Immune-related adverse events requiring hospitalization in patients with lung cancer: implications and insights.

BACKGROUND: Immune checkpoint inhibitors (ICI) are associated with a distinct spectrum of toxicities. Data on irAE hospitalization rates and clinical course of patients with thoracic malignancies are lacking. METHODS: Patients with advanced thoracic malignancy treated with ICI (2/2016 to 6/2021) were retrospectively identified. Demographic and clinical data of confirmed irAE hospitalizations were extracted from the medical record and a descriptive analysis was performed. RESULTS: From February 2016 to June 2021, 1312 patients with thoracic malignancy received ICI (monotherapy, combination with 2nd ICI or other agents) with 102 patients (7.7%) hospitalized for irAEs. Treatment intent was first-line therapy in most patients (N = 50, 49%) with 9% (n = 9) receiving adjuvant ICI (N = 9). Sixty patients (59%) received ICI alone, 32% (N = 33) chemo plus immunotherapy, and 7% (N = 7) dual ICI. The median age on admission was 68 years. The median time between ICI initiation and admission was 64 days (1-935 days). Pneumonitis (32.3%; 33/102) was the most frequent indication for admission followed by gastroenterocolitis (19.6%; 20/102), hepatitis (12.7%; 13/102), myo/pericarditis (9.8%; 10/102), and endocrinopathies (9.8%; 10/102). Multi-organ toxicity occurred in 36% (N = 37) of patients. Overall, 85.2% (87/102) of patients received systemic corticosteroids and 17.6% (18/102) required additional lines of immunosuppression. The median length of hospitalization stay was 7 days (2-28 days) with a 25.5% (n = 26) readmission rate within 60 days and an 11.8% (n = 12) in house mortality rate. CONCLUSIONS: Severe irAE requiring inpatient admission, although infrequent, results in considerable morbidity, mortality, and healthcare utilization. Pneumonitis was the most common irAE requiring inpatient management in our patient population with a significant risk of mortality despite the use of guideline-directed systemic immunosuppression. This study highlights the continued need for collaborative efforts amongst medical specialties for improving the diagnostic and therapeutic management of patients with irAEs.

Toxicities from BRAF and MEK Inhibitors: Strategies to Maximize Therapeutic Success.

PURPOSE OF REVIEW: This report highlights several of the recent therapeutic advancements in the treatment of BRAF-mutant tumors, discusses the most common adverse events observed with BRAF-targeted agents, and suggests strategies to manage and mitigate treatment-related toxicities. RECENT FINDINGS: BRAF and MEK inhibitors represent a significant advancement in the treatment of BRAF-mutated malignancies with data across tumor types demonstrating the anti-tumor efficacy of dual MAPK inhibition. Although these agents have a reasonable toxicity profile, variable side effects across organ systems can develop. The discovery of activating BRAF mutations and subsequent development of BRAF and MEK inhibitors has transformed the treatment algorithms of BRAF-mutant malignancies. With increased application of these targeted regimens, identification and prompt management of their unique adverse events are crucial.

Durvalumab After Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer.

Importance: The PACIFIC trial established consolidation durvalumab as the standard of care following chemoradiotherapy (CRT) for patients with unresectable stage III non-small cell lung cancer (NSCLC). Understanding its benefit in routine US clinical practice is critical. Objective: To report characteristics, treatment patterns, and outcomes of patients who did or did not receive durvalumab. Design, Setting, and Participants: Two prespecified cohorts were curated in this retrospective cohort study (SPOTLIGHT). Deidentified patient-level data from a US database (Flatiron Health) were analyzed. Patients had unresectable stage III NSCLC, were diagnosed on or after January 1, 2011, had 2 or more visits on or afterward, and received CRT. Data were analyzed from May 2021 to October 2023. Exposures: Patients started durvalumab after CRT (durvalumab cohort) or ended CRT without durvalumab (nondurvalumab cohort) by June 30, 2019, to allow 15 or more months of follow-up from CRT end. Main Outcomes and Measures: End points included progression-free survival (PFS), overall survival (OS), time to first subsequent therapy or death (TFST), and time to distant metastasis or death (TTDM). Results: The durvalumab cohort included 332 patients (median [IQR] age, 67.5 [60.8-74.0] years; 187 were male [56.3%], 27 were Black [8.7%], 33 were other races [10.7%], and 249 were White [80.6%]) and the nondurvalumab cohort included 137 patients (median (IQR) age, 70.0 [64.0-75.0] years; 89 [65.0%] were male, 11 [8.9%] were Black, 19 [15.4%] were other races, and 93 [75.6%] were White). Most patients had a smoking history (durvalumab, 316 patients [95.2%] and nondurvalumab, 132 patients [96.4%]) and Eastern Cooperative Oncology Group performance status 0 through 1 (durvalumab, 251 patients [90.9%] and nondurvalumab, 88 patients [81.5%]). Median (IQR) CRT duration was 1.6 (1.4-1.8) months for the durvalumab cohort and 1.5 (1.4-1.8) months for the nondurvalumab cohort. Median time to durvalumab discontinuation was 9.5 months (95% CI, 7.8-10.6 months). Median TFST and TTDM were not reached (NR) in the durvalumab cohort and 8.3 months (95% CI, 4.8-11.8 months) and 11.3 months (95% CI, 6.4-14.5 months), respectively, in the nondurvalumab cohort. Median PFS and OS were 17.5 months (95% CI, 13.6-24.8 months) and NR in the durvalumab cohort and 7.6 months (95% CI, 5.2-9.8 months) and 19.4 months (95% CI, 11.7-24.0 months) in the nondurvalumab cohort. In Cox regression analyses of patients who completed concurrent CRT without progression, durvalumab was associated with a lower risk of progression or death (hazard ratio [HR], 0.36; 95% CI, 0.26-0.51) and lower risk of death (HR, 0.27; 95% CI, 0.16-0.43), adjusted for prior platinum agent and patient characteristics. Conclusions and Relevance: In this cohort study, findings were consistent with PACIFIC, and durvalumab was associated with a lower risk of progression and/or death. Further investigation is warranted to explain why patients did not receive durvalumab after its approval.

Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy.

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

Multicenter Evaluation of Radiation and Immune Checkpoint Inhibitor Therapy in Mucosal Melanoma and Review of Recent Literature.

Purpose: Optimal integration of local therapy and systemic immune therapy for patients with mucosal melanoma (MM) is uncertain. We evaluated treatment patterns and outcomes following radiation therapy (RT) in combination with immune checkpoint inhibition (ICI) in MM. Methods and Materials: Thirty-seven patients with localized (n = 32, 87%) or node-positive (n = 5, 14%) MM were treated across 4 institutions with RT to the primary tumor with or without oncologic resection (n = 28, 76%) and ICI from 2012 to 2020. Recurrence rates were estimated using cumulative incidence in the presence of the competing risk of death. Results: Mucosal sites were head/neck (n = 29, 78%), vaginal (n = 7, 19%), and anorectal (n = 1, 3%). Patients received ICI prior to or concurrent with RT (n = 14, 38%), following RT (n = 5, 14%), or at recurrence (n = 18, 49%). The objective response rate for evaluable patients was 31% for ICI as initial treatment (95% CI, 11%-59%) and 19% for ICI at recurrence (95% CI, 4%-46%). Median follow-up was 26 months for living patients; median overall survival (OS) was 54 months (95% CI, 31 months-not reached). Two-year OS was 85%; distant metastasis-free survival 44%. The 2-year cumulative incidence of local recurrence (LR) was 26% (95% CI, 13%-41%). For 9 patients with unresectable disease, 2-year OS was 88% (95% CI, 35%-98%); LR was 25% (95% CI, 3%-58%). For 5 patients with positive nodes at diagnosis, 2-year OS was 100%; LR was 0%. Conclusions: High rates of local control were achieved with RT with or without oncologic resection and ICI for localized and locally advanced MM. In particular, favorable local control was possible even for patients with unresectable or node-positive disease. Although risk of distant failure remains high, patients with MM may benefit from aggressive local therapy including RT in the setting of immunotherapy treatment.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600- mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.