Initial Immune Checkpoint Inhibitors Research Articles

Immune-related adverse event-myocarditis with marked ST-segment elevation requiring differentiation from COVID-19-induced myocarditis: a case report

Abstract Background Immunotherapy with immune checkpoint inhibitors (ICIs) enhance the host immune reaction against tumour cells by inhibiting intrinsic down-regulators of the T cell-mediated immune response. Although the advent of ICIs has dramatically changed oncology, ICIs may also trigger an overactivation of T cells against non-cancerous tissues, leading to off-target immune-related adverse events (irAEs). Case Summary A 64-year-old man with a history of seven courses of atezolizumab, an ICI, for small-cell lung cancer and Coronavirus disease 2019 (COVID-19) as admitted to the hospital complaining of acute chest pain. Transthoracic echocardiography showed preserved ejection fraction (EF), but electrocardiography indicated precordial ST elevations and marked increases in biomarkers for myocardial injury were observed. Emergent cardiac catheterization showed no significant coronary stenosis. On the fifth hospital day, EF decreased to 25% and pericardial effusion occurred. Endomyocardial biopsy was immediately performed, and prednisolone (60 mg/day) was administered. Troponin I level rapidly reduced, ST change and EF improved. Histological examinations demonstrated CD8-predominant T lymphocytic infiltration with myocardial cell injury, consistent with irAE-myocarditis. Discussion In irAEs, myocarditis is the most common and severe cardiac manifestation with a high mortality. Even at 20 weeks after the initial ICI treatment, irAE-myocarditis occurs and the clinical presentation may mimic ST elevation myocardial infarction. The histopathological findings suggested the high possibility of irAE-myocarditis rather than COVID-19-induced myocarditis, but COVID-19 has possibly played a role in the development of late-onset irAE-myocarditis. This educational case implies the importance of immediate recognition of irAE even after stable ICI treatment.

Durability of immune checkpoint inhibitor (ICI) response following treatment discontinuation in advanced merkel cell carcinoma (MCC).

9596 Background: Advanced MCC has a high response rate to ICI therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced MCC patients at our institution who discontinued ICI treatment after achieving favorable initial response. Methods: In an IRB-approved single institution retrospective review of advanced MCC patients, we analyzed all patients who received at least one dose of anti-PD(L)1 monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression. Duration of response and outcomes of subsequent therapy were assessed. Results: Of 195 advanced MCC patients treated with ICI, we identified 45 who met study criteria. Of these, 21 (47%) had a complete response (CR) to initial ICI treatment, 23 (51%) a partial response (PR) and 1 (2%) SD. Twenty-five (56%) patients discontinued ICI electively and 20 (44%) discontinued due to toxicity. In total, 21 of the 45 patients (47%) experienced disease progression at a median of 11.2 months (range 2.1-22.7 months) from ICI cessation. The median follow-up after ICI discontinuation for patients who have not experienced progression is 22.8 months (5.8-82.0 months). There was a lower rate of progression in patients who achieved CR vs. non-CR (24% vs 67%, p=0.006) and a trend towards a lower rate in those who discontinued electively vs. due to toxicity (36% vs 60%, p=0.14). For patients in whom the molecular subtype was known, there was a higher risk for progression in patients with viral MCC (12 of 16, 75%) compared to UV-associated MCC (4 of 13, 31%, p=0.02). Fifteen of the 21 patients (71%) who experienced progression were rechallenged with ICI therapy, including both single agent (12 patients, 57%) and combination (3, 14%) therapy. The remaining patients received locally-directed therapy only (3, 14%), chemotherapy (1, 5%), declined further treatment (1, 5%), or transferred care and were lost to follow up (1, 5%). Eleven of 15 ICI-retreated patients (73%) achieved an objective response to rechallenge, including all 3 patients who received combination therapy with ipilimumab+nivolumab. Twelve of the 45 patients have expired; 6 due to progressive MCC and remaining 6 known or suspected from unrelated causes. Conclusions: Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICI response, 47% in our series with a median time to event of 11.2 months, particularly in those that achieve less than a complete response. In the setting of disease progression post-ICI discontinuation, most patients maintain sensitivity to retreatment with the same drug class. Virus-positive MCC may be a risk factor for post-discontinuation relapse, which should be validated in future studies.

Immune related adverse events: Timing, identification patterns, and impact on survival.

e14705 Background: Increased use of immune checkpoint inhibitors (ICI) has resulted in a rise in immune related adverse events (irAEs), which many non-oncology clinicians may underrecognize. Controversy exists surrounding whether irAE presence has an impact on survival. Our primary goal was to evaluate the timing between detection to diagnosis of irAE, and determine the department responsible for making the irAE diagnosis. We also assess the incidence of single vs multisystem irAEs, impact of irAE on survival, and assess whether standard irAEs (s-irAEs) those diagnosed within 90 days of initial ICI administration vs delayed irAE (d-irAEs) those diagnosed >90 days impacts survival. Methods: We performed an IRB approved retrospective study of patients 18 years and older who received ICIs for a malignancy at Gundersen Health System between January 1, 2011 and December 31, 2021. Statistical analysis included Chi-square, Fisher’s Exact, and Wilcoxon rank sum tests and Kaplan-Meier survival analysis. All analysis was completed in R version 4.2.3 with a p-value <0.05 considered significant. Results: Our study included 664 patients who were 99.6% white, 60% male, and an average age of 67 years. Median Charlson Comorbidity Index was 10. There were 245 (36.8%) patients with at least 1 irAE, and 62 (9.3%) with a multisystem irAE. While 28 (11%) irAEs were initially detected by non-oncology providers, only 10 (4.1%) irAEs were diagnosed by a non-oncology department. Median time (days) from symptoms to diagnosis was 3 for those diagnosed in non-oncology departments and 0 for those diagnosed in oncology (p<0.01). A total of 142 (58.0%) s-irAEs were detected with grades 1-2-3-4-5 accounting for 21.1%-54.9%-19.7%-1.4%-2.8%. There were 103 (42.0%) d-irAEs with grades 1-2-3-4-5 accounting for 23.3%-53.4%-17.4%-5.8%-0%. Of the d-irAEs, 17 (16.5%) occurred >365 days from initiation of ICI. The 3 most common irAE in this patient population included thyroiditis (34%), dermatitis (21%), and pneumonitis (12%). Our data shows a significant survival difference in patients with an irAE compared to those without (p<.01). No significant survival difference was noted between patients who had s-irAE vs d-irAE (p=.069). Conclusions: Our results show that irAEs may be underrecognized and often not formally diagnosed by non-oncology providers. However, median time to diagnosis is short within this context. This may be due to non-oncology providers feeling uncomfortable making the final decision, which emphasizes the importance for oncologists to finalize irAE diagnoses. We did see a positive impact on survival with irAE presence. While oncologists often clinically expect irAEs to surface within the first 6-10 weeks of treatment, our study demonstrates that 42% of irAEs occur after 12 weeks from ICI initiation. There is no difference in survival between s-irAEs vs d-irAEs, and overall grade distribution between these two groups appears similar.

Immune checkpoint inhibitor (ICI) rechallenge after immune-related adverse events (irAE) requiring hospitalization: A single-center 10-year experience.

e14609 Background: ICI rechallenge after irAE has become a significant clinical dilemma, with irAE recurrence rates of 30-40% after rechallenge. Here we examine factors influencing ICI rechallenge rates across a 10-year period at the Massachusetts General Hospital (MGH), where the Severe Immunotherapy Complications service is available to provide multidisciplinary irAE expertise. Methods: We included patients admitted to MGH for an irAE from August 2011 to July 2023. We collected baseline demographics, ICI regimens, and irAE features. The choice of ICI used at rechallenge was grouped into 3 categories: 1) restarting an ICI within the same class, 2) switching classes (CTLA-4 to PD-(L)1 or vice versa), or 3) de-escalating from combination to monotherapy. Chi-square and Mann-Whitney U tests were applied to descriptive statistics. Results: Among 5882 patients treated with ICI, 671 (11.4%) patients were admitted for irAE. The median age was 67.6 (IQR, 59-74.9) years and 58% were male. Initial ICI regimens consisted of anti-PD-(L)1 (64.8%), anti-CTLA4 (10.9%), and ICI combinations (24.3%). 174 of 671 patients (25.9%) were rechallenged after an irAE requiring hospitalization. Rechallenge was common after rheumatologic, endocrine, dermatologic irAE and GI irAE, but rare after cardiac, neurologic, or pulmonary irAE (Table 1). The median time to rechallenge was 25 days (IQR 18-91) after endocrine irAE and 72 days (IQR 40-209) after non-endocrine irAE (p<0.001). Rechallenge was more common in melanoma (35%, p<0.001), and less common in lung (13.6%, p<0.001) and GU cancers (10%, p=0.003). Rechallenge rates were significantly higher in patients initially on combination therapy (39.6%) versus PD-(L)1 monotherapy (15.5%), p<0.001. Of those rechallenged, 43.2% initially on combination therapy were de-escalated to monotherapy and 53% were restarted within the same class. Amongst the PD-(L)1 monotherapy group, 88.4% were restarted within the same class and 11.6% switched classes. Conclusions: Here we examine practice patterns at a large academic center, where 25.9% of patients with irAE requiring hospitalization were rechallenged. Rechallenge was more prevalent in patients with melanoma or on ICI combination therapy, whereas it was less frequent following cardiac, neurologic, or pulmonary irAE. Under adequate risk-benefit evaluation, close monitoring, and multidisciplinary care, ICI rechallenge can be considered. [Table: see text]

Efficacy of NSCLC Rechallenge with Immune Checkpoint Inhibitors following Disease Progression or Relapse.

Immune checkpoint inhibitors (ICIs) are at the forefront of advanced non-small-cell lung cancer (NSCLC) treatment. Still, only 27-46% of patients respond to initial therapy with ICIs, and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post hoc analyses of several clinical trials. Future research on ICI rechallenge for NSCLC should focus on better patient stratification to reflect the underlying biology of immunotherapy resistance more accurately. In this review, we summarize evidence regarding rechallenge immunotherapy efficacy following NSCLC disease progression or relapse, as well as ongoing trials on immunotherapy rechallenge.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis

BackgroundRecent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and...

Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study.

Immune checkpoint inhibitors (ICIs) have dramatically changed the first-line treatment pattern of non-small cell lung cancer (NSCLC) without driver gene alterations. However, the optimal choice for second-line treatment after initial treatment with ICIs is unclear. This study aimed to clarify the efficacy and safety of ICI rechallenge therapy in locally advanced and advanced NSCLC. We retrospectively analyzed the histories of 224 patients with locally advanced or advanced NSCLC treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy and/or antiangiogenic therapy in first-line treatment. Progression-free survival 2 (PFS2) was the time from the first defined progress disease (PD) to the second disease progression or death. Efficacy evaluation was performed directly in accordance with RECIST v1.1 criteria. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Survival data were estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test in overall cohort and other subgroups. There were no significant differences in objective response rate (ORR) and median PFS2 (mPFS2) between the ICI rechallenge group and non-rechallenge group (ORR: 10.3% vs. 15.3%, P=0.308; mPFS2: 5.33 vs. 4.40 months, P=0.715). And the ICI rechallenge group showed no new safety signals compared with non-rechallenge group. In ICI rechallenge group, patients resistant to first-line immunotherapy had a lower ORR and shorter PFS2 compared with those who responded to initial ICIs treatment (ORR: 7.0% vs. 17.6%, P=0.038; mPFS2: 3.68 vs. 5.91 months, P=0.014). No significant difference in mPFS2 was observed among different second-line treatment groups (P=0.362). Radiotherapy in second-line treatment and ICI rechallenge therapy were not the main factors affecting PFS2. ICI rechallenge therapy beyond disease progression did not improve clinical outcomes in patients with NSCLC, but no new safety signals emerged. However, patients with favorable response to initial ICIs treatment still showed significant efficacy of subsequent ICI rechallenge therapy.

An increased relative eosinophil count as a predictive dynamic biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

An increased relative eosinophil count (REC) has potential as a predictive biomarker for a beneficial clinical response and outcome to cancer immunotherapies. Therefore, the present study investigated the impact of an increased posttreatment REC on the prognosis of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). We retrospectively reviewed all 151 patients diagnosed with NSCLC and treated with ICI monotherapy and blood test data between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. A total of 151 patients with a mean age of 69 years were included. REC after 4 weeks of initial ICI monotherapy was higher than pretreatment REC in 87 patients but not in 64. REC after 4 weeks of the ICI treatment with and without an increased REC were 4.4 and 1.8%, respectively (p < 0.001). Disease control rates (DCR) were significantly higher in patients with than in those without an increased REC (84% vs. 47%, p < 0.001). The median overall survival (OS) of lung cancer patients with or without an increased REC were 674 and 234 days, respectively. A Kaplan-Meier univariate analysis revealed a significant difference in OS between the two groups (p < 0.001). A Cox proportional regression analysis identified an increased REC as an independent predictor of OS (p = 0.003). ICI-treated NSCLC patients with an increased REC after 4 weeks of treatment had a better DCR and prognosis than the other patients examined.

Occurrence of irAEs after Immune Checkpoint Inhibitor Rechallenge: An Updated Meta-Analysis

What Is Known? and Objective. Immune checkpoint inhibitors (ICIs) play an important role in various cancers. The efficacy and safety of rechallenge with ICIs after immune-related adverse events (irAEs) were not well known. Accumulating studies report inconsistent findings. Thus, we conducted an updated meta-analysis by including more studies. Methods. We searched PubMed, Web of Science, Embase, and Cochrane Library for studies reporting the rechallenge of ICIs after irAEs. The evaluation outcomes included the incidence of irAEs, objective response rate (ORR), and disease control rate (DCR). Results and Discussion. A total of 896 ICI rechallenge cases from 24 studies were included. Compared to the initial treatment with ICIs, rechallenge showed a higher incidence of all-grade irAEs (OR, 2.78; 95% CI, 1.51–5.10; p = 0.001 ) and high-grade irAEs (OR, 1.88; 95% CI, 1.27–2.78; p = 0.002 ), but ORR (OR, 1.01; 95% CI, 0.55–1.84; p = 0.97 ) and DCR (OR, 1.21; 95% CI, 0.68–2.15; p = 0.52 ) were not further improved after the rechallenge of ICIs. What Is New? and Conclusion. More studies are included in this paper to compare and analyze the efficacy and safety of ICIs after rechallenge, so as to update the previous meta-analyses, and finally get different conclusions from the previous meta-analyses in terms of safety. Our results suggest that rechallenged ICIs after irAEs showed similar efficacy and lower safety than initial ICIs. However, these results need to be further verified by high-quality studies with large samples. In addition, we added subgroup analysis not available in previous meta-analyses to explore the association of cancer type, age, and gender factors with the incidence of irAE after ICI rechallenge.

Assessments of therapeutic effects according to timings for combined therapy with axitinib and immune check point inhibitor in a mouse renal cell carcinoma model

Recently, several types of systemic therapy using tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been performed for advanced renal cell carcinoma (aRCC) patients; however, the optimal strategy of sequential treatment with these agents has not been well established. The objective of this study was to determine the differences of therapeutic effects according to timing for the introduction of TKI and ICI using a mouse RCC, RenCa model. The effects of combined treatment of TKI and/or ICI with axitinib, anti-mouse programmed death (PD)-1, or PD-ligand 1 (PD-L1) antibody on tumor growth and survival after subcutaneous and intravenous injection of RenCa cells, respectively, were compared according to three different treatment schedules: simultaneous administration, initial axitinib administration, and initial ICI administration. Infiltrating patterns of lymphocytes into tumors after combined treatments were evaluated by immunohistochemical staining. In mice treated with anti-PD-1 and anti-PD-L1 antibodies, significantly marked inhibitory effects on subcutaneous growth of tumors were observed in the simultaneous and initial ICI treatment groups, but not the group with the initial axitinib administration, compared to controls without treatment. Survival intervals of mice after intravenous injection of RenCa cells were significantly longer in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Furthermore, both CD8+ to CD3+ and CD8+ to CD11b+ T-lymphocyte ratios in subcutaneous RenCa tumors were significantly higher in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Favorable control against aRCC progression may be achieved by administering TKI and ICI simultaneously or ICI followed by TKI.

Large-scale comparative analysis of clinico-genomic characteristics, treatment outcomes and resistant mechanisms of ALK/ROS1/RET-rearranged non-small cell lung cancer (NSCLC) in a nationwide genomic screening project (LC-SCRUM-Asia/TRY).

9026 Background: There is limited understanding of the clinico-genomic differences among ALK/ROS1/RET-rearranged NSCLC due to their low frequency. We aimed to characterize these fusions using a large-scale LC-SCRUM-Asia/TRY database. Methods: We conducted a prospective screening of treatment-naïve and refractory lung cancer to identify genomic alterations using RT-PCR and/or targeted next-generation sequencing (NGS) assays in LC-SCRUM-Asia/TRY. We compared clinico-genomic characteristics, treatment outcomes and resistant mechanisms among ALK/ROS1/RET-rearranged NSCLC. Results: Between February 2013 and December 2022, 18,616 lung cancer patients (pts) were enrolled in LC-SCRUM-Asia/TRY and 16,583 were NSCLC pts. ALK/ROS1/RET fusions were identified in 430 (2.6%)/240 (1.4%)/202 (1.2%) pts in NSCLC. The patient characteristics were as follows ( ALK/ROS1/RET): median age, 58/60/63 years; females, 53/54/54%; never-smokers, 57/55/59%; adenocarcinoma, 93/95/96%. The frequencies of brain metastasis at diagnosis were 26/20/19% (p = 0.15). Among pts tested by NGS, the frequencies of TP53, TET2 and NOTCH1 mutations were lower in ALK than in ROS1 and RET ( TP53; 23/34/27%, NOTCH1; 17/34/35%, TET2; 17/30/32%). Overall survival (OS) was significantly longer in ALK than in ROS1 (mOS [ ALK/ROS1/RET] 108.8 vs. 43.6 vs. not reached [NR] months, ALK vs. ROS1; p &lt; 0.01, ALK vs. RET; p = 0.04) among stage IV pts underwent TKI therapy. TP53 mutation was associated with shorter OS in all three fusions (mOS [ TP53 mt+/mt-] ALK; 35.7 vs. 108.8, p &lt; 0.01, ROS1; 26.4 vs. 47.4, p = 0.06, RET; 28.9 vs. 76.1 months, p = 0.05), shorter PFS with first line alectinib in ALK (mPFS [ TP53 mt+/mt-] 11.0 vs. 38.4 months, hazard ratio [HR] 2.5 [95% CI, 1.5-4.2], p &lt; 0.01) and shorter PFS with initial crizotinib in ROS1 (mPFS [ TP53 mt+/mt-] 5.8 vs. 25.2 months, HR 2.6 [95% CI, 1.3-4.8], p &lt; 0.01). There was no significant difference in PFS with first-line platinum plus pemetrexed among fusions (mPFS 12.6 vs. 10.7 vs. 9.2 months) and PFS with initial immune checkpoint inhibitors among fusions (mPFS 3.9 vs. 5.1 vs. 3.0 months). Among 60/13/10 re-biopsy samples refractory to TKI, on-target resistant mutations were identified in 14 (23%) /3 (23%) /1 (10%) samples. Conclusions: Pts with ALK/ROS1/RET-rearranged NSCLC shared similar characteristics, but the occurrence of concomitant mutations was lower in ALK than in ROS1 and RET. TP53 mutation was associated with worse prognosis in pts with ALK/ROS1/RET-rearranged NSCLC. Among those received TKI, pts with ALK-rearranged NSCLC had better prognosis than those with ROS1 and RET-rearranged NSCLC. The development of highly effective molecular targeted therapies for ROS1- and RET-rearranged NSCLC is warranted.

Phase 1b trial of IFx-Hu2.0, a novel personalized cancer vaccine, in checkpoint inhibitor resistant merkel cell carcinoma and cutaneous squamous cell carcinoma.

9534 Background: Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC) exhibit high response rate to immune checkpoint inhibitor (ICI) therapy. However, patients with advanced disease who fail initial ICI therapy have limited treatment options. IFx-Hu2.0 (IFx) is a plasmid DNA encoding for an immunogenic bacterial protein, Emm55, formulated with a transfection agent for direct intratumoral injection. In a phase 1 study in advanced melanoma, biomarker analyses demonstrated robust immune priming effects of IFx administration. As part of an ongoing Phase 1b study, we evaluated the safety and immunologic response of different schedules of IFx intratumoral administration in patients with advanced MCC or cSCC. We report the initial results of the first stage of this study. Methods: In the first trial stage (n = 9), IFx was administered intratumorally in up to 3 lesions on 3 schedules; weekly x 1, 2, or 3. We report safety data for these patients. Given the proposed potential for immune priming effects of IFx, we performed an unplanned exploratory analysis of post-protocol treatment efficacy to evaluate for response to ICI rechallenge if given. Results: Five patients with advanced MCC and four with cSCC were enrolled. Prior to trial enrollment, all patients with MCC received ICI with pembrolizumab (4) or avelumab (1), all had progressive disease with median 3 months treatment (2.0-4.5mo). All 4 patients with cSCC previously received cemiplimab with median 6 months treatment (3.0-11.5mo). IFx was well tolerated at all dose schedules evaluated with no treatment-related G3-5 adverse events observed. Best response to trial therapy was SD in 2 patients and PD in seven. One MCC patient experienced complete clinical response in 2 injected lesions, but progression of disease overall with development of new disease areas. Following completion of protocol therapy, all 5 MCC patients and 2 of 4 cSCC patients were treated with anti-PD(L)1 therapy as the immediate post-protocol therapy: pembrolizumab (3) or avelumab (2) in MCC and cemiplimab (2) in cSCC. Four of 5 MCC patients and 1 of 2 cSCC patients, or 5 of 7 total (71%), experienced objective response to ICI rechallenge in this setting, with duration of response ongoing in 4 patients (7+, 8+, 9+, 20+ months) and one response lasting 23 months. Conclusions: IFx-Hu2.0 is safe and well tolerated at weekly dosing repeated up to 3 weeks. An exploratory analysis showed that five of seven patients (71%) treated with standard of care ICI agents following protocol therapy experienced a durable objective response despite prior failure of this same drug class prior to protocol enrollment. An additional 11 patients are planned for enrollment in the expansion stage of the study using the weekly x3 dosing schedule. Preliminary biomarker analyses from the first nine patients are ongoing and will be presented. Clinical trial information: NCT04160065 .

Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma.

Aims: Chronomodulation of immune checkpoint inhibitors (ICIs) is not well understood. The authors evaluated the circadian timing of initial ICI infusions. Patients & methods: A retrospective cohort study of patients with advanced melanoma (n=121) was conducted. Results: Exclusive afternoon timing of the first four infusions was associated with worse overall survival (5.5 vs 24.9months; p<0.001) and progression-free survival (3.3 vs 7.6months; p=0.009) on Kaplan-Meier curves. In multivariable Cox analysis, the rate of overall survival was lower in patients who received all first four ICI infusions in the afternoon versus patients who received ≥1 of the first four infusions in the morning (hazard ratio: 2.4; p=0.004). Conclusion: Deliberate morning scheduling for the first several ICI treatments may improve patient-centered outcomes.

Disease progression status during initial immune checkpoint inhibitor (ICI) affects the clinical outcome of ICI retreatment in advanced non-small cell lung cancer patients.

It is still unclear whether patients with advanced non-small cell lung cancer (NSCLC), with disease progression after initial immune checkpoint inhibitor (ICI) therapy, would benefit from ICIs readministration. We retrospectively collected data from patients with advanced NSCLC who received ICI retreatment. Depending on the disease status at the discontinuation of the initial ICI therapy, the patients were divided into two groups: with disease progression (PD group) and without disease progression (Without PD group). Patients in the Without PD group were required to experience disease progression during the treatment-free period. Efficacy was assessed by measuring the objective response rate (ORR) and progression-free survival in retreatment (PFS-R), while safety was assessed using the incidence of immune-related adverse events (irAEs). 30 (46.7%) of 64 eligible patients were included in the PD group and 34 (53.1%) in the Without PD group. Patients in the Without PD group had better clinical outcomes than those in the PD group (ORR, 29.4% vs. 6.7%; p = 0.03, median PFS-R, 4.1 months vs. 2.2 months, hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.36-1.04; p = 0.07). Multivariate Cox regression analysis showed that patients in the Without PD group had significantly longer PFS-R than those in the PD group (HR 0.42, 95% CI, 0.21-0.85; p = 0.015). In terms of safety, 28.1% of patients observed irAEs during ICI retreatment, and the incidence rate of grade 3 or higher irAEs was 7.8%. Specifically, of the 28 patients who discontinued their initial ICI treatment because of irAEs, 35.7% developed irAEs, and 28.6% experienced relapsed irAEs during ICI retreatment. Immune checkpoint inhibitor retreatment demonstrated efficacy in patients who discontinued initial ICI therapy for reasons other than disease progression. However, ICI retreatment was ineffective in patients with disease progression during the initial ICI treatment.

MP28-03 CYTOREDUCTIVE NEPHRECTOMY FOLLOWING IMMUNE CHECKPOINT INHIBITORS IS SAFE AND FACILITATES TREATMENT FREE INTERVALS

You have accessJournal of UrologyCME1 Apr 2023MP28-03 CYTOREDUCTIVE NEPHRECTOMY FOLLOWING IMMUNE CHECKPOINT INHIBITORS IS SAFE AND FACILITATES TREATMENT FREE INTERVALS Daniel Shapiro, Ali Ghasemzadeh, Jose Karam, Logan Zemp, Viraj Master, Wade Sexton, Facundo Davaro, Benjamin Schmeusser, Dattatraya Patil, Surena Matin, Philippe Spiess, and E. Jason Abel Daniel ShapiroDaniel Shapiro More articles by this author , Ali GhasemzadehAli Ghasemzadeh More articles by this author , Jose KaramJose Karam More articles by this author , Logan ZempLogan Zemp More articles by this author , Viraj MasterViraj Master More articles by this author , Wade SextonWade Sexton More articles by this author , Facundo DavaroFacundo Davaro More articles by this author , Benjamin SchmeusserBenjamin Schmeusser More articles by this author , Dattatraya PatilDattatraya Patil More articles by this author , Surena MatinSurena Matin More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , and E. Jason AbelE. Jason Abel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Immune checkpoint inhibitors (ICI) are first line therapy for metastatic renal cell carcinoma (mRCC). Additionally, cytoreductive nephrectomy (CN) is often performed after initial ICI therapy. Few data exist on the effect of upfront ICI therapy on perioperative CN outcomes. This study evaluated intraoperative and postoperative CN outcomes for patients who underwent upfront ICI. METHODS: Four tertiary level institutions retrospectively evaluated perioperative outcomes among consecutive patients who received upfront ICI followed by deferred CN. Intraoperative and postoperative outcomes were tabulated. Complications were graded according to the Clavien-Dindo complication scale with complications grade ≥III considered to be high grade. RESULTS: A total of 75 patients were identified between 2017-2022. Clinical characteristics are listed in Table 1. The patients were generally healthy with good performance status. Majority were IMDC intermediate risk (71%) and received ipilimumab and nivolumab therapy (90%). Median time on ICI therapy was 3 months (IQR 2-9). The majority underwent an open radical nephrectomy (71%) of which 13% had an IVC thrombus. The median operative time was 177 minutes (IQR 112-239) with median blood loss of 195cc (IQR 100-400). Three patients had intraoperative complications. Median length of stay was 4 days. The 90-day complication rate was 19/75 (25%), of which only 2/75 (3%) were high grade (Clavien ≥III). This included one patient who aspirated and required intubation and another patient with an upper GI bleed requiring endoscopy. None died within 90 days, and 1 patient was readmitted within 30 days. Regarding postoperative therapy, 36/75 (48%) were rendered with minimal or no residual disease and have not restarted ICI therapy at last follow-up. Of those that did restart therapy, the median time to restart ICI was 34 days (IQR 23-56 days). CONCLUSIONS: In this select group of consecutive patients with good PS treated at tertiary level hospitals, deferred CN following ICI therapy was safe with rare incidence of high-grade complications. Additionally, many patients were rendered with minimal residual disease allowing them to be placed on surveillance thus avoiding the toxicity of further ICI therapy. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e369 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Shapiro More articles by this author Ali Ghasemzadeh More articles by this author Jose Karam More articles by this author Logan Zemp More articles by this author Viraj Master More articles by this author Wade Sexton More articles by this author Facundo Davaro More articles by this author Benjamin Schmeusser More articles by this author Dattatraya Patil More articles by this author Surena Matin More articles by this author Philippe Spiess More articles by this author E. Jason Abel More articles by this author Expand All Advertisement PDF downloadLoading ...

Contrast-enhanced CT parameters predict short-term tumor response in patients with hepatocellular carcinoma who received sequential combined anti-angiogenesis and immune checkpoint inhibitor treatment

PurposeTo evaluate whether relative Hounsfield unit attenuation index (rHUAI) on contrast-enhanced computed tomography (CECT) can predict tumor response in advanced hepatocellular carcinoma (HCC) patients who received sequential combined treatment of immune checkpoint inhibitor (ICI) and anti-angiogenesis therapy. MethodOne hundred seventeen advanced HCC patients who underwent the sequential combined treatment in a tertiary hospital between March 2020 and December 2021 were allocated to prediction and validation cohorts (with a ratio of 2:1) based on the time of initial ICI treatment. rHUAI from the arterial to the portal-venous phase (rHU_ap) and from the portal-venous to the delayed phase (rHU_pd) was calculated. The optimal cut-off values (COVs) of rHU_ap and rHU_pd for predicting tumor response were identified using Youden’s index. Univariate and multivariable analyses were performed to assess the relationship between the COVs and tumor response. The validity of COVs was verified in the validation cohort using the chi-square test and Cramer’s V coefficient (V). ResultsThe optimal COVs of the two observers were 0.5316 and 0.3265 for rHU_ap, and −0.0208 and −0.0048 for rHU_pd, respectively. Multivariable analysis suggested that the COVs were independently associated with tumor response in the prediction cohort (rHU_ap, Odds ratio: 7.727 and 7.808, 95 % CI: 2.516–23.728 and 2.399–25.410, p value < 0.001 and 0.001; rHU_pd, Odds ratio: 0.034 and 0.011, 95 % CI: 0.002–0.600 and 0.001–0.209, p value of 0.021 and 0.003). In the validation cohort, the optimal COVs of rHU_ap had a moderate to a strong association with tumor response (V = 0.362–0.545, p < 0.05). The association between COVs of rHU_pd and tumor response was slight to strong (V = 0.24–0.545, p = 0.001 to 0.134). ConclusionrHUAI obtained from CECT has the potential as a non-invasive tool for predicting tumor response in advanced HCC patients who have received combined ICI and anti-angiogenesis treatment.

Resistance to immune checkpoint inhibitors in advanced lung cancer: Clinical characteristics, potential prognostic factors and next strategy.

Immune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance. 190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance. We found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs. Patients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance.

Rechallenge with Anti-PD-1 Inhibitors in Patients with Recurrent Gynecologic Malignancies.

We investigated the treatment outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with recurrent gynecologic cancers. We retrospectively reviewed the medical records of 20 patients who underwent rechallenge with PD-1 inhibitors for recurrent gynecologic cancers at two tertiary centers between January 2018 and September 2022. The median age of the patients was 56 years (range, 35-79). Seven (35%), 1 (5%), 11 (55%), and 1 (5%) patients presented with cervical, vulvar, ovarian, and endometrial cancers, respectively. Sixteen (80%) patients received pembrolizumab and 4 (20%) received nivolumab at first treatment. Eight (40%) and 12 (60%) patients received pembrolizumab and nivolumab, respectively, at second treatment. At initial ICI treatment, 1 (5%) and 4 (20%) cases of a complete response (CR) and a partial response (PR) were observed, respectively, with a median progression-free survival (PFS) of 2.8 months (range, 1.4-49.6). Reasons for first ICI discontinuation were disease progression (n=16), severe adverse events (AEs) (n=2), and treatment withdrawal (n=2). During second ICI treatment, 1 (5%) patient achieved CR, 2 (10%) showed PR, and 5 (25%) experienced stable disease. The median PFS to second ICI was 1.8 months (range, 0.4-10.4). The median overall survival was 21.3 months (range, 10.1-52.7). Neither patient who discontinued ICI treatment due to AEs experienced AE relapse during second ICI treatment. These results suggest that responses to ICI rechallenge are not as intolerable as responses to previous ICI. Clinicians should carefully consider rechallenge with PD-1 inhibitors outside of clinical trials until there are sufficient data to routinely support this practice.

Preconditioning of the immune system modulates the response of papillary thyroid cancer to immune checkpoint inhibitors

BackgroundThe response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown.MethodsTo test the hypothesis...

Prognostic value of plasma D-dimer levels in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: a retrospective study.

Plasma D-dimer is of great significance for the clinical exclusion of tumor-related thrombosis. Previous studies have shown its predictive role in non-small cell lung cancer (NSCLC) treated with chemotherapy. However, whether pretreatment D-dimer could predict the efficacy and prognosis in NSCLC patients treated with immune checkpoint inhibitors (ICIs) remains unclear. Advanced NSCLC patients treated with ICIs at the Chinese PLA General Hospital between January 2015 and March 2019 were enrolled. Patients were divided into a pretreatment normal D-dimer group (≤0.5 µg/mL) and high D-dimer group (>0.5 µg/mL). Optimization-based approach was applied to balance baseline covariates between the 2 groups, including age, sex, histological type, smoking history, stage, Eastern Cooperative Oncology Group Performance Status (ECOG PS), lines of treatment, ICI drugs, brain metastasis, treatment type, and D-dimer levels. Kaplan-Meier analysis and Cox proportional hazards model were used for analyzing survival data, including progression-free survival (PFS, the time from initial ICI treatment to PD or death), overall survival (OS, the time between initial ICI treatment and death), and hazard ratio (HR). Follow-up of all patients was performed by searching electronic medical records and counseling telephone. The follow-up cut-off date was July 6, 2020. This study included 277 advanced NSCLC patients. Among the enrolled patients, 23.1% were female, 64.6% had non-squamous cell lung cancer, and 79.4% were stage IV. Univariate and multivariate analysis showed that pretreatment high D-dimer levels were independently associated with shortened PFS and OS (P<0.01). Subgroup analysis confirmed that pretreatment high D-dimer levels were associated with poor prognosis in most subsets. After balancing baseline covariates between the high D-dimer group and normal D-dimer group, the results indicated that patients with pretreatment high D-dimer levels had significantly shorter PFS [median: 6.4 vs. 11.5 months; HR, 1.70; 95% confidence ratio (CI): 1.25-2.37; P<0.001] and OS (median: 12.7 vs. 30.4 months; HR, 2.29; 95% CI: 1.54-3.41; P<0.001) than those with pretreatment normal D-dimer levels. Pretreatment plasma D-dimer could serve as a convenient prognostic biomarker for advanced NSCLC patients receiving ICI treatment. Patients with pretreatment high D-dimer levels may have poor PFS and OS.