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New anti-cancer therapeutics have been developed in the recent years and dramatically change prognosis and patient management. Either used alone or in combination, immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD1/PD-(L)1, act by removing T-cell inhibition to enhance their antitumor response. This change in therapeutic targets leads to a break in immune-tolerance and a unique toxicity profile resulting in immune complications. These side effects, called Immune-Related Adverse Events (IrAEs), can affect all organs, with a wide range of clinical and biological presentations and severity. Various rheumatic and musculoskeletal manifestations have been reported in the literature, ranging from mild arthralgia, polymyalgia rheumatica, to genuine serodefined rheumatoid arthritis and myositis. Tolerance studies suggest some correlations between IrAEs occurrence and tumor response. Assessment of patient musculoskeletal status prior to the start of the ICI is warranted. Management of rheumatic IrAEs does not usually request ICI discontinuation, exception for myositis or very severe forms where it should be discussed. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs) or low dose glucocortioids (

The immune checkpoint inhibitors (CPI) such as anti-PD(L)1 or anti-CTLA4 had improved long-term patients' outcomes in different malignancies. Thyroid disorders are the most frequent endocrine side effects from CPI reported in clinical trials and in clinical routine practice. The incidence of thyroid dysfunction is variable according to ICP used (more frequent under anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1)). Most thyroid dysfunctions have been reported to occur 2 to 4 courses after CPI initiation. The clinical symptoms are generally nonspecific (asthenia, weight change, rarely cardiac rhythm disorder). These thyroid dysfunctions are commonly painless thyroiditis with a biphasic evolution: thyrotoxicosis followed by a secondary hypothyroidism frequently definitive. Diagnosis is made on a thyroid test (TSH and FT4). In most cases, no further exam is necessary. Beta blockers therapy is recommended in symptomatic thyrotoxicosis with palpitations. Thyroid hormones therapy will be introduced quickly in case of hypothyroidism. Thyroid dysfunctions are not a contra-indication to the continuation of immunotherapy. Due to the high frequency of these complications, close monitoring of the thyroid status is recommended under CPI.

Immunotherapy (IO) with checkpoint inhibitors with or without anti-angiogenic tyrosine kinase inhibitor (TKI)-based combinations have demonstrated superior efficacy over sunitinib for treatment-naive patients with metastatic clear-cell renal cell carcinoma (mRCC). Four of these combinations (nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and pembrolizumab plus lenvatinib) represent new front-line standard-of-care options for mRCC patients, according to the International Metastatic RCC Database Consortium (IMDC) subgroups. Questions over the optimal treatment between IO-IO or IO-TKI combinations for mRCC patients in intermediate/poor IMDC risk groups and the optimal IO-TKI regimen for all IMDC risk groups remain unanswered. This review will focus on the biological pathways that have driven the hypothesis of a synergistic combination of such agents and their efficacy results, with consideration of response and survival outcomes in the overall population of phase three pivotal trials as well as in specific subgroups of interest.

Checkpoint inhibitors immunotherapy is more and more prescribed in oncology, causing new immune related endocrine adverse events. Hypophysitis occurs in approximately 10 % of patients treated with anti-CTLA4. It occurs two to three months after initiation of the immunotherapy. The initial presentation is characterized, in typical forms, by the association of headache, asthenia and hyponatremia. Hormonal exploration usually shows ACTH, gonadotropic and thyrotropic deficiencies. ACTH deficiency may be life-threatening and requires urgent supplementation, without awaiting for biological results. MRI is warranted in order to exclude differential diagnoses, such as pituitary metastases. Hypophysitis induced by anti-PD1/PDL1 seems to be a different nosologic entity characterized by a later onset and a less symptomatic presentation. Biologically ACTH deficiency seems to be constant and permanent, and often isolated. Treatment requires high-dose steroids only in case of severe tumor syndrome (resistant headache, visual disturbance) or acute decompensation of ACTH deficiency. Patients always need lifelong hormonal supplementation of pituitary deficits and must be followed and educated specifically. Immunotherapy can be delayed during the acute phase, but can be secondarily continued if there is an oncological benefit. As it is a pauci-symptomatic but potentially life-threatening complication, biological screening must be systematic in patients treated with checkpoint inhibitors.

New anti-cancer therapeutics have been developed in the recent years and dramatically change prognosis and patient management. Either used alone or in combination, immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD1/PD-(L)1, act by removing T-cell inhibition to enhance their antitumor response. This change in therapeutic targets leads to a break in immune-tolerance and a unique toxicity profile resulting in immune complications. These side effects, called Immune-Related Adverse Events (IrAEs), can affect all organs, with a wide range of clinical and biological presentations and severity. Various rheumatic and musculoskeletal manifestations have been reported in the literature, ranging from mild arthralgia, polymyalgia rheumatica, to genuine serodefined rheumatoid arthritis and myositis. Tolerance studies suggest some correlations between IrAEs occurrence and tumor response. Assessment of patient musculoskeletal status prior to the start of the ICI is warranted. Management of rheumatic IrAEs does not usually request ICI discontinuation, exception for myositis or very severe forms where it should be discussed. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs) or low dose glucocortioids (20mg per day). Dose should be adjusted according to severity. The use of disease modifying anti-rheumatic drugs (DMARDs), either conventional and/or biological should be very cautious and result from a shared decision between oncologist and rheumatologist to best manage dysimmunitary complications without hampering the antitumor efficacy of ICI.

The immune checkpoint inhibitors (CPI) such as anti-PD(L)1 or anti-CTLA4 had improved long-term patients' outcomes in different malignancies. Thyroid disorders are the most frequent endocrine side effects from CPI reported in clinical trials and in clinical routine practice. The incidence of thyroid dysfunction is variable according to ICP used (more frequent under anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1)). Most thyroid dysfunctions have been reported to occur 2 to 4 courses after CPI initiation. The clinical symptoms are generally nonspecific (asthenia, weight change, rarely cardiac rhythm disorder). These thyroid dysfunctions are commonly painless thyroiditis with a biphasic evolution: thyrotoxicosis followed by a secondary hypothyroidism frequently definitive. Diagnosis is made on a thyroid test (TSH and FT4). In most cases, no further exam is necessary. Beta blockers therapy is recommended in symptomatic thyrotoxicosis with palpitations. Thyroid hormones therapy will be introduced quickly in case of hypothyroidism. Thyroid dysfunctions are not a contra-indication to the continuation of immunotherapy. Due to the high frequency of these complications, close monitoring of the thyroid status is recommended under CPI.