ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment

Our plain-English summary of ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment, by S. Ponce, S. Cedrés, C. Ricordel, et al (Journal for Immunotherapy of Cancer, 2023).

The study

• Authors: S. Ponce, S. Cedrés, C. Ricordel, N. Isambert, S. Viteri, M. Herrera-Juarez, A. Martinez-Marti, A. Navarro, M. Lederlin, X. Serres, J. Zugazagoitia, S. Vetrhus, M. Jaderberg, T.B. Hansen, V. Levitsky, L. Paz-Ares
• Journal: Journal for Immunotherapy of Cancer
• Published: 2023;11(9)
• Type of article: Randomized trial
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes.

Methods: In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×1011 virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed.

Results: In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort.

Conclusions: ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This open-label study in Spain and France tested a treatment for malignant pleural mesothelioma that could not be removed surgically. It did not study asbestos exposure. Between 2016 and 2019, 31 patients were enrolled. Twenty were given ONCOS-102, an engineered virus (an oncolytic adenovirus) injected into the tumor, with pemetrexed plus cisplatin or carboplatin chemotherapy planned: 6 in a safety lead-in group and 14 assigned at random. One of them stopped before chemotherapy began. Eleven were randomly assigned chemotherapy alone. The main goal was safety. Fever was the most frequent ONCOS-102-related side effect (75.0% of that group); no patient stopped ONCOS-102 because of side effects. Survival differences were not statistically significant. Among 17 patients with no prior chemotherapy, median survival was 20.3 months with ONCOS-102 versus 13.5 months with chemotherapy alone. By day 36, biopsies from the ONCOS-102 group showed more T cells (immune cells) in tumors, unlike chemotherapy alone. The authors concluded the combination was feasible, well tolerated and may offer a survival advantage in previously untreated patients. They cautioned that this small, exploratory study's results need careful interpretation.

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: Open-label, multicenter, two-part clinical trial: a phase Ib safety lead-in followed by a phase II randomized comparison. All statistical analyses were exploratory.
• Who was studied: 31 adults with histologically confirmed, unresectable, advanced malignant pleural mesothelioma, enrolled June 17, 2016 to April 17, 2019 at sites in Spain and France. Six were in the safety lead-in and 25 were randomized (14 to ONCOS-102 plus chemotherapy, 11 to chemotherapy alone). That gave 20 ONCOS-102 patients and 11 chemotherapy-alone patients in total.
• Exposure: This was a treatment study, not an asbestos exposure study. ONCOS-102, an oncolytic adenovirus expressing GM-CSF (3 times 10 to the 11th virus particles), was injected into the tumor on days 1, 4, 8, 36, 78 and 120, with cyclophosphamide priming. It was given with pemetrexed plus cisplatin or carboplatin from day 22 for up to six 21-day cycles. The comparison group received pemetrexed plus cisplatin or carboplatin alone.
• Main results:
  • One patient in the ONCOS-102 group stopped before chemotherapy started on day 22. Patients who started chemotherapy received a median of 6 (range 1 to 6) cycles of pemetrexed.
  • Anemia (15.0% ONCOS-102 group vs 27.3% chemotherapy-alone group) and neutropenia (25.0% vs 36.4%) were the most frequent grade 3 treatment-emergent adverse events.
  • Fever (75.0% of the ONCOS-102 group) was the most frequent adverse event considered related to ONCOS-102. All ONCOS-102-related adverse events were grade 1 or 2 except one grade 3 fever.
  • No patients stopped ONCOS-102 because of treatment-emergent adverse events.
  • Twelve patients died during study treatment. Eleven deaths were from disease progression (7 ONCOS-102, 4 chemotherapy alone). One ONCOS-102 patient with a history of cardiac disease died of cardiac failure, which was considered unrelated to ONCOS-102.
  • In all 31 patients, the 30-month overall survival rate was 34.3% (ONCOS-102) vs 18.2% (chemotherapy alone). Median overall survival was 16.6 vs 18.3 months (p greater than 0.05), and median progression-free survival was 8.5 vs 8.3 months.
  • In the 17 chemotherapy-naive patients, the authors reported a numerical trend that was not statistically significant. The 30-month overall survival rate was 34.1% (ONCOS-102) vs 0% (chemotherapy alone), and median overall survival was 20.3 vs 13.5 months.
  • Objective response (by RECIST V.1.1) occurred in 4 patients (21.1%) in the ONCOS-102 group and 5 patients (45.5%) in the chemotherapy-alone group.
  • Tumor infiltration by CD4+ and CD8+ T cells and related immune measures increased from baseline to day 36 in biopsies from the ONCOS-102 group (n=16). This was not observed in the chemotherapy-alone group (n=5).
  • Within the ONCOS-102 group, increased immune activation was associated with being alive at month 18.
• The authors' conclusion: The authors concluded that ONCOS-102 given with pemetrexed plus cisplatin/carboplatin was feasible and well tolerated and may provide a survival advantage in treatment-naive patients with malignant pleural mesothelioma. They supported further evaluation in larger studies.
• Limitations the authors state:
  • No formal sample size calculation was done; the study was exploratory.
  • The authors said efficacy data from this small, exploratory study should be interpreted with caution.
  • Baseline tumor burden suggested the ONCOS-102 group may have had more severe disease than the chemotherapy-alone group.
  • Blood sampling times differed between the two arms, which limits interpretation of the blood cytokine results.
  • The prognostic markers found need further validation.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Chemotherapy, Pleural Mesothelioma, Tumor Microenvironment, Macrophage, Unresectable, Cisplatin, Carboplatin.

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• Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy — G. Toyokawa, M. Takenoyama, et al. (2014)

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