- Maurice Perol (FR)
- Joachim G. Aerts (NL)
135O - A phase 1b study of necitumumab in combination with abemaciclib in patients with stage IV non-small cell lung cancer
- Benjamin Besse (FR)
- Benjamin Besse (FR)
- Fabrice Barlesi (FR)
- Ingel Demedts (BE)
- Jose Fuentes Pradera (ES)
- Aldo Renault (FR)
- Gilles Robinet (FR)
- Bente Frimodt-Moller (DK)
- Maciej Gil (PL)
- Johan Vansteenkiste (BE)
Abstract
Background
Necitumumab and abemaciclib inhibit tumor progression by different, independent mechanisms, and both have shown activity in patients with non-small cell lung cancer (NSCLC).
Methods
This Phase 1b study was a single arm, multicenter trial to explore the safety and efficacy of necitumumab plus abemaciclib in adults with confirmed Stage IV NSCLC, who had received a maximum of 1 other prior chemotherapy for advanced and/or metastatic disease. Part A was a dose escalation study for abemaciclib in combination with necitumumab 800 mg D1D8 Q3W in up to 18 patients to determine the recommended dose for the expansion cohort (Part B, planned for 50 patients). The primary endpoint was progression-free survival (PFS) rate at 3 months compared to the historical PFS rate with single agent epidermal growth factor receptor inhibitors (50%). Secondary efficacy endpoints included PFS, overall response rate (ORR), disease control rate (DCR), and overall survival (OS).
Results
Sixty-six patients entered the study: 71% male, 61% <65 years of age, 77% ECOG performance status 1, 41% squamous histology, and 15% never smokers. In Part A (n = 15), the maximum tolerated abemaciclib dose was determined to be 150 mg every 12 hours; overall 57 patients received this treatment. The 3-month PFS rate was 32.3% (95% CI: 20.4, 44.8); median PFS was 2.14 months (1.41, 2.76). ORR was 5.3% (1.1, 14.6), and DCR was 47.4% (34.0, 61.0). The median OS was 6.93 months (4.96, 12.85). Treatment-emergent adverse events occurring in ≥30% of all patients (n [%]) included fatigue (34 [51.5]), diarrhea (33 [50.0]), dermatitis acneiform (31 [47.0]), decreased appetite (26 [39.4]), nausea (26 [39.4]), anemia (24 [36.4]), dyspnea (22 [33.3]), hypomagnesemia (21 [31.8]), vomiting (21 [31.8]), and dry skin (20 [30.3]).
Conclusions
In patients with Stage IV NSCLC, the combination of abemaciclib with necitumumab did not meaningfully impact the PFS rate at 3 months. The safety profile was consistent with the individual study drugs, and no new significant safety concerns emerged.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
Funding
Eli Lilly and Company
Disclosure
B. Besse: Research support from Eli Lilly and Company. B. Frimodt-Moller, M. Gil: Employee and stockholder of Eli Lilly and Company. All other authors have declared no conflicts of interest.
Invited Discussant 135O
- Maurice Perol (FR)
- Maurice Perol (FR)
112O - Primary result of an investigator-initiated phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study (NCCH1505)
- Takashi Seto (JP)
- Takashi Seto (JP)
- Yuki Katsuya (JP)
- Hidehito Horinouchi (JP)
- Shigeki Umemura (JP)
- Yukio Hosomi (JP)
- Miyako Satouchi (JP)
- Aya Kuchiba (JP)
- Yuichiro Ohe (JP)
Abstract
Background
Thymic carcinoma (TC) is a rare cancer with a poor prognosis. Treatment options are limited, especially after relapse. We previously reported that PD-L1 positivity was observed in 70% of TCs by immunohistochemistry suggesting anti PD-1/PD-L1 agents could be a promising treatment.
Methods
In this open-label, two-stage, multi-center, single-arm, phase II trial, the main eligibility criteria were: unresectable or recurrent TC, an ECOG-PS of 0 or 1, the presence of measurable disease, progression after at least one previous platinum-based chemo(radio)therapy treatment, and no history of autoimmune disease. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the response rate (RR) as evaluated by central review using the RECIST v1.1; secondary endpoints include progression-free survival (PFS), overall survival, disease control rate, and safety. The planned sample size was 15 for the first stage and 15 for the second stage, with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5% and power of 80%. This trial was registered with UMIN000022007.
Results
Between July 1 and August 16, 2016, 15 patients were accrued in the first stage; at the data cutoff (August 31, 2017), all were assessable for a response. Median follow-up time was 3.8 months (range 1.4–12.0). All were Japanese, 12 were male, median age was 55 (range 34–70), 13 had squamous histology. The median number of nivolumab cycles received was 8 (range 3–29). RR by central review was 0% (no patient with complete or partial response; 95% confidence interval [CI]: 0–21.8). Eleven patients had stable disease and four had progressive disease. Median PFS was 3.8 months (95% CI: 1.9–5.6), and 12-month PFS rate was 13.3% (95% CI: 2.2–34.6). Two patients experienced a treatment-related serious adverse events (grade 3 AST increase and grade 2 adrenal insufficiency). Because the early termination criteria at the first stage (less than one responder) was fulfilled, the patient accrual was terminated.
Conclusions
Despite of the small number of patients, our results suggested further development of nivolumab is not recommended in previously treated unresectable or recurrent TC.
Legal entity responsible for the study
None
Funding
Japan Agency for Medical Research and Development
Disclosure
T. Seto: Consulting and advisory services, speaking or writing engagements, public presentations; AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Taiho, Takeda. Direct research support to the responsible project lead (e.g., Principal Investigator); Eisai, MSD, Nippon Boehringer Ingelheim, AstraZeneca, Astellas, Chugai, Daiichi Sankyo, Eli Lilly, Merck Serono, Novartis, Pfizer. H. Horinouchi: Research Grant; Ono pharmaceutical, BMS, MSD, Taiho, Chugai, Novartis, Astellas, Merck Serono. Honoraria; Ono pharmaceutical, BMS, Taiho, Chugai, Novartis, Lilly, AstraZeneca. S. Umemura: Corporate-sponsored research; MSD, AstraZeneca. Honoraria; AstraZeneca, Chugai pharmaceutical, Ono, Boehringer ingelheim. Y. Hosomi: Honoraria; Lilly, Ono pharmaceutical, BMS, Chugai, AstraZeneca. Corporate-sponsored research; Lilly, Ono pharmaceutical, Chugai, AstraZeneca, Taiho, MSD. M. Satouchi: Corporate-sponsored research; Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Novartis, Ono Pharmaceutical, Pfizer Japan. Lecture fees and/or honoraria; AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Merck, Novartis, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical. Y. Ohe: Corporate-sponsored research; Taiho, AstraZeneca, Chugai, Lilly, Pfizer, MSD, Novartis, Kyorin, Dainippon-Sumitomo, Ignyta. Membership on an advisory board or board of directors or other substantive relationships; Taiho, AstraZeneca, Chugai, Lilly, Pfizer, MSD, Novartis, Daiichi-Sankyo, Nipponkayaku, Boehringer Ingelheim, Bayer. All other authors have declared no conflicts of interest.
213O - Nintedanib + pemetrexed/cisplatin in malignant pleural mesothelioma (MPM): Phase II biomarker data from the LUME Meso study
- Nick Pavlakis (AU)
- Nick Pavlakis (AU)
- Federica Grosso (IT)
- Nicola Steele (GB)
- Anna Nowak (AU)
- Silvia Novello (IT)
- Sanjay Popat (GB)
- Laurent Greillier (FR)
- Martin Reck (DE)
- Thomas Kitzing (DE)
- Giorgio Scagliotti (IT)
Abstract
Background
The randomised Phase II/III LUME-Meso study is evaluating nintedanib + pemetrexed/cisplatin versus placebo + pemetrexed/cisplatin (≤6 cycles), followed by nintedanib or placebo maintenance, in chemo-naïve MPM. In the Phase II part, nintedanib treatment led to improved progression-free survival (PFS; hazard ratio [HR] = 0.54; p = 0.010) and a trend for longer overall survival (OS; HR = 0.77; p = 0.319) compared with placebo. Patients with epithelioid tumours derived greatest benefit. Plasma angiogenic factors and genomic markers were explored for potential associations with treatment outcome in the Phase II epithelioid population.
Methods
Baseline plasma levels of 58 angiogenic factors were analysed by multiplex immunoassay (Human AngiogenesisMAP®, Myriad RBM). Genes implicated in the nintedanib mode of action and/or mesothelioma pathophysiology (VEGFR1, VEGFR3 and mesothelin) were evaluated for known single-nucleotide polymorphisms (SNPs). Biomarker associations with PFS/OS treatment effects were analysed by Cox regression and interaction tests with false-discovery rate (FDR) adjustment. Analyses were exploratory and hypothesis generating.
Results
Angiogenic factor and genomic data were available for 71 and 67 patients, respectively, in the epithelioid population (n = 77). Of the angiogenic factors evaluated, only endoglin showed a possible trend for association with both PFS and OS improvement, with potentially greater benefit in patients with low plasma levels. Major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A) showed weak association with OS effect, while the VEGFR1 SNP rs9582036 A/A genotype was potentially correlated with PFS benefit. However, all biomarker treatment associations were limited by small subgroup size (especially for minor genotypes) and FDR-adjusted interaction tests were not significant.
Conclusions
These first biomarker results for nintedanib-treated MPM showed potential signals for greater PFS/OS benefits in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, but no biomarkers showed clear and significant association with nintedanib efficacy.
Clinical trial identification
NCT01907100
Legal entity responsible for the study
Boehringer Ingelheim
Funding
Boehringer Ingelheim
Disclosure
N. Pavlakis: Advisory Boards: Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Bayer, Novartis, Pfizer, Roche, Ipsen Speaking Honoraria: Boehringer Ingelheim, Bayer, Novartis, Pfizer, Roche Travel Support: BMS, Astra Zeneca, Roche. N. Steele: Honoraria: Pfizer, Novartis Consulting/advisory role: MSD, Boehringer Ingelheim, BMS Research funding: Merck Serono, AstraZeneca, Boehringer Ingelheim, BMS, Novartis, Roche Travel, accommodation, expenses: Pfizer, MSD Oncology, Boehringer Ingelheim. A. Nowak: Consulting/ Advisory Role: Aduro Biotech, Morphotek, Bayer, AstraZeneca, Sellas Life Sciences, Trizell, Boehringer Ingelheim, Epizyme, Roche Research Funding: Boehringer Ingelheim, AstraZeneca Travel and expenses: Amgen, AstraZeneca, Boehringer Ingelheim. S. Novello: Speakers’ Bureau: AstraZeneca, MSD, Bristol-Myers Squibb, Roche, Pfizer, Eli Lilly. S. Popat: Honoraria: Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novartis, Roche Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche Research funding: Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Eli Lilly, Roche. L. Greillier: Honoraria: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca, Novartis Pharma, Roche Consulting/advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Roche Research funding: Roche. M. Reck: Honoraria: Boehringer Ingelheim, Proacta, BMS, MSD, Pfizer, Eli Lilly, AstraZeneca, Merck Inc., Celgene, Novartis Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, BMS, MSD, Pfizer, AstraZeneca, Merck Inc., Celgene, Novartis, Roche Speaker's bureau: Roche, Eli Lilly, MSD Oncology, Merck, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Pfizer, Novartis. T. Kitzing: Employment: Boehringer Ingelheim. G. Scagliotti: Honoraria: Eli Lilly, Pfizer, MSD, AstraZeneca, Roche Consulting/Advisory role: Eli Lilly Speakers’ Bureau: Eli Lilly, MSD. All other authors have declared no conflicts of interest.
214O - Multiplexed proteomics biomarkers for malignant pleural mesothelioma detection in blood
- Ferdinando W. Cerciello (CH)
- Ferdinando W. Cerciello (CH)
- Meena Choi (US)
- Sara L. Sinicropi-Yao (US)
- Emanuela Felley-Bosco (CH)
- Rolf A. Stahel (CH)
- Bruce Robinson (AU)
- Jenette Creaney (AU)
- Harvey I. Pass (US)
- Olga Vitek (US)
- David P. Carbone (US)
Abstract
Background
Blood biomarkers are not routinely applied for the diagnosis of malignant pleural mesothelioma (MPM). We investigated a multiplexed biomarkers signature composed of 6 glycopeptides for the diagnosis of MPM in blood using mass spectrometry based targeted proteomics.
Methods
We applied the targeted proteomics technology selected reaction monitoring (SRM, also known as multiple reaction monitoring – MRM) to investigate more than 400 serum samples from early and advanced stages MPM patients and asbestos exposed donors. Samples were from biobanks in the USA, Australia and Europe. Samples were enriched for N-linked glycoproteins using hydrazide chemistry. After tryptic digestion, N-linked glycopeptides were separated by liquid chromatography before analysis on a triple quadrupole mass spectrometer (LC-MS/MS). Logistic regression was fitted on a training set of 212 samples followed by evaluation of predictive accuracy of the signature in a validation set of 193 samples.
Results
The proteomics platform for serum processing on 96-well plates and LC-MS/MS analysis had coefficient of variation between 2.0 and 11.4% for peptide quantification over more than 700 measurements, and standard deviation of 0.42 for processing more than 400 replicates. The predictive accuracy for MPM discrimination was significantly higher using multiplexed biomarkers by mass spectrometry compared to using single biomarkers alone. The multiplexed proteomics signature separated MPM patients and asbestos exposed donors with an area under the receiver operating characteristic curve (AUC) of 0.72 in the validation set, and AUC for discriminating early stage MPM from asbestos exposed donors was 0.74. Predictive accuracy of the proteomics signature was not inferior to the currently best available MPM blood biomarker soluble-mesothelin related peptides (SMRP) measured in the samples of the validation set using an enzyme-linked immunosorbent assay (ELISA) approved by the US food and drug administration (FDA). Furthermore, signature was significantly associated with survival of MPM patients after treatment.
Conclusions
Mass spectrometry based proteomics biomarkers have potential for MPM diagnosis in blood.
Legal entity responsible for the study
The Ohio State University Medical Center
Funding
Kathy and Jay Worly Lung Cancer Early Detection Fund Don Ward, President, Special Claims Services, Inc. at The Ohio State University Comprehensive Cancer Center (OSUCCC) The Swiss National Science Foundation (postdoc mobility fellowship)
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 112O, 213O and 214O
- Nicolas Girard (FR)
- Nicolas Girard (FR)