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P. Baas
Moderator of
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OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 8
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OA13.01 - A Phase II Study of Nivolumab in Malignant Pleural Mesothelioma (NivoMes): With Translational Research (TR) Biopies (Abstract under Embargo until December 6, 7:00 CET) (ID 3881)
14:20 - 14:30 | Author(s): J. Quispel-Janssen, G. Zago, R.D. Schouten, W. Buikhuisen, K. Monkhorst, E. Thunissen, P. Baas
- Abstract
- Presentation
Background:
No studies have reported any survival benefit in recurrent MPM. We examined the effect of nivolumab, in patients who presented with progressive disease and agreed to have biopsies taken before and during treatment.
Methods:
In this single center, phase II study, patients received nivolumab (3mg/kg q2w) until progression or toxicity. The primary endpoint was an improvement of disease control rate at 12 weeks of 20 to >40% compared to historic control according to a Simon two-stage design. A total of 33 patients were planned with paired biopsies at week -1 and 6 according to treatment start. PD-L1 status and other biomarkers were analyzed.
Results:
From 09-2015 until 06-2016, 38 patients were included with 33 having paired biopsies; 4 were not evaluable. There were no treatment related death and DCR at 12 weeks was 50%. Five patients had a confirmed PR; 12 had SD and 17 PD. Three patients showed pseudo-progression. Grade 3 toxicity occurred in 8 patients leading to discontinuation of the treatment in 4. The table shows the patients/tumor details. PD-L1 ≥1% was expressed in 9/32 evaluable patients with 2/9 having a confirmed PR at 12 weeks.
Conclusion:
Nivolumab in 2[nd] or later lines in recurrent MPM met the primary endpoint. The toxicity was mild and long lasting results were observed. A clear correlation between PD-L1 expression and response was obeserved.Outcome Age mean 66 yrs (51-81) M/F 28 / 6 Epithelial/mixed/non epithelial 28 / 4 / 2 PR/SD/PD 5 / 12 / 17 PD-L1 + (1-10; 10-25; 25-50; >50%) 2 / 1 / 3 / 3 Correlation PR/SD/PD according to PD-L1 expression <1% : 3/8/12 1 - 10% : 0/1/1 10-25% : 0/0/1 25-50% : 1/1/1 > 50% : 1/1/1 Correlation PR/SD/PD with histology Epithelioid : 4/9/15 Mixed : 1/2/1 Non-epithelial : 0/1/1
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OA13.02 - Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis (ID 6232)
14:30 - 14:40 | Author(s): H. Lee Kindler, T. Karrison, Y.C. Tan, B. Rose, M.I. Ahmad, C.M. Straus, R.M. Sargis, T. Seiwert
- Abstract
- Presentation
Background:
Pembrolizumab showed significant activity in PD-L1+ MM in a phase IB study (Alley, 2015). We are conducting a phase II trial (NCT02399371) of pembrolizumab in previously-treated MM patients to further characterize its activity in a larger, non-selected population, determine a PD-L1 expression threshold, and interrogate the microenvironment.
Methods:
Eligible patients have histologically-confirmed pleural or peritoneal MM, measurable disease, PS 0-1, disease progression on/after pemetrexed/platinum, 1-2 prior regimens, normal organ function, and available tissue. Patients receive 200 mg pembrolizumab IV Q21 days and CT scans Q9 weeks. Primary objectives: 1) determine the objective response rate in: A] an unselected population and, B] a PD-L1 positive population; 2) determine the optimal threshold for PD-L1 expression using the 22C3 antibody-based IHC assay (Qualtek). Exploratory correlatives profile the inflammatory microenvironment via: a) multi-color immunofluorescence of tumor infiltrating lymphocytes (TILs) and macrophages, b) RNA-based inflammation signatures/pathway activation, c) characterizing underlying mutations/copy number changes. Proceeding to a 2[nd] stage requires ≥3 responses in 35 patients. If an optimal threshold for PD-L1 expression is determined, the 2[nd] stage only enrolls above that threshold.
Results:
35 patients enrolled 5/15-2/16. 1 withdrew. Male 82%; median age 63 (range 26-85); PS 0/1 63%/37%; epithelial/sarcomatoid/biphasic/NOS: 69%/26%/3%/3%; pleural/peritoneal 86%/14%; 1 prior regimen: 60%. Mean cycles: 8.5 (range 1-18). Median progression-free survival: 6.2 months (95% CI: 3.2, 8.2). Median overall survival has not been reached. Partial response: 7 (21%), stable disease (SD): 19 (56%); progression: 6 (18%); early death: 2 (6%). Ten patients received treatment beyond progression; 20% subsequently achieved SD. Grade 3/4 toxicity: pneumonitis 6%, fatigue 6%, adrenal insufficiency 6%, colitis 3%, confusion 3%, hyponatremia 3%, neutropenia 3%. Grade 1/2 immune-related toxicities: hypothyroidism 17%, rash 14%, pruritus 11%, diarrhea 9%, uveitis 6%, arthralgia 6%, hepatitis 3%, infusion reaction 3%, mucositis 3%. Grade 5 toxicities: autoimmune hepatitis 3%, unknown 3%. PD-L1 expression by tumor proportion score (N=31): none (< 1%): 55%; low (1%-49%): 19%; high (≥ 50%): 26%. PD-L1 expression did not correlate with response (ROC area 0.62; 95% CI: 0.32, 0.94).
Conclusion:
Pembrolizumab has robust activity in PD-L1 unselected, previously-treated MM patients, with a response rate of 21% and a disease control rate of 76%. An optimal PD-L1 threshold could not be established in this small sample. The 2nd stage is enrolling an additional 30 patients without PD-L1 pre-selection. Correlative studies including CD8 TILs, macrophage characterization, and presence of T-regulatory cells will be presented. Funded by a grant from the Mesothelioma Applied Research Foundation.
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OA13.03 - Long-Term Overall Survival for Patients with Malignant Pleural Mesothelioma on Pembrolizumab Enrolled in KEYNOTE-028 (ID 6165)
14:40 - 14:50 | Author(s): E.W. Alley, J. Lopez, A. Santoro, A. Morosky, S. Saraf, B. Piperdi, J.H.M. Schellens
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with poor prognosis and limited treatment options after progression on platinum-containing chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present long-term overall survival (OS) data for patients with malignant pleural mesothelioma enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.
Methods:
KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. 25 patients with MPM were treated with pembrolizumab in the mesothelioma cohort. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. 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 objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and OS.
Results:
As of June 9, 2016, median duration of follow-up was 18.7 months (range, 1.5-24.6 months), and 4 patients (16%) are still on treatment. ORR was 28% (n = 7); 12 (48%) patients had stable disease, resulting in a disease control rate of 76%; median duration of response was 9.2 months (range, 2.4-20.5+ months); median PFS was 5.8 months (95% CI, 3.4-8.2 months), with 6- and 12-month PFS rates of 50% and 25%, respectively. Median OS was 18.0 months (95% CI, 9.4 months-not reached) with 6- and 12-month OS rates of 83.5% and 62.6%, respectively. No new safety signals have been identified. Sixteen (64%) patients experienced a drug-related adverse event (DRAE), and 5 (20%) experienced grade 3/4 DRAEs. Three patients required dose interruption because of immune-related adverse events (1 each, ALT increased, iridocyclitis, and pyrexia/arthralgia]). There was no treatment-related mortality or discontinuation due to DRAE.
Conclusion:
Single-agent pembrolizumab has significant clinical activity in patients with PD-L1–positive MPM. Responses from pembrolizumab in patients with MPM are durable; the 62.6% 12-month OS rate in this mostly pretreated patient population warrants further investigation. Long-term administration of pembrolizumab is feasible in patients with MPM, and no new safety signals were identified.
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OA13.04 - Discussant for OA13.01, OA13.02, OA13.03 (ID 7085)
14:50 - 15:05 | Author(s): C. Waller
- Abstract
- Presentation
Abstract not provided
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OA13.05 - Somatic Genetic Alterations and Immune Microenvironment in Malignant Pleural Mesothelioma (ID 5087)
15:05 - 15:15 | Author(s): W.T. Vigneswaran, H. Inoue, J. Park, S. Olugbile, Y. Nakamura
- Abstract
- Presentation
Background:
The genomic landscape of malignant pleural mesothelioma (MPM) is not well understood. Advanced high-throughput sequencing technologies allow comprehensive characterization of genetic alterations. Knowledge of the somatic mutations and the immune microenvironment in patients with MPM will help to develop effective targeted therapies.
Methods:
We examined biopsy specimens from 12 MPM patients (8 epithelioid and 4 biphasic) that were removed during maximal cyto-reductive surgery. Specimens from 3 different sites (anterior, posterior and diaphragm, a total of 36 tissue samples) were studied through whole exome sequencing, T cell receptor (TCR) repertoire analysis of tumor-infiltrating T cells (TILs), and expression levels of immune-related genes. We also performed in silico prediction of potent neoantigens derived from non-synonymous somatic mutations in each specimen. For the comparison of tumor tissues from 3 different sites, we performed hierarchical clustering to assess the tumor heterogeneity and differences in immune environment.
Results:
High mutation/neoantigen load was significantly correlated with higher clonal expansion of TILs (R=0.46) and high expression levels of immune-associated cytolytic factors, granzyme A (R=0.25) and perforin 1 (R=0.48), in tumor tissues. In the clustering analysis, heterogeneous MPM cases revealed unique neoantigens and clonotypes of TILs that were restricted to each of tumor site, suggesting infiltration of the neoantigen-specific T cells. Further sub-analysis according to histologic types showed that biphasic tumors had higher mutation/neoantigen load and stronger oligo-clonal T cell expansion (p=0.01) than epithelioid tumors.
Conclusion:
Our analysis demonstrated a significant correlation between somatic mutation/neoantigen load, clonality of TILs, and the immune-related tumor microenvironment in MPM. Our findings suggest that high mutation/neoantigen load in tumor cells might promote effective expansion and infiltration of functional (tumorocidal) T cells into the tumor bed. These findings provide a rationale for selecting MPM patients who can benefit from treatment with immune checkpoint blockades. This may accelerate development of the neoantigen targeting TCR-engineered T cell therapy for MPM.
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OA13.06 - Autologous Dendritic Cells Loaded with Allogeneic Tumor Cell Lysate (Pheralys®) in Patients with Mesothelioma: Final Results of a Phase I Study (ID 5631)
15:15 - 15:25 | Author(s): J.G. Aerts, R. Cornelissen, C. Van Der Leest, J. Hegmans, K. Bezemer, M. Kaijen-Lambers, F. Eskens, E. Braakman, B. Van Der Holt, R. Hendriks, H. Hoogsteden
- Abstract
- Presentation
Background:
Mesothelioma is an aggressive malignancy without curative treatment options. We have previously shown promising activity of dendritic cell (DC) immunotherapy loaded with autologous tumor cell lysate (Hegmans 2013, Cornelissen 2016). Because of quality and quantity issues (availability, standardization etc) with the autologous lysate, we have developed an off-the-shelf allogenic tumor cell lysate from human mesothelioma cell lines (Pheralys.[®]).
Methods:
Patients (pts) with advanced mesothelioma, either treatment naive, or non-progressing after chemotherapy, were included. Leucapheresis was performed to obtain an enriched monocyte fraction from which immature DC were generated which were loaded with the allogenic lysate. The DC were matured, frozen and stored. In subsequent cohorts of 3 pts 10, 25, or 50 × 10[6 ]DC were administered IV and intradermally, 3 times at a bi-weekly interval and after 3 and 6 months. Primary endpoint was toxicity occurring within 8 weeks after the first vaccination. Secondary endpoints were response rate (RR), progression free survival (PFS) and overall survival (OS). PFS and OS were determined from time of registration in the trial. Immunological read-outs were performed (DTH skin testing, peripheral blood testing).
Results:
Nine pts (median age 69yrs, 8 male, 1 female) were included. All patients developed transient grade 1-fever and a grade 1-2 injection site reaction. No dose limiting toxicities or autoimmunity signs were observed. In 2 pts (22%), both treated with 25 ×10[6] cells, a partial response (PR) was observed, the other 7 pts had stable disease as best overall response. All patients are alive with a median follow up of 11.9 months after trial inclusion(range 7.6-16.5 months). Median PFS was 8.3 months (95% confidence interval (CI) 3.7-not yet reached), PFS at 12 months was 33% (95% CI 8%-62%). Data on immunological read outs are pending.
Conclusion:
DC immunotherapy with allogenic tumor cell lysate is safe and clinically active. Data on PFS and OS are promising and still maturing. The recommended dose for future studies will be 25 * 10[6] cells based on the responses and logistic reasons (the number of monocytes obtained during leucapheresis to generate 5 vaccinations). A randomized trial comparing DC therapy with Pheralys versus best supportive care as maintenance treatment after chemotherapy is planned to start in Q1 2017.
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OA13.07 - Intrapleural Modified Vaccine Strain Measles Virus Therapy for Patients with Malignant Pleural Mesothelioma (ID 5655)
15:25 - 15:35 | Author(s): T. Peikert, S. Mandrekar, A. Mansfield, V. Van Keulen, S. Albelda, S. Aderca, S. Carlson, A. Dietz, M. Gustafson, R. Kratzke, V. Lowe, F. Maldonado, J. Molina, M. Patel, A. Roden, J. Sun, A. Tan, M. Tippmann-Peikert, E. Galanis
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MM) remains an almost universally fatal disease with limited treatment options. Preclinical models indicate the preferential oncolytic activity of the modified vaccine strain measles virus carrying the gene for the human sodium-iodine symporter (NIS) – MV-NIS. Intraperitoneal and intravenous administration of MV-NIS was recently found to be potentially effective in patients with refractory ovarian cancer and multiple myeloma. However, whether MV-NIS is directly oncolytic or triggers an anti-tumor immune response remains unclear.
Methods:
We conducted a phase I dose escalation study with 3+3 design and ongoing maximal tolerated dose (MTD) expansion cohort. MV-NIS was administered as first or second line therapy via a tunneled intrapleural catheter to patients with MM. MV-NIS dose ranged from 10[8] TICID~50~ to 9 x 10[9] TICID~50~. In the absence of dose limiting toxicity and disease progression, patients received up to 6 cycles of MV-NIS therapy (Phase I). Currently additional patients are being randomized between a single and multiple cycles. MV-NIS infection and replication are monitored by Iodine[123] SPECT/CT (Phase I only) as well as by RT-PCR and/or plaque-assay. Anti-tumor immunity is monitored in the blood and pleural fluid and patients are followed clinically by chest CT using the modified RECIST criteria.
Results:
Twelve patients (3/dose level) received MV-NIS therapy. There were no dose limiting adverse events and therapy was well tolerated. The best therapeutic response was stable disease, which was achieved at 1 month by 8/12 evaluable patients (67%). Median overall survival was 449 days (95%CI: 221, 484) (~15 months) (4/12 patients remain alive), and median progression free survival was 63 days (95% CI: 33, 174) (~2 months). MV infection and replication were detectable by RT-PCR and plaque assay in the pleural fluid between 24-72 hours after treatment. I[123] SPECT-CT demonstrated only marginal viral gene expression in a single patient treated with the highest dose level. MV-NIS therapy effectively boosted pre-existing anti-MV neutralizing antibody responses in the plasma and pleural fluid of most patients. We observed a transient inflammatory response in the pleural space after MV-NIS administration. In addition, induction or boosting of anti-tumor antibody responses was observed.
Conclusion:
The intrapleural administration of MV-NIS is safe, resulted in stable disease for 67% of patients and may be associated with favorable overall survival in MM. While there was only transient infection and viral replication, we observed the induction of anti-tumor immune responses supportive of potential long-term therapeutic impact. The study continues with the MTD expansion cohort.
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OA13.08 - Discussant for OA13.05, OA13.06, OA13.07 (ID 6965)
15:35 - 15:50 | Author(s): A. Nowak
- Abstract
- Presentation
Abstract not provided
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ED13 - Treatment of Malignant Pleural Mesothelioma (ID 282)
- Event: WCLC 2016
- Type: Education Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Lee Kindler, N. Van Zandwijk
- Coordinates: 12/07/2016, 11:00 - 12:30, Hall C1
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ED13.04 - Systemic Induction Therapy of Malignant Pleural Mesothelioma (ID 6498)
11:45 - 12:00 | Author(s): P. Baas
- Abstract
- Presentation
Abstract:
Over the last 3 decades clinical researchers have focused on the optimal treatment of patients with mesothelioma (MPM). In the 80’s surgery had become a standard approach in some centers but it became clear that a complete resection (R0) was not achievable. The anatomical location of the mesothelioma simply does not allow a resection with save margins of normal tissue. Therefore additional therapies were looked for and a different number of approaches have been taken. To answer the question if any systemic induction therapy is considered the best, this can be answered with a clear No. reasons for this is the lack of randomized studies in this patient population and the fact that patients with MPM are grouped together despite differences in pathology, surgical approach (EPP vs Pleurectomy decortication) and biological behavior. There has been a number of preferential approaches with chemotherapy in this disease ranging from Induction chemotherapy; Intracavitary therapy and Adjuvant chemotherapy. (table) In the case of induction therapy it is clear that one aims at reducing the tumor bulk and to prevent metastases during surgery. The preferred treatment is cisplatin with pemetrexed since this is considered to be the standard of this disease.(1) Other regimens have been tested in small extend but usually involved. The use of intra-cavitary treatment has attracted attention since MPM cells show the tendency to stay localized in the thoracic cavity for a relative long period. The administration of a local cytotoxic drug would allow an improvement in local control and limited systemic effects. Cisplatin has been used frequently during surgery and were combined with heating of the lavage fluid to 40[0]Celsius. (2) Special precautions for this so-called Hyperthermic lavage approach have to be taken in the operating suite with protection of the staff to avoid exposure to the drugs. In general the lavage procedure adds another hour to the debulking surgery. Measurements of platin adducts in the blood during this procedure have shown that there is no important systemic levels measured. Unfortunately there has not been any comparison of these approaches. Most series only report the feasibility of the treatment with sometimes impressive survival figures. These are partly due to the strong selection of patients for the studies. A relative new approach is the use of a platin containing fibrin glue that can be applied to the thoracic wall after debulking using a spray system. The initial results indicate that the treatment is fast and serial biopsies show that the effect is sustained for many weeks.(3) Finally, adjuvant therapies can be applied. In this field, there are no data to support any specific treatment and the choices are generally defined based on the study protocol. No prospective trials have been reported Most of the studies are trimodality therapies where RT is an important part of the protocol. One typical example is the EORTC study where the feasibility of trimodality therapy in a phase II trial (EORTC 08031) with clearly defined timelines was tested(5). Patients with pathologically proven mesothelioma received induction chemotherapy (3 courses cisplatin and pemetrexed ) followed by EPP within 21–56 days after the last dose of chemotherapy in the absence of progressive disease and unacceptable toxicity. A ‘‘success of treatment’’ was defined as a patient who had received the full protocol and was alive after 90 days without progressive disease and without grade 3 or 4 toxicity. Of the 57 patients included, 42 had EPP (73.7%) after induction therapy. The 90-day mortality was 6.5% with an overall survival time of 18.4 months and progression-free median survival time of 13.9 months. Only 24 (42.1%) patients met the definition of success, thereby failing the primary endpoint. This study shown how difficult it is to complete a trimodality study in this patient group and only when a standard is defined, proper comparative studies can be performed. Other important studies addressing the neo-adjuvant approach are presented in the table. 1.Baas P, Fennel D, Kerr K, van Schil PE. Malignant Pleural Mesothelioma: Guidelines for Diagnosis, treatment and follow-up. Annals Oncology 2015 2.Sugarbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, Bueno R, Richards WG. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural Mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg. 2013 Apr;145(4):955-63. 3.Opitz I. Use of fibrin glue in malignan pleural mesothelioma, presented at the xxth IMIG conference Birmingham UK 4.Van Schil P, Baas P, Gafaar R, Maat AP, van der Pol M, Hassan B et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. 5.Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18:1196-202 6.Cao C, Tian D, Manganas C, Matthews P, Yan TD. Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothor Surg 2012;1:428-37 TableStudy type # pts drugs Completed Chemotherapy Completed Surgery Completed Radiotherapy Outcome (mOS) SAKK 17/04 Lancet Onc 2015;16;1651 Neo-adj 151 Cis/pem 145 125 23/27 in 2nd stage 7.6-9.4 Frederico BMC Cancer 2013;13;22 Neo-adj 54 Cis/pem 96% 83% 41% 15.5 Krug JCO 2009;27;3007 Neo-adj 77 Cis/pem 83% 74% 52% 16.8 Weder JCO 2004;22;3451 Neo-adj 20 Cis/gem 90% 80% n.a. 23 Van Schil ERJ 2010;36;1362 Neo-adjuvant 59 Cis/pem 93% 79% 65% 18.4 Richards JCO 2006;24;1561 intracavitary 61 Cispl 50-225 n.a. 72% n.a. 9.0 Tilleman JTCS 2009;138;405 intracavitary 121 Cispl 225 n.a 79% n.a. 12.8
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MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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MA14.07 - Real Life Experience with Immunotherapy in the Netherlands (ID 4689)
16:42 - 16:48 | Author(s): P. Baas
- Abstract
- Presentation
Background:
Randomized phase III trials have shown that the PD-1 blocking monoclonal antibody Nivolumab is effective in advanced NSCLC. Nivolumab is registered by the FDA and EMA for treatment of NSCLC. However, approval in The Netherlands was put on hold because of Nivolumab's high price per quality adjusted life year (QALY). From August 2015, Nivolumab was provided through a compassionate use program. Here we present our experience in treating NSCLC patients with Nivolumab in real life.
Methods:
Efficacy and safety of Nivolumab was assessed in patients with advanced NSCLC, previously treated with at least one line of platinum-based chemotherapy and an ECOG-PS of ≤2. Nivolumab was administered 2-weekly at a dose of 3 mg/kg intravenously. Response evaluation took place according to RECIST 1.1 at 12 and 24 weeks after start of treatment.
Results:
In the 10-month period in a single center 189 patients started treatment with Nivolumab, with a mean follow up time of 106 days after start of treatment. Mean age was 62 years (range 29–83), 57% male, 18,5% never smoked, 68% had adenocarcinoma, 20% had squamous histology and 12% were other, mixed or unspecified types. Figure 1 Twenty-four percent of patients experience immunotherapy related toxicity, most toxicities were short-term or easily manageable. No grade 5 toxicities, one grade 4 hepatitis and one grade 3 hypophysitis were observed. Hypothyroidism was most frequently observed (gr.1-2; 9,5%), followed by skin-reactions (gr.1-3; 3,8%) and colitis (gr.1-2; 3,2%). Other immune related toxicities were hepatitis (gr.1-4; 2,5%), infusion reactions (gr.1; 2,5%), pneumonitis (gr.2; 1,9%), hyperthyroidism (gr.1; 1,3%), arthritis (gr.2; 0,6%), hypophysitis (gr.3; 0,6%) and diabetes mellitus type 1 (gr.3, 0,6%).
Conclusion:
Although follow up is short and response data not yet mature, real-life efficacy and safety data from Nivolumab are comparable to phase III trial data.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.07 - KEYNOTE-010: Durable Clinical Benefit in Patients with Previously Treated, PD-L1-Expressing NSCLC Who Completed Pembrolizumab (ID 6769)
12:05 - 12:15 | Author(s): P. Baas
- Abstract
- Presentation
Background:
Checkpoint inhibitors such as the anti–PD-1 monoclonal antibody pembrolizumab have demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Although checkpoint inhibitors are rapidly becoming a standard-of-care therapy in multiple tumor types, the optimal treatment duration has not been established. We assessed outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study (NCT01905657), in which pembrolizumab provided superior OS over docetaxel in patients with previously treated, PD-L1–expressing advanced NSCLC.
Methods:
1034 patients with advanced NSCLC that progressed after ≥2 cycles of platinum-based chemotherapy (and an appropriate therapy for targetable EGFR and ALK aberrations if present) and had a PD-L1 tumor proportion score ≥1% were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg Q3W or to docetaxel 75 mg/m[2] until disease progression, intolerable toxicity, or physician or patient decision; the maximum duration of pembrolizumab was 24 months of uninterrupted treatment or 35 cycles, whichever was later. Response was assessed per RECIST v1.1 by independent central review every 9 weeks. After completion of 24 months/35 cycles, patients continued to undergo imaging every 9 weeks; patients with subsequent disease progression were eligible for a second treatment course if they did not receive other anticancer therapy after stopping pembrolizumab.
Results:
In the overall population, median OS was longer (10.5 months for pembrolizumab Q2W, 13.4 months for pembrolizumab Q3W, and 8.6 months for docetaxel) and 24-month OS rates were higher (30.1%, 37.5%, and 14.5%, respectively) with pembrolizumab compared with docetaxel. Of the 691 patients allocated to pembrolizumab, 47 patients received 35 cycles of pembrolizumab and were included in this analysis. As of the September 30, 2016 data cutoff date, all patients had completed all 35 cycles of treatment, but one withdrew from the study treatment after completing 35 cycles. Best overall response (ORR) among these 47 patients was complete response (CR) in 3 (6%) patients and partial response (PR) in 39 (83%) patients, for an ORR of 89%; 5 (11%) patients experienced stable disease (SD). Two of these patients experienced disease progression since stopping pembrolizumab and two of these patients resumed pembrolizumab therapy. As of the cutoff date, none of the 47 patients had died.
Conclusion:
With long-term follow-up, the OS benefit has been maintained and pembrolizumab continues to demonstrate superiority over docetaxel. Pembrolizumab provides durable clinical benefit with few patients progressing after completing two years of therapy.
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OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
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OA13.01 - A Phase II Study of Nivolumab in Malignant Pleural Mesothelioma (NivoMes): With Translational Research (TR) Biopies (Abstract under Embargo until December 6, 7:00 CET) (ID 3881)
14:20 - 14:30 | Author(s): P. Baas
- Abstract
- Presentation
Background:
No studies have reported any survival benefit in recurrent MPM. We examined the effect of nivolumab, in patients who presented with progressive disease and agreed to have biopsies taken before and during treatment.
Methods:
In this single center, phase II study, patients received nivolumab (3mg/kg q2w) until progression or toxicity. The primary endpoint was an improvement of disease control rate at 12 weeks of 20 to >40% compared to historic control according to a Simon two-stage design. A total of 33 patients were planned with paired biopsies at week -1 and 6 according to treatment start. PD-L1 status and other biomarkers were analyzed.
Results:
From 09-2015 until 06-2016, 38 patients were included with 33 having paired biopsies; 4 were not evaluable. There were no treatment related death and DCR at 12 weeks was 50%. Five patients had a confirmed PR; 12 had SD and 17 PD. Three patients showed pseudo-progression. Grade 3 toxicity occurred in 8 patients leading to discontinuation of the treatment in 4. The table shows the patients/tumor details. PD-L1 ≥1% was expressed in 9/32 evaluable patients with 2/9 having a confirmed PR at 12 weeks.
Conclusion:
Nivolumab in 2[nd] or later lines in recurrent MPM met the primary endpoint. The toxicity was mild and long lasting results were observed. A clear correlation between PD-L1 expression and response was obeserved.Outcome Age mean 66 yrs (51-81) M/F 28 / 6 Epithelial/mixed/non epithelial 28 / 4 / 2 PR/SD/PD 5 / 12 / 17 PD-L1 + (1-10; 10-25; 25-50; >50%) 2 / 1 / 3 / 3 Correlation PR/SD/PD according to PD-L1 expression <1% : 3/8/12 1 - 10% : 0/1/1 10-25% : 0/0/1 25-50% : 1/1/1 > 50% : 1/1/1 Correlation PR/SD/PD with histology Epithelioid : 4/9/15 Mixed : 1/2/1 Non-epithelial : 0/1/1
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-025 - Evaluation of NGS and RT-PCR Methods for ALK Assessment in European NSCLC Patients: Results from the ETOP Lungscape Project (ID 5001)
14:30 - 14:30 | Author(s): P. Baas
- Abstract
Background:
The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%, depending on population and detection method. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase-polymerase chain reaction (RT-PCR) has been advocated and most recently the advent of targeted Next-Generation Sequencing (NGS) for ALK and other fusions has become possible. This is one of the first studies comparing all 4 techniques in resected NSCLC from the large ETOP Lungscape cohort.
Methods:
96 cases from the ETOP Lungscape iBiobank (N=2709) selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK) were examined by FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014), central RT-PCR and NGS. H-score 120 is used as cutoff for IHC+. For both RT-PCR and NGS, RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers were used covering the most frequent ALK translocations. For NGS, the Oncomine™ Solid Tumour Fusion Transcript Kit was used, allowing simultaneous sequencing of 70 ALK, RET and ROS1 specific fusion transcripts associated with NSCLC, as well as novel ALK translocations using 5’-3’ ALK gene expression ‘Imbalance Assay’.
Results:
NGS provided results for 90 cases, while RT-PCR for 77. Overall, 70 cases have results for all 4 methods, with fully concordant 60 (85.7%) cases (49 ALK-, 11 ALK+). Before employing the ‘Imbalance Assay', in 5 of the remaining 10 cases, NGS differs from the other methods (3 NGS-, 2 NGS+), while in the other 5, NGS agrees with RT-PCR in all, IHC in 2, and FISH in 1. Using the concordant result of at least two of the three methods as true negative/positive, the specificity and sensitivity of the fourth is 96/94/100/96% and 94/94/89/72% for IHC/FISH/RT-PCR/NGS, respectively (incorporating imbalance: NGS sensitivity=83%). Imbalance scores are presented here for 18 NGS- cases: 9 ‘NGS-/FISH+/IHC+’, 9 ‘NGS-/FISH-/IHC-‘. Among the ‘NGS-/FISH+/IHC+’, there is strong evidence of imbalance in 4 cases (score’s range: 0.0144-0.0555), uncertain in 5 (range: 0.0030-0.0087), and no evidence (scores≤0.0004) in the 9 negative cases.
Conclusion:
NGS is a useful screening tool for ALK rearrangement status, superior to RT-PCR when RNA yield is limited. When using NGS, it is critically important to integrate the 5’-3’ imbalance assay and to confirm with one or more additional methods in the ‘imbalance’ cases. Data further highlight the possibility of missing actionable rearrangements when only one screening methodology is available.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-052 - Electronic Nose: An Early Response Biomarker for Anti-PD1 Therapy in Patients with NSCLC (ID 4528)
14:30 - 14:30 | Author(s): P. Baas
- Abstract
Background:
Multiple studies have shown the activity of the anti-PD(L)-1 agents in patients with advanced non-small-cell lung cancer (NSCLC). There is an urgent need to explore biomarkers that predict outcome to anti-PD-1 therapy. The electronic (e) Nose is used to analyse the exhaled gasses and is under development as a diagnostic tool for lung cancer. We aimed to determine the diagnostic accuracy of exhaled breath analysis for responders vs. non-responders to anti-PD-1 treatment in NSCLC patients.
Methods:
Patients with NSCLC who were about to receive Nivolumab, were asked to participate. At baseline and after 6 weeks of treatment exhaled breath analysis took place. Breathprints were collected in duplicate by an e-Nose positioned at the rear end of a pneumotachograph (SpiroNose) (de Vries J Breath Res 2015). RECIST 1.1 criteria were used for response evaluation at three months and six months and reported accordingly: Complete response (CR), Partial response (PR), stable disease (SD), and progressive disease (PD). Data-analysis involved signal processing, environment correction and statistics based on principal component analysis (PCA), followed by discriminant analysis (Matlab2014/SPSS20).
Results:
From August 2015 until April 2016, 56 patients participated in this trial. Forty-two patients had a response evaluation. Principal component 3 and 4 showed a significant difference (p=0.005 and p=0.001) between responders (PR and SD) and non-responders (PD) [Figure A]. Twenty-five patients had a second exhaled breath analysis after 6 weeks. Analysis showed significant differences in PC3 and PC4 between both SD vs. PR (p<0.001) and PD vs. PR (p=0.002) [Figure B].Figure 1
Conclusion:
E-Nose is able to discriminate between responders and non-responders to anti-PD-1 treatment at baseline and 6 weeks follow-up and may therefor be of great value to predict outcome.
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WS04 - Mesothelioma Workshop (Ticketed Session) (ID 416)
- Event: WCLC 2016
- Type: Workshop
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/04/2016, 08:00 - 11:00, Stolz 2
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WS04.02 - Debate – Immunotherapy Does Work in Mesothelioma (ID 6983)
09:00 - 09:50 | Author(s): P. Baas
- Abstract
- Presentation
Abstract not provided
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