of ICI initiation, but the timing of onset is quite unpredictable, and may arise any time on therapy or even several months after therapy discontinuation”

In the paper

“whereas hypothyroidism is usually accompanied by mild symptoms, cases of diabetes mellitus have proven fatal when presenting in diabetic ketoacidosis (DKA).”

In the paper

“has been increasing in recognition and diagnosis.66”

What the sources say

• Not checked yetcites [66] Min, L., Vaidya, A. & Becker, C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur. J. Endocrinol. 164, 303–307 (2011). source

In the paper

“Any type of irAE occurs in 80-90% of patients, with higher grade events (as categorized by the Common Terminology Criteria for Adverse Events) occurring in 15-20% of patients treated with anti-PD-1/PD-L1 monotherapy, and up to 60% of patients treated with combination of ipilimumab and nivolumab.9”

What the sources say

• Not checked yetcites [9] Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018). source

In the paper

“The combination of ipilimumab and nivolumab has demonstrated enhanced response rates in melanoma, lung cancer, renal cell carcinoma, and mismatch repair deficient colon cancer compared with single agent therapy, although at a cost of increased toxicities (see next section).9–11”

What the sources say

• Not checked yetcites [9] Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018). source
• Not checked yetcites [10] Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010). source
• Not checked yetcites [11] Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015). source

In the paper

“other suggested a potentially causative role of Epstein-Barr Virus infection or reactivation in a case of ICI-encephalitis.20”

What the sources say

• Not checked yetcites [20] Berner, F. et al. Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer. JAMA Oncol. 5, 1043–1047 (2019). source

In the paper

“It should be noted, however, that all treatment for irAEs are based on expert-opinion and clinical-judgment rather than large-scale clinical trials or high level evidence.”

In the paper

“Median time to presentation is 9-12 weeks into treatment for ipilimumab-treated patients (monotherapy or combination) and 26 weeks into treatment for anti-PD-1/PD-L1.61”

What the sources say

• Not checked yetcites [61] Kurimoto, C. et al. Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors. Cancer Sci. 111, 1468–1477 (2020). source

In the paper

“The targets of ICI (CTLA-4, PD-1, and PD-L1) are key regulators of immune tolerance, and prevent autoimmunity in the physiologic state.”

In the paper

“A low morning cortisol (< 5 mcg/dL) and low ACTH are indicative of secondary adrenal insufficiency, with low TSH and low free T4 indicative of secondary hypothyroidism, and low sex hormones, FSH, and LH indicative of secondary hypogonadism.”

In the paper

“Normal brain imaging does not rule out hypopituitarism/hypophysitis, however.”

In the paper

“Another study using large scale autoantibody screening identified autoantibodies targeting guanine nucleotide-binding protien G(olf) subunit alpha (GNAL) and integral membrane protein 2B (ITM2B) in the serum of a patient who developed hypophysitis; further study revealed that these proteins were expressed in the pituitary gland.60”

What the sources say

• Not checked yetcites [60] Koyama, J. et al. Correlation between thyroid transcription factor-1 expression, immune-related thyroid dysfunction, and efficacy of anti-programmed cell death protein-1 treatment in non-small cell lung cancer. J. Thorac. Dis. 11, 1919–1928 (2019). source

In the paper

“pituitary glands expressed CTLA-4 in a subset of these cells, which were targets for CTLA-4 antibody binding, and resulted in complement deposition.”

What the sources say

• Not checked yetcites [59] Toi, Y. et al. Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer. JAMA Oncol. 5, 376–383 (2019). source

In the paper

“Ipilimumab (anti-CTLA-4) was the first approved ICI, receiving approval in 2011. Substantial clinical activity was observed primarily in melanoma, producing approximately 15-20% response rates, with 20% long-term survival, persisting even 10 years beyond treatment.7”

What the sources say

• Not checked yetcites [7] Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018). source

In the paper

“Although the general mechanisms of toxicity are understood (removal of self-tolerance and activation of T cells), the specific mechanisms of individual toxicities in particular patients are only beginning to be unraveled.”

In the paper

“One study suggested that ICI-colitis correlated with particular strains of microbial flora colonization,19”

What the sources say

• Not checked yetcites [19] Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019). source

In the paper

“These symptoms are commonly related to neuro-compression, including headache, nausea, emesis, diplopia, and visual field defects, or more often, to secondary adrenal insufficiency including fatigue and nausea.”

In the paper

“Male gender and older age may be risk factors although this has only been observed in one small series.58”

What the sources say

• Not checked yetcites [58] Kobayashi, T. et al. Patients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: a prospective study. J. Endocr. Soc. 2, 241–251 (2018). This paper provides clinical characterization of thyroiditis associated with ICIs, and demonstrates that high-dose steroids do not affect clinical outcomes. source

In the paper

“Anti-PD-1/PD-L1 agents pared with chemotherapy have also improved response rates and survival in many diseases including lung cancer, triple negative breast cancer, head and neck squamous cell carcinoma, and others.12–14”

What the sources say

• Not checked yetcites [12] Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017). source
• Not checked yetcites [13] Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019). source
• Not checked yetcites [14] Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018). source

In the paper

“Secondary hypothyroidism and secondary hypogonadism are also quite common (see Figure 4).”

In the paper

“Rarely, some events may be fatal, including ~0.35% of those treated with anti-PD-1/PD-L1, and 1.2% treated with combination therapy.24”

What the sources say

• Not checked yetcites [24] Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Invest. 128, 715–720 (2018). source

In the paper

“Pharmacologic blockade, therefore, can result in not only anti-tumor immunity, but autoinflammation at other sites, which clinically manifest as immune related adverse events.16”

What the sources say

• Not checked yetcites [16] Horn, L. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018). source

In the paper

“though glucose management may be more challenging in ICI-DM”

In the paper

“PD-L1 expression is increased in pancreatic beta cells of older mice and in mice with immune infiltration of their islets69,70”

What the sources say

• Not checked yetcites [69] Azmat, U., Liebner, D., Joehlin-Price, A., Agrawal, A. & Nabhan, F. Treatment of ipilimumab induced Graves’ disease in a patient with metastatic melanoma. Case Rep. Endocrinol. 2016, 2087525 (2016).
• Not checked yetcites [70] Iadarola, C. et al. Nivolumab induced thyroid dysfunction: unusual clinical presentation and challenging diagnosis. Front. Endocrinol. 9, 813 (2018). source

In the paper

“Approximately 40-50% of individuals with ICI-DM have detectable islet auto-antibodies at diagnosis, compared to >90% in T1D 64,65”

What the sources say

• Not checked yetcites [64] Yu, C., Chopra, I. J. & Ha, E. A novel melanoma therapy stirs up a storm: ipilimumab-induced thyrotoxicosis. Endocrinol. Diabetes Metab. Case Rep. 2015, 140092 (2015).
• Not checked yetcites [65] Yonezaki, K. et al. Combination therapy of ipilimumab and nivolumab induced thyroid storm in a patient with Hashimoto’s disease and diabetes mellitus: a case report. J. Med. Case Rep. 12, 171 (2018). source

In the paper

“The somewhat predictable onset (at least in a defined proportion of patients) of ICI related endocrine toxicities”