Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti-PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Our plain-English summary of Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti-PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma, by F.X. Danlos, M. Texier, B. Job, et al (Cancer Discovery, 2023).

The study

• Authors: F.X. Danlos, M. Texier, B. Job, S. Mouraud, L. Cassard, C. Baldini, A. Varga, A.A. Yurchenko, A. Rabeau, S. Champiat, D. Letourneur, D. Bredel, S. Susini, Y. Blum, A. Parpaleix, C. Parlavecchio, L. Tselikas, J.E. Fahrner, A.G. Goubet, M. Rouanne, S. Rafie, A. Abbassi, I. Kasraoui, M. Breckler, S. Farhane, S. Ammari, S. Laghouati, A. Gazzah, L. Lacroix, B. Besse, N. Droin, M. Deloger, S. Cotteret, J. Adam, L. Zitvogel, S.I. Nikolaev, N. Chaput, C. Massard, J.C. Soria, C. Gomez-Roca, G. Zalcman, D. Planchard, A. Marabelle
• Journal: Cancer Discovery
• Published: 2023;13(4):858-879
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799.

©2023 The Authors; Published by the American Association for Cancer Research.

In plain English

This was one cohort of PEMBIB, a multicenter phase Ib trial. It tested pembrolizumab (an immunotherapy) plus nintedanib (a blood-vessel growth blocker) in advanced malignant pleural mesothelioma previously treated with platinum chemotherapy. Of 32 patients enrolled from October 2017 to April 2019, 30 were treated. Asbestos exposure was not studied. Of 29 patients evaluated, 7 (24.1%) had a partial response, 17 (58.6%) stable disease and 5 (17.2%) progressive disease. Median progression-free survival was 6.2 months (95% CI 3 to 8.7) and median overall survival 14.1 months (95% CI 9.89 to not reached). Twelve of 30 patients (40%) had grade 3 to 5 treatment-related adverse events; one death was attributed to both drugs. Researchers compared 14 patients with durable benefit at 6 months and 16 without. Tumors of patients without benefit drew in killer T cells during treatment but gained cells resembling regulatory T cells. These patients had higher IL6, CXCL8 and VEGF and more chromosome copy-number changes. The authors concluded the combination showed antitumor activity with manageable toxicity, and that resistance was associated with this profile. They noted the small sample size.

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: Expansion cohort of a multicenter phase Ib clinical trial (PEMBIB, NCT02856425), with exploratory biomarker analyses of blood and tumor biopsies taken before and during treatment
• Who was studied: 32 patients with advanced pleural mesothelioma enrolled between October 10, 2017 and April 11, 2019; 2 failed screening and 30 were treated. All had previously received platinum-based chemotherapy and had not received immunotherapy.
• Exposure: Not asbestos. The exposure studied was drug treatment: nintedanib 150 mg by mouth twice daily plus pembrolizumab 200 mg intravenously every 3 weeks, after a 1-week lead-in of nintedanib alone.
• Main results:
  • Best response among 29 evaluable patients: partial response in 7 of 29 (24.1%)
  • Stable disease in 17 of 29 (58.6%); progressive disease in 5 of 29 (17.2%)
  • Whole cohort: median progression-free survival 6.2 months (95% CI, 3 to 8.7)
  • Whole cohort: median overall survival 14.1 months (95% CI, 9.89 to not reached)
  • 16 patients (53.3%) had no durable clinical benefit at 6 months and 14 (46.7%) had durable clinical benefit
  • Median overall survival was 9.1 months (95% CI, 5.88 to 14.1) for patients without durable benefit and 26.3 months (95% CI, 23.03 to not reached) for patients with durable benefit
  • Grade 3/4/5 treatment-related adverse events occurred in 12 patients (40%) and immune-related ones in 3 of 30 (10%); one patient's death was attributed to both drugs
  • Median tumor PD-L1 expression was 2.5 (95% CI, 0 to 12.5) in patients with durable benefit and 0 in patients without
  • Tumor secretion of the T-cell-attracting chemokine CXCL9 rose about tenfold from baseline to on-treatment in both groups
  • T cells, including CD8+ T cells, increased in tumors mainly in patients without durable benefit, who had little T-cell infiltration at baseline
  • On treatment, patients without durable benefit had more tumor CD4+ T cells with features compatible with activated regulatory T cells
  • Patients without durable benefit had a proinflammatory, proangiogenic profile at baseline, with increased tumor secretion of IL6, CXCL8 and VEGF during treatment
  • Patients without durable benefit had a higher somatic copy-number alteration score than patients with durable benefit (exome sequencing was usable for only 13 biopsies)
  • Copy-number alteration score correlated with IL6 levels: Pearson R = 0.52, P = 0.029; Spearman R = 0.46, P = 0.056
• The authors' conclusion: The authors concluded that the combination provided antitumor activity with manageable toxicities. They found that primary resistance was associated with high VEGF, CXCL8 and IL6 in blood and tumor together with high copy-number alterations, and said more mechanistic studies are needed to establish the link.
• Limitations the authors state:
  • Limited sample size; the results need validation in larger trials
  • The 6-month cutoff used to define durable clinical benefit was arbitrary
  • Clinical trial outcomes overestimate what could be achieved in routine care
  • Biomarker tests were exploratory, and most P values were not adjusted for multiple comparisons

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: Inflammation, Pleural Mesothelioma, Immunotherapy, Overall Survival, Mesothelioma, Pembrolizumab (Keytruda), Tyrosine Kinase Inhibitor, Cytokine.

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