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F. Griesinger
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.05 - P53 Non-Disruptive Mutation is a Negative Predictive Factor for OS and PFS in EGFR M+ NSCLC Treated with TKI (ID 5879)
16:00 - 17:30 | Author(s): F. Griesinger
- Abstract
- Presentation
Background:
P53 mutations are common in lung cancer, and have also been described in EGFR mutated patients The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.
Methods:
484 patients diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing, hybrid cage next generation sequencing. P53 mutations were detected by Sanger Sequencing and either Miseq or hybrid cage NGS. Clinical characteristics including smoking status were available for more than 97%.
Results:
484 consecutive patients were studied. The overall EGFR M+ rate was 17.8% (86/484) in all patients, 84.9% (73/86) showing common mutations of exon 19 or 21. In 21/86 (24.4%) patients’ p53 analysis was not successful. P53 disruptive mutations were demonstrated in 24.6% (16/65) of successfully tested patients, and p53 non-disruptive mutation occurred in 27.7% (18/65) whereas p53 WT configuration was found in 47.7% (31/65). Median OS was 28 months in p53 disruptive mutation and 44 month in p53 WT compared to 23 months in p53 non-disruptive mutation (p<0.023). PFS on 1[st] line TKI therapy was 14 months in p53 disruptive mutation, 27 months in p53 WT and 10 months in p53 non-disruptive mutation (p<0.040). Similar results were shown in the EGFR common mutation subgroup. 11/16 (68.8%) patients with a disruptive p53 M+ and 25/29 (86.2%) patients with a p53 WT constellation achieved an objective response on the 1[st] line TKI therapy compared to 7/13 (53.8%) patients with a non-disruptive p53 status. The patients with an unknown p53 status achieved an objective response on the 1[st] line TKI therapy of 82.4.8% (14/17).
Conclusion:
Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 M+ status. P53 mutational status is predictive when disruptive and non-disruptive p53 M+ are differentiated. A p53 WT constellation has a positive effect on OS and PFS. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.02 - Clinical Research Platform into Molecular Testing, Treatment, Outcome (CRISP): A Prospective German Registry in Stage IV NSCLC AIO-TRK-0315 (ID 5911)
11:00 - 12:30 | Author(s): F. Griesinger
- Abstract
- Presentation
Background:
Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore registry data are of ever increasing importance to patients, physicians and reimbursement institutions.
Methods:
Therefore, we have started a prospective, clinical registry for patients with metastatic non-small cell lung cancer. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of first-line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing.
Results:
This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death. The first patients have been included as of December 2015. As of yet, 82 centers have been initiated, 211 patients have been recruited. Preliminary data will be presented at the meeting in terms of molecular test rates, demographic data as well as treatment stratification in the 1[st] line setting.
Conclusion:
The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany. ClinicalTrials.gov Identifier: NCT02622581 CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.
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MTE08 - Immunotherapy in Early and Locally Advanced NSCLC: Challenges and Perspectives (Ticketed Session) (ID 302)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 07:30 - 08:30, Lehar 3-4
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MTE08.01 - Immunotherapy in Early and Locally Advanced NSCLC: Challenges and Perspectives (ID 6552)
07:30 - 08:30 | Author(s): F. Griesinger
- Abstract
- Presentation
Abstract:
The demonstration that therapies directed at the programmed death-1 (PD-1) receptor or its ligand (PD-L1) result in durable responses and improved survival in a number of solid tumours including non-small cell lung cancer has awakened interest in cancer immunotherapy. The activity of PD-1/PD-L1 therapy in NSCLC implies that endogenous T-cells can recognize antigens on tumour cells and eliminate those cancer cells. The success of checkpoint inhibitor therapy in the metastatic setting has led to a immunotherapy trials in early stage (adjuvant) and stage lll NSCLC. This session will provide perspective on the current state and challenges facing immunotherapy in these settings. Current perspectives: The concept of using immunotherapy to prevent recurrence of NSCLC after resection of early stage NSCLC is not new. More recently, two randomized phase lll trials of therapeutic cancer vaccine strategies have been completed in resected, early stage NSCLC (MAGRIT) or after chemoradiation in stage lll disease (START). The MAGRIT trial (1) assessed the efficacy of an active, specific cancer immunotherapy (ASCI) against the MAGE-A3 cancer testis antigen in completely resected stage IB-IIIA NSCLC. Tumors from more than 13,000 patients were screened for MAGE-A3 expression and 2312 patients whose tumours expressed MAGE A3 were randomized 2:1 to MAGE-A3 (ASCI) or placebo. The MAGRIT trial failed to meet its primary end-point of improvement in disease free survival with MAGE-A3 ASCI. The START trial(2) assessed a MUC1 vaccine in stage III NSCLC patients who had response or stable disease after standard chemoradiation. The chemoradiation could have been delivered concurrently or sequentially. The modified intention to treat population included 1239 patients. The primary end-point was not met (adj. HRO .88, 95% CI 0.75 -103, p=0.123). Further development of this agent has been abandoned. The failure of these two large global phase III studies raises doubt about vaccine strategies used in isolation in early stage NSCLC. There are a number of possible explanations for these negative results (3). One of the primary reasons is that cancer vaccines , when used alone, fail to address the many immunosuppressive factors operating in the tumour microenvironment (TME). Clinical trials evaluating anti PD-1/PD-L1 therapy in early stage or locally advanced NSCLC have not yet reported results. The PACIFIC trial (NCT 20125461) is a randomized phase III trial of MEDI4736 versus placebo following concurrent chemoradiation in patients with stage III NSCLC. The primary outcome measures are OS and PFS. This trial completed accrual in April 2016 and has randomized more than 700 patients. In addition to the important efficacy outcomes, a number of exploratory objectives will assess tissue and blood for potential biomarkers. The Canadian Cancer Clinical Trials Group is assessing MEDI 4736 versus placebo in completely resected stage IB-IIIA NSCLC (NCT 02273375). This trial will randomize 1100 patients with the primary outcome measure being DFS in PD-L1 positive patients. PD-L1 positive is defined as > % positive tumour cells. Immune Based Prognostic Markers: The TME consists of stromal cells including endothelial cells and fibroblasts and a number of immune cell types. Tumours may escape immune recognition in large part by modulating the recruitment and function of various immune cells into the TME (4). A comprehensive review of the prognostic value of different immune cells in NSCLC has been reported (5). Two recent studies have separately assessed tumour lymphocytic infiltration (TLI) (6) or stromal CD8+ T-cell density (7) as potential prognostic markers in early stage NSCLC. Using the large, relatively homogenous population of curative resected NSCLC patients from the LACE-Bio collaboration, Brambilla et al examine the prognostic and predictive value of TLI. Patients were separated into discovery and validation sets. An intense TLI (>50% stromal lymphocytes in tumour bulk) was strongly prognostic of favourable overall survival and disease free survival. Based on previous work, Donner et al selected stromal CD8+ tumour infiltrating lymphocyte as the most promising immuno-based prognostic marker. Using four separate cohorts of curatively resected stage I-III patients, they established training and validation sets. Tissue microarrays were scored for stromal CD8 TLI's; stromal CD8 TIL density was found to be an independent prognostic factor and retained significant prognostic impact within each stage. The value of PD-L1 as a biomarker in NSCLC has been investigated primarily in advanced disease and focused on prediction of response and/or survival. Studies investigating the value of PD-L1 as a prognostic marker in early stage NSCLC have many limitations. These studies are small, include heterogenous populations, assess PD-L1 using different antibodies and scoring systems and included PD-L1 on tumour cells only or tumour cells and TLI's. It is not surprising that these studies show conflicting results. Based on the available evidence, the prognostic value of PD-L1 expression in early stage NSCLC remains uncertain. The adjuvant trials of anti-PD1/PD-L1 therapy currently being conducted may clarify the value of PD-L1 as both prognostic and predictive biomarkers in this setting. Challenges One of the fundamental challenges to developing effective cancer immunotherapies is our limited understanding of the human immune system in steady state and its response to stress. Animal models do not necessarily translate to humans. The Human Vaccines Project (8) is a global initiative that has as one of its primary objectives the decoding of the human immune system and providing a map of the human “immunome”. This private-public partnership uses state-of-the-art machine learning and technologies to elucidate the principles of immunogenicity to accelerate the development of new immunotherapies against infectious diseases and cancer. A second challenge is how best to target micrometastases in the adjuvant and locally advanced setting. While the primary tumor and metastatic lesions have many mutations in common, metastatic tumors possess mutations that are distinct from the primary. Do adjuvant therapies need to target the metastatic cascade and if so, which steps are the most susceptible to intervention? (9) The complex of the TME would predict that focusing on TIL’s or PD-L1 is likely to result in only modest improvements in outcome. Blank et al (10) argue that it will take a combination of biomarkers, the “cancer immunogram” , to determine the best approach in individual patients. References: Lancet Oncol 2016. 17;(8): 22-35 Lancet Oncol 2014; 15 : 59-68 Ann Oncol 2015; 26: 2213-2220 Nat Rev Immunology, 2015; 15: 73-86 Clin Cancer Res 2011; 17(16): 5247-56 J Clin Oncol 2016; 34:1223-30 Clin Cancer Res 2015; 21(11): 2635-43 Science Translational Medicine 2016; 8(334): 334-339 Nature Reviews Cancer 2015; 16: 201-218 Science 2016; 352(6286):658-660
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-039 - Intercalated EGFR and Chemotherapy in Locally Advanced NSCLC with EGFR Mutations: Data on 5 Patients and Clinical Study (ID 5896)
14:30 - 15:45 | Author(s): F. Griesinger
- Abstract
Background:
EGFR TKI’s are standard of care in patients with EGFR mt+ NSCLC IV. However, induction concepts including intercalated TKI / CTx, in locally advanced NSCLC with EGFR mutation including TKI have not been studied extensively. This concept was used as induction regimen in 5 patients with activating EGFR mutations in stages IIIA and IIIB and is now carried on in a phase II study (NeoIntercal).
Methods:
Patients with EGFR mt+ NSCLC locally advanced were treated on an individual basis, remission induction was measured by RECIST 1.1, regression grading by Junker criteria.
Results:
3 female never smokers (pt #1, #3, #5), 59, 62, 62 y.o. 2 male light smokers (pt#2 and #4) , 58 and 69 y.o. were diagnosed with with TTF1+ adenocarcinomas of the lung, 2 with exon 21 L858R (#1,2) and 3 with exon 19 deletions (#3,4,5). 4/5 patients (#1-4) carried p53 mutations. Tumor stages were IIIB in pts. #1, 2, 5, IIIA pt. #3, oligometastastic OMD with one organ involved pt. #4. Induction therapy was TKI (Erlotinib or Gefitinib) days -12 to -1, followed by 3 cycles of chemotherapy (Docetaxel 75 mg/m[2] d1/Csplatin 50 mg/m[2] d 1+2 qd22 or Paclitaxel 200 mg/m2 and Carboplatin AUC 6.0 d1, q22) in combination with TKI (Erlotinib d4-20 100 mg/ die p.o. or Gefitinib 250 mg d4-20 of each cycle). PR was achieved after 2 cycles in all patients. All 5 patients were resected, regression grade IIB or III was remarked in mediastinal lymph nodes (#1-4). Pt. #5 had regression grade III. All 5 patients received adjuvant radiotherapy of the mediastinum. One patient died of secondary cancer (rectal cancer) 52 months after diagnosis of NSCLC. 4 pts are alive for 20 to 24 months. Pts 1 and 2 developed isolated CNS mets 8 and 12 months after primary diagnosis which were treated by surgery and/or radiosurgery. Pts 2, 4 and 5 relapsed with distant mets. No resistance mutation was observed and pts are on 1[st] or 2[nd] gen. TKI therapy. A phase II trial (NeoIntercal) trial is currently under way in 9 German centers in stages II and III supported by AstraZeneca Pharmaceuticals. Preliminary results of these patients will be presented at the meeting.
Conclusion:
Intercalated TKI treatment is a promising treatment in patients with EGFR mt+ locally advanced NSCLC that is pursued in a prospective phase II Trial in Germany. CNS mets seems to be the primary site of relapse in most patients.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-022 - Outcome in Molecularly Defined NSCLC within the NOWEL Network: The Influence of Sequential 2nd and 3rd Generation TKI in EGFR mt+ and ALK+ pts (ID 5902)
14:30 - 15:45 | Author(s): F. Griesinger
- Abstract
Background:
Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with a proved mutation. Targeted therapies achieve a better quality of life, a higher PFS and ORR and in some cases increased OS. The aim of the study was therefore to systematically analyze retrospective data from three cancer centers in the north of Germany. The study compares these three cancer centers in reference to the test rate and the therapeutic success of targeted therapy.
Methods:
1383 patients from the three cancer centers diagnosed with non-small lung cancer stage IV (UICC 7) were examined. Methods for the detection of mutations included Sanger Sequencing, hybridization based COBAS testing as well as hybrid cage next generation sequencing. Clinical characteristics including smoking status were available for more than 92% of the patients.
Results:
880 consecutive patients from the three cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The overall mutation testing rate was 63.6% (880/1383). EGFR mutations were found in 18.4% (86/467)/ 13.1% (38/289)/ 11.3% (14/124) in the Pius-Hospital, Bremen-Ost or Hamburg Harburg respectively, ALK in 3.9% (18/467)/ 1.7% (5/289)/1.6% (2/124) yielding an overall EGFR M+ rate of 15.7% (138/880) and overall ALK M+ rate of 2.9% (25/880). Median OS was 43 (n=86) vs. 25 (n=38) vs. 16 (n=14) months (Pius vs. Bremen vs. Hamburg) (p<0.035). PFS on the 1[st] line TKI therapy was 25 (n=77) vs. 22 (n=31) vs. 10 (n=13) months respectively. Pts receiving 3[rd] generation TKI (Osimertinib n=12) had a significantly longer OS than pts not receiving 3[rd] gen. TKI (n=134). PFS on 3[rd] gen TKI was significantly longer than for other therapies (p<0.020). Median OS in ALK mutated patients was 31 (n=18) vs. 17 (n=5) vs. 10 (n=2) months (Pius vs. Bremen vs. Hamburg). Median OS of pts treated with Crizo alone (n=14) was 18 months, pts treated sequentially with Crizo and Ceritinib (n=6) 31 months, median OS without Crizotinib (n=4) was 17 months.
Conclusion:
The results illustrate differences between the three Lung Cancer Centers in the north of Germany. Significant differences in OS were observed, depending on the center and a significant difference in PFS between the therapy with Osimertinib and other therapies could be established. The differences mentioned could depend on the selection of the patients and their clinical characteristics. The clinical characteristics should be observed in detail.
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P2.03b-081 - Comparison of Genomic Alterations Derived from Matched Tumor Tissue and Liquid Biopsy (ID 6010)
14:30 - 15:45 | Author(s): F. Griesinger
- Abstract
Background:
In the last decade, translational research led to the identification of oncogenic drivers and the successful development of targeted inhibitors. Today, especially patients with lung carcinoma with a non-squamous histology benefit from targeted inhibition, for example of EGFR, ALK, ROS1, MET. However, in many cases tumor material is limited and does not allow for complete molecular diagnostics or, in a relapse setting, a re-biopsy may not be possible. Thus, reliable and comprehensive detection of genomic alterations by non-invasive means, such as liquid biopsies are required. In addition, repeated analysis of cell-free tumor DNA allows for disease monitoring while, at the same time, displaying the tumor heterogeneity.
Methods:
At NEO New Oncology we have developed two hybrid-capture based NGS assays, designed for the detection of genomic alterations in tissue or blood with high sensitivity and specificity. NEOplus is applied to FFPE tumor tissue and detects somatic alterations in a panel of more than 90 cancer related genes. NEOliquid is specifically designed for detection of genomic alterations from cell-free DNA of liquid biopsies and covers a panel of 39 clinically relevant genes. To evaluate the performance of liquid biopsies in the routine setting, we applied both NEO tests on matched FFPE and blood samples to correlated results.
Results:
Overall, a selection of matched FFPE and blood samples of more than 60 patients with non-squamous histology were analyzed. We were able to identify the same therapy relevant genomic alterations in FFPE and blood samples in a majority of the cases. Discrepancies in mutation spectrum of the blood and tissue sample were due to insufficient tumor DNA in cfDNA as well as tumor heterogeneity across multiple tumor manifestations.
Conclusion:
By comparing 60 matched tissue and blood sample we were able to identify concordant mutations across a broad spectrum of genes.
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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-091 - Final Phase Ib Results of RNActive® Cancer Vaccine BI 1361849 and Local Radiation as Maintenance Therapy for Stage IV NSCLC (ID 4735)
14:30 - 15:45 | Author(s): F. Griesinger
- Abstract
Background:
Preclinical studies demonstrated that local radiotherapy (RT) acts synergistically with RNActive[® ]vaccines to increase tumor-infiltrating immune cells and enhance anti-tumor effects. BI 1361849 (CV9202) is an immunotherapeutic cancer vaccine comprising optimized mRNA constituents (RNActive[®]) encoding six NSCLC-associated antigens. Here we report clinical outcomes and immune response data of a phase Ib study, employing local RT and BI 1361849 in advanced NSCLC.
Methods:
Patients (Pts) with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) were enrolled in three cohorts based on histological and molecular NSCLC subtypes (non-squamous vs. squamous vs. EGFR-mutated NSCLC). Pts received two initial vaccinations with BI 1361849 prior to local RT to the primary tumor or a metastatic lesion (four consecutive daily fractions of 5 Gy), followed by further vaccinations until start of another treatment. Maintenance Pemetrexed (mP) and EGFR-TKIs were continued according to the label. Primary endpoint was safety; secondary endpoints included objective response, PFS and OS. Cellular and humoral immune responses were measured ex vivo by multifunctional intracellular cytokine staining, IFN-γ ELISpot, and ELISA in pre- and post-treatment blood samples.
Results:
26 pts were enrolled. 15 pts received mP, two received EGFR TKIs. Most frequent AEs were mild to moderate injection-site reactions and flu-like symptoms. Two pts experienced BI 1361849-related grade 3 AEs (fatigue, pyrexia). No BI 1361849-related SAE or grade 4 AE was reported. Interim results indicate one confirmed PR in a patient receiving mP and SD in 13/25 evaluable pts (52%, 8 pts on mP, 3 pts without maintenance therapy, 2 pts on EGFR-TKI), with two pts showing remarkably long-lasting disease stabilization of up to 72 and 54 weeks, respectively. Shrinkage of lesions outside the irradiated field of ≥15% occurred in 7 pts, all but one receiving mP. Longitudinal assessment of tumor response allows for further insight into patterns of progression. BI 1361849 was capable of eliciting antigen-specific immune responses in the majority of the patients including both cellular and humoral immune responses.
Conclusion:
BI 1361849 elicits antigen-specific immune responses and can be safely combined with local RT and mP treatment. Shrinkage of non-irradiated lesions and prolonged disease stabilization was observed in a subset of pts, mainly in combination with mP. Final clinical outcomes and analyses of cellular and humoral immune responses will be presented.
