Niraparib and dostarlimab efficacy in patients with platinum-sensitive relapsed mesothelioma: MIST5, a phase IIa clinical trial.
Authors: Fennell Dean Anthony , Branson Amy , King Amy , Poile Charlotte , Barber Shaun , Antoniou Marina , Darlison Liz , Taylor Paul , Scotland Molly , Belcher Clare , Bajaj Amrita , Morgan Bruno , Brookes Cassandra , Wells-Jordan Peter , Dulloo Sean 
Published: June 2024

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Background: Prognosis for patients with relapsed malignant mesothelioma remains dismal. Mesotheliomas exhibit multiple somatic alterations in DNA damage response (DDR) genes which may in part, account for platinum sensitivity. Inhibition of poly ADP ribose polymerase or the immune checkpoint PD1 have demonstrated meaningful clinical activity in this setting [1,2]. We hypothesized that in patients exhibiting platinum-sensitive mesothelioma, a combination of PARP and PD1 inhibition would be synergistic. Niraparib (N) and dostarlimab (D) was therefore evaluated in a multi-centre single arm phase IIa clinical trial. Mesothelioma Stratified Therapy 5 (MIST5) trials.gov identifier NCT03654833. Methods: Patients with any histological subtype or site of malignant mesothelioma (MM - pleural or peritoneal) were enrolled. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-doublet 1st line chemotherapy (any line allowed) with >6 months disease control, evidence of disease progression with measurable disease by CT (mRECIST), and adequate haematological/organ function. Patients received niraparib (N) in combination with dostarlimab (D). The primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 5.0). Patients could undergo an optional re-biopsy upon disease progression. Tissue was collected at baseline (n=24) to enable multiplex immunofluorescence microscopy, whole exome and RNA transcriptome sequencing. Gut microbiome 16s RNA sequencing also was undertaken at baseline (n=26). Results: Between September 2021 and November 2022, 26 patients with MM started treatment and received at least one dose of N + D. Median age: 69.5 (range, 33-85) years; Gender: 80.8% male, 19.2% female. Histology: 80.8% epithelioid, 3.8% Biphasic, 7.7% Sarcomatoid, 7.7% NOS. Performance status: ECOG =0, 7.7%, ECOG=1, 92.3%. Line of therapy: 2nd line 76.9%, 3rd line 23.1%. The median cycles received was 5 (IQR, 3-8) and D was 5 (IQR, 3-8). DCR12w: 65.4% (90% confidence limit (CI, 47.4% –80.6%; 17 of 26 patients), DCR24w: 30.8% (95%CI, 14.3% – 51.8%; 8 of 26 patients). Best responses (within 24w): partial – 15.4% (95%CI, 4.4- 34.9%); stable disease – 65.4% (44.3 – 82.8%); progression – 15.4% (4.4 – 34.9%). Adverse events (any cause): ≥ grade 3 toxicities affected 19.2% of pts. Conclusions: MiST5 met its primary endpoint with an overall disease control rate of 80.8%. Analysis of the cellular and molecular correlates of response are ongoing and will be presented.[1] Fennell et al, Lancet Respiratory Medicine 2019 9(6) p593-600; [2] Fennell et al, Lancet Oncology, 2021 22(11) p1530-1540. Clinical trial information: NCT03654833 .