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Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma.

ABSTRACT: Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies. Here we report a pilot study of anti-CTLA-4 (tremelimumab) with (n = 15) or without (n = 14) cryoablation in patients with metastatic renal cell carcinoma (NCT02626130), 18 patients with clear cell and 11 patients with non-clear cell histologies. The primary endpoint is safety, secondary endpoints include objective response rate, progression-free survival, and immune monitoring studies. Safety data indicate ≥ grade 3 treatment-related adverse events in 16 of 29 patients (55%) including 6 diarrhea/colitis, 3 hepatitis, 1 pneumonitis, and 1 glomerulonephritis. Toxicity leading to treatment discontinuation occurs in 5 patients in each arm. 3 patients with clear cell histology experience durable responses. One patient in the tremelimumab arm experiences an objective response, the median progression-free survival for all patients is 3.3 months (95% CI: 2.0, 5.3 months). Exploratory immune monitoring analysis of baseline and post-treatment tumor tissue samples shows that treatment increases immune cell infiltration and tertiary lymphoid structures in clear cell but not in non-clear cell. In clear cell, cryoablation plus tremelimumab leads to a significant increase in immune cell infiltration. These data highlight that treatment with tremelimumab plus cryotherapy is feasible and modulates the immune microenvironment in patients with metastatic clear cell histology.

SUBMITTER: Campbell MT

PROVIDER: S-EPMC8569213 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma.

Campbell Matthew T MT Matin Surena F SF Tam Alda L AL Sheth Rahul A RA Ahrar Kamran K Tidwell Rebecca S RS Rao Priya P Karam Jose A JA Wood Christopher G CG Tannir Nizar M NM Jonasch Eric E Gao Jianjun J Zurita Amado J AJ Shah Amishi Y AY Jindal Sonali S Duan Fei F Basu Sreyashi S Chen Hong H Espejo Alexsandra B AB Allison James P JP Yadav Shalini S SS Sharma Padmanee P

Nature communications 20211104 1

Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies. Here we report a pilot study of anti-CTLA-4 (tremelimumab) with (n = 15) or without (n = 14) cryoablation in patients with metastatic renal cell carcinoma (NCT02626130), 18 patients with clear cell and 11 patients with non-clear cell histologies. The primary endpoint is safety, secondary endpoints include objective response rate, progression-free surv ...[more]

PMID: 34737281

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Project description:ObjectiveHead and neck squamous cell carcinoma (HNSCC) ranks as the sixth most prevalent cancer worldwide, significantly impacting patients' quality of life. Immune checkpoint inhibitors (ICI) have been employed in the treatment of recurrent/metastatic (R/M)-HNSCC patients. This meta-analysis aims to assess the efficacy and safety of durvalumab monotherapy compared to the combination of durvalumab and tremelimumab in R/M-HNSCC patients.MethodsRelevant studies were systematically searched in PubMed, Embase, and Cochrane Library databases. All articles comparing durvalumab monotherapy with the combination with durvalumab and tremelimumab in R/M-HNSCC treatment were included. Additionally, the references of identified studies were screened if necessary.ResultA total of 1298 patients from three studies comparing durvalumab with durvalumab and tremelimumab in treating R/M-HNSCC were include in this meta-analysis. Our findings revealed no significant difference in objective response rate (ORR) [odds ratio (OR): 1.15, 95% confidence interval (CI): 0.85 to 1.56, P = 0.36] and disease control rate (DCR) (OR=1.08, 95%CI: 0.86 to 1.37, P = 0.51). Similar outcomes were observed in overall survival (OS), progression-free survival (PFS), and duration of response (DoR). Regarding safety, there was no significant difference in the incidence of treatment-related adverse events (trAEs) between the two groups (OR=1.26, 95%CI: 0.81 to 1.94, P = 0.30). However, patients treated with the combination therapy exhibited a higher incidence of grade 3-4 trAEs (OR=1.93, 95%CI: 1.36 to 2.73, P = 0.0002) and a greater likelihood of discontinuing treatment due to trAEs (OR=2.07, 95%CI: 1.12 to 3.85, P = 0.02). There was no significant difference in the occurrence of severe trAEs leading to death (OR=1.36, 95%CI: 0.47 to 3.96, P = 0.57).ConclusionThis meta-analysis suggests that R/M-HNSCC patients receiving the combination of durvalumab and tremelimumab may achieve comparable outcomes in terms of ORR, DCR, OS, PFS, and DoR, without significant differences. However, the combination therapy is associated with a higher incidence of grade 3-4 trAEs and an increased likelihood of treatment discontinuation due to trAEs. These findings highlight the need for cautious consideration of the combination of durvalumab and tremelimumab in R/M-HNSCC patients, which should be further evaluated in high-quality studies.

Project description:PurposeCirculating tumor DNA (ctDNA) has been validated across multiple indications in the adjuvant and surveillance settings. We evaluated whether targeted digital sequencing (TARDIS) may distinguish a partial response (PR) from a complete response (CR) among patients with metastatic renal cell carcinoma (mRCC) receiving immune checkpoint inhibitor (ICI) therapy.Materials and methodsEligible patients had mRCC that yielded a PR or CR to ICI therapy. Peripheral blood was obtained at a single time point for ctDNA analysis. TARDIS was used for quantification of average variant allele fractions (VAFs). Our primary objective was to determine the association between VAFs and depth of response (PR v CR). A secondary objective was to determine whether VAFs were associated with disease progression.ResultsTwelve patients were analyzed, nine of whom achieved a PR (75%). Patients received either nivolumab monotherapy (50%) or nivolumab plus ipilimumab (50%). ctDNA analysis incorporated an average of 30 patient-specific mutations (range, 19-35); average coverage depth was 103,342 reads per target. TARDIS quantified a significant difference in VAFs between PR and CR (median, 0.181% [IQR, 0.077%-0.420%] v 0.007% [IQR, 0.0%-0.028%], respectively [P = .014]). Of the 12 patients in the series, six patients demonstrated radiographic progression subsequent to ctDNA assessment. Patients who progressed on subsequent scans had significantly higher ctDNA than those who maintained their response (median, 0.362% [IQR, 0.181%-2.71%] v 0.033% [IQR, 0.007%-0.077%], respectively [P = .026]).ConclusionIn this pilot study, TARDIS accurately differentiated PR from CR among patients with mRCC receiving immunotherapy, and also prospectively identified patients at risk for subsequent progression. Given these findings, we envision subsequent studies that validate these results and investigate the utility of this assay to discern appropriate candidates for discontinuation of immunotherapy.

Dataset Information

Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma.

Publications

Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma.

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