Immune Checkpoint Inhibitor Therapy for Kidney Transplant Recipients - A Review of Potential Complications and Management Strategies.

Immune checkpoint inhibitor (ICI) therapy has enabled a paradigm shift in Oncology, with the treatment of metastatic cancer in certain tumor types becoming akin to the treatment of chronic disease. Kidney transplant recipients (KTR) are at increased risk of developing cancer compared to the general population. Historically, KTR were excluded from ICI clinical trials due to concern for allograft rejection and decreased anti-tumor efficacy. While early post-marketing data revealed an allograft rejection risk of 40%-50%, 2 recent small prospective trials have demonstrated lower rates of rejection of 0%-12%, suggesting that maintenance immunosuppression modification prior to ICI start modulates rejection risk. Moreover, objective response rates induced by ICI for the treatment of advanced or metastatic skin cancer, the most common malignancy in KTR, have been comparable to those achieved by immune intact patients. Non-invasive biomarkers may have a role in risk-stratifying patients before starting ICI, and monitoring for rejection, though allograft biopsy is required to confirm diagnosis. This clinically focused review summarizes current knowledge on complications of ICI use in KTR, including their mechanism, risk mitigation strategies, non-invasive biomarker use, approaches to treatment of rejection, and suggestions for future directions in research.

Improving Patient Understanding and Outcomes in Lung Cancer Using an Animated Patient's Guide with Visual Formats of Learning.

Lung cancer patient education resources that address barriers to health literacy, improve understanding, and demonstrate improved patient outcomes are limited. Our study aim was to evaluate and report on learner knowledge improvement and intent to implement behavior change, and validate the benefits of the You and Lung Cancer website and YouTube resources. Our study occurred from November 2017 to December 2023. We evaluated audience reach (visit sessions, unique visitors, country origins, page views) and calculated top views by media type (animations, expert videos, patient videos). We assessed the impact and commitment to change through learner surveys (areas of interest, intention to modify behaviors, and intention to discuss disease management with providers) and tested the knowledge of learners pre- and post-reviewing of website content. Our program reached 794,203 views globally; 467,546 were unique visitors; and 243,124 (51%) were unique visitors from the USA. Of US visitors, 46% identified as lung cancer patients. These were patients in treatment (38%), survivors (8%), family members or caregivers (21%), and healthcare providers (14%) with other audiences unspecified (19%). Three areas of highest learner importance were the animations "Understanding Non-Small Cell Lung Cancer" (180,591), "Staging of Lung Cancer" (144,238), and "Treatment and Management of Small Cell Lung Cancer" (49,244). Our study confirmed areas of importance to lung cancer patients and suggests that visual formats of learning, such as animations, can mitigate health literacy barriers and help improve patient understanding and outcomes. Exporting this format of learning to other cancers has the potential to benefit patients and improve health outcomes.

Phase I study of procaspase-activating compound-1 (PAC-1) in the treatment of advanced malignancies.

BACKGROUND: Procaspase-3 (PC-3) is overexpressed in multiple tumour types and procaspase-activating compound 1 (PAC-1) directly activates PC-3 and induces apoptosis in cancer cells. This report describes the first-in-human, phase I study of PAC-1 assessing maximum tolerated dose, safety, and pharmacokinetics. METHODS: Modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered orally at 7 dose levels (DL) on days 1-21 of a 28-day cycle. Dose-limiting toxicity (DLT) was assessed during the first two cycles of therapy, and pharmacokinetics analysis was conducted on days 1 and 21 of the first cycle. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study. RESULTS: Forty-eight patients were enrolled with 33 completing ≥2 cycles of therapy and evaluable for DLT. DL 7 (750 mg/day) was established as the recommended phase 2 dose, with grade 1 and 2 neurological adverse events noted, while NNCF testing showed stable neurologic and cognitive evaluations. PAC-1's t1/2 was 28.5 h after multi-dosing, and systemic drug exposures achieved predicted therapeutic concentrations. PAC-1 clinical activity was observed in patients with neuroendocrine tumour (NET) with 2/5 patients achieving durable partial response. CONCLUSIONS: PAC-1 dose at 750 mg/day was recommended for phase 2 studies. Activity of PAC-1 in treatment-refractory NET warrants further investigation. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov: NCT02355535.

Markers of endothelial glycocalyx dysfunction in Clarkson disease.

BACKGROUND: Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia. METHODS: We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining. RESULTS: Serum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells. CONCLUSIONS: eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS. Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses.

Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy.

PURPOSE: TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer. METHODS: This was an accelerated dose escalation study with the primary endpoint of maximum tolerated dose that evaluated five dose levels of TTC-352 in breast cancer progressing after at least two lines of hormonal therapy including one in combination with a CDK4/6 inhibitor. The secondary objectives were to determine treatment tolerability, pharmacokinetics of TTC-352, best response, progression-free survival (PFS), and PKCα expression in tumors. RESULTS: The study enrolled 15 patients. No dose-limiting toxicity was observed. Patients experienced the following grade 3 toxicities: asymptomatic pulmonary embolism, diarrhea, aspartate transaminase elevation, and myalgia, and one grade 4 toxicity of gamma glutamyltransferase elevation. Pharmacokinetic half-life was 7.6-14.3 h. The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS. CONCLUSIONS: TTC-352 demonstrates safety and early clinical evidence of antitumor activity against heavily pretreated hormone-refractory breast cancer. Based upon TTC-352 plasma concentrations and tolerability, the 180 mg twice a day is recommended for further testing. (ClinicalTrials.gov Identifier: NCT03201913).

Profound impairment of adaptive immune responses by alkylating chemotherapy.

Overall, cancer vaccines have had a record of failure as an adjuvant therapy for malignancies that are treated with alkylating chemotherapy, and the contribution of standard treatment to that failure remains unclear. Vaccines aim to harness the proliferative potential of the immune system by expanding a small number of tumor-specific lymphocytes into a large number of antitumor effectors. Clinical trials are often conducted after treatment with alkylating chemotherapy, given either as standard therapy or for immunomodulatory effect. There is mounting evidence for synergy between chemotherapy and adoptive immunotherapy or vaccination against self-Ags; however, the impact of chemotherapy on lymphocytes primed against tumor neoantigens remains poorly defined. We report that clinically relevant dosages of standard alkylating chemotherapies, such as temozolomide and cyclophosphamide, significantly inhibit the proliferative abilities of lymphocytes in mice. This proliferative impairment was long-lasting and led to quantitative and qualitative defects in B and T cell responses to neoantigen vaccines. High-affinity responder lymphocytes receiving the strongest proliferative signals from vaccines experienced the greatest DNA damage responses, skewing the response toward lower-affinity responders with inferior functional characteristics. Together, these defects lead to inferior efficacy and overall survival in murine tumor models treated by neoantigen vaccines. These results suggest that clinical protocols for cancer vaccines should be designed to avoid exposing responder lymphocytes to alkylating chemotherapy.

Convolutional Neural Networks for Segmentation of Pleural Mesothelioma: Analysis of Probability Map Thresholds (CALGB 30901, Alliance).

The purpose of this study was to evaluate the impact of probability map threshold on pleural mesothelioma (PM) tumor delineations generated using a convolutional neural network (CNN). One hundred eighty-six CT scans from 48 PM patients were segmented by a VGG16/U-Net CNN. A radiologist modified the contours generated at a 0.5 probability threshold. Percent difference of tumor volume and overlap using the Dice Similarity Coefficient (DSC) were compared between the reference standard provided by the radiologist and CNN outputs for thresholds ranging from 0.001 to 0.9. CNN-derived contours consistently yielded smaller tumor volumes than radiologist contours. Reducing the probability threshold from 0.5 to 0.01 decreased the absolute percent volume difference, on average, from 42.93% to 26.60%. Median and mean DSC ranged from 0.57 to 0.59, with a peak at a threshold of 0.2; no distinct threshold was found for percent volume difference. The CNN exhibited deficiencies with specific disease presentations, such as severe pleural effusion or disease in the pleural fissure. No single output threshold in the CNN probability maps was optimal for both tumor volume and DSC. This study emphasized the importance of considering both figures of merit when evaluating deep learning-based tumor segmentations across probability thresholds. This work underscores the need to simultaneously assess tumor volume and spatial overlap when evaluating CNN performance. While automated segmentations may yield comparable tumor volumes to that of the reference standard, the spatial region delineated by the CNN at a specific threshold is equally important.

Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease.

Clarkson disease, or monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

Real-world evidence on efficacy and toxicity of targeted therapy in older melanoma patients treated in a tertiary-hospital setting.

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal-Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3-4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Introduction: Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. Methods: In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. Results: The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Conclusion: Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Cancer Surveillance in Solid Organ Transplant Recipients With a Pretransplant History of Malignancy: Multidisciplinary Collaborative Expert Opinion.

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population.

Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases.

Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAF(V600E)), which is commonly found in metastatic melanoma. Clinical trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with corrected efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the ratio of area under the concentration-time curve (AUC)(brain) to AUC(plasma) (K(p)) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b(-/-)Bcrp1(-/-) mice to 0.42. Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b(-/-)Bcrp1(-/-) mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ~10-fold with a resulting K(p) of 0.25. Further, compared with vemurafenib, another BRAF(V600E) inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases.

Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer.

BACKGROUND: AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). PATIENTS AND METHODS: AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤ 2 of the first 20 evaluable patients achieved an objective tumor response. Cmax was assessed on days 1 and 8 of cycle 1. RESULTS: None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥ 8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥ 3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. CONCLUSIONS: AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.

BACKGROUND: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. METHODS: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. FINDINGS: 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). INTERPRETATION: Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. FUNDING: Boehringer Ingelheim Inc.

Convolutional Neural Networks for Segmentation of Malignant Pleural Mesothelioma: Analysis of Probability Map Thresholds (CALGB 30901, Alliance).

Malignant pleural mesothelioma (MPM) is the most common form of malignant mesothelioma, with exposure to asbestos being the primary cause of the disease. To assess response to treatment, tumor measurements are acquired and evaluated based on a patient's longitudinal computed tomography (CT) scans. Tumor volume, however, is the more accurate metric for assessing tumor burden and response. Automated segmentation methods using deep learning can be employed to acquire volume, which otherwise is a tedious task performed manually. The deep learning-based tumor volume and contours can then be compared with a standard reference to assess the robustness of the automated segmentations. The purpose of this study was to evaluate the impact of probability map threshold on MPM tumor delineations generated using a convolutional neural network (CNN). Eighty-eight CT scans from 21 MPM patients were segmented by a VGG16/U-Net CNN. A radiologist modified the contours generated at a 0.5 probability threshold. Percent difference of tumor volume and overlap using the Dice Similarity Coefficient (DSC) were compared between the standard reference provided by the radiologist and CNN outputs for thresholds ranging from 0.001 to 0.9. CNN annotations consistently yielded smaller tumor volumes than radiologist contours. Reducing the probability threshold from 0.5 to 0.1 decreased the absolute percent volume difference, on average, from 43.96% to 24.18%. Median and mean DSC ranged from 0.58 to 0.60, with a peak at a threshold of 0.5; no distinct threshold was found for percent volume difference. The CNN exhibited deficiencies with specific disease presentations, such as severe pleural effusion or disease in the pleural fissure. No single output threshold in the CNN probability maps was optimal for both tumor volume and DSC. This study emphasized the importance of considering both figures of merit when evaluating deep learning-based tumor segmentations across probability thresholds. This work underscores the need to simultaneously assess tumor volume and spatial overlap when evaluating CNN performance. While automated segmentations may yield comparable tumor volumes to that of the reference standard, the spatial region delineated by the CNN at a specific threshold is equally important.

Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299.

Introduction: We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of unresectable mesothelioma. Methods: This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen. Ramucirumab and nivolumab were given intravenously every 14 days for up to 24 months. The primary end point was ORR; secondary end points were progression-free survival (PFS) rate at 24 weeks and overall survival (OS). Results: Between April 2018 and October 2021, 34 patients were recruited. Median age was 72 (range: 40-89) years, 12% were women, and 79% of tumors had epithelial histology. Median follow-up was 10.2 months (interquartile range 19.6 mo [4.3-23.8]). ORR was 22.6% (95% confidence interval [CI]: 9.6%-41.1%) in all population and 43% (95% CI: 10%-82%) in patients with nonepithelioid histology. Of all patients, 45.2% (95% CI: 27.3%-64.0%) had stable disease. PFS rate at 24 weeks was 32% (95% CI: 17%-51%). Median PFS was 4.2 months (95% CI: 1.9-6.4 mo). Median OS was 12.5 months (95% CI: 6.3-23.5 mo). There was no grade greater than or equal to four toxicity. Programmed death-ligand 1 expression in the tumor did not correlate with benefit from treatment. Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS. Conclusions: Nivolumab and ramucirumab combination was safe and generated PFS and OS rates and ORR that compare favorably with single-agent nivolumab in a similar patient population. The primary end point of 40% ORR was not reached. Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746.

The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma.

The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6-6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832.

Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas.

Background: Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. Methods: A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1-21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Results: Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Conclusions: Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses.

Introduction: Metastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM. Methods: We developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-ß) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNß-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM. VSV-IFNß-TYRP1 was injected into a liver metastasis, then administered on the same day as a single intravenous (IV) infusion. The primary objective was safety. Efficacy was a secondary objective. Results: 12 patients with previously treated MUM were enrolled. Median follow up was 19.1 months. 4 dose levels (DLs) were evaluated. One patient at DL4 experienced dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). 4 patients had stable disease (SD) and 8 patients had progressive disease (PD). Interferon gamma (IFNγ) ELIspot data showed that more patients developed a T cell response to virus encoded TYRP1 at higher DLs, and a subset of patients also had a response to other melanoma antigens, including gp100, suggesting epitope spreading. 3 of the patients who responded to additional melanoma antigens were next treated with ICIs, and 2 of these patients experienced durable responses. Discussion: Our study found that VSV-IFNß -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNß-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen.