Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry

Higuita, Lina María Serna; Amaral, Teresa; Forschner, Andrea; Leiter, Ulrike; Flatz, Lukas; Seeber, Olivia; Thomas, Ioannis; Garbe, Claus; Eigentler, Thomas; Martus, Peter

doi:10.3390/cancers13236141

Cited by 14 publications

(17 citation statements)

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“…Longer mOS has been reported in melanoma patients treated with ICIs who presented toxicity compared to those who did not (21.9 vs. 9.7 m), respectively ( 31 ). Higher disease control rate has also been reported in patients with irAEs (69.8 vs. 49.3%) ( 32 ). In a real-world cohort including almost 200 patients, a greater OS and PFS was observed in melanoma patients who experienced irAEs than in those who did not, with reported data of NR vs. 9 m and 28 m vs. 5 m, respectively ( 33 ).…”

Section: Association Between Iraes and Prognosis In Solid Tumorsmentioning

confidence: 82%

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer

Iranzo

Callejo²,

Assaf³

et al. 2022

Front. Med.

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In recent years, immunotherapy-based regimens have been included into the treatment's algorithm of several cancer types. Programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) interact with their ligands found on the surface of antigen presenting cells (APC) or tumor cells (PD-L1/2 and CD80/86). Through these interactions, stimulatory or inhibitory signals are established. Immune checkpoint inhibitors (ICIs), block these interactions, and when administered not only as monotherapy but also as part of combination regimens, have shown to improve survival results in multiple advanced cancers leading to an increasing number of patients treated with ICI and, as a consequence, a rise in the number of patients developing immune-related adverse events (irAEs). Presence of irAEs has been associated with greater benefit from treatment, especially when blocking PD-L1. Recent data suggests that treatment benefit persists after discontinuation of ICIs due to a treatment related adverse event, regardless of the grade. Patients experiencing grade 3-4 irAEs are at risk of toxicity recurrence after reintroducing immunotherapy and therefore, the decision to resume the treatment is challenging. In these cases, a multidisciplinary approach is always needed and several factors should be considered. Management of severe toxicities may require systemic corticosteroids which can impact on T-cell function. Due to their immunosuppressive properties, it is necessary to deeper determine how corticosteroids influence responses. In terms of overall survival (OS), the use of steroids as therapy for irAEs seems not to reduce OS and several studies have reported durable responses in patients experiencing autoimmune toxicities treated with corticosteroids.

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Section: Association Between Iraes and Prognosis In Solid Tumorsmentioning

confidence: 82%

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer

Iranzo

Callejo²,

Assaf³

et al. 2022

Front. Med.

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“…Of the included studies, 46 were retrospective ( 13 – 17 , 32 , 34 , 35 , 39 , 41 , 43 – 52 , 54 , 55 , 57 , 59 – 72 , 74 – 78 , 82 – 85 ), 13 were prospective ( 18 , 33 , 36 – 38 , 40 , 53 , 56 , 58 , 73 , 79 – 81 ) (including four studies that extracted data from clinical trials ( 18 , 33 , 73 , 79 )), and one included both retrospective and prospective data ( 42 ). All included studies assessed the relationship between the presence of irAEs and prognosis (12 of them examined the effect of irAE grades ( 14 , 37 , 45 , 57 , 58 , 68 , 71 , 73 , 76 , 82 , 84 , 85 )), 18 studies assessed endocrine irAEs (any, thyroiditis, or hypophysitis) ( 32 , 34 , 44 , 46 – 48 , 51 , 55 , 56 , 60 , 68 – 70 , 73 , 76 , 78 , 81 , 85 ), five assessed pulmonary irAEs ( 32 , 34 , 46 ...…”

Section: Resultsmentioning

confidence: 99%

“…All included studies assessed the relationship between the presence of irAEs and prognosis (12 of them examined the effect of irAE grades ( 14 , 37 , 45 , 57 , 58 , 68 , 71 , 73 , 76 , 82 , 84 , 85 )), 18 studies assessed endocrine irAEs (any, thyroiditis, or hypophysitis) ( 32 , 34 , 44 , 46 – 48 , 51 , 55 , 56 , 60 , 68 – 70 , 73 , 76 , 78 , 81 , 85 ), five assessed pulmonary irAEs ( 32 , 34 , 46 , 56 , 76 ), 21 assessed skin irAEs (any, rash, or vitiligo) ( 32 , 34 , 38 , 40 , 42 , 46 – 48 , 51 , 53 , 54 , 56 , 62 – 64 , 73 , 74 , 76 , 79 , 81 , 85 ), nine assessed gastrointestinal irAEs (any, colitis, or diarrhea) ( 32 , 34 , 46 , 56 , 58 , 73 , 76 , 77 , 85 ), and five assessed hepatic irAEs ( 32 , 34 , 36 , 76 , 85 …”

Section: Resultsmentioning

confidence: 99%

“…A total of 57 studies included OS data ( 13 – 18 , 32 – 39 , 41 – 58 , 60 – 71 , 73 – 85 ) and 34 included PFS data ( 14 , 15 , 18 , 32 , 33 , 36 – 42 , 47 , 49 , 54 , 55 , 58 – 60 , 62 , 64 , 66 , 68 – 72 , 75 , 76 , 78 , 79 , 81 , 82 , 85 ). Geographically, 18 studies were from Asian countries ( 35 , 39 , 48 , 56 , 61 – 66 , 69 , 76 – 81 , 85 ), 24 from European countries ( 13 – 16 , 33 , 36 – 38 , 41 – 43 , 45 , 47 , 50 , 53 – 55 , 58 , 59 , 68 , 74 , 75 , 82 , 84 ), six from the United States ( 32 , 44 , 46 , 52 , 67 , 70 ...…”

Section: Resultsmentioning

confidence: 99%

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Patients with melanoma treated with immune checkpoint inhibitors who had non-thyroid endocrine and skin immune-related adverse events have better prognosis: A systematic review and meta-analysis

Sun

et al. 2022

Front. Oncol.

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BackgroundSeveral studies have reported an association between the occurrence of immune-related adverse events (irAEs) and prognosis in patients with melanoma treated with immune checkpoint inhibitors (ICIs), but the results remain controversial. We conducted a systematic review and meta-analysis to investigate the association between irAEs and survival in patients with melanoma treated with ICIs.MethodsWe searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases through May 5, 2022 for clinical studies evaluating the association between irAEs and in melanoma patients treated with ICIs. Combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were calculated using fixed- or random-effects models based on heterogeneity. ResultsA total of 60 articles were included, with 16,520 patients. In patients with melanoma treated with ICIs, the occurrence of irAEs was significantly associated with better OS (HR, 0.58; 95% confidence interval [CI], 0.51–0.66; P<0.00001) and PFS (HR, 0.61; 95%CI, 0.51–0.72; P<0.00001). Endocrine irAEs (OS, HR, 0.81; 95%CI, 0.72–0.92; P=0.001; PFS: HR, 0.84; 95%CI, 0.73–0.96, P=0.009), skin irAEs (OS, HR, 0.59; 95%CI, 0.41–0.85; P=0.004; PFS: HR, 0.43; 95%CI, 0.36–0.52; P<0.00001), vitiligo (OS, HR, 0.22; 95%CI, 0.15–0.31; P<0.00001; PFS, HR, 0.33; 95%CI, 0.25–0.44; P<0.00001), and grade 1–2 irAEs (OS, HR, 0.67; 95%CI, 0.58–0.78; P<0.00001; PFS, HR, 0.62; 95%CI, 0.51–0.76; P<0.00001) showed similar results. However, thyroid, lung, gastrointestinal, liver, and grade 3–4 irAEs were not significantly associated with OS and PFS. The occurrence of non-thyroid endocrine irAEs was significantly associated with better OS (HR, 0.22; 95%CI, 0.15–0.31; P<0.00001). In patients with melanoma treated with anti-programmed cell death protein 1 (OS, HR, 0.61; 95%CI, 0.51–0.72; P<0.00001; PFS, HR, 0.59; 95%CI, 0.47–0.74; P<0.00001), the association between irAEs and clinical benefit was clearer than in patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (OS, HR, 0.68; 95%CI, 0.52–0.89; P=0.005; PFS, HR, 0.93; 95%CI, 0.49–1.78; P=0.83).ConclusionAmong patients with melanoma treated with ICIs, those who developed non-thyroid endocrine irAEs and cutaneous irAEs have better prognosis. This suggests that non-thyroid endocrine irAEs and cutaneous irAEs may be a prognostic biomarker for patients with melanoma treated with ICIs.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022338308.

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“…Published data suggest that objective responses rates appear to be superior in ICI-treated patients who develop IrAEs. In a recent cohort study with 319 stage IV MM patients treated with first-line PD-1-based ICI, the presence of any grade IrAEs was significantly associated with longer OS and a higher percentage of patients with IrAEs had disease control compared to those without IrAEs [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups

Trommer

Adams

Celik

et al. 2022

Cancers

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While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184–3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059–3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285–3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112–3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309–0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271–0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299–0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253–6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288–0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm3 (HR 1.947 (1.007–3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose <60 Gy (p = 0.014), PTV > 3 cm3 (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naïve patients (p < 0.001), low NLR (p = 0.039), steroid intake ≤4 mg (p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.

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Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry

Cited by 14 publications

References 50 publications

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer

Patients with melanoma treated with immune checkpoint inhibitors who had non-thyroid endocrine and skin immune-related adverse events have better prognosis: A systematic review and meta-analysis

Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups

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