Multi-organ immune-related adverse events from immune checkpoint inhibitors and their downstream implications: a retrospective multicohort study.

BACKGROUND: Understanding co-occurrence patterns and prognostic implications of immune-related adverse events is crucial for immunotherapy management. However, previous studies have been limited by sample size and generalisability. In this study, we leveraged a multi-institutional cohort and a population-level database to investigate co-occurrence patterns of and survival outcomes after multi-organ immune-related adverse events among recipients of immune checkpoint inhibitors. METHODS: In this retrospective study, we identified individuals who received immune checkpoint inhibitors between May 31, 2015, and June 29, 2022, from the Massachusetts General Hospital, Brigham and Women's Hospital, and Dana-Farber Cancer Institute (Boston, MA, USA; MGBD cohort), and between April 30, 2010, and Oct 11, 2021, from the independent US population-based TriNetX network. We identified recipients from all datasets using medication codes and names of seven common immune checkpoint inhibitors, and patients were excluded from our analysis if they had incomplete information (eg, diagnosis and medication records) or if they initiated immune checkpoint inhibitor therapy after Oct 11, 2021. Eligible patients from the MGBD cohort were then propensity score matched with recipients of immune checkpoint inhibitors from the TriNetX database (1:2) based on demographic, cancer, and immune checkpoint inhibitor characteristics to facilitate cohort comparability. We applied immune-related adverse event identification rules to identify patients who did and did not have immune-related adverse events in the matched cohorts. To reduce the likelihood of false positives, patients diagnosed with suspected immune-related adverse events within 3 months after chemotherapy were excluded. We performed pairwise correlation analyses, non-negative matrix factorisation, and hierarchical clustering to identify co-occurrence patterns in the MGBD cohort. We conducted landmark overall survival analyses for patient clusters based on predominant immune-related adverse event factors and calculated accompanying hazard ratios (HRs) and 95% CIs, focusing on the 6-month landmark time for primary analyses. We validated our findings using the TriNetX cohort. FINDINGS: We identified 15 246 recipients of immune checkpoint inhibitors from MGBD and 50 503 from TriNetX, of whom 13 086 from MGBD and 26 172 from TriNetX were included in our propensity score-matched cohort. Median follow-up durations were 317 days (IQR 113-712) in patients from MGBD and 249 days (91-616) in patients from TriNetX. After applying immune-related adverse event identification rules, 8704 recipients of immune checkpoint inhibitors were retained from MGBD, of whom 3284 (37·7%) had and 5420 (62·3%) did not have immune-related adverse events, and 18 162 recipients were retained from TriNetX, of whom 5538 (30·5%) had and 12 624 (69·5%) did not have immune-related adverse events. In both cohorts, positive pairwise correlations of immune-related adverse events were commonly observed. Co-occurring immune-related adverse events were decomposed into seven factors across organs, revealing seven distinct patient clusters (endocrine, cutaneous, respiratory, gastrointestinal, hepatic, musculoskeletal, and neurological). In the MGBD cohort, the patient clusters that predominantly had endocrine (HR 0·53 [95% CI 0·40-0·70], p<0·0001) and cutaneous (0·61 [0·46-0·81], p=0·0007) immune-related adverse events had favourable overall survival outcomes at the 6-month landmark timepoint, while the other clusters either had unfavourable (respiratory: 1·60 [1·25-2·03], p=0·0001) or neutral survival outcomes (gastrointestinal: 0·86 [0·67-1·10], p=0·23; musculoskeletal: 0·97 [0·78-1·21], p=0·78; hepatic: 1·20 [0·91-1·59], p=0·19; and neurological: 1·30 [0·97-1·74], p=0·074). Similar results were found in the TriNetX cohort (endocrine: HR 0·75 [95% CI 0·60-0·93], p=0·0078; cutaneous: 0·62 [0·48-0·82], p=0·0007; respiratory: 1·21 [1·00-1·46], p=0·044), except for the neurological cluster having unfavourable (rather than neutral) survival outcomes (1·30 [1·06-1·59], p=0·013). INTERPRETATION: Reliably identifying the immune-related adverse event cluster to which a patient belongs can provide valuable clinical information for prognosticating outcomes of immunotherapy. These insights can be leveraged to counsel patients on the clinical impact of their individual constellation of immune-related adverse events and ultimately develop more personalised surveillance and mitigation strategies. FUNDING: US National Institutes of Health.

Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear. OBJECTIVE: To investigate the association of cirAEs with survival among ICI recipients. METHODS: ICI recipients were identified from the Mass General Brigham healthcare system and Dana-Farber Cancer Institute. Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival. RESULTS: Of the 3731 ICI recipients, 18.1% developed a cirAE. Six-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (hazardratio [HR] = 0.87, P = .027), particularly in patients with melanoma (HR = 0.67, P = .003). Among individual morphologies, lichenoid eruption (HR = 0.51, P < .001), psoriasiform eruption (HR = 0.52, P = .005), vitiligo (HR = 0.29, P = .007), isolated pruritus without visible manifestation of rash (HR = 0.71, P = .007), acneiform eruption (HR = 0.34, P = .025), and non-specific rash (HR = 0.68, P < .001) were significantly associated with better survival after multiple comparisons adjustment. LIMITATIONS: Retrospective design; single geography. CONCLUSION: CirAE development is associated with improved survival among ICI recipients, especially patients with melanoma.

Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy.

BACKGROUND: Emerging evidence suggests that cutaneous immune-related adverse events (cirAEs) are associated with a survival benefit in the setting of advanced melanoma treated with immune checkpoint inhibitor (ICI) therapy. Previous studies have not examined the role of melanoma subtypes on cirAE development and downstream therapeutic outcomes. OBJECTIVE: Examine the impact of melanoma subtypes on cirAE onset and survival among ICI recipients. METHODS: Retrospective multi-institutional cohort study. Multivariate time-series regressions were utilized to assess relationships between melanoma subtype, cirAE development, and survival. RESULTS: Among 747 ICI recipients, 236 (31.6%) patients developed a cirAE. Patients with acral melanoma were less likely to develop a cirAE (hazard ratio [HR] = 0.41, P = .016) compared to patients with nonacral cutaneous melanoma. Across all melanoma subtypes, cirAEs were associated with reduced mortality (HR = 0.76, P = .042). Patients with acral (HR = 2.04, P = .005), mucosal (HR = 2.30, P < .001), and uveal (HR = 4.09, P < .001) primaries exhibited the worst survival. LIMITATIONS: Retrospective cohort study. CONCLUSION: This is the first study to demonstrate differences in cirAE development among melanoma subtypes. The presence of cirAEs was associated with better survival. Further, the lower incidence of cirAEs may be a marker of immunotherapy response, which is reflected in the association between acral melanoma and mortality.

Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: a multi-institutional cohort study.

Background: Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear. Objective: To investigate the association of cirAEs with survival among ICI recipients. Methods: ICI recipients were identified from the Mass General Brigham healthcare system (MGB) and Dana-Farber Cancer Institute (DFCI). Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival. Results: Of the 3,731 ICI recipients, 18.1% developed a cirAE. 6-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (HR=0.87,p=0.027), particularly in melanoma patients (HR=0.67,p=0.003). Among individual morphologies, lichenoid eruption (HR=0.51,p<0.001), psoriasiform eruption (HR=0.52,p=0.005), vitiligo (HR=0.29,p=0.007), isolated pruritus without visible manifestation of rash (HR=0.71,p=0.007), acneiform eruption (HR =0.34,p=0.025), and non-specific rash (HR=0.68, p<0.001) were significantly associated with better survival after multiple comparisons adjustment. Limitations: Retrospective design; single geography. Conclusion: CirAE development is associated with improved survival among ICI recipients, especially melanoma patients. Capsule Summary: Patients on immune checkpoint inhibitors (ICIs) who developed cutaneous immune-related adverse events (cirAEs) had favorable outcomes. This was especially notable for melanoma patients who had cirAEs, both those with vitiligo and other morphologies.Development of cirAEs in ICI-treated patients can be used to prognosticate survival and guide treatment decisions.

Real-world incidence and impact of pneumonitis in patients with lung cancer treated with immune checkpoint inhibitors: a multi-institutional cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts. METHODS: A combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP. RESULTS: The attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1-7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71). CONCLUSIONS: In a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.

Association of Cutaneous Immune-Related Adverse Events With Increased Survival in Patients Treated With Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Therapy.

IMPORTANCE: Despite the efficacy of immune checkpoint inhibitors (ICIs), cutaneous immune-related adverse events (cirAEs) occur in 20% to 40% of all treated patients. To our knowledge, little is known about the predictive value of these cutaneous eruptions and their subtypes regarding cancer survival. OBJECTIVE: To determine the association of developing cirAEs following treatment with anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) therapy with patient survival. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from the TriNetX Diamond Network, a database of health records and claims data from more than 200 million US and European patients, to conduct a population-level cohort analysis. The study included 7008 eligible patients who developed cirAEs after treatment with anti-PD-1 or anti-PD-L1 therapy for malignant neoplasms of digestive organs, bronchus or lung, melanoma of skin, and urinary tract who were identified through the TriNetX Diamond Network along with 7008 matched controls. EXPOSURES: Development of cirAEs within 6 months following anti-PD-1 or anti-PD-L1 therapy. MAIN OUTCOMES AND MEASURES: A 6-month analysis using a Cox proportional hazards model was performed to determine the association of cirAEs with overall survival after adjusting for demographic characteristics, cancer type, and cancer stage. RESULTS: A total of 7008 patients (3036 women [43.3%]; mean [SD] age, 68.2 [11.2] years) were matched to 7008 (3044 women [43.4%]; mean [SD] age, 68.3 [11.1] years) controls. Pruritus (hazard ratio [HR], 0.695; 95% CI, 0.602-0.803; P < .001), drug eruption (HR, 0.755; 95% CI, 0.635-0.897; P = .001), xerosis (HR, 0.626; 95% CI, 0.469-0.834; P = .001), nonspecific rashes (HR, 0.704; 95% CI, 0.634-0.781; P < .001), and appearance of any cirAE (HR, 0.778; 95% CI, 0.726-0.834; P < .001) were significantly protective of mortality using a Benjamini-Hochberg correction with a significance level of .05. Additionally, psoriasis (HR, 0.703; 95% CI, 0.497-0.994; P = .045) and lichen planus/lichenoid dermatitis (HR, 0.511; 95% CI, 0.279-0.939; P = .03) were significant. Eczematous dermatitis (HR, 0.612; 95% CI, 0.314-1.195), vitiligo (HR, 0.534; 95% CI, 0.254-1.123), bullous pemphigoid (HR, 0.524; 95% CI, 0.140-1.956), and Grover disease (HR, 0.468; 95% CI, 0.115-1.898) were all associated with strong protective clinical effects. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that the development of cirAEs is strongly associated with response to ICI therapy and patient survival.

Surgeons' Views on Shared Decision-Making.

PURPOSE: Shared decision-making (SDM) has a significant role in surgical encounters, where decisions are influenced by both clinician and patient preferences. Herein, we sought to explore surgeons' practices and beliefs about SDM. METHODS: We performed a qualitative study consisting of semi-structured individual interviews with 18 surgeons from private practice and academic surgery practices in Baltimore, Maryland. We purposively sampled participants to maximize diversity of practice type (academic vs private), surgical specialty, gender, and experience level. Interview topics included benefits and challenges to patient involvement in decision-making, communicating uncertainty to patients, and use of decision aids. Interviews were audio-recorded and transcribed. Transcripts were analyzed using content analysis to identify themes. RESULTS: Surgeons were supportive of patients being involved in decision-making, particularly in cases with uncertainty about treatment options. However, surgeons identified SDM as being more appropriate for patients whom surgeons perceived as interested in decision-making involvement and for decisions in which surgeons did not have strong preferences. Additionally, surgeons reported typically presenting only a subset of available options, remaining confident in their ability to filter less suitable options based on intuitive risk assessments. Surgeons differed in their approach to making recommendations, with some guiding patients towards what they saw as the correct or optimal decision while others sought to maintain neutrality and support of the patients' chosen decision. CONCLUSIONS: Many surgeons do not believe SDM is universally optimal for every surgical decision. They instead use assessments of patient disposition or potential clinical uncertainty to guide their perceived appropriateness of using SDM.

Biomechanical interplay between anisotropic re-organization of cells and the surrounding matrix underlies transition to invasive cancer spread.

The root cause of cancer mortality and morbidity is the metastatic spread of the primary tumor, but underlying mechanisms remain elusive. Here we investigate biomechanical interactions that may accompany invasive spread of melanoma cells. We find that metastatic cells can exert considerable traction forces and modify local collagen organization within a 3D matrix. When this re-organization is mimicked using a nano-fabricated model of aligned extracellular matrix fibers, metastatic cells, including less invasive melanoma cells, were in turn induced to align, elongate and migrate, guided by the local ridge orientations. Strikingly, we found that this aligned migration of melanoma cells was accompanied by long-range regulation of cytoskeletal remodeling that show anisotropic stiffening in the direction of fiber orientation suggestive of a positive feedback between ECM fiber alignment and forces exerted by cancer cells. Taken together, our findings suggest that the invasive spread of cancer cells can be defined by complex interplay with the surrounding matrix, during which they both modify the matrix and use the matrix alignment as a persistent migration cue, leading to more extensive and rapid invasive spread.