Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma

Our plain-English summary of Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma, by J. Quispel-Janssen, V. van der Noort, J.F. de Vries, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: J. Quispel-Janssen, V. van der Noort, J.F. de Vries, M. Zimmerman, F. Lalezari, E. Thunnissen, K. Monkhorst, R. Schouten, L. Schunselaar, M. Disselhorst, H. Klomp, K. Hartemink, S. Burgers, W. Buikhuisen, P. Baas
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(10):1569-1576
• Cited by: 200 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) has limited treatment options and a poor outcome. Programmed death 1/programmed death ligand 1 (PD-L1) checkpoint inhibitors have proven efficacious in several cancer types. Nivolumab is a fully humanized monoclonal antibody against programmed death 1 with a favorable toxicity profile. In MPM, the immune system is considered to play an important role. We therefore tested nivolumab in recurrent MPM.

Methods: In this single-center trial, patients with MPM received nivolumab 3 mg/kg intravenously every 2 weeks. Primary endpoint was the disease control rate at 12 weeks. Pre- and on-treatment biopsy specimens were obtained to analyze biomarkers for response.

Results: Of the 34 patients included, 8 patients (24%) had a partial response at 12 weeks and another 8 had stable disease resulting in a disease control rate at 12 weeks of 47%. One reached a partial response at 18 weeks. In 4 patients with stable disease, the tumor remained stable for more than 6 months. Treatment-related adverse events of any grade occurred in 26 patients (76%), most commonly fatigue (29%) and pruritus (15%). Grades 3 and 4 treatment-related adverse events were reported in 9 patients (26%), with pneumonitis, gastrointestinal disorders, and laboratory disorders mostly seen. One treatment-related death was due to pneumonitis and probably initiated by concurrent amiodarone therapy. PD-L1 was expressed on tumor cells in nine samples (27%), but did not correlate with outcome.

Conclusions: Single-agent nivolumab has meaningful clinical efficacy and a manageable safety profile in pre-treated patients with mesothelioma. PD-L1 expression does not predict for response in this population.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This single-center phase II trial in Amsterdam tested nivolumab, an immunotherapy drug, in people with malignant pleural mesothelioma that had returned after chemotherapy. It did not study asbestos exposure. Between July 2015 and June 2016, 34 patients received nivolumab 3 mg/kg intravenously every 2 weeks. At 12 weeks, 8 of the 34 (24%, 95% CI 11% to 42%) had a partial response (tumor shrinkage) and 8 more had stable disease, a disease control rate of 47% (95% CI 30% to 65%). One more patient later reached a partial response. Median overall survival from treatment start was 11.8 months (95% CI 9.7 to 15.7). Treatment-related side effects occurred in 26 patients (76%), and grade 3 or 4 side effects in 9 (26%). One treatment-related death was from lung inflammation (pneumonitis), which the authors judged most likely started by the heart drug amiodarone and enhanced by nivolumab. The marker PD-L1 appeared in 9 of 33 evaluable pre-treatment samples (27%) but did not correlate with outcome. The authors concluded that nivolumab has meaningful clinical activity and an acceptable safety profile in previously treated mesothelioma patients.

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: Prospective, single-arm, single-center phase II clinical trial of a drug treatment
• Who was studied: 34 adults with malignant pleural mesothelioma that had recurred after at least one chemotherapy regimen, treated at the Netherlands Cancer Institute, Amsterdam, between July 2015 and June 2016. Of 38 who gave consent, 34 met the entry criteria.
• Exposure: Not an asbestos exposure study. The intervention was nivolumab, an anti-PD-1 antibody, given at 3 mg/kg intravenously every 2 weeks for up to 1 year or until progression or unacceptable toxicity.
• Main results:
  • At 12 weeks, 8 of 34 patients (24%, 95% CI 11% to 42%) had a partial response and 8 had stable disease, for a disease control rate of 47% (95% CI 30% to 65%).
  • One patient with stable disease at 12 weeks reached a partial response at 18 weeks, for a total of 9 patients (26%) with a partial response. 13 patients (39%) were considered to have clinical benefit.
  • Measured from the start of treatment, median progression-free survival was 2.6 months (95% CI 2.23 to 5.49) and median overall survival was 11.8 months (95% CI 9.7 to 15.7). Overall survival at 1 year was 50% (95% CI 36% to 70%).
  • Among all 34 treated patients, treatment-related adverse events of any grade occurred in 26 (76%), most commonly fatigue (29%) and pruritus (15%). Grade 3 to 4 treatment-related adverse events occurred in 9 (26%).
  • There was one treatment-related death, from pneumonitis, in a patient taking amiodarone. The authors judged that it was most likely initiated by amiodarone and enhanced by nivolumab.
  • Of 33 patients evaluable for PD-L1, 9 pre-treatment samples (27%) showed PD-L1 on more than 1% of tumor cells. PD-L1 expression in neither pre-treatment nor on-treatment biopsies correlated with outcome (p = 0.43 and 0.66).
  • An increase in neutrophil-to-lymphocyte ratio (NLR) of more than 25% from baseline to week 6 correlated with nonresponse. LDH, CRP and leucocyte count did not predict outcome.
• The authors' conclusion: The authors concluded that nivolumab has meaningful clinical activity and an acceptable safety profile as second-line treatment in an unselected population of mesothelioma patients. They also concluded that PD-L1 expression did not predict response in this group.
• Limitations the authors state:
  • The authors stated that the predictive value of the NLR finding must be validated in a larger patient cohort.
  • The authors noted that PD-L1 is often expressed unevenly within a tumor, which may lead to sampling errors.
  • The authors stated that the limited number of patients in these trials is likely to make differences between trials statistically insignificant.

Topics

Medical terms in this study, explained in our Lexicon: Nivolumab (Opdivo), Pleural Mesothelioma, PD-L1, checkpoint inhibitors, Monoclonal Antibody, Biopsy, Biomarker, Pneumonitis.

Related studies

• Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma — D.A. Fennell (2018)
• CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial — D.A. Fennell, E. Kirkpatrick, et al. (2018)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• Ipilimumab/Nivolumab-related Opsoclonus-Myoclonus-Ataxia Syndrome Variant in a Patient with Malignant Pleural Mesothelioma — B. Maller, E. Peguero, et al. (2018)
• Nivolumab for malignant peritoneal mesothelioma — T. Tanaka, Y. Miyamoto, et al. (2020)
• Effectiveness of Nivolumab on Sarcomatoid Malignant Pleural Mesothelioma With Eosinophilia and Eosinophilic Pleural Effusion — M. Yamazoe, H. Ozasa, et al. (2019)

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