Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial

Our plain-English summary of Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial, by P.M. Forde, V. Anagnostou, Z. Sun, et al (Nature Medicine, 2021).

The study

• Authors: P.M. Forde, V. Anagnostou, Z. Sun, S.E. Dahlberg, H.L. Kindler, N. Niknafs, T. Purcell, R. Santana-Davila, A.Z. Dudek, H. Borghaei, M. Lanis, Z. Belcaid, K.N. Smith, A. Balan, J.R. White, C. Cherry, I.K. Ashok Sivakumar, X.M. Shao, H.Y. Chan, D. Singh, S. Thapa, P.B. Illei, D.M. Pardoll, R. Karchin, V.E. Velculescu, J.R. Brahmer, S.S. Ramalingam
• Journal: Nature Medicine
• Published: 2021;27(11):1910-1920
• Cited by: 115 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial ( NCT02899195 ) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.

© 2021. The Author(s).

In plain English

PrE0505 was a phase 2, single-arm trial of the immunotherapy drug durvalumab with platinum and pemetrexed chemotherapy for previously untreated, unresectable malignant pleural mesothelioma. It enrolled 55 patients at 15 US cancer centers between June 2017 and June 2018. Asbestos exposure was not examined. Median overall survival was 20.4 months (95% CI 13.0–28.5). This was significantly longer than a historical control of 12 months; the trial had no comparison group of its own. Median progression-free survival was 6.7 months (95% CI 6.1–8.4), and 31 of 55 patients (56.4%, 95% CI 42.3–69.7%) had a tumor response, all partial. In an unplanned subgroup analysis, patients with epithelioid tumors lived longer than those with non-epithelioid tumors (median 24.3 versus 9.2 months). Grade 3 or higher adverse events occurred during treatment in 65.5% of patients; events with a possible immune cause were grade 2 or lower. Exploratory analyses linked two features with longer survival: inherited harmful mutations in mesothelioma-predisposing genes, and a more diverse T cell repertoire. The authors concluded that the combination showed promising activity. They noted the small sample size and the lack of a control arm.

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: Phase 2, single-arm, multicenter clinical trial (PrE0505), with exploratory genomic and immunologic analyses; survival was compared with a historical control rather than a randomized control group
• Who was studied: 55 patients aged 18 or older with previously untreated, surgically unresectable malignant pleural mesothelioma, enrolled at 15 academic and community cancer centers in the United States between 12 June 2017 and 21 June 2018. Median age was 68 years (range 35–83); 45 of 55 (81.8%) were male; 41 of 55 (74.5%) had epithelioid tumors.
• Exposure: This was a medical treatment, not an asbestos exposure. Patients received durvalumab at a fixed dose of 1,120 mg intravenously once every 3 weeks with standard-dose pemetrexed and cisplatin (carboplatin substitution permitted) for up to six cycles. This was followed by maintenance durvalumab for up to 1 year from first treatment. Asbestos exposure was not assessed in the study.
• Main results:
  • All 55 patients: median overall survival was 20.4 months (95% CI 13.0–28.5; 80% CI 15.1–27.9), significantly longer than the historical control of 12 months (one-sided P = 0.0014)
  • All patients: estimated percentages alive at 6, 12 and 24 months were 87.2%, 70.4% and 44.2%
  • All patients: median progression-free survival was 6.7 months (95% CI 6.1–8.4)
  • Objective response rate was 56.4% (95% CI 42.3–69.7%). There were no complete responses, 31 partial responses, 20 with stable disease, 3 with progressive disease and 1 unevaluable.
  • Non-predefined subgroup analysis: patients with epithelioid tumors had a higher response rate than those with non-epithelioid tumors (65.9% versus 28.6%, P = 0.03)
  • Epithelioid versus non-epithelioid patients: median overall survival was 24.3 versus 9.2 months (HR 0.27, 95% CI 0.13–0.57, P less than 0.001)
  • Grade 3 or higher treatment-emergent adverse events (events arising during treatment) occurred in 65.5% of patients. No grade 5 events were observed, and adverse events with a potential immune-mediated mechanism were grade 2 or lower.
  • No statistically significant differences in progression-free or overall survival were seen by which platinum drug was received
  • Exploratory: patients with known deleterious germline mutations in mesothelioma-predisposing genes had longer overall survival (log-rank P = 0.05 for all patients; P = 0.032 for epithelioid). A narrower analysis limited to DNA repair genes showed trends only (P = 0.12 and P = 0.082).
  • Exploratory: responding tumors had a higher MHC class II immunogenic mutation burden (P = 0.023); the MHC class I difference was P = 0.064
  • Exploratory: baseline tumors of patients surviving 12 or more months had a more diverse T cell receptor repertoire than those of patients with shorter survival (P = 0.018 and P = 0.006 for two measures)
  • No association was seen between PD-L1 expression on tumor cells and response, progression-free survival or overall survival
• The authors' conclusion: The authors concluded that durvalumab with standard chemotherapy as first-line therapy delivered promising rates of response, progression-free survival and overall survival in unresectable malignant pleural mesothelioma. They reported that treatment was well tolerated with low rates of immune-mediated toxicity.
• Limitations the authors state:
  • Small sample size and no control arm without durvalumab
  • The historical control assumption may have underestimated the expected survival with chemotherapy alone, because recent randomized data have shown both shorter and longer survival with pemetrexed-cisplatin
  • Whether the molecular findings predict benefit from treatment or simply reflect prognosis remains to be assessed in the ongoing phase 3 trial

Topics

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

Medical terms in this study, explained in our Lexicon: Durvalumab (Imfinzi), Platinum-Pemetrexed, Unresectable Pleural Mesothelioma, Mesothelioma, PD-L1, Chemotherapy, Overall Survival, Cisplatin.

Related studies

• Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in — A.K. Nowak, W.J. Lesterhuis, et al. (2020)
• Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905) — A.S. Tsao, J. Moon, et al. (2017)
• A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma — A.K. Nowak, A.M. Cook, et al. (2015)
• JME-001 phase II trial of first-line combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma — Y. Miyamoto, T. Kozuki, et al. (2021)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial — P.S. Kok, P.M. Forde, et al. (2022)

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