High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients

Our plain-English summary of High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients, by L. Cantini, F. Pecci, D.P. Hurkmans, et al (European Journal of Cancer, 2021).

The study

• Authors: L. Cantini, F. Pecci, D.P. Hurkmans, R.A. Belderbos, A. Lanese, C. Copparoni, S. Aerts, R. Cornelissen, D.W. Dumoulin, I. Fiordoliva, S. Rinaldi, J.G.J.V. Aerts, R. Berardi
• Journal: European Journal of Cancer
• Published: 2021;144:41-48
• Cited by: 104 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients treated with PD-1 inhibitors.

Methods: A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated.

Results: Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P = .02), PFS (median 6.7 versus 2.9 months, hazard ratio [HR] 0.57, 95% CI 0.39-0.83, P < .01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45-1.00, P = .05). In the control MPM cohort treated with chemotherapy (n = 77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P = .05), PFS (median 6.7 versus 2.4 months, P < .01), and OS (median not reached versus 6.0 months, P = .01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P = .04) and PFS (median 7.8 versus 3.6 months, P = .03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P = .30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P = .02 and P = .59, respectively).

Conclusions: Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner.

Copyright © 2020 Elsevier Ltd. All rights reserved.

In plain English

The authors reviewed records from Ancona, Italy, and Rotterdam, the Netherlands, for 82 people with malignant pleural mesothelioma and 179 with advanced non-small cell lung cancer. All received the immunotherapy drugs nivolumab or pembrolizumab (PD-1 inhibitors) after earlier treatment. The authors compared patients taking cholesterol-lowering statins when treatment began with those not taking them; 253 had statin information. Overall, statin users more often had tumor shrinkage (32% versus 18%) and went longer without cancer worsening or death (median 6.7 versus 2.9 months). Among mesothelioma patients, statin users lived longer (median survival not reached versus 6.0 months). Among lung cancer patients, the survival difference was not statistically significant. In a separate group of 77 mesothelioma patients given first-line chemotherapy, statins showed no association. Only high-intensity statins, taken by 14 patients, were linked with better outcomes. The authors concluded that statin use was associated with better results, depending on statin intensity. They said randomized trials are needed to tell whether statins cause this. They did not adjust for some tumor features and could not determine how long patients had taken statins.

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: Multicenter observational study of patient records from two centers (correlative analysis), with a comparison group of mesothelioma patients treated with chemotherapy
• Who was studied: 261 patients treated with PD-1 inhibitors alone as second- or further-line treatment: 82 with malignant pleural mesothelioma (MPM) and 179 with advanced non-small cell lung cancer (aNSCLC). Patients came from Universita Politecnica delle Marche (Ancona, Italy) and Erasmus Medical Center (Rotterdam, Netherlands). The lung cancer patients were treated between January 2016 and December 2019, and the MPM patients were in the Erasmus nivolumab expanded access program. 253 patients had statin data (80 MPM, 173 aNSCLC). The control cohort was 77 MPM patients given standard first-line chemotherapy at Ancona, of whom 13 (17%) were taking statins.
• Exposure: Statin use at the start of PD-1 inhibitor treatment (67 users). The authors recorded statin type (atorvastatin, rosuvastatin, simvastatin, others), lipophilicity, and intensity, with intensity defined by the 2018 American College of Cardiology/American Heart Association cholesterol guideline (low 2, moderate 42, high 14, unknown 9). The article does not study asbestos exposure.
• Main results:
  • Whole cohort, statin users versus non-users: objective response rate 32% versus 18% (P = .02). Median progression-free survival (time to radiological progression or death) 6.7 versus 2.9 months (HR 0.57, 95% CI 0.39 to 0.83, P less than .01). Median overall survival 13.1 versus 8.7 months (HR 0.67, 95% CI 0.45 to 1.00, P = .05).
  • MPM patients on PD-1 inhibitors: objective response rate was 22% in statin users versus 6% in non-users (P = .03).
  • MPM patients on PD-1 inhibitors, statin users versus non-users: median progression-free survival 6.7 versus 2.3 months (HR 0.42, 95% CI 0.23 to 0.77, P less than .01). Median overall survival not reached versus 6.0 months (HR 0.43, 95% CI 0.21 to 0.85, P = .01).
  • aNSCLC patients: objective response rate was 40% in statin users versus 22% in non-users (P = .04).
  • aNSCLC patients, statin users versus non-users: median progression-free survival 7.8 versus 3.6 months (HR 0.59, 95% CI 0.37 to 0.97, P = .03). Overall survival showed no difference: median 13.1 versus 10.1 months (HR 0.79, 95% CI 0.49 to 1.28, P = .35).
  • In the multivariable analysis of MPM patients, adjusted for age, gender, smoking, performance status and histological subtype, statin use remained significant for progression-free survival (HR 0.36, 95% CI 0.16 to 0.81, P = .01) and overall survival (HR 0.27, 95% CI 0.10 to 0.74, P = .01).
  • In the multivariable analysis of aNSCLC patients, statin use was not significantly associated with overall survival (HR 0.68, 95% CI 0.38 to 1.22, P = .20). It remained significantly associated with progression-free survival (HR 0.52, 95% CI 0.29 to 0.93, P = .03).
  • In the control group of 77 MPM patients treated with standard first-line chemotherapy, no association was found between statin use and outcomes. The article reports response rates of 18% versus 17% (P = 1), median progression-free survival of 6.0 versus 6.3 months (P = .60), and median overall survival of 11.3 versus 16.7 months (P = .20). It does not state which figure belongs to which group.
  • Whole cohort, high-intensity statin users versus non-users: objective response rate 46% versus 18% (P = .03). Median progression-free survival not reached versus 2.9 months (HR 0.20, 95% CI 0.06 to 0.65, P less than .01). Median overall survival not reached versus 8.7 months (HR 0.10, 95% CI 0.01 to 0.76, P = .02).
  • Whole cohort, low/moderate-intensity statin users versus non-users: no differences. Objective response rate 24% versus 18% (P = .43). Median progression-free survival 5.1 versus 2.8 months (HR 0.76, 95% CI 0.51 to 1.13, P = .17). Median overall survival 9.5 versus 8.7 months (HR 0.89, 95% CI 0.59 to 1.35, P = .59).
  • No difference in progression-free or overall survival was found according to statin type or lipophilicity.
• The authors' conclusion: The authors concluded that statin use was associated with improved clinical activity of PD-1 inhibitors in thoracic cancer patients in an intensity-dependent manner. They said randomized trials are still needed to assess whether this reflects a general prognostic association or a causal link.
• Limitations the authors state:
  • Patient characteristics other than statin use could have influenced the difference in prognosis.
  • The authors did not adjust their estimates for tumor-intrinsic factors such as PD-L1 status and tumor mutational burden.
  • It was not possible to determine how long patients had been taking statins before PD-1 inhibitor treatment.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Non-Small Cell Lung Cancer, Chemotherapy, Progression-Free Survival, Overall Survival, Hazard Ratio.

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