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Investigating the Impact of Immune-Related Adverse Events, Glucocorticoid Use and Immunotherapy Interruption on Long-Term Survival Outcomes.

ABSTRACT: It remains unclear whether immune-related adverse events (irAEs) and glucocorticoid use could impact long-term outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective unicentric study. The objectives were to assess the impact of grade ≥3 irAEs, glucocorticoid use and the interruption of immunotherapy on progression-free survival (PFS) and overall survival (OS). In this 828-patient cohort, the first occurrence of grade ≥3 irAEs had no significant impact on PFS or OS. Glucocorticoid administration for the irAEs was associated with a significantly shorter PFS (adjusted HR 3.0; p = 0.00040) and a trend toward shorter OS. ICI interruption was associated with a significantly shorter PFS (adjusted HR 3.5; p < 0.00043) and shorter OS (HR 4.5; p = 0.0027). Glucocorticoid administration and ICI interruption were correlated. In our population of patients treated with single agent ICI, grade ≥3 irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade ≥3 irAEs reported in other studies might then be explained by the management of the irAEs.

SUBMITTER: Bruyere CL

PROVIDER: S-EPMC8156819 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION:Objective response rates (ORR) appear to be higher in melanoma patients who develop immune-related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown. MATERIALS AND METHODS:Patients with advanced melanoma treated with single-agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti-programmed cell death protein 1 (PD-1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression-free survival (PFS) and ORR. RESULTS:Among 186 patients, any-grade and grade ?3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12?weeks, the median follow-up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p = .006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p = .001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ?3 irAEs and no grade ?3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p = .001), whereas each additional cycle of treatment received (HR, 0.94; p <?.001) and development of grade ?3 irAEs (HR, 0.29, p = .024) were significantly associated with longer OS. CONCLUSION:Anti-PD-1-associated grade ?3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival. IMPLICATIONS FOR PRACTICE:Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population-based real-world study in advanced melanoma reports an association with anti-programmed cell death protein 1 (PD-1)-induced grade ?3 immune-related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD-1-directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes.

Project description:BackgroundThe development and rapid uptake of immune checkpoint inhibitors (CPI) has changed the outlook for patients with cancer. However, CPIs have different adverse event (AE) profiles to other systemic therapies, and prompt AE management is essential to assure optimal outcomes. In order to understand what and when adverse events are experienced, reported and managed during CPI treatment, a mixed methods study was conducted, including a case note review of patients who were receiving immunotherapy and semi-structured interviews with patients to understand their experience, management and reporting of AEs after receiving immune CPI treatment.MethodsThis mixed methods study was conducted at a large cancer hospital in the United Kingdom. A case note review identified how and where patients reported AEs. Data relating to patients with lung, bladder, prostate and head & neck cancers who received CPI treatment between 01/04/2015 and 31/07/2018 were extracted from e-prescribing databases and clinical data were included for analysis at a single time point (31 July 2018). Semi-structured interviews were conducted with patients receiving CPI treatment, exploring experience of AEs and reasons for delays in AE reporting and management.ResultsSixty-two patients were included in the case note review, with 78 AEs being experienced by 36 patients (58%), including one patient experiencing 10 AEs. Serious AEs were experienced by 12 patients (19%) and ten AEs (17%) required oral steroids as treatment. The majority of AEs were reported to clinicians prior to further dosing, although milder AEs were often not addressed until subsequent clinic appointments. Interviews with 13 patients yielded major themes: variability, causality, decision making and impact.ConclusionMost CPI-associated AEs are manageable if reported and treated promptly. Both the case note review and interviews found that reporting of non-serious AEs is often left until routine clinic visits, despite impacting patient experience, leaving the opportunity for AEs to be left unreported and implying a potential benefit for real time monitoring. Our study highlights a need to provide patients with reminders around AEs and their timely reporting even when apparently innocuous; patients must understand that AEs can occur at any cycle and even following treatment completion.

Project description:Background The long-term effectiveness of atherectomy treatment for peripheral arterial disease is unknown. We studied 5-year clinical outcomes by endovascular treatment type among patients with peripheral arterial disease. Methods and Results We queried the Medicare-linked VQI (Vascular Quality Initiative) registry for endovascular interventions from 2010 to 2015. The exposure was treatment type: atherectomy (with or without percutaneous transluminal angioplasty [ PTA] ), stent (with or without PTA ), or PTA alone. The outcomes were major amputation, any amputation, and major adverse limb event (major amputation or any reintervention). We used the center-specific proportions of atherectomy procedures performed in the 12 months before a patient's procedure as the instruments to perform an instrumental-variable Cox model analysis. Among 16 838 eligible patients (median follow-up: 1.3-1.5 years), 11% underwent atherectomy, 40% received PTA alone, and 49% underwent stenting. Patients receiving atherectomy commonly underwent femoropopliteal artery treatment (atherectomy: 65%; PTA : 49%; stenting: 43%; P<0.001) and had worse disease severity (Trans-Atlantic Inter-Society Consensus score [TASC] B and greater; atherectomy: 77%; PTA : 68%; stenting: 67%; P<0.001). The 5-year rate of major adverse limb events was 38% in patients receiving atherectomy versus 33% for PTA and 32% for stenting (log rank P<0.001). Controlling for unmeasured confounding using instrumental-variable analysis, patients treated with atherectomy experienced outcomes similar to those of patients treated with PTA , except for a higher risk of any amputation (hazard ratio: 1.51; 95% CI , 1.08-2.13). However, compared with stenting, atherectomy patients had a higher risk of major amputation (hazard ratio: 3.66; 95% CI , 1.72-7.81), any amputation (hazard ratio: 2.73; 95% CI , 1.60-4.76), and major adverse limb event (hazard ratio: 1.61; 95% CI , 1.10-2.38). Conclusions Atherectomy is used to treat severe femoropopliteal and tibial peripheral arterial disease even though long-term adverse outcomes occur more frequently after this treatment modality.

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Investigating the Impact of Immune-Related Adverse Events, Glucocorticoid Use and Immunotherapy Interruption on Long-Term Survival Outcomes.

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