tbuckley/cabot-search huggingface dataset:
Breaking from the paradigm of antibody-drug conjugates: Evaluation of clinical pharmacokinetics and safety of bicycle toxin conjugates (BTCs).
Authors: Justin Bader, Meredith McKean, Leslie Robbins DeMars, Yasong Lu, Mengyao Li, Amy Dickson, Gavin Bennett, Santiago Arroyo, Elisa Fontana, Louise Carter, Jordi Rodon Ahnert, Gerald Steven Falchook, Hongmei Xu
Journal: Journal of Clinical Oncology (2024)

3088 Background: Bicycle toxin conjugates (BTCs) are chemically synthesized molecules comprising a small (~4.5 kDa) bicyclic peptide linked to a cytotoxin. BT8009 and BT5528 are BTCs linked to monomethyl auristatin E (MMAE) targeting nectin-4 and EphA2, respectively, and have shown preliminary activity. BTCs are a unique therapeutic class of small size, with corresponding pharmacokinetic (PK) properties distinct from antibody-drug conjugates (ADCs). MMAE-containing ADCs demonstrate anti-tumor efficacy but substantial safety issues attributable to the slow clearance of ADCs, which increases uptake into off-target tissues and exposure to plasma proteases (ie, payload release).To evaluate BTC PK and safety relative to ADCs, we present results of the ongoing Phase I/II trials for BT8009 (NCT04561362) and BT5528 (NCT04180371). Methods: Patients with advanced solid tumors receiving IV BT8009 (n=147) or BT5528 (n=109) monotherapy were evaluated. Doses were given as 2.5–10 mg/m 2 weekly (QW), every 2 weeks (Q2W), or 2 weeks on/1 week off for BT8009 and 2.2–10 mg/m 2 QW or Q2W for BT5528. Population PK (PPK) models for BT8009 and BT5528 were developed. PK exposures (Cycle 1 area under the concentration curve [AUC]) for BTCs, conjugated MMAE, and unconjugated MMAE were simulated for 5 mg/m 2 QW BT8009 and BT5528 and compared with those of an MMAE-containing ADC (approved regimen, using the PPK model in the literature). Treatment-related adverse events (TRAEs) were tabulated for BT8009 and BT5528. Results: BTCparent drugs were rapidly eliminated (half-life [t 1/2 ] &lt;1 hour) while unconjugated MMAE exhibited persistent exposures and gradual elimination (MMAE t 1/2 , 1.9 days [D] for both BT8009 and BT5528), in contrast with the ADC (parent drug t 1/2 , 3.6 D; MMAE t 1/2 , 2.6 D). Conjugated MMAE exposures for the ADC were higher than for BT8009 and BT5528 (75- and 73-fold, respectively). Unconjugated MMAE exposures for BT8009 and BT5528 were comparable to the ADC (25% and 8% higher, respectively). Among the BTC regimens most thoroughly evaluated (BT8009 5 mg/m 2 QW and BT5528 6.5 mg/m 2 Q2W), TRAEs of interest occurred with low frequency and severity (Table). Conclusions: Preliminary data show substantial differences between BTC and ADC PK, and a promising BTC safety profile, possibly resulting from the distinct PK and selectivity (and specificity) of Bicycle peptides. These data highlight the potential value of BTCs as a platform for developing therapies against advanced malignancies. Clinical trial information: NCT04561362 and NCT04180371 . [Table: see text]
Integrated analysis of single-cell data on role of NKG7<sup>high</sup> CD8<sup>+</sup> T<sub>eff</sub> cells in driving immune-related adverse events.
Authors: Minghui Zhang, Ti Wen, Xiujuan Qu
Journal: Journal of Clinical Oncology (2024)

e24114 Background: Immune-related adverse events (irAEs) frequently occur during immunotherapy and can impact various organ systems, which dampen the clinical outcomes of immune checkpoint inhibitors (ICIs). However, the precise immune hallmarks associated with irAEs remain further explored. Methods: We collected public (Bukhari et al., Zhu et al., Su et al., and Ma et al.) and our own scRNA-seq data across patients with different irAE types or without irAEs. By comparing T cell compositions between irAE and no-irAE patients, the subcluster correlated with the occurrence of irAE was identified. Subsequently, the integrated analyses were performed to explore its mechanisms in driving irAEs in both peripheral blood and local tissues. Results: Compared to no-irAE patients, a subcluster of effector T (T eff ) cells was observed to increase notably in the peripheral blood of irAE patients during immunotherapy. This specific subcluster, named "NKG7 high CD8 + T eff cells," was characterized by the significant expression of effector genes such as GZMH, CCL5, and especially NKG7. In contrast to other CD8 + T cells, the NKG7 high CD8 + T eff cells exhibited stronger cytotoxicity functions, increased exosome secretion, and enhanced MIF-CD74 interaction with monocytes, which suggests the mechanistic link between its increased infiltration and the development of irAEs. Further investigation showed these characteristics were more remarkable in NKG7 high CD8 + T eff from irAE patients than no-irAE patients. Subsequently, the increase of NKG7high CD8+ Teff during immunotherapy was validated in our own scRNA from immune thyroiditis patients, which was not observed in no-irAE patients. Across various irAE types, NKG7 high CD8 + T eff subsets, along with their NKG7 expression, demonstrated heightened infiltration and expression in immune-related arthritis and myocarditis samples. After investigating the role of NKG7 high CD8 + T eff in peripheral blood, we focused on its distribution and roles in local irAE tissue. NKG7 high CD8 + T eff cells accumulated in immune-related thyroiditis tissues, and recruited macrophages through the IFNG and CSF1 signaling pathways, thereby inducing an immune overreaction. Meanwhile, in immune-related myocarditis mice heart tissues, NKG7 high CD8 + T eff cells could interact with macrophages via the SPP1 signaling pathway and cause endothelial cell damage through the FASL-FAS pathway. Conclusions: This comprehensive study revealed the intricate mechanisms of NKG7 high CD8 + T eff in inducing irAEs, providing valuable insights into their roles and potential implications in irAE treatment.
Preventing 5-fluorouracil-induced ischemic events in very high-risk cardiac patients: A retrospective cohort analysis (SQCCCRC protocol).
Authors: Ahmad Basuoni, Ahmad Ghoche, Rami Abu Omar, Waleed d A, Mansour Al-Moundhri
Journal: Journal of Clinical Oncology (2024)

e24112 Background: 5-Fluorouracil (5-FU), a potent chemotherapy agent for various cancers, is linked to cardiotoxicity, particularly in patients with pre-existing ischemic heart disease. The incidence varies, necessitating effective preventive strategies. Among the several mechanisms responsible for 5-FU-induced myocardial ischemia are coronary vasospasm and endothelial injury. Therefore, prevention of ischemic events in very high-risk patients by controlling modifiable cardiac risk factors and good medical treatment including vasodilators are a potential strategy in preventing 5-FU ischemic events. Methods: To assess the effectiveness and safety of a protocol involving Amlodipine and Isosorbide dinitrate in preventing 5-FU-induced ischemic events in very high-risk cardiac patients with documented ischemic heart disease. Nineteen patients underwent 252 cycles of 5-FU chemotherapy, with 12 patients (181 cycles) following the pre-defined protocol (5-FU Protocol Group) and 7 patients (71 cycles) not adhering (Missed 5-FU Protocol Group). The primary outcome measure was the prevention of 5-FU-induced ischemic events, evidenced by the absence of chest pain, elevated Troponin levels, or ECG changes during 5-FU infusion. Results: The 5-FU Protocol Group demonstrated significant reductions in ischemic events, chest pain with p-values of 0.009 for both outcomes. Additionally, the occurrence of ECG changes post-5FU and an increase in Troponin levels was significantly lower in the 5-FU Protocol Group, with p-values of 0.036 for both parameters. Although not statistically significant, there was a lower 5FU-related mortality rate in the 5-FU Protocol Group compared to the missed 5-FU Protocol Group (0% vs. 14.3%, p = 0.37). The incidence of cancer-related mortality did not exhibit a statistically significant difference between the two groups. To evaluate this, we specifically examined and compared the occurrence of ischemic events in both the 5-FU Protocol Group and the Missed 5-FU Protocol Group. The comparison was conducted using the Fisher exact test. Conclusions: The use of vasodilators may be effective in preventing 5-Fluorouracil-Induced ischemic events in very high-risk cardiac patients with documented coronary artery disease. This approach may help reduce the risk of cardiac events and improve the safety of chemotherapy in this vulnerable patient population. Monitoring cardiotoxicity with maximum tolerated medical treatment and dedicated hospital protocols may be a good prophylaxis approach. Further studies are needed to confirm the safety and efficacy of this approach in a larger patient population, and to assess its impact on long-term cardiac outcomes.
Nivolumab combined with high dose multisite radiotherapy in previously untreated advanced melanoma (NIRVANA): A non-randomised, open-label, multicenter, phase 2 trial.
Authors: Henri Montaudie
Journal: Journal of Clinical Oncology (2024)

e21505 Background: Outcome of advanced melanoma remains poor for the majority of patients (pts) and new treatment strategies are needed. Preclinical and clinical data suggest a potential increase of the immunotherapy efficacy when combined with hypofractionated multisite radiotherapy (HMR). Objective: To assess the impact of HMR combined with nivolumab in advanced melanoma. Methods: This is a non-randomised, open-label, multicentre phase 2 trial(NCT02799901). Pts must have locally advanced or metastatic melanoma (AJCC7), previously untreated. Pts with mucosal or uveal melanoma, those with brain metastasis and LDH ≥ 1.5 the upper limit were not included. Pts received (until progression or unacceptable toxicity) nivolumab (fixed dose 240 mg/15 days) plus radiotherapy (day 15) delivered 3 x 6 Gy every second day, at every metastatic organ, if feasible.At progression, second irradiation was authorized while pursuing nivolumab (rechallenging strategy).The primary endpoint was 1-year overall survival (OS) (hypothetic improvement of 1-year OS from 71% 1 ). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Subgroups and multivariate analyses were performed. Results: A total of 64 pts were included, from 03/2017 to 07/2019. Median follow-up was 23.5 months [IQR 2.3-43.8]. Median age was 64 years [35-95], majority of pts were male (67%), had an ECOG-PS 0 (75%), a stage IV-M1C disease (47%) and were BRAF-wild-type (67%).] The 1-year OS and PFS rates were 79% and 56% respectively (p = 0.12 and p = 0.0.3 in comparison with the 1-year OS and PFS of 71% and 43% of Robert et al’study 1 ). 39 pts were irradiated at 1 target, 25 at ≥2 targets (total of 92 tumor targets). The 2-years OS rates were 83% and 52% for pts who were irradiated on several sites and one site respectively (p = 0.03). The ORR in the whole cohort was 53% [95% CI, 40.23; 65.72], 33% [95% CI, 14.59; 56 .97] and 62% [95% CI, 45.64; 76.43] in BRAF mutated and BRAF-wild type respectively. Among BRAF status, gender, PS, stage, age, LDH level and number of irradiated sites (1 vs ≥ 1), the independent prognostic factors for OS in multivariate analysis were number of irradiated sites (HR = 0.26, p = 0.03) and ECOG-PS (HR = 6.2, p = 0.001). Rechallenging was performed in 11 pts, among them; 3 were progression-free at last follow-up, 10 were reirradiated once and 1 was reirradiated 3 times. ICI was stopped due to toxicities for 6 pts. Drug-related adverse events of grade 3-4 occurred in 8.3% of the patients (no grade 5). Conclusions: Combined nivolumab and HMR did not improve significantly OS compare to nivolumab alone but improve significantly PFS 1 . However, this strategy has an acceptable safety and could be a treatment option for some patients. Multisite irradation and rechallenging strategies deserve to be considered. 1 Robert et al, J Clin Oncol 2020. Clinical trial information: NCT02799901 .
Spatially mapping the single-cell immune landscapes of melanoma brain metastases using imaging mass cytometry.
Authors: Jamie Magrill, Sarah Allard-Puscas, Claris Gu, LeeAnn Ramsay, Mathieu Lajoie, Elham Karimi, Sarah M Maritan, Matthew Dankner, Morteza Rezanejad, Dongmei Zuo, Yuhong Wei, Kevin Petrecca, Marie-christine Guiot, Bertrand Routy, Peter M Siegel, Daniela Quail, Logan Walsh, Catalin Liviu Dragos Mihalcioiu, John Stagg, Ian Watson
Journal: Journal of Clinical Oncology (2024)

e21517 Background: Up to 60% of metastatic melanoma patients develop brain metastases, and 5% develop leptomeningeal disease (LD), which presents with the worst prognosis of any melanoma brain metastasis (MBM) infiltration pattern. Median survival duration for MBM is ~12 months, however for LD patients it can be &lt; 10 weeks. The spatial immune landscape of MBM with and without LD remains poorly understood. Methods: To spatially characterize the tumor microenvironment (TME) of MBM, we performed CyTOF Imaging Mass Cytometry (CyTOF-IMC) on a highly multiplexed panel of 35 antibodies for 21 MBMs (13 with LD, 8 without LD). We performed a novel cell segmentation, cell type assignment and identification approach to identify cell lineages to spatially characterize the TME of MBMs, segmenting and classifying 130,000 cells into 19 cell types. Results: We found enrichment of dendritic cells in the direct neighbourhood of melanoma cells of patients with LD (p = 0.019) and trends towards elevation of anti-tumoral monocyte populations in the TME of patients without LD. To investigate survival outcomes, we divided our cohort into long (≥365days) and short-survivors ( &lt; 365 days), and found significant elevation of anti-tumoral T-cell populations (Total T-cells, CD8+ T-cells, CD4+ T-cells and CD3+CD4-CD8- T-cells, p &lt; 0.05), and closer proximity of T-cells (CD8+ &amp; CD4+ T-cells) to melanoma cells (p &lt; 0.05). Survival analysis using median cell-proportion for each T-cell subset showed statistically significant (p &lt; 0.05) survival differences between patients with high and low cell-proportions of CD8+ T-cells and CD4+ T-cells, with similar trends observed for a subset of patients (n = 13) with LD and a subset of patients treated with ICIs (n = 10), and results were confirmed by a Cox Regression Model. Cellular neighborhood (CN) analysis was performed generating N = 12 stable CNs. We found patients with higher proportions of CN9 (M1-like-microglia/M2-like-microglia/melanoma), CN10 (M1-like-macrophages/M2-like-macrophages/melanoma) and CN12 (Cytotoxic-T-cells/Helper-T-cells/melanoma) was associated with longer overall survival after diagnosis with MBM (p &lt; 0.01). Conclusions: Proportion and proximity of anti-tumoral monocyte and T-cell populations may play a key role in modulating tumor response and overall survival for patients with MBM, including for patients with LD or for patients treated with ICIs.
Real-world treatment patterns and outcomes of patients with advanced melanoma treated with nivolumab plus relatimab.
Authors: Sach Thakker, Micah Belzberg, Chelsea Stahl, Sekwon Jang, Jafar Al-Mondhiry
Journal: Journal of Clinical Oncology (2024)

e21501 Background: Programmed death-1 (PD-1) receptor inhibitors significantly increase survival rates for advanced melanoma, yet first-line PD-1 inhibitor therapy shows limited overall response rates (32.6%) and progression-free survival (4.6 months). Relatimab (RELA) was recently approved for the treatment of metastatic and unresectable stage III to IV melanoma in combination with nivolumab (NIVO). RELATIVITY-047 showed an ORR of 43% as a first-line treatment while RELATIVITY 020 showed an ORR of 9-12% in patients progressed on anti-PD-1 therapy. Although clinical trials have demonstrated NIVO-RELA provides benefit for patients with advanced melanoma, little is known about real-world treatment patterns and outcomes. Methods: We performed a retrospective review of all patients with stage III and IV melanoma treated with NIVO-RELA as first-(1L) or second-line or beyond (2L+) therapy at Inova Schar Cancer Institute between September 2021 to September 2023. Primary endpoints were overall response rate (ORR), complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) which were evaluated using the RECIST v1.1 criteria. The Kaplan–Meier method was used to generate overall survival (OS) and progression free survival (PFS) median values. Results: Eighty-eight patients were followed for an average of 6.5 months following NIVO-RELA initiation. For 1L treated patients, ORR was 58% (21% PR, 37% CR). Median PFS was 11 months (95% CI 3.1-11). For 2L+ treated patients, ORR was 33% (14% PR, 19% CR). Median PFS was 9.8 months (95% CI 4.7-17.2). Subgroup analyses observed significantly different ORR between patients previously treated with versus without anti-CTLA4 therapy (29% v 44%; p = 0.017), patients treated with NIVO-RELA more than vs within 6 months from their last other therapy (50% v 27%; p = 0.004), and among patients with stage III vs stage IV disease (67% v 30%; p = 0.031) (Table 1). Conclusions: These real-world results support the use of NIVO + RELA in patients with advanced melanoma and emphasize the impressive efficacy of the drug combination in the IL and 2L+ settings compared to RELATIVITY-020 and 047. PFS and OS for 1L and 2L+ therapy with NIVO + RELA in this study aligned with or superposed results from previous trials. Further analyses with increased sample sizes and longer follow-up is warranted. [Table: see text]
Real world experience of bispecific fusion protein in patients with metastatic uveal melanoma: Can we deliver?
Authors: Liz Joseph, Christopher Herbert, Hannah Taylor, Helen Winter, Adrienne Howe
Journal: Journal of Clinical Oncology (2024)

e21504 Background: Effective treatments for patients with metastatic uveal melanoma has remained a longstanding unmet need. Poor response rates to checkpoint inhibitors has increased the need for patients to access new ways of targeting this disease. Tebentafusp is a first in class T Cell receptor bispecific fusion protein that has demonstrated an overall survival benefit. However although licensed it has yet to be approved in the UK for wider use. Methods: Prospective data collection on five patients receiving tebentafusp through the Managed Access Programme at a cancer centre that had not taken part in any trials of this therapy before. Patients were permitted with metastatic uveal melanoma; ECOG performance status 0-1 and were HLA-A*02:01 positive. Protocols were disseminated across the wider cancer teams for the management of side effects including cytokine release syndrome. Patients received extended monitoring for at least 16 hours, and vital signs (blood pressure, heart rate, temperature and pulse oximetry) taken every 2-4 hours. Drop in systolic BP &lt; 20mmHg treated with IV fluids. Results: Five patients with advanced uveal melanoma participated in the Access Programme at one cancer site to assess efficacy, tolerability and workforce upskilling and capability with a first in class bispecific fusion protein therapy. All patients were HLA-A*02:01 positive. The patients commenced therapy between November 2021 and July 2023. All were male; median age 66. Four patients developed cytokine release syndrome commencing at cycle one. These patients required intravenous fluids for CRS grade 2, no patients required vasopressors. One patient required IV hydrocortisone. Four patients developed skin toxicity. These were managed with antihistamines and steroids. Three patients stopped due to confirmed disease progression, receiving 2-7 cycles; one made an informed decision to stop due to grade 3 skin toxicity. One patient continues on tebentafusp and has received 32 cycles to date. They recently had treatment paused for ablation and resection of oligometastatic disease that found residual uveal melanoma and have restarted. Conclusions: Real-world data suggests that using a gp100-targeting TCR/anti-CD3 bispecific fusion protein is tolerated and deliverable in new settings. Tebentafusp was delivered without any medical emergencies and CRS was successfully managed with proactive fluid management and steroids. The rate and grading of side effects reflects that described in the large randomised controlled trial. Patients with uveal melanoma can derive ongoing clinical benefit - including one patient who has received 32 cycles and proceeded to surgical resection of oligometastatic disease. Through workplace education and upskilling, the proactive management of the side effects including cytokine release syndrome can be managed in the oncology inpatients and seamlessly moved to outpatient settings.
First-line therapy for metastatic uveal melanoma: Experience from a single reference center.
Authors: Valery V. Nazarova, Zakhra R. Magomedova, Kristina V. Orlova, Vladimir Unguryan, Denis Romanov, Vera Yarovaya, Andrey Yarovoy, Oxana Trofimova, Lev V. Demidov
Journal: Journal of Clinical Oncology (2024)

e21514 Background: Metastatic uveal melanoma (mUM) continues to have a poor prognosis with distinct biology from cutaneous melanoma and limited effective treatment options. The main options include immunotherapy (IT, anti-PD-1+/- anti-CTLA-4, tebentafusp), chemotherapy, targeted therapy and local treatment methods for patients with isolated liver metastasis (isolated hepatic perfusion, transarterial chemoembolization, percutaneous hepatic perfusion, radiofrequency ablation). Methods: We conducted a single-center retrospective observation IRB-approved study of first-line therapy for pts age 18 and older with mUM treated at the N.N. Blokhin National Medical Research Center of Oncology from 2020 to 2023. Our objectives were to evaluate clinical outcomes in real-world settings, as well as treatment patterns, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events (AEs). Results: A total of 125 pts included. The mean age was 54 yrs (range: 20-74), and the median time to metastasis from primary tumor was 2 years (range: 0-21). Liver metastases were diagnosed in 92% of patients, lung metastases in 20%, bone metastases in 17%, and soft tissue metastases in 9%. Conclusions: Our data suggest that the combination of systemic and local liver-directed treatment methods may be associated with a survival benefit and higher treatment response to IT in patients with mUM. [Table: see text]