Integration of the PD-L1 inhibitor atezolizumab and WT1/DC vaccination into standard-of-care first-line treatment for patients with epithelioid malignant pleural mesothelioma-Protocol of the Immuno-MESODEC study.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a very poor prognosis. Recently, immune checkpoint inhibition (ICI) has taken center stage in the currently ongoing revolution that is changing standard-of-care treatment for several malignancies, including MPM. As multiple arguments and accumulating lines of evidence are in support of the existence of a therapeutic synergism between chemotherapy and immunotherapy, as well as between different classes of immunotherapeutics, we designed a multicenter, single-arm, phase I/II trial in which both programmed-death-ligand 1 (PD-L1) inhibition and dendritic cell (DC) vaccination are integrated in the first-line conventional platinum/pemetrexed-based treatment scheme for epithelioid MPM patients (Immuno-MESODEC, ClinicalTrials.gov identifier NCT05765084). Fifteen treatment-naïve patients with unresectable epithelioid subtype MPM will be treated with four 3-weekly (±3 days) chemo-immunotherapy cycles. Standard-of-care chemotherapy consisting of cisplatinum (75mg/m2) and pemetrexed (500mg/m2) will be supplemented with the anti-PD-L1 antibody atezolizumab (1200 mg) and autologous Wilms' tumor 1 mRNA-electroporated dendritic cell (WT1/DC) vaccination (8-10 x 106 cells/vaccination). Additional atezolizumab (1680 mg) doses and/or WT1/DC vaccinations (8-10 x 106 cells/vaccination) can be administered optionally following completion of the chemo-immunotherapy scheme. Follow-up of patients will last for up to 90 days after final atezolizumab administration and/or WT1/DC vaccination or 24 months after diagnosis, whichever occurs later. The trial's primary endpoints are safety and feasibility, secondary endpoints are clinical efficacy and immunogenicity. This phase I/II trial will evaluate whether addition of atezolizumab and WT1/DC vaccination to frontline standard-of-care chemotherapy for the treatment of epithelioid MPM is feasible and safe. If so, this novel combination strategy should be further investigated as a promising advanced treatment option for this hard-to-treat cancer.

Van den Bossche J ，De Laere M ，Deschepper K ，Germonpré P ，Valcke Y ，Lamont J ，Stein B ，Van Camp K ，Germonpré C ，Nijs G ，Roelant E ，Anguille S ，Lion E ，Berneman Z ... -  《PLoS One》

Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in.

There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. AstraZeneca.

Nowak AK ，Lesterhuis WJ ，Kok PS ，Brown C ，Hughes BG ，Karikios DJ ，John T ，Kao SC ，Leslie C ，Cook AM ，Pavlakis N ，Briscoe K ，O'Byrne KJ ，Karapetis CS ，Lam WS ，Langford A ，Yip S ，Stockler MR ... -  《-》

Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905).

Tsao AS ，Miao J ，Wistuba II ，Vogelzang NJ ，Heymach JV ，Fossella FV ，Lu C ，Velasco MR ，Box-Noriega B ，Hueftle JG ，Gadgeel S ，Redman MW ，Gandara DR ，Kelly K ... -  《-》

A Phase II Trial of Nivolumab With Chemotherapy Followed by Maintenance Nivolumab in Patients With Pleural Mesothelioma After Surgery: The NICITA Study Protocol.

In selected patients with early-stage malignant pleural mesothelioma (MPM), a multimodal therapy that includes surgical cytoreduction, chemotherapy, and/or radiotherapy is recommended. Several clinical trials have demonstrated the beneficial effects of immune checkpoint inhibitors in pretreated MPM patients with advanced disease. Recent clinical data have suggested that the combination of chemotherapy and checkpoint inhibition might improve efficacy. The NICITA (nivolumab with chemotherapy in pleural mesothelioma after surgery) trial is a prospective, 1:1 randomized, open-label, multicenter phase II clinical trial (ClinicalTrials.gov identifier, NCT04177953). Ninety-two patients with MPM epithelioid subtype, who had undergone extended pleurectomy and decortication with or without hyperthermic intrathoracic chemoperfusion, will be included to receive adjuvant treatment. All patients will receive ≤ 4 cycles of platinum-based chemotherapy with pemetrexed (arms A and B). Patients in arm B will additionally receive nivolumab, together with the adjuvant chemotherapy, and subsequently for ≤ 12 cycles as maintenance therapy. The primary endpoint of this study is the time-to-next-treatment. The secondary endpoints include progression-free survival, overall survival, proportion of patients with treatment beyond progression, duration of treatment beyond progression in this population, and quality of life. This prospective trial will contribute data to assess the efficacy of standard chemotherapy combined with nivolumab in the context of multimodal management of early-stage MPM. The study is currently enrolling patients.

Shah R ，Klotz LV ，Chung I ，Feißt M ，Schneider MA ，Riedel J ，Bischoff H ，Eichhorn ME ，Thomas M ... -  《-》

Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial.

There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial. This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m2) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. AstraZeneca. CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021. ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.

Kok PS ，Forde PM ，Hughes B ，Sun Z ，Brown C ，Ramalingam S ，Cook A ，Lesterhuis WJ ，Yip S ，O'Byrne K ，Pavlakis N ，Brahmer J ，Anagnostou V ，Ford K ，Fitzpatrick K ，Bricker A ，Cummins MM ，Stockler M ，Nowak AK ，Thoracic Oncology Group of Australasia (TOGA) and PrECOG, USA ... -  《BMJ Open》