Cycle Of Immune Checkpoint Inhibitors Research Articles

Patterns of thyroid dysfunctions during treatment with immune checkpoint inhibitors (ICI) in 59 solid cancer patients.

e18567 Background: Immune checkpoint inhibitors (ICI) have now become the mainstay treatment in patients with many kinds of cancers. Thyroid dysfunction as the most common endocrine toxicity is poorly understood. This study aimed to report hypothyroidism and exam its changing dynamtic in our first series of patients treated with ICI. Methods: This is a retrospective study. Patients received nivolumab or pembrolizumab between July 2018 and December 2019 were considered. Patient must have euthyroidism within the 3 months before immunotherapy and those had previous use of levothyroxine were excluded. They were monitored by thyroid function tests every cycle until stopping ICI. Patients must have received at least 3 cycles of antibody treatment. Results: Among 89 patients treated, 59 met the inclusion criteria. There were 33 males, 26 females, including 26 (44.1%) nivolumab, and 33 (55.9%) pembrolizumab. Median age was 62 years [range: 27-88]). Cancer diagnoses observed were non small cell lung cancer 17(28.8%), small cell lung cancer 4 (6.8%),liver cancer 9 (15.3%), head and neck cancer 5 (8.5%), esophageal cancer4 (6.8%) colon cancer 3 (5.1%), nasopharygeal carcinoma 3 (5.1%) melanoma 3 (5.1%) and other cancers 11(18.6%). There were 9 patients (15.3%) developed a thyroid dysfunction, including 5 females. Four patients had thyrotoxicosis (median onset: 8 weeks) followed by hypothyroidism. There were three types of thyroid dysfunctions: the first type patients 3 (33.3%) had a brief time period of TSH flair (peak 17.4-57.8) after the first cycle of ICI, followed by TSH dramatic drop companied with rising fT4, which usually returned to normal level during 3-4 cycles of . The other 4 patients (44.4%) with thyroid dysfunction presented with remarkably elevated TSH (15.43-125.2) after 3.5-10 months’ treatment, followed by hypothyroidism development with a need of levothyroxine. The remaining 1 patient had a third type of thyroid dysfunction with elevated TSH, elavated more while the treatment continue, the patient should be given levothyroxine as soon as possible. Additionally, 1 patient developed hypopituitarism presented with both low level of TSH and fT4 after 10 month treatment. There was no significant difference in patient characteristics between patients with hypothyroidism and those without. Conclusions: There are heterogeneity in thyroid function and hypothyroidism after ICI. Before more experience is gained, frequent monitoring of thyroid function during ICI is warranted for prompt management of the hypothyroidism.

Peripheral blood biomarkers associated with outcome in non-small cell lung cancer patients treated with nivolumab and durvalumab monotherapy.

e21732 Background: Selecting patients that potentially benefit from immune checkpoint inhibitors (ICIs) is critical. Programmed death ligand-1 (PD-L1) protein immunohistochemical expression on cancer cells or immune cells and Next generation sequencing based tumor mutational burden (TMB) are the hot spots in studies on ICIs, but there is still confusion in the testing methods. Due to blood samples are much easier for clinical application, many potential peripheral biomarkers have been proposed. This study identify blood parameters that associated with outcome of non-small cell lung cancer (NSCLC) patients with ICIs monotherapy. Methods: Data of 76 NSCLC patients were analyzed retrospectively. To assess the connection between survival and peripheral blood markers measured before and after treatment, we utilized COX regression model survival analysis and receiver operating characteristic (ROC) curve to assess the markers. Results: In the nivolumab cohort, the optimal cutoff for predicting 11 month overall survival (OS) were 168.13 and 43g/L in Plateletto-lymphocyte ratio (PLR) and albumin, respectively. When patients are grouped with PLR and albumin the cut-offs, a significant difference in SD-PR vursus PD rate were found between high and low groups, separately. which was not found when grouped by PD-L1 expression. Patients with high PLR ( > 168.13) or low albumin ( < = 43g/L) before ICI had a significantly raised hazard of progression, separately (for PLR, P = 0.006; for albumin, P = 0.033) and of death (for PLR, P = 0.014; for albumin, P = 0.009) compared with those patients who had low PLR or albumin level. More importantly, we found that higher PLR ( > 168.13) after the fourth cycle of ICIs was also an prognostic biomarker, which significantly correlated with shorter OS in both Nivolumab (P = 0.046) and durvalumab cohort (P = 0.028). Conclusions: PLR and albumin may help the stratification of high progression and death risk group in advanced NSCLC patients treated with nivolumab and durvalumab monotherapy.

Atypical Stevens-Johnson syndrome-like reaction in the setting of immune checkpoint inhibition.

102 Background: Stevens-Johnson syndrome (SJS) is a rare, life-threatening mucocutaneous toxicity that can occur in patients receiving immune checkpoint inhibitors (ICIs). ICI-induced SJS is scarcely reported in the literature and thus remains poorly understood, particularly regarding features that may distinguish it from classic SJS. Methods: To describe the timing, clinical manifestations, and treatment course of ICI-induced SJS, this multicenter, retrospective study identified seven patients with SJS in the setting of ICI use from January 2011 through May 2019. Results: All seven patients presented initially as benign, limited drug eruptions after a median of 4 ICI cycles (range, 1-7) and 63 days (range, 13-253 days) from ICI initiation. While none of the patients had prior drug allergies, all 7 were receiving new, recently initiated – i.e., within two months – medications at the time of rash onset. Cases demonstrated characteristic histologic findings of SJS, such as epidermal necrosis, and occasional unusual features, including interface dermatitis. All patients responded favorably and rapidly to systemic therapy, primarily intravenous corticosteroids, with near immediate symptomatic resolution and cessation of progressive skin blistering or detachment. Median length of stay was 11 days and no patients died from SJS. Conclusions: Our cohort defines an atypical SJS-like reaction secondary to ICI use, which is distinct from classic SJS in its delayed onset, mild initial presentation, and rare ocular involvement. The association with concomitant medication use suggests a potential mechanism whereby ICIs reduce patient immune tolerance to subsequent drug exposures. Reassuringly, this atypical SJS-like phenomenon exhibits a benign clinical course and favorable response to standard treatments.

Immune Checkpoint Inhibitor Therapy for Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes: A Single-Center Experience

Immune Checkpoint Inhibitor Therapy for Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes: A Single-Center Experience

An analysis of 30-day mortality after the last cycle of immune checkpoint inhibitors treatment

Abstract Background Immune checkpoint inhibitors (ICIs) have been increasingly used for patients with advanced incurable cancer, although the criteria of interruption has not been established. According to the proposition from 2011 national cancer strategy for England, 30-day mortality might be as a potential national clinical indicator of avoidable harm of systemic anticancer therapy (SACT). In this study, we investigated the details of patients who died within 30 days after the last cycle of ICIs treatment. Methods The data of all oncologic patients who received SACT between January 2016 and June 2018 were collected retrospectively. The characteristics of the patients who died within 30 days after ICIs were compared with patients who died within 30 days after conventional SACT mainly consisting of cytotoxic agents (non-ICIs). Users of oral anticancer drugs and local artery or intrathecal injections were excluded from this study. Results Of 1442 patients who received SACT, 90 patients were treated with ICIs as the final regimen. 15 patients (16.7%) died within 30 days after the last cycle of ICIs. The mortality of ICIs was higher than 22 patients (1.6%) that used non-ICIs regimen. The characteristics were as follows: median age (interquartile range); 71 years old (60-86), sex male/female; 14/1, performance status (PS) 0-1/2-4 at the last cycle; 4/11. The reasons for death were tumor progression 11, infection 3, immune related hepatitis 1, primary region; lung cancer 12, head and neck 2, melanoma 1. Among them, the proportion of PS2-4 and the expense in ICIs users were significantly higher than that in non-ICIs users (p = 0.040 and p Conclusion It is possible that ICIs continued to be used in frail patients who could not tolerate cytotoxic agents and should be offered best supportive care. Moreover, the last cycle of ICIs gave a poor cost performance. PS2-4 might be a clinical indicator as decision support for interruption of ICIs treatment at the end of life.

1280P - A burst of highly differentiated CD4 TL identifies a subset of fast progressors, and correlates with hyperprogressive disease in NSCLC patients treated with ICI

BackgroundHyperprogressive disease (HPD) is a new pattern of tumor response described with immune checkpoint inhibitors (ICI), characterized by a sharp acceleration of tumor growth after the administration of the treatment. Several definitions based on clinical and/or radiological criteria have been proposed, although different factors limit their applicability. The mechanistic rationale has still not been elucidated. Our group has monitored lymphocyte populations in peripheral blood from non-small cell lung cancer patients (NSCLC) under ICI treatment with flow cytometry, and correlated the findings with HPD. Methods41 NSCLC patients treated with ICI after progression to≥1 lines of chemotherapy for advanced disease have been included. We analyzed lymphocyte subpopulations from peripheral blood samples obtained immediately before the administration of the 1st and 2nd cycle of ICI. The expression of the following markers has been considered: CD3, CD4, CD8, CD27, CD28, CD45RA, CD62L, PD1. We correlated the findings with HPD as defined by TGR (Champiat S, 2017) and TGKR (Sâada-Bouzid E, 2017). ResultsOverall response rate (ORR) was 23.8%, and disease control rate (DCR) was 31%. 10 patients (23.8%) presented HPD by TGKR, and 7 patients (16.7%) by TGR. 9 patients (21.4%) could not be evaluated for HPD, mainly due to progression by non-measurable disease or death before further radiological. Median progression free survival (mPFS) was 6 weeks for HPD by TGR and 6.3 weeks by TGKR. We found that the mean proportion of post/pre-treatment LT CD4+ CD27- CD28- was significantly higher for HPD patients (1.86; CI95% 1.14 to 2.58 than non-HPD (1.09; CI95% 0.89 to 1.30) (p=0.0033). An increase > 30% in LT CD4+/CD27-/CD28- after the first cycle of immunotherapy was associated with fast progression (ORR 0%, mPFS 6 weeks [CI95% 5.8 to 6.2], 8-weeks PFS 0%). Cohen’s kappa between HPD by TGR and by LT was 0.503 (p=0.004). ConclusionsHPD as defined by LT CD4+ CD27- CD28- burst > 30% might complement the limitations of radiological criteria as it does not require the evaluation of the tumor kynetics previous to the beggining of immunotherapy, nor it is influenced by non-measurable disease or tumor burden. Legal entity responsible for the studyThe authors. FundingAECC, ISCIII. DisclosureAll authors have declared no conflicts of interest.

Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition

BackgroundCompared to conventional chemotherapy, Immune checkpoint inhibitors (ICI) are known to have a distinct toxicity profile commonly identified as immune-related adverse events (irAEs). These irAEs that are believed to be related to immune dysregulations triggered by ICI can be serious and lead to treatment interruptions and in severe cases, precipitate permanent discontinuation. Isolated neutropenia secondary to ICI has been rarely documented in the literature and needs further description.We report a case of pembrolizumab related severe isolated neutropenia in a patient with metastatic non-small cell lung cancer. We were also able to obtain serial blood and plasma-based biomarkers for this patient during treatment and during neutropenia to understand trends that may correlate with the irAE. In addition we summarize important findings from other studies reporting on ICI related neutropenia.Case presentationA 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging. Our literature review reveals that hematological toxicities constitute < 1% irAEs with isolated neutropenia roughly accounting for one-fourth of the hematological irAEs. Based on the handful of ICI related neutropenia cases reported to date, we identified nivolumab to be the most common offender. The median number of ICI cycles administered before presenting with neutropenia was three, and the median time to recovery was approximately two weeks. All of these neutropenic episodes were ≥ grade 3 and led to permanent ICI discontinuation. Using immunosuppressive therapies in conjunction with granulocyte-colony stimulating factor was the most common strategy described to have favorable results.ConclusionNeutropenia as an isolated irAE secondary to ICI is rare but represents a severe toxicity that needs early recognition and can often result in treatment discontinuations. Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI.

Bone metastases as predictors of treatment response and rapidly progressive disease in NSCLC patients on PD-1/PD-L1 immune checkpoint inhibitors (ICI).

e20667 Background: The tissue microenvironment associated with specific organ metastases potentially influences the efficacy of checkpoint inhibitors. The presence of liver metastases is a predictor of poor response and survival in melanoma and is correlated with reduced CD8+ T cell infiltration. Our study examined clinicopathologic characteristics, focusing on sites of metastatic disease, that are associated with poor outcomes. Methods: Advanced NSCLC patients treated with ≥1 cycle of ICI were reviewed. Baseline age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and sites of metastases were recorded. Best overall response (BOR) was determined by clinical imaging response and categorized ordinally as shrinkage, stable, or progression, adapted from RECIST for CR/PR, SD, PD. A rapidly progressive phenotype (RPP) was defined as BOR of progression and ICI use of ≤2 months. The association between sites of metastases and clinical outcomes were investigated using logistic and cox regression models. Results: Among 219 eligible patients, bone was the most common metastatic site (34.7%), followed by brain (21.5%), adrenals (14.2%), and liver (13.7%). Bone metastases (OR 0.45, p = 0.004) were associated with a worse BOR, while only a trend was observed for liver metastases (OR 0.47, p = 0.06). Adrenal metastases were associated with a better BOR (OR 2.08, p = 0.04). But thorax limited disease did not associate with BOR (OR 1.08, p = 0.76). In a multivariate model, bone was the only metastatic site associated with a worse BOR (OR 0.50, p = 0.01). Further, bone metastases were associated with RPP (adjusted OR 1.91, p = 0.04). Both bone (adjusted hazard ratio/aHR 1.61, p = 0.01) and liver metastases (aHR 1.80, p = 0.02) were associated with a shorter time-to-treatment-failure. The presence of liver (aHR 2.63, p &lt; 0.001) but not bone (aHR 1.04, p = 0.86) metastases was a significant predictor of poor OS. Conclusions: We report a novel finding that the presence of bone metastases was associated with a worse clinical overall response on ICI and a rapidly progressive phenotype. Further investigations into the mechanisms of RPP in the presence of bone metastases are needed.

Immune-related adverse events (IRAEs) in metastatic lung cancer patients receiving PD-1/PD-L1 inhibitors and thoracic radiotherapy.

9079 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with unique IRAEs, including pneumonitis (PNS). Thoracic radiotherapy (TRT) is also associated with PNS but it is unknown whether TRT+ICI increases the risk of PNS or other IRAEs. Furthermore, low serum LDH levels are associated with better response/survival to ICI but its potential role as a biomarker for IRAEs is unexplored. Methods: We retrospectively reviewed 164 pts with metastatic lung cancer (95% NSCLC, 5% SCLC) consecutively treated at our institution from 2013-2016 with PD-1/PD-L1 inhibitors and a minimum of one month follow-up, except in cases of rapid death from an IRAE ( n =4). Pts were grouped according to TRT received (+ vs -). IRAE grades were assigned using NCI CTCAE v4.0. Outcomes were compared using Fisher’s exact test and two-sided Student’s t-test. Results: Baseline characteristics such as age, gender, smoking status, supplemental oxygen requirement, median number of chemotherapy lines prior to ICI (1 vs 1), median ICI cycles (5 vs 3), and median follow-up after ICI initiation (8 vs 7 months) were similar in the +TRT ( n = 73) and -TRT ( n =91) groups. Rates of grade ≥ 2 IRAEs (18.1 vs 14.4%, p = 0.67), all-grade PNS (8.2 vs 5.5%, p= 0.54), and grade ≥ 2 PNS (4.1 vs 3.3%, p = 1) were not significantly different between the +TRT and -TRT cohorts. Mean TRT dose was similar between those pts who developed PNS and those who did not (55.8 vs 55.9 Gy). In the +TRT group, 85% received TRT a median of 8.6 months before ICI. Among 7 pts (10%) who had concurrent TRT+ICI, none developed symptomatic PNS. Patients who developed grade ≥ 2 IRAEs ( n= 26) had significantly higher mean serum LDH before initiation of ICI than patients who did not (283 vs 214, ref 98-192 IU/L, p= 0.03). Conclusions: TRT in lung cancer pts receiving ICI was not associated with increased risk of PNS in this series. LDH may be a negative predictive biomarker as pts who suffered grade ≥ 2 IRAEs had significantly higher baseline LDH than those who did not. Larger cohorts and prospective studies would be helpful to validate these findings.