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A promising response of refractory uterine leiomyosarcoma to pembrolizumab and temozolomide combination therapy.

ABSTRACT: Uterine leiomyosarcomas (ULMS) are a rare cause of uterine malignancy. Due to their aggressive nature, resistance to standard therapy and high rates of recurrence, they are associated with a very poor prognosis, irrespective of their stage at diagnosis. A 68-year-old female, Chinese patient was diagnosed with Stage IVB uterine leiomyosarcoma with lung metastasis. Disease progression occurred after fourth-line treatment and the patient was commenced on pembrolizumab and temozolomide combination therapy. At the time of writing, our patient has experienced partial response to treatment with minimal adverse effects at cycle 7 of Pembrolizumab in combination with Temozolomide.

SUBMITTER: Lin R

PROVIDER: S-EPMC10837061 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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A promising response of refractory uterine leiomyosarcoma to pembrolizumab and temozolomide combination therapy.

Lin Rebecca R Muaadz Asyraf A Gwo Fuang Ho H

Gynecologic oncology reports 20240117

Uterine leiomyosarcomas (ULMS) are a rare cause of uterine malignancy. Due to their aggressive nature, resistance to standard therapy and high rates of recurrence, they are associated with a very poor prognosis, irrespective of their stage at diagnosis. A 68-year-old female, Chinese patient was diagnosed with Stage IVB uterine leiomyosarcoma with lung metastasis. Disease progression occurred after fourth-line treatment and the patient was commenced on pembrolizumab and temozolomide combination t ...[more]

PMID: 38314319

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Project description:BackgroundMetastatic colorectal cancers (MCRCs) with microsatellite stability (MSS) are resistant to immunotherapy with programmed cell death protein 1 (PD-1) and programmed death-ligand 1 inhibitors. However, the addition of regorafenib to nivolumab was recently associated with a high response rate and a protracted progression-free survival in a small cohort of MSS Japanese patients with metastatic colorectal cancer.Materials and methodsWe evaluated the outcome of patients with MSS metastatic colorectal cancer who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib in a single U.S. center.ResultsA total of 18 patients were treated with a combination of regorafenib and PD-1 inhibitors. No treatment-related grade 3 or above toxicities were noted. Thirteen patients (69%) had progressive disease, and five patients (31%) experienced stable disease as best response. Four out of five stable diseases occurred in patients without liver metastases, whereas only 1 of 14 patients with history of liver metastases had a short disease stabilization. A rise in circulating tumor DNA (ctDNA) at the 4-week time pointuniversally predicted tumor progression at 2 months, whereas a decline was associated with radiographic disease stabilization.ConclusionsRegorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant metastatic colorectal cancer. Selection for patients without history of liver metastases may identify a cohort of patients with MSS colorectal cancer with a higher likelihood of benefit from this combination. ctDNA may represent a powerful tool for predicting early therapeutic efficacy of immunotherapy in the MSS colorectal cancer population.Implications for practiceThis study showed that the combination of regorafenib and nivolumab was associated with a modest clinical activity in patients with advanced microsatellite stability (MSS) metastatic colorectal cancer. This combination should be avoided in clinical practice, especially in patients with MSS colorectal cancer with liver metastases. Further investigation of regorafenib plus PD-1 inhibitors should be considered in MSS colorectal cancer without liver metastases.

Project description:BackgroundUterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting.MethodsA cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting.ResultsAll 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs.ConclusionsOur work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

Dataset Information

A promising response of refractory uterine leiomyosarcoma to pembrolizumab and temozolomide combination therapy.

Publications

A promising response of refractory uterine leiomyosarcoma to pembrolizumab and temozolomide combination therapy.

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