Proffered Paper session II Proffered Paper session

DOI session (ID 518)

Lecture Time
09:00 - 09:00
Session Name
Proffered Paper session II
Location
Room A, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
09:00 - 10:30
Poster Display session Poster Display session

73P - Cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with advanced or metastatic hepatocellular carcinoma (HCC): Data from an expansion cohort (EC) in a phase I study (ID 409)

Presentation Number
73P
Lecture Time
12:30 - 12:30
Speakers
  • A. He (Washington, United States of America)
Session Name
Poster Display session
Location
Room B, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
12:30 - 13:00
Authors
  • A. He (Washington, United States of America)
  • G. J. Weiss (Phoenix, AZ, United States of America)
  • G. Falchook (Denver, CO, United States of America)
  • N. S. Yee (Hershey, PA, United States of America)
  • M. Gil-Martin (Barcelona, Spain)
  • S. Shahda (Indianapolis, IN, United States of America)
  • V. Moreno (Madrid, Spain)
  • I. Brana (Barcelona, Spain)
  • M. Crittenden (Portland, OR, United States of America)
  • S. Formenti (New York, NY, United States of America)
  • R. Al-Rajabi (Kansas City, KS, United States of America)
  • K. P. Papadopoulos (San Antonio, TX, United States of America)
  • M. J. Pishvaian (Washington, United States of America)
  • E. Stankevich (Basking Ridge, NJ, United States of America)
  • M. Feng (Basking Ridge, NJ, United States of America)
  • J. Li (Basking Ridge, NJ, United States of America)
  • M. Mathias (Tarrytown, NY, United States of America)
  • G. Kroog (Tarrytown, NY, United States of America)
  • I. Lowy (Tarrytown, United States of America)
  • M. G. Fury (Tarrytown, NY, United States of America)

Abstract

Background

For pts with unresectable HCC, systemic therapy options are limited. Sorafenib and lenvatinib are approved in the US and Europe for HCC treatment. For pts who progress on sorafenib, regorafenib and nivolumab are approved as second-line therapy. Cemiplimab (REGN2810) has demonstrated encouraging efficacy and safety profile in a Phase 1 dose escalation study in pts with advanced malignancies (NCT02383212). We present results of the Phase 1 HCC EC.

Methods

HCC pts who are not candidates for surgery and had progressed on, could not tolerate, or refused first-line systemic therapy received cemiplimab 3 mg/kg Q2W IV for up to 48 weeks. The objectives were to evaluate the safety and tolerability (primary) and antitumour activity (secondary) of cemiplimab.

Results

As of 1 Sept 2017, 26 pts were enrolled (25 M/1 F; median age: 65 [range: 40–78] years; ≥1 prior systemic therapy: 24 pts [92.3%]; ECOG PS: 1 in 19 pts [73.1%], 0 in 6 [23.1%], and missing in 1). Median duration of follow-up was 7.2 (range: 1.8–15.5) months. By investigator assessment, 5 pts (19.2%) had partial response, 14 (53.8%) had stable disease, 6 (23.1%) had progressive disease and 1 was not evaluable. Median progression-free survival was 3.7 months (95% CI: 2.3–9.1). Five pts (19.2%) completed the planned 48-week treatment, and 21 (80.8%) discontinued prematurely, primarily due to disease progression (65.4%). Three of the 5 pts who completed planned treatment remain without disease progression at the last response assessment. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (26.9%), decreased appetite, increased aspartate aminotransferase (AST), abdominal pain, pruritus, and dyspnoea (each 23.1%). Grade ≥3 TEAEs occurring in ≥ 2 pts were hyponatraemia (3 pts), autoimmune hepatitis (2 pts) and increased AST (2 pts). Two pts (7.7%) had a TEAE resulting in death: 1 with pulmonary embolism that was considered unrelated to treatment and another with hepatic failure considered possibly related to treatment.

Conclusions

Cemiplimab demonstrated evidence of antitumour activity in pts with advanced or metastatic HCC. The safety profile is comparable with that of other anti-PD-1 inhibitors.

Editorial acknowledgement

Medical writing support under the direction of the authors was provided by Emmanuel Ogunnowo, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc. and Sanofi according to Good Publication Practice guidelines.

Clinical trial identification

NCT02383212.

Legal entity responsible for the study

Regeneron Pharmaceutical Inc. and Sanofi.

Funding

Regeneron Pharmaceutical Inc. and Sanofi.

Disclosure

G.J. Weiss: Personal fees and ownership interest: Circulogene; Ownership interest: Angiex; Personal fees: Paradigm, Igynta, IDEA Pharma, GLG Council, Guidepoint Global; Travel/lodging fees: Cambridge Health tech Institute, Tesaro; Patent PCT/US2011/020612 issued. G. Falchook: Funding for trial for submitted work. N.S. Yee: Research, travel, accommodation and expenses: Daiichi Sankyo, Foundation Medicine, Caris Life Sciences. S. Shahda: Advisory board fees: Ipsen, Bayer; Research grants: Incyte, Apexian. M. Crittenden: Research funding: Jounce, Nanobiotix. R. Al-Rajabi: Grants: Regeneron Pharmaceuticals Inc., during the conduct of the study. E. Stankevich: Shareholder and employee: Regeneron Pharmaceuticals, Inc.; Shareholder: Celgene, Bristol-Myers Squibb, Merck. M. Feng: Shareholder and employee of Regeneron Pharmaceuticals, Inc.; Shareholder: Bayer. J. Li, M. Mathias, G. Kroog: Shareholder and employee: Regeneron Pharmaceuticals, Inc. I. Lowy: Shareholder and employee, fees for travel and accommodation expenses, leadership: Regeneron Pharmaceuticals, Inc. M.G. Fury: Shareholder, employee, patents, royalties, other intellectual property: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

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Poster Display session Poster Display session

105P - The impact of HIPEC on the anticancer immune response (ID 362)

Presentation Number
105P
Lecture Time
12:30 - 12:30
Speakers
  • L. Roth (Zurich, Switzerland)
Session Name
Poster Display session
Location
Room B, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
12:30 - 13:00
Authors
  • L. Roth (Zurich, Switzerland)
  • E. Breuer (Zurich, Switzerland)
  • A. Gupta (Zurich, Switzerland)
  • R. Graf (Zurich, Switzerland)
  • P. Clavien (Zurich, Switzerland)
  • K. Lehmann (Zurich, Switzerland)

Abstract

Background

The outcome of peritoneal carcinomatosis, often occurring due to appendix or colorectal cancer, has dramatically improved with the combination of cytoreductive surgery (CRS) and hyperthermic (43 °C) intraperitoneal chemotherapy (HIPEC). Nevertheless, recurrence of the disease presumably due to remnant cancer cells limits survival of the patients suggesting further optimization in HIPEC treatment. Therefore, it is important to understand mechanisms operating behind HIPEC treatment. Since chemotherapy may induce immunogenic changes, we analyzed effects of MitomycinC/Doxorubicin (M/D), widely used chemotherapeutics in HIPEC settings, on the immunogenicity of colorectal cancer cells in-vitro.

Methods

Colorectal cell-lines were treated with M/D for 30 minutes with and without hyperthermia (430C). After the treatment, cells were further incubated at 370C for 72 hours. The expression of immunogenic cancer-testig antigens (CTA) was analyzed using qRT-PCR and western blot. To assess DC maturation, we set up a co-culture between differentially treated colorectal cells and monocyte-derived DC`s. We analyzed surface markers such as HLA-DR, CD 86 and CD 83 to assess DC maturation using flow cytometry. Further, the activation of cytotoxic T-cells was measured by intracellular IFN-y staining after co-culture with DC`s that were pre-incubated with treated and untreated colorectal cancer cells.

Results

Initial qRT-PCR screening of CTA revealed that two namely, Cyclin A1 and SSX-4 were upregulated after HIPEC treatment. Compared to the control condition (no drug, 370C), M/D in HIPEC condition led to an increase of Cyclin A1 up to 53 folds and SSX-4 to 30 folds. The amount of Cyclin A1 protein was doubled compared to the control treatment (p = 0.0015, CI mean volume intensity 0.1989 – 0.4233). After co-culturing with HIPEC treated colorectal cancer cells, we noticed significant expression in CD 83, a DC activation marker. DCs that were activated upon incubation with HIPEC-treated cancer cells were able to prime cytotoxic T-cells leading to enhance IFN-y production.

Conclusions

HIPEC treatment can cause immunogenic changes in colorectal cancer cells. This could explain a part of the mechanism, how HIPEC treatment may work and inclusion of an immunotherapy may improve outcome of this treatment.

Legal entity responsible for the study

Kuno Lehmann.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Combinations with other modalities Educational session

Vaccination strategies in combination with other I/O (ID 22)

Lecture Time
17:10 - 17:30
Speakers
  • M. Van den Heuvel (Nijmegen, Netherlands)
Location
Room C, Geneva Palexpo, Geneva, Switzerland
Date
13.12.2018
Time
16:30 - 18:00
Authors
  • M. Van den Heuvel (Nijmegen, Netherlands)
What’s new in melanoma & Merkel cell carcinoma (MCC) Educational session

General discussion / Q&A (ID 44)

Lecture Time
15:35 - 15:45
Location
Room C, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
14:15 - 15:45
Modern anticancer vaccines Educational session

Neoantigen-based vaccine approaches (ID 66)

Lecture Time
14:35 - 14:55
Speakers
  • M. Bassani-Sternberg (Lausanne, CH, Switzerland)
Location
Room A, Geneva Palexpo, Geneva, Switzerland
Date
15.12.2018
Time
14:15 - 15:45
Authors
  • M. Bassani-Sternberg (Lausanne, CH, Switzerland)
Immuno-oncology: State of the art II Educational session

Spatially correlated high-plex protein (~ 100-plex) and high-plex mRNA (~ 1000-plex) profiling on FFPE tissue using Digital Spatial Profiling microscopy for immuno-oncology studies (ID 108)

Lecture Time
09:10 - 09:30
Speakers
  • J. Beechem (Seattle, United States of America)
Location
Room C, Geneva Palexpo, Geneva, Switzerland
Date
16.12.2018
Time
09:10 - 10:40
Authors
  • J. Beechem (Seattle, United States of America)
Poster Display session Poster Display session

27P - Reliability of the detection of the mutation burden status by targeted next generation sequencing applying a large gene panel (ID 455)

Presentation Number
27P
Lecture Time
12:30 - 12:30
Speakers
  • N. Pfarr (Munich, Germany)
Session Name
Poster Display session
Location
Room B, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
12:30 - 13:00
Authors
  • N. Pfarr (Munich, Germany)
  • M. Boxberg (Munich, Germany)
  • K. Riedmann (Munich, Germany)
  • M. Jesinghaus (Munich, Germany)
  • B. Konukiewitz (Munich, Germany)
  • H. Glimm (Dresden, Germany)
  • P. J. Jost (Munich, Germany)
  • S. Fröhling (Heidelberg, Germany)
  • W. Weichert (Munich, Germany)

Abstract

Background

In the emerging field biomarker analysis the need for testing of tumor mutation burden in routine diagnostic becomes more and more important. Currently most analysis is done by exome sequencing but regarding time for diagnosis and limitation of tissue material for testing the applicability of large gene panels becomes of great value. To test the feasibility of targeted next generation sequencing using formalin-fixed paraffin-embedded tissue for assessing tumor mutation burden statuswe applied the 1.95 Mb Illumina TSO500 panel covering an exonic region of about 1.24 Mb.

Methods

A three-phase approach was applied: 1. Validation of the panel using DNA derived from 8 different cell lines (mutation high vs. mutation low). 2. Comparison of data from whole exome sequencing (mutation high vs. mutation low) vs.the TSO500 panel from 36 FFPE tumor samples. 3. Testing of ten samples with a) high PD-L1, or b) high MSI status or c) POLE mutation. Sequencing was performed on a NextSeq® system with the NextSeq® 500 hi-Output Kit v2 (300 cycles) and 40ng DNA as input. Data analysis was performed using a bioinformatics pipeline (“TSO500“) provided by Illumina with a limit of detection of 5% allele frequency.

Results

The mutation burden status of all validation samples (phase 1) were confirmed applying our NGS panel approach achieving a concordance of 100%. In phase 2 we were able to confirm the mutation burden status high or low derived from exome sequencing for all except for two cases achieving a concordance of 94% between the different approaches. In further testing a UDG pre-treatment of DNA samples will be performed to decrease the amount of fixation artefacts and therefore improve the quality of the tested samples. Analysis of the samples from phase 3 confirmed a high mutation status for the MSI high and the POLE mutated cases all revealing a mutation burden values whereas the PD-L1 cases showed only borderline values.

Conclusions

We here show that data generated by targeted NGS data approaches can be used to determine the mutation burden status in tumor samples of different entities in high concordance with exome sequencing. Furthermore, additional genetic events (e.g. MSI) that may be clinically exploitable can be identified using a single assay.

Legal entity responsible for the study

Nicole Pfarr.

Funding

Illumina.

Disclosure

N. Pfarr: Member of the immune oncology Consortium (Thermo Fisher Scientific). H. Glimm: Clinical studies: Pfizer, AstraZeneca; Honoraria and travel: Roche, Lilly, Amgen. S. Fröhling: Clinical studies: Pfizer, PharmaMar, AstraZeneca; Honoraria and travel: PharmaMar, Roche, Lilly, Amgen.  W. Weichert: Advisory board and/or speakers bureau: Lilly, BMS, Merck/Sharpe, Dome, Novartis, Pfizer, Roche, AstraZeneca, Boehringer, Merck; Research funding: BMS, Roche, MSD. All other authors have declared no conflicts of interest.

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Poster Display session Poster Display session

61P - The real-world impact of cancer immunotherapy on the survival of patients with metastatic melanoma (ID 327)

Presentation Number
61P
Lecture Time
12:30 - 12:30
Speakers
  • M. Donia (Herlev, Denmark)
Session Name
Poster Display session
Location
Room B, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
12:30 - 13:00
Authors
  • M. Donia (Herlev, Denmark)
  • E. Ellebaek (Herlev, Denmark)
  • T. H. Oellegaard (Aarhus, Denmark)
  • L. Duval (Aarhus, Denmark)
  • J. B. Aaby (Odense, Denmark)
  • L. Hoejberg (Odense, Denmark)
  • U. H. Koehler (Odense, Denmark)
  • H. Schmidt (Aarhus C, Denmark)
  • L. Bastholt (Odense, Denmark)
  • I. Svane (Herlev, Denmark)

Abstract

Background

Between 2010 and 2015, pivotal trials with strict enrolment criteria led to the approval of several new immunotherapies for metastatic melanoma (MM). We sought to determine the impact of these treatments in the “real-world” of a population-based study.

Methods

The Danish MM database contains data on the entire unselected population diagnosed with MM within a nationwide area. To evaluate the impact of novel treatments, all 843 MM cases (excluding ocular) diagnosed in the three non-consecutive years marked by major changes in the availability of 1st line treatments (2012: i.v. IL-2 and BRAFi; 2014: anti-CTLA-4; 2016: anti-PD-1 and MEKi) were retrieved. Patients were grouped into “trial-like” and “trial-excluded” based on seven predefined eligibility criteria used in all MM registration immunotherapy clinical trials, including CNS metastases and PS ≥ 2.

Results

The baseline characteristics of patients diagnosed in 2012, 2014 and 2016 were similar. In the “trial-like” population (39% of all MM), the median overall survival (OS) was not yet reached in the 2016 group versus 18.8 months in 2014 (hazard ratio [HR] for death 0.52, 95% CI 0.36-0.75; p = 0.0005) and 16.5 months in 2012 (HR 0.41, 95% CI 0.27-0.62; p < 0.0001). In the “trial-excluded” population (61% of all MM), 75% of patients had known CNS metastases and/or PS ≥ 2. Here, the median OS was improved to 6.9 months in the 2016 group versus 5.2 months in 2014 (HR 0.66, 95% CI 0.52-0.84; p = 0.0007) and 4.3 months in 2012 (HR 0.65, 95% CI 0.52-0.83; p = 0.0005). To isolate the effects of immunotherapy, the BRAF wild-type population of 2014 and 2016 was analyzed. Here, “trial-like” patients diagnosed in 2016 had an improved overall survival (median OS not reached in 2016 vs 13.3 months in 2014, HR 0.33, 95% CI 0.20-0.55; p < 0.0001), while “trial-excluded” patients had a 1-year improved survival rate in 2016 (35.9% vs 18.8% in 2014, p = 0.0153).

Conclusions

The introduction of modern treatments has led to an improved survival of real world patients with MM, regardless of their eligibility to clinical trials and BRAF status. These data support indirectly the application of modern treatments, including anti-PD-1, to patient populations which are not represented in pivotal trials.

Legal entity responsible for the study

Herlev and Gentofte Hospital.

Funding

Herlev and Gentofte Hospital Research Council.

Disclosure

M. Donia: Honoraria for lectures: Bristol-Myers Squibb, MSD, Sanofi Genzyme, AstraZeneca. H. Schmidt: Honoraria for consultancies and lectures: Novartis, Merck, Bristol-Myers Squibb, Incyte; Restricted research grants: MSD. L. Bastholt: Advisory board: Bristol-Myers Squibb, Roche, Novartis, Merck, Eisai, Bayer Healthcare. I-M. Svane: Honoraria for consultancies and lectures: Novartis, Roche, Merck, Bristol-Myers Squibb, Incyte; Restricted research grants: Novartis, BMS. All other authors have declared no conflicts of interest.

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Poster Display session Poster Display session

96P - Preliminary pharmacokinetic results from a phase I study of GBR 1302 in patients with HER2 positive cancers (ID 374)

Presentation Number
96P
Lecture Time
12:30 - 12:30
Speakers
  • G. Gudi (Mahwah, United States of America)
Session Name
Poster Display session
Location
Room B, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
12:30 - 13:00
Authors
  • G. Gudi (Mahwah, United States of America)
  • V. Ca (Mumbai, India)
  • S. Gn (Mumbai, India)
  • C. Von Gunten (La Chaux-de-Fonds, Switzerland)
  • E. Fluhler (Paramus, AL, United States of America)
  • J. Back (La Chaux-de-Fonds, Switzerland)

Abstract

Background

HER2 is dysregulated in a wide range of solid tumors, including breast cancer, and is an attractive target for tailored oncologic treatment. GBR 1302 is a HER2xCD3 bispecific antibody that redirects cytotoxic T-cells to kill HER2 overexpressing cancer cells. This unique mode of action is anticipated to result in superior antitumor activity in HER2-positive tumors by harnessing the cytotoxic capabilities of patients’ existing T-cells.

Methods

This ongoing, phase 1, first-in-human, open-label, multicenter, dose-escalation study is evaluating GBR 1302 in adults with progressive HER2-positive solid tumors for which no standard or curative treatment is available. Subjects receive intravenous GBR 1302 on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels, starting at 1 ng/kg. The first 4 cohorts consisted of a single subject; subsequent cohorts are being enrolled using a 3 + 3 design. Blood samples were collected for pharmacokinetic (PK) and anti-drug antibody (ADA) analyses (secondary endpoints). Quantification of GBR 1302 serum concentrations (for PK) and detection/confirmation of anti GBR 1302 antibodies (for immunogenicity) were performed using validated LC/MS/MS and ELISA methods, respectively. PK parameters were evaluated using standard non-compartmental methods.

Results

As of 21 August 2018, PK data were available from 31 subjects over dose range of 1 ng/kg to 750 ng/kg. Serum concentrations were less than the lower limit of quantification of 50 pg/mL at the first dose (1 ng/kg), and only transient concentrations were observed at 3 and 10 ng/kg dose levels. Evaluable PK profiles were observed from 30 ng/kg onwards. GBR 1302 showed maximum serum concentration (Cmax) around the end of infusion, after which serum concentrations declined bi-exponentially with a mean terminal half-life of around 4 to 7 days. Both Cmax and area under the curve (AUC0-t) showed a near dose-proportional increase up to 750 ng/kg (maximum evaluated dose). None of the samples collected from subjects up to cohort 5 showed positive ADA response.

Conclusions

Per ongoing analysis, GBR 1302 showed a favorable, linear PK. None of the subjects evaluated so far showed positive ADA response.

Editorial acknowledgement

Editorial assistance was provided by Jacqueline Benjamin, PhD of Prescott Medical Communications Group, Chicago, IL.

Clinical trial identification

NCT02829372.

Legal entity responsible for the study

Glenmark Pharmaceuticals SA.

Funding

Glenmark Pharmaceuticals SA.

Disclosure

G. Gudi, E. Fluhler: Employee of Glenmark Pharmaceuticals Inc., V. Ca, S. Gn: Employee of Glenmark Pharmaceuticals, Ltd., C. von Gunten, J. Back: Employee of Glenmark Pharmaceuticals SA.

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Adoptive T cell therapy Educational session

DOI session (ID 508)

Lecture Time
14:30 - 14:30
Location
Room A, Geneva Palexpo, Geneva, Switzerland
Date
13.12.2018
Time
14:30 - 16:00
What’s new in chest tumours Educational session

Immunotherapy combos in NSCLC (ID 36)

Lecture Time
14:35 - 14:55
Speakers
  • S. Peters (Lausanne, Switzerland)
Location
Room A, Geneva Palexpo, Geneva, Switzerland
Date
14.12.2018
Time
14:15 - 15:45
Authors
  • S. Peters (Lausanne, Switzerland)