Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial

Our plain-English summary of Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial, by D.A. Fennell, A. King, S. Mohammed, et al (The Lancet. Respiratory Medicine, 2021).

The study

• Authors: D.A. Fennell, A. King, S. Mohammed, A. Branson, C. Brookes, L. Darlison, A.G. Dawson, A. Gaba, M. Hutka, B. Morgan, A. Nicholson, C. Richards, P. Wells-Jordan, G.J. Murphy, A. Thomas, MiST1 study group
• Journal: The Lancet. Respiratory Medicine
• Published: 2021;9(6):593-600
• Type of article: Randomized trial
• Cited by: 101 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant mesothelioma remains an incurable cancer, with no effective treatments in the setting of relapsed disease. Homologous recombination deficiency predicts sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In mesothelioma, BRCA1-associated protein 1 carboxy-terminal hydrolase (BAP1), which regulates DNA repair, is frequently mutated. We aimed to test the hypothesis that BAP1-deficient or BRCA1-deficient mesotheliomas would be sensitive to PARP inhibition by rucaparib.

Methods: We did a single-centre, open-label, single-arm, phase 2a trial in Leicester, UK, with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]). Patients aged 18 years or older who had radiologically progressing, histologically confirmed, malignant mesothelioma after at least one course of systemic treatment; with cytoplasmic-BAP1-deficient or BRCA1-deficient mesothelioma (pleural or peritoneal or other primary localisation), and who met the other inclusion criteria, were deemed eligible. All eligible patients who consented to take part were given rucaparib 600 mg twice a day orally, for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response was measured by CT scan every 6 weeks. The primary outcome was disease control (complete response, partial response, or stable disease) at 12 weeks in all patients who received study drug; secondary outcomes were the safety and toxicity profile, objective response rate (proportion of complete or partial responses), and disease control rate at 24 weeks. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03654833.

Findings: Between Feb 9 and June 10, 2019, we enrolled 26 molecularly and clinically eligible patients. Ten (38%) of 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative, and 13 patients (50%) were BRCA1 negative. Disease control rate at 12 weeks was 58% (95% CI 37-77; 15 of 26 patients), and at 24 weeks was 23% (9-44; six of 26 patients). Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients, and there were no deaths. The most common grade 1-2 adverse events were nausea (18 [69%] of 26 patients), fatigue (14 patients [54%]), and decreased appetite (ten patients [38%]). The most common grade 3-4 adverse events were upper respiratory tract infection (three patients [12%]) and anaemia (three patients [12%]). All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%).

Interpretation: Rucaparib in patients with BAP1-negative or BRCA1-negative mesothelioma met the prespecified criteria for success, showing promising activity with manageable toxicity. Further investigation of homologous recombination deficiency mutations is planned to refine the identification of predictive biomarkers for PARP inhibition in mesothelioma.

Funding: University of Leicester (Leicester, UK), Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation (Toronto, ON, Canada).

Copyright © 2021 Elsevier Ltd. All rights reserved.

In plain English

This was a single-centre, open-label, single-arm phase 2a trial (MiST1) in Leicester, UK. It tested oral rucaparib in people whose malignant mesothelioma had worsened after at least one course of systemic treatment that included first-line pemetrexed with cisplatin or carboplatin, and whose tumours were BAP1 or BRCA1 deficient. Between February and June 2019, 26 patients were enrolled. Twenty-five had pleural and one had peritoneal mesothelioma; 15 were recorded as asbestos-exposed. At 12 weeks the disease was controlled (shrinking or stable) in 15 of 26 patients (58%, 95% CI 37 to 77), and at 24 weeks in six (23%, 9 to 44). Three patients (12%) had partial tumour shrinkage, and none had a complete response. There was no evidence that BAP1 or BRCA1 status was linked to response. Of 166 adverse events, most were grade 1. Twelve serious adverse events occurred in nine patients, and there were no treatment-associated deaths. The authors concluded that rucaparib met the trial's success criteria and appears clinically active. They noted possible bias in a single-arm trial and called for randomised studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Investigator-initiated, molecularly stratified, single-arm, open-label, phase 2a clinical trial at a single centre
• Who was studied: 26 adults with relapsed malignant mesothelioma, enrolled February to June 2019 at University Hospitals of Leicester, UK. All had progressed after at least one course of systemic treatment that included first-line pemetrexed with cisplatin or carboplatin. Their tumours were BAP1 deficient or BRCA1 deficient: 23 BAP1 deficient, 13 BRCA1 deficient, 10 both. Median age was 67 years and 22 were male. Twenty-five had pleural and one had peritoneal mesothelioma. Asbestos exposure was recorded as yes for 15 (58%), no for 2 (8%) and unknown for 9 (35%).
• Exposure: Treatment with the PARP inhibitor rucaparib, starting at 600 mg twice a day by mouth in 28-day cycles for up to six cycles (24 weeks). Patients with disease control could continue. The study did not examine asbestos fiber types; asbestos exposure was only recorded as a baseline characteristic.
• Main results:
  • Among all 26 treated patients, disease control was 15 patients (58%, 95% CI 37 to 77) at 12 weeks and six patients (23%, 95% CI 9 to 44) at 24 weeks. This met the prespecified success threshold of at least 11 of 26.
  • Best overall response was a partial response in three of 26 patients (12%). There were no complete responses.
  • In post-hoc exploratory analyses, median progression-free survival was 17.9 weeks (95% CI 12.0 to 24.9). Median overall survival was 41.4 weeks (95% CI 28.6 to not reached).
  • Disease control was durable in four patients, three of whom continued on treatment beyond 12 months.
  • There was no evidence of a correlation between BAP1 (p=0.22) or BRCA1 (p=0.39) expression and objective response.
  • 166 adverse events occurred among 24 patients, most of them grade 1 (119 of 166). Thirteen events were grade 3 and two were grade 4. The most common grade 1 to 2 events were nausea (18 of 26 patients), fatigue (14) and decreased appetite (10).
  • Twelve serious adverse events occurred in nine of 26 patients (35%). The most common was neutropenic sepsis (two events, in two patients), and both were judged related to rucaparib. There were no treatment-associated deaths.
  • 17 patients (65%) needed no dose reduction, eight (31%) had one and one (4%) had two.
• The authors' conclusion: The authors concluded that rucaparib met the trial's criteria for success. They wrote that it appears clinically active in a subset of patients with BRCA1-deficient or BAP1-deficient mesothelioma, with evidence of objective radiological responses. They added that BRCA1 or BAP1 status did not specifically predict response.
• Limitations the authors state:
  • Patients differed substantially from one another, including some with slower-growing mesothelioma, so there is potential for bias, particularly in a single-arm trial.
  • Well-powered randomised studies would be needed to remove bias.
  • All three partial responders had BRCA1 loss, but the small sample size might have prevented detection of a significant interaction.
  • Molecular prescreening used diagnostic biopsies rather than biopsies taken just before treatment.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma, Clinical Trial, Malignant Mesothelioma, Disease Progression, CT Scan, Biomarker.

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