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Arnaud Scherpereel

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    MS13 - Immunotherapy for Mesothelioma (ID 76)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 6
    • Now Available
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      MS13.01 - Immunotherapy and Mesothelioma: Rationale and Strategies (Now Available) (ID 3514)

      11:30 - 13:00  |  Presenting Author(s): Jan P Van Meerbeeck

      • Abstract
      • Presentation
      • Slides

      Abstract

      Unresectable malignant pleural mesothelioma (MPM) is a uniformly fatal rare cancer with increasing incidence worldwide. Combination chemotherapy with platinum/antifolate –either pemetrexed or raltitrexed- is the only standard of care 1st line treatment with proven improvement of survival, which varies according to series and patient selection between 12-16 months median overall survival (mOS), with corresponding 1 year survival rate of 50-60%. After a median progression-free survival of ~ 3 months, patients relapse and few if any drugs have any proven efficacy at this stage. Survival after progression varies from 3-18 months according to tumors’ biological behavior and patient’s prognostic factors. Therefore, innovative drugs are urgently needed.

      Although called ‘immunologically cold tumours’ and presenting with a low mutational burden, MPM express distinct targetable antigens (WT1, mesothelin), contain tumour-infiltrating lymphocytes (TILs) and PDL-1 expression is variably present, mostly on the sarcomatoid subtype. Experimental models have demonstrated chronic inflammation and local tumor suppression as crucial to MPM pathogenesis. This led to the investigation of immunotherapy in MPM.

      Monoclonal antibodies against immune check point inhibition (ICI-) molecules have been evaluated as salvage therapy after first-line chemotherapy in several phase 2 trials, either as single agent or in combination. The randomized DETERMINE trial evaluated in 564 patients the anti–CTLA-4 antibody tremelimumab versus placebo in second or third line and found no benefit in outcome (hazard ratio 0.92; p = 0.408). Results from the anti–PD-1 or anti–PD-L1 trials with nivolumab, pembrolizumab and durvalumab are fairly consistent with a response rate of 19-30%, a median PFS of 3.5 – 6.0 months and mOS of 12-18 m, all uncontrolled in selected patients with good prognostic features. Addition of CTLA-4 inhibitors to PD(L)-1 seem to increase efficacy and prolong the time-to-event endpoints. Preliminary results suggest that PD-L1 tumour proportional score (TPS) is both a predictive and prognostic biomarker.

      Several trials are underway investigating ICI alone or in combination with SOC-chemotherapy as frontline treatment. The DREAM trial, a single-arm, open-label phase II trial of durvalumab with cisplatin/pemetrexed, followed by durvalumab maintenance therapy for 1 year. The primary endpoint was PFS at 6months. Interim results in the first 54 patients show a mPFS of 6.2 months, with 48% achieved a partial response based on immune-modified RECIST. The -immature- 1-year OS estimate is 65% at a median follow-up of 14.4 months.

      Other randomized studies of triplet combinations are ongoing, including SOC-chemotherapy w/wo pembrolizumab (NCT02784171) or durvalumab (NCT02899195). The phase III CheckMate743 (NCT02899299) trial randomly selected 600 patients with treatment-naïve MPM to nivolumab plus ipilimumab -until progression or unacceptable toxicity- versus up to six cycles of SOC-chemotherapy.

      Surgical management in resectable MPM represents an excellent opportunity for window-of-opportunity trials when treating patients with neo-adjuvant immunotherapies to improve resectability, fight residual disease and improve patient outcome. Several studies are ongoing with anti–PD(L)-1 with or without CTLA-4 inhibitors or chemotherapy in the neo-adjuvant setting, but results have not yet been published.

      Immunotherapy beyond ICI have been also tested in MPM but with discordant results. Several randomized phase II trials have targeted mesothelin, including amatuximab, an antimesothelin chimeric monoclonal antibody, anetumab-ravtansine, an antibody drug conjugate, and CRS-207, a vaccine targeting mesothelin: these have not yet shown any efficacy in MPM (unpublished data). Cell therapies in phase I trials are being investigated in MPM, including chimeric antigen receptor (CAR) T cells targeting surface antigens such as mesothelin, given both intravenously (NCT02159716) and intrapleuraly (NCT02414269).

      Vaccines targeting the Wilms tumor-1 (WT-1) antigen have also been tested in MPM with variable results. Dendritic cell vaccination was found to be efficacious in small trials of MPM, providing the rationale for ongoing trials, such as the large randomized phase II trial (DENIM) with dendritic cell therapy as maintenance after P/P frontline chemotherapy or a phase I/II trial testing autologous dendritic cells loaded with WT-1 tumor antigen following standard first-line chemotherapy. Autologous tumor infiltrating lymphocytes and interleukin-2 (IL-2) infusion after lympho-depletion are also currently under investigation in a phase I/II trial in MPM. Immune-gene therapy using intrapleural delivery of adenovirus-expressing interferon-α combined with celecoxib and chemotherapy was well tolerated and provided a remarkable mOS of 21.5 months as second-line treatment. Finally, oncoviral therapy is being assessed in a phase I trial with intrapleural injection of measles virus (NCT01503177), or with an oncolytic adenovirus coding for GM-CSF combined with chemotherapy and cyclophosphamide versus chemotherapy alone in a randomized phase II trial (NCT02879669).

      In conclusion, immunotherapies are being investigated in different settings of MPM. Regulatory approval is anticipated soon for ICI (anti–PD-1 with or without anti–CTLA-4) as salvage treatment in MPM. However, state of the art phase III trials comparing ICI with SOC-chemotherapy are needed to firmly establish immunotherapy, either alone or in combination with standard treatment, and to validate biomarkers for patient selection.

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      MS13.02 - Pro - Hedy Kindler Is Right (Immuno Works for Mesothelioma) (Now Available) (ID 3512)

      11:30 - 13:00  |  Presenting Author(s): Hedy Lee Kindler

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS13.03 - Con - Raphael Bueno Is Right (It Does Not Work) (Now Available) (ID 3513)

      11:30 - 13:00  |  Presenting Author(s): Raphael Bueno

      • Abstract
      • Presentation
      • Slides

      Abstract

      Mesothelioma is a heterogeneous cancer and it is not always correctly staged in the absence of surgical extirpation. While some clinical trials utilizing a remarkably small number of patients showed some response to immunotherapy in mesothelioma, the response rate is relatively low (in the 10% rate) and it is unclear how durable. The heterogeneity of the tumor makes interpretation of such small number difficults leading to the conclusion that at this time immunotherapy remains experimental in mesothelioma

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      MS13.04 - Biomarkers of Anti-PD1 Therapy in Mesothelioma (Now Available) (ID 3515)

      11:30 - 13:00  |  Presenting Author(s): Paul Baas

      • Abstract
      • Presentation
      • Slides

      Abstract

      Biomarkers of Anti-PD1 Therapy in Mesothelioma.

      Biomarkers have attracted attention for their usefulness in selecting the right treatment for the right patient. There are different types of biomakers; blood based, clinical markers and histological markers. Most of the biomarker studies have focused on the prognosis of patients while only a limited number examined the predictive value of a marker; to correctly predict the outcome of a certain treatment.

      After the reported successes of check-point inhibitors in melanoma and NSCLC (1-4), the use of these agents have found its way to mesothelioma(5-8).
      Since 2015 many studies have been initiated whit a comparable efficacy compared to NSCLC outcomes. Around 20-25% of cases do respond favorably to this approach. This is considered to be of great importance since there is a limited 2 years survival rate (8) and no standard second line therapy has yet been defined. There are a number of factors that have to be considered before embarking on Immuno-Oncology (IO) therapies as single agent or in combination. The choice of the drug or combination; the expected outcome in short time; the toxicity profile and the costs. Because of the lack of registration, there is a limited availability and patients can only join in studies or be part of a compassionate use program. When registration is a fact we merely have to deal with the questions; who will benefit, who will experience toxicity and is the treatment cost effective?

      In a series of studies we performed in patients with pleural mesothelioma we have collected samples to be used as biomarkers (6,7). Currently we are analyzing the predictive value of these biomarkers.
      1. Histological biopsies: It is well known that the expression PD-L1 can be predictive in NSCLC of a success while in melanoma there is a better correlation with tumor mutational burden. For mesothelioma the expression of PD-L1 varies between the different subtypes of mesothelioma (with sarcomatoid type expressing higher PD-L1 levels) (9). In general the high expression correlates with a worse survival. In addition, the expression of PD-L1 on tumor stroma also influences the outcome of IO treatment. In our study of 34 patients (7), we observed a clinical benefit of 18% in PD-L1 tumor negative patients compared with 15% in the (TIL+) stroma and 32% versus 35% in stroma for any PD-L1 expression. When analyzed for PD-L1 > 50% the stromal T+ cells showed a factor of 2 higher clinical benefit. This implies that a single analysis of the PD-L1 of the tumor cells might underestimate the effect of IO therapy.

      2. eNose analyses. The use of exhaled air has attracted clinical interest since early data indicate that the Volatile Organic Compounds (VOCs) can predict an outcome of IO therapy (11). These VOCs probably represent a complex combination of tumor and immune cell interactions. Ongoing studies focus on the use of these electronic noses to select only patients for whom a treatment has a high chance of success.

      3. Blood based biomarkers have been tested in many studies in mesothelioma. For well-known markers such as mesothelin, cyfra 21-1, osteopontin and fibulin-3 no positive outcomes have been reported in prediction studies.

      4. MicroRNAs. These short, non-coding RNA sequences have attracted attention because of their prognostic capability in mesothelioma and other cancers. The huge number of miR’s identified and the lack of comparative studies to date indicate that these markers can only be used for diagnostic and perhaps treatment purposes. (12)

      5. BAP1 is a nuclear deubiquitinase which regulates the ubiquitination of selected histones and other translational factors. This mutation is occurring both in germline or, more frequently, as a somatic mutation in mesothelioma. It has different functions and can influence the inflammation status of the microenvironment. Although not tested in a proper study setting this marker may well have a predictive potential(13).

      6. Other biomarkers. Finally there are a number of interesting biomarkers including chemokines like IL-6 which acts as a pro-inflammatory cytokine and is closely related to T cell function. Ongoing studies will try to elucidate the predictive effect of this and other markers.

      To date there is a lot of activity ongoing in mesothelioma and the introduction of the IO drugs have been welcomed full-heartedly. Although we have identified an abundant number of prognostic factors in cancer, the high costs of IO therapies presses us to find solid predictive markers. The combination therapies of IO drugs now proposed do increase the toxicity profile and we must not lose precious time of patients and doctors spend on ineffective and costly therapies.

      References are available at the author at request

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      MS13.05 - CaR T Cell in Mesothelioma (Now Available) (ID 3516)

      11:30 - 13:00  |  Presenting Author(s): Prasad S Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in hematological malignancies and was approved by FDA for the treatment of leukemia and lymphoma patients. Adotpive cell therapy by use of CARs involves transducing patient's own T lymphocytes with antigen-specific CAR by retro or lenti virus, and infusing back to the patient following Cyclophosphamide preconditioning. This presentation will dicuss the challenges in developing CAR T-cell therapy, progress to date in translation of CAR T-cell therapy for thoracic cancers.

      Advances in understanding thoracic cancers tumor immune microenvironment and successes with checkpoint blockade agents has opened doors to devlop combiantion immunotherapy for thoracic cancer patients. Our laboratory has shown that in the presence of high tumor burden as in patients with metastases, a low-dose of CAR T cells adminsitered in phase I clinical trials can be exhausted. Addition of anti-PD-1 agents can rescue functionally exhausted CAR T cells and prolong their anti-tumor efficacy. Based on this strong rationale, our laboratory has translated mesothelin-targeted CAR T-cell therapy for patients with malignant pleural mesothelioma and demonstrated anti-tumor efficacy in addition to safety in combination with anti-PD-1 agents. The results of the ongoing trials will be discussed.

      While extrinsic anti-PD-1 agent administration requires multiple doses and potential off-tumor side effects, we have developed T-cell intrinsic anti-PD-1 strategies which are in translation. The preclinical and clinical data supporting this upcoming clinical trial will be presented.

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      MS13.06 - Role of Second Line Chemotherapy and New Target Treatment in Recurrent Mesothelioma (Now Available) (ID 3517)

      11:30 - 13:00  |  Presenting Author(s): Silvia Novello  |  Author(s): Paolo Bironzo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is a highly lethal disease, with a median overall survival (OS) between 12 and 18 months. Following first-line treatment, neither chemotherapy nor target treatments have clearly shown to increase overall survival (OS), to date. Historically, second-line cytoxic drugs, such as gemcitabine and vinorelbine have been the backbone in pre-treated patients, with response rates ranging from 7% to 16% [Zucali PA, Perrino M, Lorenzi E, et al. Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Lung Cancer 2014; 84:265-270; Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009; 63:94-97; van Meerbeck JP, Baas P, Debruyne C, et al. A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organisation for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999;85(12):2577-2582]. Pemetrexed rechallenge was assessed in small retrospective studies, suggesting its role, especially when combined with platinum compounds, in selected patients with a pemetrexed-free interval of at least 3 to 6 months [Zucali PA, Simonelli M, Michetti G, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung cancer 2012; 75: 360-367]. “Omics” studies have enlarged our knowledge of MPM, describing high prevalence of TP53, NF2, BAP1 and cyclin dependent kinase inhibitor 2A (CDKN2A) mutations, along with the lack of tyrosine receptor kinase (TRK) activating mutations [Lo Iacono M, Monica V, Righi L, et al. Targeted next-generation sequencing of cancer genes in advanced malignant pleural mesothelioma: a retrospective study.J Thorac Oncol 2015;10(3):492-9]. For this reason, the development of target treatment approaches in MPM has been more difficult and slower as compared to non-small-cell lung cancer (NSCLC), for example. However, many drugs have been tested, while others are currently under evaluation. Among the first studied agents, mTOR inhibitors failed to show activity in pre-treated MPM patients [Ou SH, Moon J, Garland LL, et al.SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). J Thorac Oncol 2015;10(2):387-91]. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is upregulated in MPM with BAP1 inactivation and its inhibition showed to be syntethic lethal in BAP1-negative tumors. The EZH2 inhibitor tazemetostat demonstrated a 51% disease control rate (DCR) in 74 MPM patients (95% with BAP1 inactivation) enrolled in a phase 2 study [Zauderer MG, Szlosarek P, Le Moulec S, et al. Phase 2, multicenter study of the EZH2 inhibitor tazemetostat as monotherapy in adults with relapsed or refrectory (R/R) malignant mesothelioma (MM) with BAP1 inactivation. J Clin Oncol 36, 2018 (suppl.abstr 8515)]. As BAP1 loss leads to homologous repair deficiency, PARP inhibitors are currently being tested in this subgroup [NCT03531840; NCT03207347; NCT03654833]. Neurofibromin 2 (NF2) inactivation, which encodes for merlin, has been proposed to be synthetic lethal to focal adhesion kinase (FAK) inhibition. However, the COMMAND trial, exploring the use of the FAK inhibitor defactinib as a maintenance treatment after first-line chemotherapy in MPM patients stratified for merlin expression, failed to show any improvement as compared to placebo [Fennell DA, Baas P, Taylor P, et al. Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND-a double-blind, randomized, phase II study. J Clin Oncol 2019;37(10):790-798]. Defactinib is currently under investigation in combination with anti programmed-death 1 (PD-1) monoclonal antibody pembrolizumab in a phase I/IIA clinical trial enrolling pretreated MPM patients along with pancreatic cancer and NSCLC ones [NCT02758587]. The identification of argininosuccinate synthetase 1 (ASS1) loss in MPM, leading to arginine auxotrophy, paved the way to the use of the arginine depletor pegylated adenosine deiminase ADI-PEG20 in a phase 2 randomized trial in 70 ASS1-deficient patients [Szlosarek PW, Steele JP, Nolan L, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol 2017;3(1):58-66]. Among the 68 treated patients, the drug improved progression free survival (PFS) as compared to best supportive care (BSC) (HR 0.56, 95% CI, 0-33-0.96), although by only 1.2 months (median PFS 3.2 vs 2.0 months for ADI-PEG20 and BSC, respectively; p=0.03). Currently, ADA-PEG20 is being explored in combination with first-line chemotherapy in biphasic and sarcomatous MPM only [NCT02709512]. Recent studies described novel prognostic MPM subsets with specific genomic characteristics that could further shape personalized treatment approaches, especially when looking at immunotherapic approaches [Hmljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov 2018;8(12):1548-1565]. Indeed, the high expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) negative immune-checkpoint in epithelioid MPM reported in this study, suggests a possible of role of specific inhibitors alone or in combination with other agents in advanced MPM.

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Author of

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    MA05 - Update on Clinical Trials and Treatments (ID 123)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 2
    • Now Available
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      MA05.01 - Second or Third Line Anti-PD-1 Therapy After Multimodality Therapy Including Total Pleurectomy in Malignant Pleural Mesothelioma (Now Available) (ID 1955)

      13:30 - 15:00  |  Author(s): Arnaud Scherpereel

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical resection plays an important role in the management of selected patients with malignant pleural mesothelioma (MPM). Early experience with anti-PD-1 immunotherapy showed promise in MPM, but it is yet uncertain if it can improve outcomes when tumour relapses following surgical resection, radiotherapy and chemotherapy. We reviewed our experience in patients who received Pembrolizumab or Nivolumab following multimodality therapy.

      Method

      Retrospective study including patients with histologically-proven MPM having completed multimodality therapy and received anti-PD-1 immunotherapy as 2nd or 3rd line treatment. Data were retrieved from a prospective mesothelioma database. Histopathology, BAP1, MTAP and PD-L1 (22C3) immunohistochemistry were performed on surgical specimens and reported by a senior pathologist. All patients had chest computed tomography and positron emission tomography (PET-CT) as part of their normal follow-up. Response evaluation was determined using RECIST 1.1 criteria.

      Result

      16 patients received anti-PD-1 immunotherapy between August 2015 and March 2019. All patients had total pleurectomy/decortication, prophylactic radiotherapy (21Gy/3) and systemic chemotherapy based on pemetrexed and platinum. Median age was 68.5 years, with male predominance (13/16). 56% had epithelioid type, 44% had biphasic type. Median time to starting immunotherapy was 20 months (range 11-42) following surgery. Median ECOG performance status was 0. Twelve patients received Pembrolizumab and 4 received Nivolumab. Median number of cycles of anti-PD-1 therapy received was 5 (range 1-33). Disease control rate at 12 weeks was 56.2% and 7 (43.7%) patients had disease progression. Adverse events were observed in 6 patients (one Grade 3). Eight patients were alive by 1st April 2019. Median OS from starting immunotherapy was 13.5 months. Three patients received treatment for 14 months or more. Five patients started further therapy after discontinuing immunotherapy.

      Conclusion

      In our cohort, second or third-line anti-PD-1 immunotherapy showed efficacy with DCR comparable to non-surgical setting. Further studies are warranted to validate our preliminary findings.

      wclc 2019 figure 1anti pd1.jpg

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      MA05.05 - Post-Discontinuation Treatments in IFCT-GFPC-0701 MAPS Trial: Real-World Effectiveness of 2nd-Line (2L) Treatments for Mesothelioma (Now Available) (ID 815)

      13:30 - 15:00  |  Author(s): Arnaud Scherpereel

      • Abstract
      • Presentation
      • Slides

      Background

      MAPS phase 3 trial assessing the addition of bevacizumab to pemetrexed-cisplatin doublet set a new standard of care in malignant pleural mesothelioma (MPM) patients, showing 18.8 months median overall survival (OS) with triplet combo. While both arms were well balanced in terms of 2L treatments, the size of the OS benefit from second-line treatments remains controversial.

      Method

      Long-term survival data were collected in the 342 MAPS patients alive at the end of the first-line (1L) treatments, in both arms. Median OS and 2-year survivals were calculated from the initiation of 2L. Multivariate analysis using Cox model included the stratification variables of the MAPS trial, along with the treatment arm (with or without bevacizumab).

      Result

      342/442(77.4%) patients received 2L treatment for disease progression after MAPS trial, of which 324 received chemotherapy (CT), 18 palliative radiotherapy (RT), while 100/442 (22.6%) remained untreated. 160/342 patients (46.8%) had a platinum-based doublet CT. 163 patients (47.7%) received a single-drug CT. 172/324 (53.1%) received a pemetrexed-containing regimen (alone or with platinum), 84 (25.9%) a gemcitabine-based CT, 16 (4.9%) vinorelbin alone, 48 (14.8%) gemcitabine alone, while in 12 (3.7%) single-agent bevacizumab was resumed. Median age was lower in patients with doublet CT (64.4 years, IQR 60.2-68.9) vs. single-drug CT patients (66.3 years, IQR 61.5-70.3), patients receiving RT (68.5 years, IQR 63.3-70.5) or untreated patients (67.8 years, IQR 63.4-71) (p=0.007). There were more PS=2 patients (10%) in the untreated group, compared with 0.6%, 1.8% and 5.6% in those receiving doublet, monotherapy or radiotherapy, respectively (p<0.001). A lower proportion of patients receiving 2L doublet CT had sarcomatoid/biphasic MPM (11.2%) compared with 21.5%, 38.9% and 25% in those with single-arm agent, RT or untreated, respectively (p=0.002). When compared with those treated with 2L single-agent, patients with 2L doublet had more frequently objective response (11.9 vs. 3.1%, p=0.005) and disease control (60.3 vs. 34.6%, p<0.0001). From the date of 2L therapy initiation, median OS was 3.2 months, 95%CI [1.7-5.0] for RT vs. 7.0 months 95%CI[5.6-7.8] for single-agent CT, or 12.2 months 95%CI [9.5-14.1] for doublet CT. HRs were adjusted for 1L treatment type (bevacizumab-containing or not), PS, smoking, and histology. Adj.HR (single-agent vs. doublet) was 1.21, 95% CI(0.96-1.53), p=0.11. Adj.HR (monotherapy vs. RT) was 0.39, 95%CI[0.24-0.65], p=0.0003. Adj.HR (combination CT vs. RT) was 0.32 95%CI[0.19-0.54], p<0.0001. 1-year OS was 11.8%, 95%CI [0.0-27.1], 48.7%, 95%CI [39.9-57.5], and 32.9%, 95%CI [25.1-40.6], in patients with RT alone, single agent CT or combination CT, while 2-year OS was 0%, 14.2%, and 20.0% respectively.

      Conclusion

      Second-line monotherapy only gave a 7-months median OS in MPM patients, comparing unfavorably to 11.9 and 15.9-months median OS with 2nd/3rd-line nivolumab or nivolumab+ipilimumab respectively, in the IFCT-1501 MAPS-2 randomized phase 2 trial. Conversely, 2L platinum-based chemo, in younger fit patients, still gave a 12.2-months median OS, not statistically different from monotherapy in the multivariate analysis, as a consequence of PS influence, although clinically meaningful. Based on these results, immunotherapy might be preferred for 2L/3L MPM patients, while monotherapy CT shows limited survival benefit.

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