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Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7–13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406). A safety and efficacy trial of a single intratumoral dose of the oncolytic adenovirus DNX-2401 followed by intravenous anti-PD-1 pembrolizumab in patients with recurrent glioblastoma shows an encouraging clinical benefit rate and 12 months overall survival.

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation. Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment.

TABLE 1 Best overall response by investigator assessment in efficacy evaluable population Patients Dose Best overall assessment, n (%) TN (n = 11) R/R (n = 30) 160 mg BID (n = 33) 320 mg QD (n = 8) Overall * (N = 41) Very good partial response 3 (27) 13 (43) 13 (39) 3 (38) 16 (39) Partial response 4 (36) 10 (33) 12 (36) 2 (25) 14 (34) Minor response 1 (9) 4 (13) 4 (12) 1 (13) 5 (12) Stable disease 2 (18) 0 (0) 1 (3) 1 (13) 2 (5) Progressive disease 1 (9) 3 (10) 3 (9) 1 (13) 4 (10) Very good partial response or complete response 3 (27) 13 (43) 13 (39) 3 (38) 16 (39) Major response rate † 7 (64) 23 (77) 25 (76) 5 (63) 30 (73) Overall response rate ‡ 8 (73) 27 (90) 29 (88) 6 (75) 35 (85) * Nine patients were excluded from the efficacy evaluable population, as they discontinued prior to the first response assessment without clinical PD or death; 41 patients, who had ≥1 response evaluation while in the study, were included in the efficacy evaluable population. † Partial response or better. ‡ Very good partial response, partial or minor response. TABLE 2 Adverse events of special interest and dose modifications due to adverse event Adverse events, n (%) (safety population) Zanubrutinib 160 mg BID (n = 41) Zanubrutinib 320 mg QD (n = 9) Overall (N = 50) ≥1 TEAE of special interest * (category) 31 (76) 5 (56) 36 (72) Anaemia 2 (5) 0 (0) 2 (4) Atrial fibrillation and flutter 1 (2) 0 (0) 1 (2) Haemorrhage 16 (39) 3 (33) 19 (38) Hypertension 5 (12) 0 (0) 5 (10) Infections 15 (37) 2 (22) 17 (34) Neutropenia 2 (5) 0 (0) 2 (4) Second primary malignancies 4 (10) 0 (0) 4 (8) Thrombocytopenia 1 (2) 1 (11) 2 (4) Tumour lysis syndrome 0 (0) 0 (0) 0 (0) Grade ≥3 TEAEs of special interest 7 (17) 1 (11) 8 (16) Hypertension 4 (10) 0 (0) 4(8) Hypertension 4 (10) 0 (0) 4 (8) Procedural hypertension 1 (2) 0 (0) 1 (2) Infection 3 (7) 1 (11) 4 (8) Pneumonia 1 (2) 1 (11) 2 (4) COVID-19 pneumonia 1 (2) 0 (0) 1 (2) Cellulitis 1 (2) 0 (0) 1 (2) Staphylococcal bacteraemia 1 (2) 0 (0) 1 (2) Atrial fibrillation and flutter 1 (2) 0 (0) 1 (2) Neutropenia 1 (2) 0 (0) 1 (2) Second primary malignancy 1 (2) 0 (0) 1 (2) Soft tissue sarcoma 1 (2) 0 (0) 1 (2) TEAEs leading to treatment discontinuation † 1 (2) 2 (22) 3 (6) TEAEs leading to dose reduction 3 (7) 1 (11) 4 (8) *TEAE of special interest categories were defined as haemorrhage, atrial fibrillation/flutter, hypertension, second primary malignancies, tumour lysis syndrome, infections, neutropenia, thrombocytopenia, and anaemia. Patients’ characteristics were similar to those of the ASPEN population[ 1]; however, key differences included age distribution, Eastern Cooperative Oncology Group performance status (ECOG PS), disease course duration, and prognosis. The overall response rate (ORR) was lower in the current study (85% vs. 95%).

BackgroundInterleukin 8 (IL-8) is a C-X-C chemokine that exerts protumorigenic effects in the tumor microenvironment, including recruiting immunosuppressive PMN-MDSCs and promoting angiogenesis.1–3 Elevated serum IL-8 (sIL-8) is a negative prognostic indicator in patients with solid tumors and may have predictive value in patients treated with immunotherapies.2 4 5 BMS-986253, a fully human-sequence IgG1κ anti–IL-8 monoclonal antibody, binds IL-8 and prevents signaling through CXCR1/CXCR2 and has been shown to be safe in patients with advanced cancers.3 We present initial results of BMS-986253 + NIVO from a phase 1/2a trial in patients with advanced cancers who had detectable sIL-8 levels, the majority of whom had progressed on/after prior anti–PD-(L)1 (NCT03400332).MethodsDuring safety evaluation/dose exploration, patients with advanced metastatic solid tumors (melanoma, NSCLC, SCCHN, RCC, or UCC) and detectable sIL-8 (>10 pg/mL at screening) received BMS-986253 600 (n=16), 1200 (n=15), or 2400 mg (n=18) Q4W, or 1200 (n=12) or 2400 mg (n=59) Q2W, + NIVO 480 mg intravenously Q4W. Safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity were evaluated (investigator-assessed, RECIST v1.1).ResultsAs of March 20, 2020, 120 patients (median age, 63 years [range, 35–87 years]) received BMS-986253 + NIVO; 97% of patients received prior anti–PD-(L)1 therapy, and 25% received prior anti–CTLA-4 therapy. BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities observed. Most TRAEs were grade 1–2. The most common (≥5% of patients) TRAEs (any grade; grade 3–4) were fatigue (9%; 1%), nausea (7%; 0%), rash/rash maculopapular (6%; 0%), pruritus (5%; 0%), and decreased appetite (5%; 0%). Grade 3–4 serious TRAEs were reported in 2 patients (infusion-related reaction, BMS-986253 2400 mg Q2W + NIVO; AST/ALT increased, BMS-986253 1200 mg Q4W + NIVO). BMS-986253 exposure increased dose proportionally and was not altered with NIVO. BMS-986253 resulted in dose-dependent reductions in free sIL-8 levels, with tumor IL-8 suppression detected in most patients evaluated; additional pharmacodynamic endpoints will be presented. Partial responses were observed in multiple tumor types, including 5 of 28 patients with melanoma who had progressed on/after prior anti–PD-(L)1; 4 of the 5 patients were also previously treated with anti–CTLA-4.ConclusionsBMS-986253 + NIVO demonstrated a tolerable safety profile with dose-proportional pharmacokinetics and robust sIL-8 suppression. Preliminary antitumor activity was observed across a range of doses/regimens in this biomarker-enriched, anti–PD-(L)1–experienced, heterogeneous patient population with advanced cancers. These findings support further evaluation of BMS-986253 in select advanced tumors.AcknowledgementsThe authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New York, NY, USA, for his contributions to the study.Trial RegistrationNCT03400332Ethics ApprovalThis study was approved by the WCG Independent Review Board, approval number 20172711.ReferencesDavid JM, Dominguez C, Hamilton DH, et al. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel) 2016;4:22.Schalper KA, Carleton M, Zhou M, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. Nat Med. 2020;26:688–692.Bilusic M, Heery CR, Collin JM, et al. Phase I trial of HuMax-IL-8 (BMS-986253), an anti–IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer 2019;7:240.Yuen KC, Liu L-F, Gupta V, et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat Med 2020;26:683–698.Sanmamed MF, Perez-Gracia JL, Schalper KA, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti–PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol 2017;28:1988–1995.