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A.K. Nowak
Moderator of
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ORAL 11 - Clinical Trials 1 (ID 100)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 8
- Moderators:A.K. Nowak, F. Detterbeck
- Coordinates: 9/07/2015, 10:45 - 12:15, 702+704+706
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ORAL11.01 - Bevacizumab 15mg/kg Plus Cisplatin-Pemetrexed (CP) vs CP in Malignant Pleural Mesothelioma (MPM): IFCT-GFPC-0701 MAPS Randomized Phase 3 Trial (ID 2142)
11:07 - 11:18 | Author(s): A. Scherpereel, J. Mazières, J. Margery, L. Greillier, C. Audigier-Valette, D. Moro-Sibilot, O. Molinier, R. Corre, I. Monnet, V. Gounant, F. Rivière, H. Janicot, R. Gervais, C. Locher, B. Milleron, Q. Tran, M.P. Lebitasy, C. Creveuil, J. Parienti, F. Morin, G. Zalcman
- Abstract
Background:
MPM median overall survival (OS) did not exceed 13 months with pemetrexed-platinum doublet, with virtually no surviving patients at 5 years. Vascular endothelial growth factor is a potent mitogen for MPM cells.
Methods:
In this French multicenter randomized phase 3 trial, eligible patients had unresectable, histologically proved MPM, age < 76, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Randomized patients (1:1) received pem 500 mg/m2, CDDP 75 mg/m2 at D1, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B non-progressive patients received bevacizumab maintenance therapy until progression or toxicity. Primary endpoint was OS. 445 patients were to be randomized, and 385 events observed, to show a significant OS improvement, with 80% statistical power, 5% a-risk.
Results:
From Feb. 2008 to Jan. 2014, 448 patients were included in 73 centers. Males: 75.4%, median age: 65.7 years (range 34.7-75.9), PS 0-1: 96.7%. The IDMC recommended a second interim analysis after 85% of events. On 01-Jan-2015, the duration since last news was < 30 days in 105 out of 106 still living patients. Overall survival was significantly longer in the experimental arm (median: 18.8 months, 95%CI[15.9-22.6] vs. 16.1 months, 95%CI[14.0-17.9] for the reference arm, (adj.HR = 0.76, 95%CI[0.61; 0.94], p = 0.012). With only 46/448 non-progressive patients at the date of analysis, median PFS was 9.6 months, 95%CI[8.5-10.6] in bevacizumab arm vs. 7.5 months, 95%CI[6.8-8.1] (adj.HR = 0.62, 95%CI[0.50-0.75], p < 0.0001). G3-4 hematological toxicities did not significantly differ in the two arms (49.5% vs. 47.3%). Significantly more G3 proteinuria (0.0 vs. 3.1%), G3 hypertension (0.0 vs. 23%), G3-4 arterial thrombotic events (0.0 vs. 2.7%) were observed in bevacizumab arm. QOL and exploratory biomarkers studies will be also presented at time of the meeting.
Conclusion:
Bevacizumab addition to pemetrexed/cis-platin provides a significantly longer survival in pts with MPM, with acceptable toxicity, making this triplet a new treatment paradigm.
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ORAL11.02 - Phase I Study of Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine (ID 1574)
10:45 - 10:56 | Author(s): R. Hassan, J.C. Bendell, G. Blumenschein, Jr., H.L. Kindler, K.N. Moore, A.D. Santin, S.M. Seward, J. Nemunaitis, P. Rajagopalan, A. Walter, N. Sarapa
- Abstract
- Presentation
Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully humanized anti-mesothelin IgG1 antibody conjugated to a ravtansine, a maytansine derivative DM4 antitubulin cytotoxic agent. We report results from a phase I study evaluating the safety, PK and tumor response in patients (pts) with advanced solid tumors treated with anetumab, with a particular focus on patients with mesothelioma.
Methods:
Anetumab was given IV every 21 days (q3w) in 77 pts: 45 pts in 10 dose escalation cohorts from 0.15 to 7.5 mg/kg (21 mesothelioma, 9 pancreatic, 5 breast, 4 ovarian, 6 other), and 32 pts in 2 expansion cohorts (12 mesothelioma and 20 ovarian); 38 pts were treated at MTD in escalation and expansion cohorts (16 mesothelioma, 21 ovarian, 1 breast). Clinical and laboratory safety assessments were made on D1, D8 and D15 in C1-C3 and on D1 in subsequent cycles. Tumor assessments were made q6wks up to C8 and q12wks thereafter. Mesothelin expression in archival tumor samples was assessed retrospecively by IHC (SP74, Ventana).
Results:
Thirty-two males and 45 females were treated [mean age 62 yrs (range, 18-84 yrs), body weight 77 kg (44-113 kg), ECOG ≤1, median prior cytotoxic regimens: overall 4 (1-9), mesothelioma 1 (1-4)]. Non-tolerated anetumab dose was 7.5 mg/kg (DLTs: 1 pt with G2 keratitis and G3 neuropathy, 1 pt with G4 keratitis and G2 neuropathy). Anetumab MTD was 6.5 mg/kg (DLT: G3 AST increase). Only one DLT occurred at doses below MTD (G3 hyponatremia, 5.5 mg/kg). No drug-related deaths and few drug-related SAEs (7 total and 5 at MTD) were reported. Seventeen of 38 (45%) pts total or 7 of 16 (44%) mesothelioma pts at MTD had drug-related AE requiring dose reduction (G1-4 keratitis, G2-3 neuropathy, G3 fatigue, anorexia, asthenia, diarrhea, N&V, AST increase). LFT increases were the most common drug-related laboratory abnormality at MTD: AST in 7 pts (2 G3), ALT in 6 pts (no G3), alkaline phosphatase in 4 pts (one G3) and bilirubin increase in 1 pt (no G3). There were no drug-related G3 hematological abnormalities at any dose. Fourteen of 38 (37%) pts total or 4 of 16 (25%) mesothelioma pts at MTD had G1-4 keratitis (worst G3-4 in 3 pts, blurred vision in 10, dose reduction in 8, dose delay in 11, all fully reversible). Anetumab at the MTD showed a PR in 6 pts (19%) and SD in 18 pts (47%) overall. Five of 16 (31%) mesothelioma pts at the MTD had durable PR (>600 days in 4 pts) and 7 (44%) had SD. Five PRs occurred in 11 mesothelioma pts who received anetumab as second line treatment (45% response rate).
Conclusion:
Anetumab at the MTD (6.5 mg/kg) showed encouraging efficacy with durable PR in pts with advanced mesothelioma. At the MTD, all drug-related AEs were reversible and non-life-threatening but required dose reduction in about half of pts, most commonly due to G1-4 keratitis and G2-3 peripheral neuropathy. Given this benefit-risk ratio, the recommended phase II dose of anetumab in second line treatment of advanced mesothelioma is 6.5 mg/kg IV q3w.
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ORAL11.03 - Single-Agent Pembrolizumab for Patients with Malignant Pleural Mesothelioma (MPM) (ID 3011)
10:56 - 11:07 | Author(s): E.W. Alley, J.H.M. Schellens, A. Santoro, K. Beckey, S.S. Yuan, J. Cheng, B. Piperdi, L..R. Molife
- Abstract
- Presentation
Background:
Targeting the programmed death receptor 1 (PD-1) pathway is a valid therapeutic target in a variety of solid tumors and hematologic malignancies. Pembrolizumab (MK-3475) is a potent, highly selective humanized monoclonal antibody against PD-1 and is approved in the United States for the treatment of advanced melanoma that progressed following ipilimumab and, if BRAF[V600] mutant, a BRAF inhibitor. We have previously reported preliminary antitumor response and safety data for pembrolizumab in patients with MPM enrolled in the KEYNOTE-028 study. Here we present updated safety and efficacy data, including survival, for these patients.
Methods:
KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Other key eligibility criteria included measurable disease, failure of standard therapy, ECOG PS 0-1, adequate organ function, and no autoimmune disease or interstitial lung disease. PD-L1 positivity was defined as expression in ≥1% of tumor cells by IHC at a central laboratory. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end point was the ORR. Secondary end points included safety and tolerability and PFS.
Results:
Of the 84 patients with MPM screened for PD-L1 expression, 38 (45%) patients had PD-L1–positive tumors. Of these 38 patients, 25 met the eligibility criteria and were treated with pembrolizumab. As of March 20, 2015, ORR is 28% (n = 7); 12 (48%) patients had stable disease, resulting in a disease control rate of 76%. In the 15 patients with only 1 prior line of therapy, ORR and DCR are 20% and 73%, respectively. Responses are durable, and 10 (40%) patients remain on treatment (duration, 24+ to 36+ weeks). With a median follow-up duration of 8.6 months, median PFS is 5.5 months (95% CI, 3.4-NR), and the 6-month PFS rate is 49.4%. No new safety signals were observed. 15 (60%) patients experienced a drug-related adverse event (DRAE), including 3 (12%) who experienced grade 3-4 DRAEs. Only 2 patients required dose interruption because of immune-related adverse events (transaminitis and uveitis [n = 1 each]). There was no treatment-related mortality, and no patients discontinued because of DRAEs.
Conclusion:
Single-agent pembrolizumab has significant clinical activity in patients with PD-L1–positive MPM. The durability of responses and the 49.4% 6-month PFS rate in this pretreated patient population warrants further investigation. Updated safety and survival data, as well as the correlation of antitumor activity with the level of PD-L1 expression, will be available at the time of presentation.
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ORAL11.04 - Discussant for ORAL11.01, ORAL11.02, ORAL11.03 (ID 3317)
11:18 - 11:28 | Author(s): D.A. Fennell
- Abstract
- Presentation
Abstract not provided
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ORAL11.05 - Phase II Trial of Single Agent Amrubicin in Patients with Previously Treated Advanced Thymic Malignancies (ID 1288)
11:28 - 11:39 | Author(s): H.A. Wakelee, S.K. Padda, M. Burns, A.J. Spittler, J.W. Riess, M. San Pedro-Salcedo, K.J. Ramchandran, M.A. Gubens, J.W. Neal, P.J. Loehrer
- Abstract
- Presentation
Background:
Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM pts in this trial.
Methods:
This was an open-label single drug trial at 2 institutions. Eligible pts had TM (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapy regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles.
Results:
From 7/11 to 4/14, a total of 33 patients (14T/19TC) were enrolled. There were 14 women and 19 men; age range of 30-81 years; 9 Asian, 1 African-American, 1 Hispanic and 22 non-Hispanic White pts. A high rate of febrile neutropenia (FN) led to an amended starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. In total, 7 pts experienced FN with 1 related death. Other grade 3/4 related events included: thrombocytopenia (n=2), neutropenia without fever (n=3), hyponatremia (n=2), hypokalemia (n=2), anemia (n=7), lethargy/fatigue (n=7), perirectal abscess (n=2), palmar-plantar erythrodysesthesia (n=3), syncope (n=2), venous embolism (n=2), and 1 pt each with sepsis, oral abscess, mucositis, chest pain, and epigastric pain. Other toxicities were generally mild and well tolerated. No significant changes in LVEF were noted on serial echocardiograms. There were 6 partial responses (4T/2TC), 21 with stable disease, and 4 with progressive disease (PD) or death at or before first assessment for a response rate (RR) of 18% and a disease control rate (DCR) of 88% (29%/11% RR in T vs TC and 100%/78% DCR in T vs TC). All but 5 patients received at least 4 cycles, and 15 tolerated >10 cycles, with 36 cycles as the highest number to date. Five patients remain on therapy.
Conclusion:
Amrubicin, at 35 mg/m[2 ]IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with an 18% RR and no unexpected toxicity. Response rate and disease control rate was higher in the thymoma patients compared to the thymic carcinoma patients. Further exploration of amrubicin as a single drug or in combination is warranted in thymic malignancies.
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ORAL11.06 - A Prospective Phase II Study of Cisplatin and Cremorphor EL-Free Paclitaxel (Genexol-PM) in Patients with Unresectable Thymic Epithelial Tumors: Can 18F-FDG PET/CT Play a Role? (ID 2221)
11:39 - 11:50 | Author(s): H.S. Kim, M. Kwak, J.Y. Lee, M. Han, S.H. Lim, H. Song, K.S. Jung, J. Sun, S. Lee, J.S. Ahn, K. Park, M. Ahn
- Abstract
- Presentation
Background:
We conducted a prospective phase II study of cisplatin plus Cremorphor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors (TETs) in order to determine the efficacy and tolerability of the combination.
Methods:
Patients were treated with cisplatin (70 mg/m[2]) and Genexol-PM (230 mg/m[2]) every three weeks for a maximum of six cycles. The primary end point of this study was objective response rate (ORR), and secondary end points included toxicity, progression-free survival (PFS), overall survival (OS), correlation between early [18]F-FDG PET/CT response and PFS, and correlation between baseline FDG uptake and histology.
Results:
Forty-two patients with unresectable thymoma (n=14) or thymic carcinoma (n=28) were enrolled. The median age was 59 years (range, 25-77) and 30 (71%) patients were male, and 39 (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range 1-6). For 40 assessable patients, the ORR was 62.5% (95% confidence interval [CI] 47.6-77.4) with rates of 46% (95% CI 23.3-76.9) for advanced thymoma (n=13) and 70% (95% CI 52.0-82.1) for thymic carcinoma (n=27). With a median follow-up of 15.5 months, the median PFS was 9.8 months (11.4 months for thymoma vs. 8.1 months for thymic carcinoma, with median follow-ups of 16.1 vs. 15.5 months, respectively). The two-year OS was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Sixteen (38%) patients experienced grade 2 hypersensitivity reactions. There was no correlation between early PET response and PFS, but tumor histology (thymoma vs. thymic carcinoma) was correlated with SUV~max~ before chemotherapy.
Conclusion:
These data suggest that the combination of cisplatin and Genexol-PM is highly effective and tolerable for the treatment of unresectable TETs, especially in patients with thymic carcinoma.
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ORAL11.07 - Computed Tomography (CT) Characteristics Associated with the Proposed IASLC/ITMIG TNM Pathologic Staging System for Thymoma (ID 1603)
11:50 - 12:01 | Author(s): S.K. Padda, D. Terrone, A. Khuong, L. Tian, J.W. Neal, J.W. Riess, M. Berry, A.N. Leung, E.J. Schwartz, J.B. Shrager, H.A. Wakelee
- Abstract
- Presentation
Background:
Preoperative CT imaging assists in the management of thymic malignancies (TMs), discerning resectability and the need for neoadjuvant chemotherapy. Here, we examine preoperative CT imaging characteristics in relation to the newly proposed IASLC/ITMIG TNM pathologic staging system for TMs.
Methods:
Inclusion criteria for this retrospective study were as follows: 1) diagnosis of thymoma, thymic carcinoma, or thymic carcinoid, 2) definitive primary surgery performed at Stanford University, and 3) pretreatment CT imaging available for review. From 01/1997-03/2015, we identified 119 TM patients who had surgery, and 47 TM patients met all inclusion criteria. The most common reason patients were excluded was for either a missing pretreatment CT (outside imaging not routinely uploaded until 2008) or having surgery for biopsy or recurrent disease. The radiologist (D.T.) was blinded to clinical data, and examined baseline CT imaging per the International Thymic Malignancy Interest Group (ITMIG) standard report terms: contour, calcification, internal density, size of longest diameter, infiltration of mediastinal fat, abutment of mediastinal vessels, vascular endoluminal invasion, abutment/invasion of mediastinal structures, elevated hemidiaphragm, pleural nodules, pleural effusion, mediastinal lymph node enlargement. A univariate analysis and a Lasso regularized general transformation prediction model were performed with all variables to examine the association with pathologic IASLC/ITMIG TNM stage (p<0.05 significant; p<0.10 trend).
Results:
Of 47 TM patients, 9 received neoadjuvant chemotherapy. IASLC/ITMIG pathologic stage included 35 I, 1 II, 7 IIIA, 2 IIIB, 1 each of IVA and IVB. By T stage, there were 36 T1 (encapsulated or unencapsulated+extension into mediastinal fat or mediastinal pleura), 1 T2 (pericardium), 8 T3 (lung, brachiocephalic vein, SVC, chest wall, phrenic nerve, or hilar pulmonary vessels) and 2 T4 (aorta, arch, main pulmonary artery, myocardium, trachea, or esophagus). Only one patient each had N2 and M1a disease (separate pleural or pericardial nodule). Histologies included 5 A/micronodular thymoma, 13 AB, 5 B1, 14 B2, 5 B3, and 5 C/carcinoid. There was a significant positive association with aggressive histology and higher stage (OR=10.0;p=0.02). The following CT characteristics had a statistically significant positive association with higher stage (stage 1 vs. others, T1 vs. others) in a univariate analysis: lobulated contour, infiltration of mediastinal fat, invasion of mediastinal structures, vascular endoluminal invasion, elevated hemidiaphragm. There was a trend for higher stage with larger size and the presence of calcification. In a prediction model, vascular endoluminal invasion and elevated hemidiaphragm were the most important for predicting higher stage followed by invasion of mediastinal structures>abutment of mediastinal vessels>calcification>lobulated contour> mediastinal lymph node enlargement. When excluding clearly invasive CT characteristics, only abutment of mediastinal vessels was significantly associated with higher stage.
Conclusion:
Preoperative CT characteristics, especially those indicating clear invasion, are most useful in delineating more advanced stage disease by ITMIG/IASLC criteria in TMs. Other primary tumor characteristics including contour, calcification, and abutment of mediastinal vessels are moderately helpful. This study is limited by the small sample size, the predominance of stage I disease, the inclusion of patients who received neoadjuvant chemotherapy, and the inherent bias of a definitive surgically treated population.
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ORAL11.08 - Discussant for ORAL11.05, ORAL11.06, ORAL11.07 (ID 3473)
12:01 - 12:11 | Author(s): N. Girard
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 24 - Epidemiology, Early Detection, Biology (ID 140)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J. Creaney, M. Carbone
- Coordinates: 9/08/2015, 16:45 - 18:15, 102+104+106
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MINI24.14 - Use of Next Generation Sequencing to Improve Lung Tumor Immunotherapy (ID 1749)
18:00 - 18:05 | Author(s): A.K. Nowak
- Abstract
- Presentation
Background:
Immunotherapy of pulmonary tumors is now a clinical reality, however most patients do not respond. To convert non-responders into responders one potential approach is to identify the tumor‐specific ‘neo‐antigens’ that arise from DNA mutations in order to follow tumor-specific responses and to design therapeutic vaccines to try to ‘enforce’ a response against these resistant tumors.
Methods:
First, in order to identify tumor neo-antigens we performed RNAseq and exome analysis to identify single nucleotide variants (SNV) in murine pulmonary tumors. An average of 485 SNVs was found. We focused on AB1 and AB1-HA (asbestos-induced mesotheliomas, which mimic human mesothelioma) and Line 1 (lung cancer). We used the NetMHCpan 2.8 algorithm to identify candidate mutation‐carrying peptides and screened them in an interferon‐γ ELISPOT assay. Second, to determine if more neo-antigens could be ‘unmasked’ by therapy, we tested three candidate therapies in our murine model then reanalyzed neo-antigen responses a) Treg depletion using Foxp3-DTR mice, b) gemcitabine, an immunogenic cytotoxic chemotherapy commonly used for pulmonary malignancies, and c) antiCTLA4 (a checkpoint blockade therapy).
Results:
We identified 20 candidate mutation‐carrying peptides in the ELISPOT assay. A strong spontaneous endogenous pre-treatment immune response was demonstrated to DUqcrc2, a component of the respiratory chain protein ubiquinol cytochrome complex. It was found to stimulate a strong response at a similar magnitude to the model neo-antigen viral haemagglutinin (HA). The DUqcrc2 peptide sequence (amino acid 405-413) is predicted to bind the H-2Kd, and the mutant has a proline to alanine substitution mutation at position 408. Treg depletion unmasked a second neo-antigen, DGANAB. GANAB is an alpha glucosidase which cleaves the 2 innermost alpha-1,3-linked glucose residues from the Glc-2-Man-9-GlcNAc-2 oligosaccharide precursor of immature glycoproteins. There is an arginine to glutamine substitution mutation at position 969 of DGANAB (965-972) sequence. This observation supports the theory that removing Treg cells may broaden the immune response to a greater number of neo-antigens, a response presumably otherwise restrained by Treg suppression. Gemcitabine and antiCTLA4 checkpoint blockade did not unmask any additional neo-antigens.
Conclusion:
Thus, removing some immune restraints may expose a greater number of neo-antigens as potential clinical targets. The results from these approaches suggest novel ways to improve the immunotherapy of lung tumor and are the basis for planning current clinical trials.
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MS 17 - Immunotherapy for Mesothelioma (ID 35)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:D.A. Fennell, T. Nakano
- Coordinates: 9/08/2015, 14:15 - 15:45, 201+203
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MS17.01 - Overview: Immunotherapy in Mesothelioma (ID 1922)
14:20 - 14:40 | Author(s): A.K. Nowak
- Abstract
- Presentation
Abstract:
Immunotherapy has recently confirmed its place as an important treatment strategy for a number of solid tumors, including melanoma and non-small cell lung cancer. Checkpoint blockade, in particular, has emerged as an ‘off-the-shelf’ immunotherapy which does not rely on known tumor antigens, costly and time-consuming individualised preparation of autologous tumor, or viral vectors. This overview will cover the history of immunotherapy in mesothelioma, recent reported clinical trials, trials in progress, and current cutting edge research with the potential for translation. Although mesothelioma is not classically considered immunogenic, there is abundant evidence that it is recognised by the immune system. Earlier studies described the relationship between tumour infiltrating lymphocytes and prognosis, occasional spontaneous remissions are seen, and there have been reports of low rates of responsiveness to a range of immunotherapies over the past 30 years. There is also a body of work demonstrating impaired immune responsiveness in people with mesothelioma and an immunosuppressive intratumoral milieu. Specifically, NK cell activity is reduced, CD4+ lymphocyte numbers are reduced, and dendritic cell function is impaired (Cornwall S, unpublished data), amongst other changes. Regulatory T cells and inhibitory cytokines within the tumour may contribute to an immunosuppressive milieu [1]. The presence of CD8+ infiltration within the tumour is a predictor of more favourable outcomes [2]. More recently, mesothelioma, in particular sarcomatoid subtype, was shown to overexpress PD-L1 and to predict poor prognosis [3] Historically, response rates below 20% have been seen in clinical trials of systemic and intrapleural interferons, generally accompanied by high toxicity [4]. Similarly, other cytokines such as Interleukin-2 or GM-CSF have shown either poor response rates, low feasibility, or excessive toxicity [5]. Gene therapy approaches have similarly shown very low response rates and are technically demanding [6]. More recent trials have focussed on antigen-specific approaches using the known tumor antigens mesothelin and WT-1, and the use of checkpoint blockade. Immunological checkpoints are inbuilt mechanisms that negatively regulate the size and duration of an immune response, both during induction of the T cell response and during the effector phase of the response, in tumor tissue. Their normal function is to prevent excessive and ongoing T cell activation which may lead to overwhelming autoimmunity. Many tumors, including mesothelioma, express ligands for these checkpoint molecules, allowing tumors to negatively regulate the anti-tumor immune response and thus evade elimination [3]. The expression of checkpoint molecules including Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and PD-1 on T cells, and the expression of ligands such as PD-L1 and PD-L2 on tumors, has allowed the development of antibody blockade which can prevent downregulation of the anti-tumor response by inhibitory signals, hence ‘taking off the brakes’ and facilitating a more effective host response to tumor. CTLA4 is expressed on T cells after activation, and counter-regulates the T cell activation which normally occurs when the co-stimulatory receptor CD28 is engaged. Whilst ligation of CTLA4 normally restricts ongoing T cell co-stimulation and activation, abrogating anti-tumour immunity[7], CTLA4 blockade using monoclonal antibody inhibitors can allow the endogenous anti-tumour response to proceed unopposed. The first report of a clinical trial of this drug class in mesothelioma was published by Calabro and colleagues in 2013 [8], with results showing some similarities to the first trials of CTLA4 blocking antibodies in melanoma. Durable partial responses were seen in two patients, with a further seven of 29 patients experiencing prolonged stable disease. The disease control rate was 31%, median progression free survival was 6·1 months, and almost 40% of participants were alive at two years. The phenomenon of early progression followed by a lengthy partial response was seen in one patient. The authors noted that the progression free survival and two year survival results were better than expected for this population, and although partial responses were uncommon they were long lasting. This study provided the rationale for the subsequent testing of tremelimumab in a large randomised phase II study in mesothelioma which has recently completed recruitment (NCT01843374). A recent presentation at the American Association for Cancer Research (AACR) reported on results from the mesothelioma cohort enrolled in the KEYNOTE-028 study. This trial used PD1 axis blockade with pembrolizumab in patients with mesothelioma selected to express the PD-L1 ligand. Of 25 patients treated, partial response was observed in 7 (28%) and stable disease in 12 (48%), giving a disease control rate of 76% with a tolerable toxicity profile. Many of the responses seen were profound and durable[9], highlighting the enormous potential of this approach in mesothelioma. Finally, mesothelin is highly expressed on mesothelioma cells, predominantly of the epithelioid subtype. A number of methods of targeting mesothelin are under development and clinical testing. The anti-mesothelin immunotoxin SS1P has been administered together with lymphodepletion using cyclophosphamide and pentostatin. Major responses were observed in a subset of patients in a small clinical trial (n=10), notably with some reports of immune pseudoprogression before eventual treatment response. Other treatments using mesothelin as a target include CRS-207, a live attenuated listeria monocytogenes strain which expresses mesothelin, and MORAb-009, a monoclonal antibody that targets mesothelin. Immunotherapy in mesothelioma remains very immature. Results of PD1 and/or PD-L1 blockade in larger numbers of treated patients are needed, and phase III studies will be important to define any benefits. Combinations of checkpoint blockade have shown outstanding efficacy in other cancer types and must be tested in mesothelioma. Underpinning these trials must be the search for biomarkers of treatment efficacy. Technologies such as tumor sequencing also have the potential to identify neoantigens with immunological reactivity in individual patients, an approach that could lead to the development of personalised vaccines, potentially in combination with other immunotherapies. References 1. Hegmans, J.P.J.J., et al., Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. European Respiratory Journal, 2006. 27(6): p. 1086-95. 2. Yamada, N., et al., CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother, 2010. 59(10): p. 1543-9. 3. Mansfield, A.S., et al., B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol, 2014. 9(7): p. 1036-40. 4. Boutin, C., et al., Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer, 1994. 74(9): p. 2460-7. 5. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 6. Schwarzenberger, P., et al., Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol, 1998. 19(2): p. 333-7. 7. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 2012. 12(4): p. 252-64. 8. Calabro, L., et al., Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol, 2013. 14(11): p. 1104-11. 9. Alley, E.W., et al., Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028, in Proc Am Assoc Cancer Res. 2015.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-075 - Network Analysis of Anti-CTLA4-Induced Regressing Tumours Identifies Novel Synergistic Drug Combinations (ID 1113)
09:30 - 09:30 | Author(s): A.K. Nowak
- Abstract
Background:
Antibodies blocking immune checkpoint molecules such as CTLA-4 have been shown to be effective in several cancer types, with some patients displaying durable complete regression. However, many patients do not respond to treatment. It is not known what molecular events control the response nor which co-treatments are likely to combine effectively with checkpoint blockade. Current strategies involve empirically testing different combinations of checkpoint blocking antibodies with other immunotherapeutic strategies or conventional anti-cancer drugs. We provide an alternative approach.
Methods:
Through performing network analysis of gene expression data from responding versus non-responding AB1-HA mesothelioma tumours from mice treated with anti-CTLA-4, we identified genetic modules and hub genes within these modules that were associated with responsiveness. We subsequently identified synergistic anti-CTLA-4/drug combinations using two different approaches: first, by pinpointing drugs that modulated hub genes within these response-associated modules, and second, by interrogating overlaps in the modular response patterns and drug-perturbation signatures in drug repurposing databases. The approaches were validated by testing the identified drugs in vivo, in combination with anti-CTLA-4 in murine cancer models.
Results:
We identified and validated several drugs that increased the response rate to anti-CTLA-4 in a highly synergistic manner. We identified four drug classes with the capacity to increase the cure rate from 10% for anti-CTLA-4 alone to 60-80% as combination therapy. These repurposed drugs are normally used in completely unrelated conditions such as cardiovascular or skin diseases.
Conclusion:
Together, our results show that using network analysis of gene expression data from immunotherapy-responsive tumours generates testable hypotheses for the identification of novel synergistic drug combinations.
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-014 - COMMAND: A Phase 2 Randomized, Double-Blind, Study of Defactinib (VS-6063) as Maintenance Therapy in Malignant Pleural Mesothelioma (ID 2847)
09:30 - 09:30 | Author(s): A.K. Nowak
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung. Median OS with frontline chemotherapy of pemetrexed/cisplatin (pem/cis) is ~12 months. There is no established second line therapy. Pem/cis has been shown to enrich cancer stem cells (CSCs) in tumors. Focal adhesion kinase (FAK) inhibitors have been found to decrease CSCs in mesothelioma models. The use of a FAK inhibitor in a maintenance setting after frontline chemotherapy may therefore extend survival of MPM patients. Furthermore, approximately 40% of MPM tumors exhibit disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Mesothelioma cell lines that lack merlin are more sensitive to FAK inhibitors than those with wild type merlin. This Phase 2 study will determine if defactinib (VS-6063), an oral inhibitor of FAK, provides superior clinical benefit compared with placebo as maintenance treatment in patients with MPM following frontline pem/platinum therapy.
Methods:
COMMAND is a multinational, randomized, double-blind, placebo-controlled trial. Approximately 370 patients with PR or SD following ≥4 cycles of frontline pem/platinum therapy will be enrolled. Patients will receive defactinib 400 mg BID or matched placebo. Randomization will be stratified by merlin status, as determined by immunohistochemistry. Primary endpoints include OS and PFS. An adaptive enrichment design at the interim analysis (projected to occur in Q2 2015) may restrict patients to those with low merlin protein expression if greater benefit is observed among this subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. The study is currently enrolling across 15 countries. Clinical trial: NCT01870609.
Results:
Not applicable
Conclusion:
Not applicable
