Combination Of Ipilimumab Research Articles

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Combination nivolumab and ipilimumab with and without camu camu in first-line treatment of metastatic renal cell carcinoma (mRCC).

TPS491 Background: Combination immune checkpoint inhibition (ICI) with ipilimumab and nivolumab (ipi/nivo) is an established first-line treatment for patients (pts) with intermediate and poor-risk mRCC. CheckMate214 demonstrated a survival advantage with ipi/nivo over sunitinib; unfortunately, 20% of cases developed primary progression to immunotherapy. Recent data suggest that the gut microbiome is key in modulating clinical responses and immune-related toxicities. Therefore, modulating the gut microbiome is a novel adjunct strategy to dual ICI in mRCC. Our group has previously proven that the addition of a live bacterial product (CBM588) enhances clinical responses in pts with mRCC treated with ICI, and the combination of ICI (Dizman et al., 2022) or with a tyrosine kinase inhibitor (Ebrahimi et al., 2023). Camu camu ( Myrciaria dubia) is a comestible berry characterized by a polyphenol-rich nutritional profile. In extract form, it is rich in castalagin, which appears to have probiotic properties. In mouse tumor models, camu camu increased the abundance of fecal Ruminococcus spp. when combined with ICI (Messaoudene et al., 2022). This shift in the gut microbiome composition was associated with stronger CD8+ T-cell and CD4+ Th1-dependent antitumor responses. Camu camu and ICI reestablished the efficacy of anti-PD1 therapy, reducing tumor size compared to ICI alone. This pilot study aims to identify the biological effect of camu camu with ipi/nivo in pts with mRCC. Methods: This is an investigator-initiated, randomized, open-label, single-center trial comparing camu camu with ipi/nivo versus ipi/nivo alone in pts with treatment-naïve mRCC. Eligibility criteria include pts ≥ 18 year old, PS 0-1, histological confirmation of clear-cell RCC with or without a sarcomatoid component, intermediate or poor risk per IMDC, no prior systemic treatment and measurable disease,. 30 pts will be enrolled and randomized in a 2:1 fashion, favoring the study arm. Pts will be treated with camu camu at 1500 mg PO daily, in with ipi/nivo at standard dosing. Pts will be followed monthly. Treatment will be continued until progression (RECIST v1.1) or toxicity. The primary endpoint is change in the abundance of Ruminococcus spp. in the stool from baseline to week 12 of therapy. We have 80% power to detect a 1 SD difference between the mean change detected in the two groups using a two-group T-test with a one-sided type I error of 0.05. Secondary endpoints include overall response rate, progression-free survival, safety, effect on gut microbiome diversity and function, comparison of the proportion of circulating cytokines and chemokines from baseline to week 12, and changes in the abundance of metabolic pathways and fungal microbiome profile. Response will be assessed by CT after the first 12 weeks of therapy and every 12 weeks, thereafter. The study is currently open to enrollment. Clinical trial information: NCT06049576 .

Analysis of Clinical Success and Molecular Mechanisms of Action of Novel Anti-glioblastoma Drugs: A Review.

Gliomas and glioblastomas (GBM) are common primary malignant brain tumors, which are highly malignant and have a poor prognosis. The presence of cancer stem cells with unrestricted proliferative capacity and ability to generate glial neoplastic cells, the diffuse nature of GBM, and other specific factors of GBM contribute to poor results of drug therapy in patients with GBM. Despite the worldwide efforts to improve the treatment, many novel anti-GBM drugs are active just in vitro, in silico, and in preclinical trials, and they sometimes demonstrate poor or no activity in clinical trials. In this paper, we have casually selected and analyzed the most promising evidence-based results related to glioblastoma treatment at FDA and Clinical Trials.gov databases. It was observed that the most prospective trend in the development of anti-GBM drugs is combination therapy vs. monotherapy. Our analysis of clinical trials has allowed us to predict that the most promising combination therapy that has shown the best results in patient's surveillance should include drugs that block different growth-promoting signals in glioblastoma cells and that are activated by the V600E BRAF mutation. One drug should inhibit signals from the BRAF protein, whereas the second drug in combination should inhibit signals from the MEK protein Methods: The content of this review is based on information obtained from PubMed, ClinicalTrials. gov, and the U.S. Food and Drug Administration (https://www.fda.gov/). In ClinicalTrials.gov, we retrieved studies published from January 1, 2015. In the data search, "Glioblastoma" was used as the keyword. A study was deleted if it studied remedies for concomitant tumor diseases, as well as if it did not include descriptions of treatment methods and/or if GBM was not mentioned. The analysis of the effectiveness of treatment was carried out according to the increasing overall survival in GBM patients, compared to the gold standard for this cancer. GBM patients treated with novel immunotherapy agents and drugs acting on epigenetic factors and receptor tyrosine kinase inhibitors have shown encouraging potential for future development in clinic. However, combinations of drugs have led to more significant improvements in the results and an increase in life expectancy of patients. For example, the combination of nivolumab and ipilimumab showed a 72% increase in life expectancy compared to using nivolumab alone (9.8 vs. 16.85). Combining anti-GBM drugs appears to be a key direction for increasing treatment effectiveness and overall survival. Radiotherapy of GBM can increase the effect of combination drug therapy.

Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3years of follow-up.

Long-term follow-up data regarding treatment outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma as a first-line therapy are limited in real-world Japanese populations. We retrospectively evaluated data of 56 advanced renal cell carcinoma patients treated with nivolumab plus ipilimumab, with a follow-up of at least 3years. Survival, tumour response and adverse event profiles were assessed. A total of 41 patients (73%) were histopathologically diagnosed with clear-cell renal cell carcinoma, and 34 (61%) were categorized into the International Metastatic renal cell carcinoma Database Consortium intermediate-risk group. The median follow-up period was 34.4months. Regarding an effectiveness profile, median progression-free survival, time to treatment failure and overall survival were 9.01, 12.5 and 49.0months, respectively. Objective response was observed in 27 patients (48%), including eight patients with complete response (14%), and the median duration of response was 30.8months. Multivariate analyses showed that clear-cell histology was an independent factor of longer overall survival (hazard ratio: 0.23, P=0.0013). Regarding safety profiles, adverse events of any grade and those with grade≥3 developed in 40 (71%) and 25 patients (45%), respectively. Median time to adverse event development was 1.68months. Treatment was interrupted in 28 patients (50%), and corticosteroid administration was needed in 25 (45%). The 3-year follow-up data showed that nivolumab plus ipilimumab combination therapy exhibited a feasible effectiveness in real-world Japanese patients with advanced renal cell carcinoma. Accordingly, the high risk of adverse event development, which often requires treatment withdrawal and corticosteroid administration, should be considered.

Efficacy of immunotherapy in patients with metastatic melanoma

Introduction. Melanoma is an aggressive form of skin cancer caused by the transformation of melanocytes into malignant cells. Currently, immunotherapy is one of the most promising treatment methods, but searching the most optimal treatment regimens is still ongoing.Objective. To evaluate the effectiveness and safety of the use of immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma.Materials and methods. The study included 229 patients (114 men and 115 women) aged 21 to 91 years who received (ICIs) as nivolumab (n = 168; 73,4%) and pembrolizumab (n = 30; 13,1%) monotherapy, and combination of nivolumab and ipilimumab (n = 31; 13,5%). The objective response of the tumor to treatment was recorded in the presence of partial or complete regression of the tumor. The tumor response to treatment was determined in accordance with the iRECIST criteria.Results. Complete regression was observed in 16.7, 15.9 and 8,7% of patients, partial – in 11.1, 11.4 and 17.4%, stabilization was detected in 51.2, 50.0 and 34.8% and progression – in 21.0, 22.7 and 39.1% of patients with first, second and third and more-line setting, respectively. The median response time was 3.14, 5.18 and 3.63 months, the median response duration was 16.21, 8.96 and 30.15 months in first, second and third and more-line setting, respectively. Grade 3–4 immuno-related adverse events (irAEs) were observed in 8 (3.5%) patients.Conclusions. Immunotherapy of metastatic melanoma allows achieving high rates of objective response and disease control (27.5 and 76.9%, respectively). This method of treatment is characterized by an insignificant amount of grade 3–4 irAEs (3.5% according to our data), which indicates an acceptable safety profile.

Cross-trial comparisons for the adjuvant treatment of MSI colorectal cancer: dare to dream the future scenarios.

The remarkable outcomes achieved with neoadjuvant checkpoint inhibitors for patients diagnosed with MSI colorectal cancer hold the potential to revolutionize the treatment landscape in this context. Specifically, the combination of nivolumab plus ipilimumab in colon cancer and dostarlimab in rectal cancer has led to an unprecedented rate of complete pathological and clinical responses. Notably, these responses have been further substantiated by the absence of relapses, with a 0% relapse rate observed during the first year of follow-up. The significance of these achievements becomes even more apparent when compared to the relatively high relapse rates, ranging from 11% to 28%, observed in MSI colorectal cancer cases treated neoadjuvantly with chemo(radio)therapy. However, it is crucial to exercise caution when interpreting such exceptional responses in oncology, especially within a short follow-up period. The future implications of these findings will depend on how the data mature over time. In this manuscript, we attempt to explore the potential scenarios that may unfold in the near future.

Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab Combination Therapy as First-line Treatment for Advanced Renal Cell Carcinoma in Japan

ObjectivesThe purpose of this study is to examine the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy (NIVO + IPI) compared with the sunitinib (SUN) therapy for Japanese patients with advanced renal cell carcinoma from the perspective of a Japanese health insurance payer. MethodsA lifetime horizon was applied, and 2% per annum was set as the discount rate. The threshold was set as $ 75 000 per quality-adjusted life-year (QALY) gained. For the analytical method, we used a partitioned survival analysis model to estimate the incremental cost-effectiveness ratio (ICER), which is calculated by dividing incremental costs by incremental QALYs. Progression-free survival, progressive disease, and death were set as health states. Additionally, cost parameters and utility weights were set as key parameters. We set the intermediate/poor-risk population as the base case. Scenario analysis was conducted for the intention-to-treat population and the favorable risk population. Furthermore, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted for each population. ResultsIn the base-case analysis, the QALYs of NIVO + IPI and SUN were 4.32 and 2.99, respectively. NIVO + IPI conferred 1.34 additional QALYs. Meanwhile, the total costs in the NIVO + IPI and SUN were $692 288 and $475 481, respectively. As a result, the ICER of NIVO + IPI compared with SUN was estimated to be $162 243 per QALY gained. The parameter that greatly affected the ICER was the utility weight of progression-free survival in NIVO + IPI. ConclusionsNIVO + IPI for advanced renal cell carcinoma seems to be not cost-effective compared with the SUN in the Japanese healthcare system.

Single agent vs combination immunotherapy in advanced melanoma: a review of the evidence.

The aim of this review is to outline the current landscape of advanced melanoma treatment options, provide insights on selecting combination therapies within different clinical scenarios, capture clinical relevance of anti-programmed cell death protein 1 (PD-1) monotherapy, and explore the unmet needs with immune check-point inhibitors (ICI) in advanced melanoma. ICI based treatment consisted of single agent ICI or dual combination ICI-ICI is the standard of care of front-line treatment of metastatic or unresectable melanoma. PD-1 inhibitors (Pembrolizumab and Nivolumab) improved progression free survival (PFS) and overall survival (OS) compared to chemotherapy and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors (Ipilimumab and Tremelimumab). The dual ICI combination (Nivolumab and Ipilimumab) provided profound and durable responses better than monotherapy, and the longest overall survival ever achieved in advanced disease, including in patients with murine sarcoma viral oncogene homolog B (BRAF)-mutated disease, but at the cost of a high risk of severe toxicity. The new dual blockage of LAG-3 and PD-1 (Nivolumab-Relatlimab) emerges as a valid option with promising efficacy outcomes and a favourable toxicity profile. Mature survival data is still needed to capture the real benefit. These new plethora of options pose new challenges not only for optimal treatment sequencing strategies but especially for management of adverse effects, endorsing the need to integrate a holistic and personalized approach for patient care.

Chemotherapy combined with immune checkpoint inhibitors may overcome the detrimental effect of high neutrophil-to-lymphocyte ratio prior to treatment in esophageal cancer patients.

Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for esophageal cancer (EC). Although ICIs enable long-term survival in some patients, the efficacy of ICIs varies widely among patients. Therefore, predictive biomarkers are necessary for identifying patients who are most likely to benefit from ICIs to improve the efficacy of the treatment. We retrospectively analyzed the outcomes of combination therapy, including nivolumab plus ipilimumab or chemotherapy plus anti-programmed cell death 1 (PD-1) antibodies in our institute to identify biomarkers. Twenty-seven patients received nivolumab plus ipilimumab, and thirty-six patients received chemotherapy plus anti-PD-1 antibodies were included in this study. We analyzed patient characteristics, efficacy, and safety. Multivariable analysis of biomarkers evaluated the correlation among overall survival (OS), progression-free survival (PFS), and the following variables: body mass index, performance status, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein level, and albumin level before treatment. In multivariable analysis, albumin level was significantly correlated with PFS in the cisplatin plus 5-fluorouracil (CF) plus pembrolizumab group. NLR and albumin level were significantly correlated with OS in the nivolumab plus ipilimumab group. Other variables, including PS, BMI, and CRP did not correlate with any of the outcomes. High NLR in EC patients prior to treatment was significantly less effective for ICIs. In chemotherapy combined with ICIs, NLR before the treatment was not associated with treatment efficacy, suggesting combination chemotherapy may be beneficial for EC patients with high NLR. NLR may be an indicator of immunocompetence in anti-tumor immunity and a convenient predictive biomarker for selecting appropriate treatments including ICIs.

PD-L1 is a biomarker of real-world clinical outcomes for anti-CTLA-4 plus anti-PD-1 or anti-PD-1 monotherapy in metastatic melanoma

BackgroundMetastatic melanoma (MM) is commonly treated with a combination of nivolumab and ipilimumab, regardless of tumor PD-L1 expression. MethodsWe conducted a population-based study including all patients with MM (except ocular melanoma) treated in Denmark with first-line combination therapy or anti-PD-1 monotherapy since January 2017. Baseline data including known prognostic characteristics were used in multivariable and propensity-matched score (PMS) analyses to assess progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) according to PD-L1 expression. ResultsWe identified 1341 eligible patients, with known PD-L1 status for 1081 patients (43% PD-L1 ≥ 1%, 57% PD-L1 < 1%). PD-L1 ≥ 1% was an independent positive prognostic biomarker for survival in the overall cohort (MSS: HR 0.66, CI 0.52–0.83, p < 0.001). In the PMS PD-L1 ≥ 1% cohort, combination therapy showed similar clinical outcomes to monotherapy (PFS: HR 1.41, CI 0.94–2.11, p = 0.101; MSS: HR 1.21, CI 0.70–2.11, p = 0.49; OS: HR 1.17, CI 0.68–2.00, p = 0.567). In contrast, in the PMS PD-L1 < 1% and in the PMS PD-L1 < 1% BRAF WT cohorts, combination therapy improved PFS (respectively with HR 0.70, CI 0.53–0.93, p = 0.013; and HR 0.54, CI 0.37–0.78, p = 0.001), but did not reach statistically significant improvements of MSS (HR 0.72, CI 0.50–1.02, p = 0.065; and HR 0.79, CI 0.51–1.21, p = 0.278) or OS (HR 0.78, CI 0.56–1.08, p = 0.135; and HR 0.81, CI 0.54–1.21, p = 0.305) compared to monotherapy. ConclusionOur findings support previous exploratory analyses of Checkmate-067, highlighting that improved clinical outcomes with combination therapy are not established in unselected patients with high (≥1%) tumor PD-L1 expression.

Efficacy and safety of nurulimab+prolgolimab with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable or metastatic melanoma: final results of the phase II OBERTON clinical study

Background. In an era of breakthroughs in cancer immunotherapy, CheckMate 067 studies declared the combination of PD-1 and CTLA-4 inhibitors a new standard of care for patients with metastatic melanoma (MM). A significant limitation of the widespread use of the combination of ipilimumab and nivolumab in routine clinical practice is the high risk of severe immune-mediated adverse events. Prolgolimab and nurulimab are a combination of fixed doses of original monoclonal antibodies (manufactured by JSC "BIOCAD," Russia) to the PD-1 receptor (prolgolimab) and the CTLA-4 receptor (nurulimab) (3:1 ratio). This paper presents the results of an international, multicenter, double-blind, placebo-controlled, comparative, randomized, phase II OBERTON clinical study to investigate the efficacy and safety of nurulimab + prolgolimab combination therapy with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable melanoma (uRM) or MM (NCT03913923).&#x0D; Materials and methods. The study included patients with uRM or MM who were not previously treated for metastatic disease. The patients were randomized into two groups (1:1). Patients in group 1 were treated with a nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) combination at a dose of 0.2 mL/kg (equivalent to 1 mg/kg of nurulimab and 3 mg/kg of prolgolimab) once every 3 weeks during the first 4 blinded infusions. Patients in group 2 received prolgolimab monotherapy at a dose of 3 mg/kg once every 3 weeks during the first 4 blinded infusions. Starting from infusion 5, patients in both groups received open prolgolimab 1 mg/kg once every 2 weeks. The primary endpoint of the study was progression-free survival (PFS). The study is registered on ClinicalTrials.gov under the number NCT05732805 and is currently ongoing, but recruitment of new patients has been completed.&#x0D; Results. One hundred seventeen patients were randomized and received at least one dose of the study therapy. At a median follow-up of 16.79 months, the median PFS was 12.2 (4.9; not achieved) months in the nurulimab + prolgolimab group and 2.8 (1.5; 4.7) months in the prolgolimab monotherapy group (95% confidence interval 0.36-0.90, hazard ratio 0.57). PFS at 24 months was 41% in the nurulimab + prolgolimab group and 25.4% in the prolgolimab monotherapy group. In both groups, the therapy was well tolerated. Grade 3-4 immune-mediated adverse events were reported in 15.5% of patients who received nurulimab + prolgolimab, compared with 1.7% of those who received prolgolimab alone. The most frequent grade 3-4 treatment-related adverse events in both treatment groups were increased alanine aminotransferase and aspartate aminotransferase and asthenia. Overall, the safety profile was favorable, as expected for the class of immune checkpoint inhibitors, anti-CTLA-4, and anti-PD-1 monoclonal antibodies.&#x0D; Discussion. The results demonstrate a favorable safety profile in both the nurulimab + prolgolimab combination and prolgolimab monotherapy groups as the first-line treatment for uRM or MM. The assessment of the primary endpoint, PFS, showed the benefit of combination immunotherapy followed by switching to prolgolimab compared to prolgolimab alone.&#x0D; Conclusion. Combination immunotherapy with the CTLA-4 inhibitor nurulimab and the PD-1 inhibitor prolgolimab, available as a combination of solutions of two drugs in a single vial, with a further switch to monotherapy with prolgolimab, can fill an important niche in the treatment of patients with uRM or MM. Confirmation of the obtained data on the efficacy and safety of the combined regimen of nurulimab + prolgolimab in comparison with PD-1 inhibitor monotherapy is expected from the ongoing phase III BCD-217-2 OCTAVA study (NCT05732805).

Clinical case of using combination of nivolumab and ipilimumab in first line of treatment for inoperable pleural mesothelioma

Cytostatic therapy still remains the gold standard for the treatment of inoperable pleural mesothelioma with a life expectancy of about 9–18 months. The article presents the results of the use of immune checkpoint inhibitors in the first treatment line for inoperable malignant pleural mesothelioma and management of immune-related adverse events in an elderly patient.

A single-center retrospective analysis of prognoses in patients with melanoma brain metastases and effectiveness of treatment in Japan.

Melanoma brain metastasis (MBM) has a poor prognosis, although recent treatments, including immune checkpoint inhibitors and targeted therapy, have improved the prognosis. However, these systemic therapies have been reported to be less efficient for Asian patients. We investigated the survival of Asian patients with MBM and the effectiveness of systemic therapies. We retrospectively reviewed the survival rates of patients diagnosed with MBM between January 2011 and December 2021 at the National Cancer Center Hospital in Tokyo, Japan. In addition, we identified factors associated with survival using Cox regression analysis. A total of 135 patients were included. The median overall survival (OS) after an MBM diagnosis was 7.8 months (95% confidence interval [CI] 6.1-9.6). The 6-month and 1-year survival rates were 60.7% and 34.8%, respectively. We identified the prognostic factors of MBM, including non-acral primary location, low serum LDH levels, systemic therapy of single-agent immune checkpoint inhibitors (ICIs) or targeted therapies (TTs), and radiotherapy of stereotactic irradiation (STI). We found no significant difference in effectiveness between single-agent ICIs, the combination of Nivolumab and Ipilimumab (COMBI-ICI), and TTs (COMBI-ICI vs. single-agent ICI, hazard ratio 0.71, 95% confidence interval 0.27-1.88, p = 0.49; COMBI-ICI vs. TT: hazard ratio 0.46, 95% confidence interval 0.14-1.55, p = 0.21). Systemic therapy and radiotherapy have improved the survival of MBM patients, but the survival of Asian patients remains poor. Our findings suggest that COMBI-ICIs are not significantly more effective than single-agent ICI or TT in treating MBM.

Tracking of Leukemia and Immune Single Cell Phenotypes during Ipilimumab-Based Treatment By Long-Read Sequencing

Activity of ipilimumab in bone marrow-involved AML has been modest compared to extramedullary AML relapse or solid tumors like melanoma. Single cell transcriptomics (scRNA-seq) could provide deeper understanding of these differences, yet leukemia and immune cell phenotypes defined by somatic mutations or differential isoform expression often cannot be resolved with native short-read scRNA-seq data due to insufficient read coverage. To overcome this limitation, we devised a workflow ( nanoranger) that leverages improved accuracy of long-read sequencing (Oxford Nanopore, ONT) and enables targeted read-out of molecular features including single-nucleotide variants, gene fusions, isoforms, or T cell receptor (TCR) sequences from intermediate scRNA-seq cDNA libraries. To determine the performance of nanoranger, we undertook a series of assessments. First, we established its genotyping accuracy based on the ability to recover highly polymorphic TCR sequences. TCRs obtained with Illumina versus ONT from the same VD(J) amplicon library were highly concordant ( r&amp;gt;0.8) in the number of reads and cells per CDR3 (5,653 [ONT] vs. 5,767 [Illumina]). Second, we tested isoform profiling by targeted sequencing of PTPRC which encodes the T cell differentiation markers CD45RA (exon 4 present) and CD45RO (exon 4 absent). Not only did targeted ONT sequencing increase the single cell coverage of PTPRC from 10 to &amp;gt;2,600 cells, but PTPRC exon 4 expression also correlated with CD45RA surface marker expression by CITE-seq ( r=0.45). Third, we benchmarked somatic mutation detection of a homozygous TP53 R248Gmutation in the AML cell line Kasumi-1. Our ONT-based approach increased genotyped cells from 0% (via native scRNA-seq) to 22% ( nanoranger); in &amp;gt;98.8% of these cells, TP53 R248G was detectable. Finally, we searched for optimal nanoranger targets by assessing whole-transcriptome coverage of 5‘ single cell cDNA and found these to be loci at the 5‘ end of highly expressed transcripts shorter than 4 kB. Altogether, nanoranger reliably recovers molecular features from scRNA-seq libraries with genotyping efficiency dictated by inherent characteristics of the underlying cDNA. To better understand determinants of response and resistance of CTLA-4 blockade in AML, we applied nanoranger to bone marrow samples collected in the context of a phase I trial investigating combined decitabine and ipilimumab (NCT02890329). We genotyped 11 genes recurrently mutated in AML across 15,258 single cell profiles from 13 samples (5 responders at screening and best response, 3 non-responders at screening). At screening, somatic mutations were detectable in myeloid progenitor, monocytic and dendritic cells but also in erythroid and megakaryocytic progenitor populations, consistent with detected copy number changes. Further, we clarified AML subclones with integrated analysis of somatic mutations and chromosomal aberrations. In AML1019, we found two separate clones defined by presence or absence of RUNX1 R320* and amp(8p) or amp(21p). In AML8007, we tracked differential therapeutic responses. At screening, 3 somatic mutations ( DNMT3A V296M, TP53 C176S, TP53 R282W) and 3 chromosomal aberrations ( amp(1p), del(3p) and del(5q)) were detected. At remission, somatic mutations and del(5q) persisted, but amp(1q) and del(3p) became undetectable except in LMPP-like cells. In all 5 responders, somatic mutations remained detectable in all cellular compartments, revealing that the cytoreductive effect of decitabine/ipilimumab was not accompanied by leukemic clone eradication. The ability of nanoranger to perform isoform profiling enabled us to resolve immune phenotypes. Following CTLA-4 blockade, the PTPRC isoform CD45RA was downregulated in CD4 + and CD8 + T cells, consistent with induction of T cell differentiation by ipilimumab. As CTLA-4 exists in two isoforms, we tracked alternative splicing of exon 3 and observed lower expression of the membranous isoform in T cells from AML bone marrow compared to circulating or tumor-infiltrating lymphocytes in melanoma, pointing to context-specific isoform expression of CTLA-4. In sum, genotyping with nanoranger substantially augmented scRNA-seq analyses of ipilimumab-based therapy in bone marrow AML. This exemplifies the great potential that long-read sequencing-based single cell studies hold to better define response and resistance mechanisms of novel immunotherapies.

Association between immune-related adverse events and prognosis in patients treated with immune checkpoint inhibitors in melanoma: A surrogacy analysis.

Immune checkpoint inhibitors (ICI) represent a breakthrough in oncology in terms of prognosis and safety. They now constitute a cornerstone in the management of metastatic melanoma. However, a new kind of adverse event called immune-related adverse events (irAE) has emerged. These irAE could be conceptually considered as an indicator of the antitumoral immune response, but the association between irAE and prognosis is still a matter of debate. The purpose of this study was to investigate the association between the overall survival (OS) and the prevalence of irAE in melanoma. MEDLINE/PubMed, WebofScience, ClinicalTrials, and WHOTrials databases were searched to identify phase 3 randomized controlled trials (RCT) assessing ICI in melanoma and published up to April 2021. A weighted regression was performed to estimate this association according to standard method of surrogacy analysis. A total of 14 RCT including 7646 patients (median age: 59.3years) with melanoma were included. All types of ICI were represented (ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, as well as ipilimumab and nivolumab combination). irAE were frequent but rarely fatal. The combination of ICI caused more irAE than anti-PD1 (or PDL1) and anti-CTLA4 monotherapies. No relationship was found between the occurrence of irAE and OS (beta coefficient 0.078, R2 3%, p = 0.52), nor between cutaneous irAE and OS (beta coefficient 0.080, R2 6%, p = 0.33). Although limited by the heterogeneity of ICI included in the regression and the low number of included RCT, the present study suggests an absence of association between irAE and prognosis in melanoma.

RADT-07. CLINICAL OUTCOMES OF MELANOMA BRAIN METASTASES TREATED WITH NIVOLUMAB AND IPILIMUMAB ALONE VERSUS NIVOLUMAB AND IPILIMUMAB WITH STEREOTACTIC RADIOSURGERY

Abstract BACKGROUND Upfront dual checkpoint blockade has demonstrated efficacy in new melanoma brain metastases (MBM) of asymptomatic patients. Whether combination stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual checkpoint blockade alone is unknown. We evaluated clinical outcomes of new MBM receiving nivolumab and ipilimumab, with and without SRS. METHODS 52 patients with 171 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and toleration of therapy were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), distant intracranial control (DIC), and intracranial control (ICC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS 25 patients with 74 MBM received nivolumab and ipilimumab alone. 27 patients with 97 MBM received concurrent SRS. No differences in age (p = 0.72), KPS (p = 0.94), presence of symptoms (p = 0.87), prior MBM (p = 0.90), prior MBM-directed surgery (p = 0.77) or SRS (p = 0.65), MBM size (p = 0.36), MBM number (p = 0.36), or treatment completion (p = 0.12) were seen. Median follow-up was 22.7 months. There was a trend towards higher rates of nivolumab and ipilimumab course completion in the combination group (44% vs. 24%; p = 0.12). The combination therapy group received prior immunotherapy more often than the monotherapy group (52% vs. 8.0%; p = 0.0003). OS, DIC, and ICC were similar (p = 0.16, p = 0.32, p = 0.57, respectively) with overall 12-month OS 70.7%, DIC 56.8%, and ICC 49.4%. The combination therapy group had higher 12-month LC compared to the monotherapy group (91% vs. 64%; p = 0.001). CONCLUSION In our analysis, SRS with nivolumab and ipilimumab shows superior LC compared to nivolumab and ipilimumab alone despite our combination cohort being more advanced with higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

The choice of treatment for chemorefractory colon cancer

Metastatic colorectal cancer (mCRC) is a major challenge in the treatment of malignant neoplasms. However, with the development of cytotoxic chemotherapy, targeted therapy and local therapies, survival rates have improved significantly. Treatment of patients with CRC in the third and subsequent lines of therapy suggests the use of regorafenib / TAS102, as well as a return to previously used chemotherapy. Late-line treatment with anti-EGFR antibodies (cetuximab, panitumumab) is the choice for mCRC as it has been shown to improve survival rates. BRAF inhibitor and an anti-EGFR antibody is effective in BRAF mutations. A feature of the HER2 / neu mutation is the requirement for dual blockade with trastuzumab + lapatinib or pertuzumab + trastuzumab. For MSI-high, anti-PD therapy (nivolumab, pembrolizumab, or nivolumab + ipilimumab combination therapy) is highly effective. Adagrasib and sotorasib have demonstrated their value in the treatment of CRC with the KRAS G12C mutation. Two inhibitors are approved for NTRK-positive colorectal cancer — larotrectinib and entrectinib. It is also worth noting that one of the local options for the treatment of mCRC is stereotactic radiation therapy. This article presents the current possibilities of therapy for chemoresistant CRC.

Abstract 17199: A Case of Ventricular Fibrillation Arrest After Immune Checkpoint Inhibitor Therapy

Description of Case: Our patient is a 65-year-old male who suffered sudden cardiac arrest due to ventricular fibrillation while receiving his second cycle of therapy for non-small cell lung cancer, which consisted of carboplatin, pemetrexed, nivolumab, and ipilimumab. Initial symptoms included sudden onset chest pain and dyspnea during infusion, which then rapidly progressed to ventricular fibrillation, and he was successfully defibrillated with ROSC. Subsequent coronary angiogram revealed patent coronary arteries, and cardiac MRI (CMR) was consistent with acute myopericarditis. Our patient was treated with high dose steroids and colchicine. Discussion: Immune checkpoint inhibitors (ICI) are a novel drug class with an emerging role in treatment of various tumors, including lung cancer. ICIs prevent the interaction between host checkpoint proteins and tumor partner proteins, allowing the immune system to appropriately attack tumor cells. Two such ICI include nivolumab and ipilimumab, which are frequently administered together. ICI therapy is linked with very rare but potentially life-threatening cardiac side effects including malignant arrhythmias, such as ventricular fibrillation and polymorphic ventricular tachycardia, along with risk of myocarditis and pericarditis. The risk is highest in the first 30 days; patients who received nivolumab and ipilimumab in combination and those treated for non-small cell lung cancer were found to have a higher risk of cardiac side effects. The timeline of events in our patient with subsequent CMR findings make the diagnosis of sudden cardiac arrest secondary to ICI therapy the most likely cause. Patients receiving ICI therapy should be monitored appropriately with algorithms in place for prompt detection and triaging of such patients who develop these side effects.

Abstract 18533: Exploring the Rising Incidence of Myocarditis and Other Cardiovascular Adverse Events of Nivolumab and Ipilimumab: Analysis of FDA Adverse Event Reporting System Database

Introduction: Nivolumab and Ipilimumab are human monoclonal antibodies that target cell surface PD1 and anti-CTLA-4 receptors respectively. Nivolumab and ipilimumab combination is used for metastatic small cell lung carcinoma, advanced renal cell carcinoma and metastatic melanoma. The pre-approval CHECKMATE trials have underestimated the occurrence of cardiovascular adverse events (AEs). In contradiction, post-marketing studies have demonstrated a higher incidence of cardiac AEs, particularly myocarditis.Therefore, it is important to establish a post-marketing safety profile of these medications. Methods: We investigated the cardiovascular AEs of nivolumab and ipilimumab using U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Healthcare professionals (HCPs) reported 79.73% and 80.92% of AEs until March 2023 for nivolumab and ipilimumab respectively. We conducted further subgroup analysis of cardiovascular AEs in male, females as well as in three age groups: 18-64, 65-85 and &gt;85 years. Results: Amongst the cardiovascular AEs reported by HCPs, myocarditis was reported in 905 (1.55 %) in nivolumab vs 445 (1.72%) in ipilimumab group. There were higher reports of other cardiovascular AEs including heart failure (1.15% vs 0.74%), pericarditis/pericardial effusion (1.19% vs 0.6% ), myocardial infarction (0.18% vs 0.71%), cardiomyopathy (0.36% vs 0.29%), cardiac arrest (0.41% vs 0.53%) and cardiac death (0.01% vs 0.02%) in nivolumab vs ipilimumab. On sub-group analysis, we observed higher incidence of myocarditis in females (1.54% vs 1.6%) males (1.73% vs. 1.84%) and in patient with age 18-65 years (1.17% vs 1.15%) in both nivolumab vs ipilimumab group as compared to previous studies. Conclusions: The reported events of myocarditis were significantly higher in FAERS reporting as compared to the CHECKMATE trials (&lt;1%) in both nivolumab and ipilimumab groups. Clinicians need to be vigilant in detecting immune-mediated myocarditis, as it often manifests with nonspecific symptoms, with early onset and rapid progression. Given the growing utilization of these medications, it is imperative to conduct additional randomized controlled trials to gain a better understanding of their cardiovascular safety profile.

Pediatric model-based dose optimization using a pooled exposure-response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma.

An exposure-response (E-R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab-ipilimumab daily average exposure and time to grade 2+ immune-mediated adverse events (gr2+ IMAEs). Results from the E-R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first-line than later-line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio [HR]: 0.830 for 15-year-olds versus 60-year-olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents greater than or equal to 40 kg and BW-based dosing for adolescents less than 40 kg. These results also support adult weight-based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune-mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab.