Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience

BackgroundCombination of T cell checkpoint blockade by CTLA-4- and PD-1-blockade is one of the most promising therapies in patients with advanced melanoma. It induces superior response rates when compared with single-agent therapy, but at the cost of a high percentage of grade 3 and 4 adverse events (AEs). This combination therapy was until July 2016 not available in the Netherlands, which prompted several physicians to treat patients with less than standard numbers of courses of ipilimumab followed directly by nivolumab or pembrolizumab.Patients and methodsIn this retrospective analysis, patients were included who were treated with two courses (day 0 and 21) anti-CTLA-4 (ipilimumab 3 mg/kg q3wk), directly followed by anti-PD-1 (starting at day 22 with nivolumab 3mg/kg q2wk or pembrolizumab 2 mg/kg q3wk). Data on treatment-related AEs were collected from electronic patient records and scored according to CTCAE 4.03 criteria. Overall response was evaluated using RECIST 1.1 for CT-scans and EORTC criteria for PET-scans.ResultsForty advanced melanoma patients could be included (29/40 pembrolizumab, 11/40 nivolumab). Median follow-up (FU) was 51 weeks (range: 4–63 weeks) with a minimum FU of 26 weeks. Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients. The best overall response rate (BORR) was 55% (95% CI 39–70) and disease control rate was 75% (95% CI 59–87). Ongoing responses were observed in 82% of responding patients.ConclusionTreatment with short-term CTLA-4 blockade directly followed by PD-1 blockade may have similar efficacy but potentially lower toxicity when compared with concurrent therapy with anti-CTLA-4 and anti-PD-1. These results warrant further investigation in a prospective randomized controlled clinical trial.     

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab

BackgroundAnti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.Patients and methodsPatients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.ResultsOne hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N=52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N=6) or neurological disorders (N=5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N=67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3–4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.ConclusionsIn melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.     

PD-1 Blockade After Avelumab in Relapsed/Refractory Classical Hodgkin Lymphoma

BackgroundAnti-PD-1 directed therapy is safe and effective in patients with relapsed/refractory (r/r) cHL and is currently being studied in the frontline setting. There are currently little data regarding the safety and efficacy of PD-1 blockade after prior PD-L1 blockade with agents such as avelumab.MethodsThis is a retrospective case series evaluating r/r cHL patients treated with avelumab who subsequently received at least 1 dose of PD-1 blockade. Primary objective is efficacy as measured by overall response rate. Secondary objectives include duration of response and time to progression on PD-1 blockade as well as safety as evaluated by incidence and severity of immune-related adverse events (irAE) with PD-1 blockade.ResultsThere were 7 patients treated with PD-1 blockade after avelumab, of whom 4 were re-treated. The median follow-up was 46.8 months. At the time of PD-1 blockade initiation median age was 36.6 years, all patients had advanced stage, 1 patient had B symptoms, and 4 patients had extranodal disease. Patients received median 7 prior lines of therapy including avelumab. Median duration on anti-PD-1 treatment was 15.9 months. A response was observed in 86% of patients with median duration of response of 26.4 months and median time to progression of 22.2 months. Only 1 patient experienced an irAE (grade 2 pneumonitis).ConclusionOur study suggests that PD-1 blockade after PD-L1 blockade in r/r cHL appears safe and may be effective with durable responses observed in a subset of patients.     

Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib

BackgroundConcurrent programmed death-ligand-1 (PD-(L)1) plus osimertinib is associated with severe immune related adverse events (irAE) in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Now that PD-(L)1 inhibitors are routinely used as adjuvant and first-line treatments, sequential PD-(L)1 inhibition followed by osimertinib use may become more frequent and have unforeseen serious toxicity.MethodsWe identified patients with EGFR-mutant NSCLC who were treated with PD-(L)1 blockade and EGFR- tyrosine kinase inhibitors (TKIs), irrespective of drug or sequence of administration (total n = 126). Patient records were reviewed to identify severe (NCI-CTCAE v5.0 grades 3–4) toxicity.ResultsFifteen percent [6 of 41, 95% confidence interval (CI) 7% to 29%] of all patients treated with sequential PD-(L)1 blockade followed later by osimertinib developed a severe irAE. Severe irAEs were most common among those who began osimertinib within 3 months of prior PD-(L)1 blockade (5 of 21, 24%, 95% CI 10% to 45%), as compared with >3–12 months (1 of 8, 13%, 95% CI 0% to 50%), >12 months (0 of 12, 0%, 95% CI 0% to 28%). By contrast, no severe irAEs were identified among patients treated with osimertinib followed by PD-(L)1 (0 of 29, 95% CI 0% to 14%) or PD-(L)1 followed by other EGFR-TKIs (afatinib or erlotinib, 0 of 27, 95% CI 0% to 15%). IrAEs occurred at a median onset of 20 days after osimertinib (range 14–167 days). All patients with irAEs required steroids and most required hospitalization.ConclusionPD-(L)1 blockade followed by osimertinib is associated with severe irAE and is most frequent among patients who recently received PD-(L)1 blockade. No irAEs were observed when osimertinib preceded PD-(L)1 blockade or when PD-(L)1 was followed by other EGFR-TKIs. This association appears to be specific to osimertinib, as no severe irAEs occurred with administration of other EGFR-TKIs.     

Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients

BackgroundImmune-related adverse events (irAEs) developed during immunotherapy with anti-PD-1 agents, could be a predictive surrogate marker of clinical benefit in patients with advanced non–small-cell lung cancer (NSCLC).MethodsPatients with NSCLC, treated with anti-PD-1 agents, were retrospectively evaluated. Univariate and multivariate analyses were performed to evaluate the relationships between types of irAEs (differentiated according to system/organ involved and to single-site/multiple-site), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). We further performed a 6-week landmark analysis.ResultsA total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed “single-site” irAEs and 40 (17.4%) “multiple-site” irAEs. At multivariate analysis, higher ORR was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine (P = .0043) and skin irAEs (P = .0005). Longer PFS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), “multiple-site” irAEs (P = .0374), endocrine irAEs (P = .0084) and skin irAEs (P = .0001). Longer OS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine irAEs (P = .0044), gastrointestinal irAEs (P = .0437), skin irAEs (P = .0006), and others irAEs (P = .0378). At the 6-week landmark analysis, irAEs of any grade was confirmed an independent predictor of higher ORR, longer PFS, and longer OS.ConclusionOur study confirmed that irAEs are concordantly related to higher ORR, longer PFS, and longer OS with anti-PD-1 immunotherapy in patients with NSCLC.     

Cutaneous,gastrointestinal, hepatic,endocrine, and renal side-effects of anti-PD-1 therapy

BackgroundAnti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.Methods and findingsIn total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.ConclusionAnti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.     

Immune checkpoint inhibitors in older adults with melanoma or cutaneous malignancies: The Wilmot Cancer Institute experience

ObjectivesThe purpose of this study was to explore the associations between age and frailty with immune-related adverse events (irAEs) among patients with cutaneous malignancies receiving immune checkpoint inhibitor (ICI) therapy.MethodsA retrospective review of all patients receiving ipilimumab, nivolumab, or pembrolizumab for treatment of cutaneous malignancies at the Wilmot Cancer Institute between 1 Jan 2011 and 3 Apr 2017.ResultsA total of 120 patients (age <70 N = 68, age ≥70 N = 52; range, 26–93) were identified. 44.1%[95%CI:32–57%] of patients age <70 and 31.4%[95%CI:19–46%] of patients age ≥70 experienced ≥1 irAE on 1st line ICI therapy (P = 0.158). A total of 3 adults died of irAEs (2 age ≥70; 1 age <70). Patients ≥70 were more frequently treated with anti-PD-1 monotherapy than dual checkpoint blockade or ipilimumab (P < 0.01) in the first line setting. Among patients on first line anti-PD-1 monotherapy for cutaneous melanoma, 21 were age <70 and 20 were age ≥70, with similar observed rates of irAEs (52.4%[95%CI 29.8–74.3] and 63.2%[95%CI 38.4–83.7]). Indirect frailty markers in patients age ≥70 such as having fallen in the prior six months, ECOG PS ≥2 or Charlson comorbidity scores ≥11 experienced similar rates of response and toxicity. Among 9 patients with a PS = 3, 8 died, 6 due to progressive disease. No deaths due to irAEs occurred in this frail subgroup.ConclusionAnti-PD-1 monotherapy for older adults with cutaneous malignancies have similar response and irAE rates when compared to those of younger patients. Deaths from disease progression were more frequent than those from toxicity in both age subgroups.     

Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy

Background

Immune-related adverse events (irAEs) are commonly encountered, when using programmed death-1/programmed death-ligand-1 (anti-PD-1/PD-L1) therapy and are often managed with corticosteroids. The effect of irAEs, particularly when steroids are required, on patient survival is not well established.

Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single-centre pharmacovigilance database analysis

AimThe growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence.Patients and methodsParticipants were recruited via Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)¹ a French registry of grade ≥2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia.ResultsOut of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjögren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjögren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both).We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57°days (interquartile range (IQR) 24–117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%).ConclusionAlthough systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable the continued administration of ICIs. Studies designed to identify at-risk patients are warranted.     

Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies

BackgroundImmune check-point blockade agents have shown clinical activity in cancer patients but are associated with immune-related adverse events that could limit their development. The aim of this study was to describe the gastrointestinal immune-related adverse events (GI-irAE) in patients with cancer treated with anti-PD-1.Methodsthis is a retrospective study of consecutive adult patients who had a suspected GI-irAE due to anti-PD-1 antibodies between 2013 and 2016. Patients were recruited through a pharmacovigilance registry. Patients’ data were reviewed by a multidisciplinary committee that included gastroenterologists, oncologists and a pathologist. Quantitative variables are described by median (range), qualitative variable by frequency (percentage).ResultsForty-four patients were addressed to a Gastroenterology unit for a suspected GI-IrAE. Twenty patients had a confirmed GI-irAE related to anti-PD-1, which occurred 4.2 months (0.2; 22.1) after the initiation of anti-PD-1. GI-IrAE incidence rate under anti-PD-1 treatment was estimated to be 1.5%. Among patients with GI-IrAE, main symptoms were diarrhoea (n = 16, 80%), abdominal pain (n = 13, 65%), nausea and vomiting (n = 11, 55%), intestinal obstruction (n = 1, 5%), and haematochezia (n = 2, 10%). No patient had colectomy. Four distinct categories of GI-irAE were observed: acute colitis (n = 8, 40%), microscopic colitis (n = 7, 35%), upper gastrointestinal tract inflammation (n = 4, 20%) and pseudo-obstruction (n = 1, 5%). Response rates to corticosteroids were 87.5% (7/8) in acute colitis, 57% (4/7) in microscopic colitis and 75% (3/4) in upper gastrointestinal tract inflammation. Median time to resolution was 36 days (6–172) in acute colitis, and 98 days (42–226) in microscopic colitis.ConclusionThis study suggests that GI-irAE are different and less frequent with anti PD-1 than with anti CTLA-4.     

Single-Agent Neoadjuvant Immunotherapy With a PD-1 Antibody in Locally Advanced Mismatch Repair-Deficient or Microsatellite Instability-High Colorectal Cancer

BackgroundPD-1 blockade has been recommended as first-line therapy for nonresectable or metastatic mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, the safety and efficacy of neoadjuvant PD-1 blockade immunotherapy for locally advanced dMMR/MSI-H CRC remain unclear.Patients and MethodsFrom June 2020 to June 2022, 11 locally advanced dMMR/MSI-H CRC patients treated at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were enrolled. All patients received 6 sintilimab (Innovent, LTD) injections (200 mg/injection, every 3 weeks) before radical laparoscopic resection. The patient clinical and pathological data were analyzed retrospectively.ResultsdMMR was confirmed by immunohistochemistry for all patients. However, polymerase chain reaction (PCR) or next-generation sequencing confirmed MSI-H for only 90.9% (10/11) of the patients, while 1 patient had microsatellite stable (MSS) disease. After 6 injections of neoadjuvant anti-PD-1 therapy, 90.9% (10/11) of the patients (those confirmed to have dMMR and MSI-H disease) achieved pathological complete response (pCR). The other patient, who achieved major pathological response with residual tumor <1%, had dMMR but MSS disease. No grade 3 or above immunotherapy-related adverse events occurred [Common Terminology Criteria for Adverse Events ; version 5.0]. Overall, 72.7% (8/11) of the patients had grade 1-2 immunotherapy-related adverse events . No operational mortality or complications occurred within 30 days after surgery.ConclusionSingle-agent neoadjuvant PD-1 antibody immunotherapy was safe and effective in locally advanced dMMR/MSI-H CRC. Dual confirmation of MMR and MSI status by immunohistochemistry and next-generation sequencing or PCR is necessary for dMMR/MSI-H CRC patients before immunotherapy. The immunotherapy regimen used in this study deserves further validation in phase II and III clinical studies.     

Association of age with survival in older patients with cutaneous melanoma treated with immune checkpoint inhibitors

IntroductionSeveral types of immune checkpoint inhibitors (ICIs) are approved to treat advanced melanoma, but their effectiveness has not been compared in older patients treated outside of a clinical trial. Moreover, evidence suggests that a patient's response to ICI therapy may vary by age and type of ICI. The purpose of this study was to compare survival by ICI type in older patients with melanoma and to investigate treatment effect modification by age.Materials and MethodsUsing the SEER-Medicare database, we identified patients with cutaneous melanoma (2012–2015) treated with an ICI (CTLA-4, PD-1, or combination CTLA-4 + PD-1 inhibitors). Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for ICI types. We used an interaction term and stratified models to test for treatment effect modification by age.ResultsOf the 1435 patients included in our analysis, 790 (55.1%) received CTLA-4 inhibitors, 512 (35.7%) received PD-1 inhibitors, and 133 (9.3%) were treated with combination ICIs. Median survival ranged from 13.4 months (95%CI: 10.7–16.3) for CTLA-4 inhibitors to 23.5 months (95%CI: 16.2–30.0) for combination ICIs. In multivariable models, the risk of death was lower with PD-1 inhibitors compared to CTLA-4 inhibitors (HR = 0.78, 95%CI: 0.68–0.89). An age*ICI type interaction term was significant (p < 0.001), and survival gains were greater the older age group (≥80) compared to the younger group (65–79).DiscussionIn a population-based setting, we identified important differences in survival by ICI type in older patients with melanoma treated with ICIs, with prolonged survival associated with PD-1 inhibitors compared to CTLA-4 inhibitors.     

Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma

BackgroundMonoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC) and are currently being developed in first-line (in combination) and in previously treated patients. The efficacy targeted therapy (TT) after PD-1/PD-L1 blockade is still unknown.MethodsMedical records of mRCC patients treated with investigational PD-1 or PD-L1 inhibitors at 4 academic institutions were reviewed. Patients who received subsequent treatment with TT were selected to collect outcome measures of subsequent TT.ResultsOf 99 patients who received PD-1/PD-L1 blockade as part of clinical trials, 56 patients have received subsequent therapy: 44 patients received vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors and 12 received mammalian target of rapamycin (mTOR) inhibitors as first subsequent TT. Median follow up, from the start of subsequent TT was 16.1 months (range: 0.2, 30.6 months). TT post PD-1/PD-L1 blockade was administered as second-line, third-line or beyond third-line in 9 (16%), 24 (43%) and 23 patients (41%) respectively. Median time to treatment failure on subsequent TT was 6.6 months (range: 0.2+, 23.0). 1-year and 2 year overall survival from the initiation of subsequent TT was 58% (95% confidence interval (CI): 41–72%) and 36% (95% CI: 18–54%), respectively.ConclusionBoth VEGF/VEGFR and mTOR inhibitors demonstrate antitumour activity following PD-1/PD-L1 blockade.     

Anti-PD-1 checkpoint blockade improves the efficacy of a melphalan-based therapy in experimental melanoma

IntroductionThe induction of adaptive cellular immunity in patients with in-transit melanoma metastasis treated with hyperthermic isolated limb perfusion (ILP) with melphalan has been shown to contribute to the effectiveness of the therapy. Activated CD8⁺ T cells appear to be of particular importance for the efficacy of melphalan-based ILP therapy, as observed in both patients and animal models. In this study, we explored the possible synergistic effects of combining melphalan-based therapy with the checkpoint inhibitor anti-PD-1 on tumours in a mouse melanoma model.MethodsA murine vaccination model that utilized melphalan-exposed melanoma cells was used to mimic certain immunological features of melphalan-based ILP. The effects of the vaccine on tumour growth and PD-1 expression on CD8⁺ tumour-infiltrating T cells were analyzed. The melphalan-based vaccine was then combined with an anti-PD-1 antibody and tumour growth was assessed.ResultsTreatment with melphalan-based therapy significantly induced the expression of PD-1 on CD8⁺ tumour-infiltrating lymphocytes. Combination therapy using melphalan-based therapy followed by treatment with PD-1 antibodies significantly reduced early-stage tumour growth relative to monotherapies and no treatment.ConclusionsThis study thus suggests that the addition of PD-1 blockade to melphalan-based therapies, such as ILP, may be therapeutically beneficial.     

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis

Background Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.Methods Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.Results Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028).Conclusions Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.Subject terms: Targeted therapies, Melanoma, Melanoma     

A Population-based Study of Immunotherapy-related Toxicities in Lung Cancer

BackgroundPopulation-level data regarding incidences of immune-related adverse events (irAEs) are lacking. This study evaluated the frequencies of irAEs among patients with non–small-cell lung cancer (NSCLC) who received immune checkpoint inhibitors.Patients and MethodsAdministrative claims data from a large United States commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify patients with NSCLC between January 1, 2015 and December 31, 2017 who received a programmed death-ligand 1/programmed cell death protein-1 (PD(L)-1) inhibitor. Cumulative risks for irAEs were estimated at 1, 3, 6, 9, and 12 months after initiation of a PD-(L)1 inhibitor. Additionally, associations between patient characteristics and frequency of irAEs were investigated utilizing multivariate logistic modeling.ResultsThe risk of developing any irAE was 52.5% (95% confidence interval, 49.9%-55.2%) after 12 months in 3164 patients with NSCLC who initiated a PD-(L)1 inhibitor (median age, 69.0 years; 1763 [55.7%] males; 1401 [44.3%] females). Cumulative risks of irAEs increased over time: pneumonitis was recorded in 2.5% of patients 1 month after initiation of treatment, and increased to 14.3% after 9 months. Risks of hypophysitis and pericarditis were 3.6% and 1.7% at 9 months, respectively. Patients who received PD-(L)1 inhibitors in the first line had lower frequencies of irAEs (hazard ratio, 0.77; 95% confidence interval, 0.67-0.87).ConclusionOur findings suggest that the frequencies of some irAEs may be higher than the rates reported in the pivotal trials that led to United States Food and Drug Administration approvals for PD-(L)1 inhibitors. These real-world data refine provider and patient expectations for outcomes in a broader population beyond what is observed in clinical trials.     

Immune Checkpoint Inhibitor Rechallenge Safety and Efficacy in Stage IV Non-Small Cell Lung Cancer Patients After Immune-Related Adverse Events

BackgroundDespite their anti-tumor efficacy, immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs). Grade ≥ 2 irAEs require ICI discontinuation. The decision to resume ICI treatment often remains challenging.MethodsWe retrospectively studied 1051 adult patients with stage IV non-small cell lung cancer (NSCLC) treated with ICIs at a single institution between January 2015 and December 2020, and identified 99 (9.4%) patients with grade≥2 irAEs necessitating treatment interruption. Forty patients underwent retreatment (rechallenged group), while 59 discontinued the treatment (discontinued group).ResultsBaseline characteristics of patients in the 2 groups were similar. Initial irAEs were less severe in the rechallenged group. After rechallenging, 24 of 40 (60%) patients had recurrence of the same or de-novo irAEs. Twenty (50%) developed second grade≥ 2 irAEs. No grade 4 irAE or irAE-related death occurred after rechallenging. Using multivariate analysis, no statistically significant differences in overall survival (OS) (HR: 1.10, 95% CI: 0.57-2.15, P = .77) or progression-free survival (PFS) (HR: 0.87, 95% CI: 0.45-1.71, P = .69) were noted between the 2 groups, while the best objective response prior to the initial irAEs was the only variable affecting OS and PFS.ConclusionsRechallenge was associated with a relative high risk of second grade≥ 2 irAEs. The risk was less if the initial irAEs were resolved. No differences were seen in survival outcomes of patients who had ICI rechallenge and those who did not. Permanent ICI discontinuation is an appropriate strategy after grade≥ 2 irAEs, especially severe irAEs.     

Immune-related adverse events in older adults: Data mining of the FDA Adverse Event Reporting System

IntroductionRecent studies reveal that there is no difference in the efficacy of immune checkpoint inhibitors (ICIs) between younger adults and older adults. However, it remains unclear whether age is a risk factor for immune-related adverse events (irAEs).Materials and methodsTo analyze the association between irAEs and age based on data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database between January 2004 and December 2020, we performed a case/noncase study on ICI-related adverse events. Cases were defined as adverse event cases with ICI therapy and irAEs, and noncases were defined as adverse event cases with ICI therapy and without irAEs. One case was matched to a noncase using the sex, reporter, report year, and type of ICI regimen. The reporting odds ratios (RORs) were used to assess the disproportionality of irAEs between older adults (≥65 years) and younger adults (<65 years).ResultsThe study shows that compared with younger adults, the ROR of older adults was 1.12 (95% confidence interval [CI]: 1.08–1.16) and 1.18 (95% CI: 1.14–1.23) before and after matching, respectively. The signal of age-related irAEs was detected in patients treated with ICI monotherapy but not in patients treated with combination therapy. Further analysis revealed a spectrum of age-related toxicities including cardiovascular toxicities, lung toxicities, musculoskeletal toxicities, nervous system toxicities, renal toxicities, and skin toxicities.ConclusionIn this analysis performed based on the FAERS, irAE cases were more likely to be reported in older adults. Our pharmacovigilance study complements the safety data of clinical trials. Further studies are expected to explore the underlying reasons for irAEs in older adults.